Conditions: Pancreatic Adenocarcinoma Metastatic
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
This is an open-label, single arm, phase II trial. Safety will be monitored on an ongoing basis. Laboratory testing (chemistry, hematology tests) will be performed every 2 weeks for the first 8 weeks followed by assessments every 4 weeks. Other safety evaluations including EKGs, urinalysis, coagulation and thyroid function studies will be performed at regular intervals.

Adverse event seriousness, severity grade, and relationship to study treatment will be assessed by the investigator. Severity grade will be defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.

Tumors will be assessed by contrast enhanced CT or MRI every 8 weeks. Pre-treatment tissue will be obtained via CT-guided FNA biopsy or collected during resection. However, archival tissue will also be requested, when available and if adequate for testing. Post-treatment tissue will be obtained on Day 15 (i.e., Week 3/Day 1) via CT-guided FNA biopsy. All tumor tissue from eligible patients will be utilized for the correlative studies which are outlined in this trial.

Each subject's course will consist of three periods:

* A Pre-Treatment Period in which subjects are consented and undergo screening assessments to be qualified for the study;
* A Treatment Period in which subjects receive study treatment and undergo study assessments. Patients who meet the eligibility criteria will be treated with cabozantinib orally at 40 mg daily and erlotinib orally at 100 mg daily without breaks;
* A Post-Treatment Period in which subjects no longer receive study treatment but undergo follow-up study assessments and contacts.

Detailed description:
Primary Objective The primary objective of this trial is to demonstrate a radiographic response rate of 15% or greater for the combination in a selected population.

Secondary Objectives

The secondary objectives of this trial are:

* To estimate progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), overall survival (OS); and
* To assess safety and tolerability of this combination in the target patient population.

Correlative Objectives

The following tests will be performed on blood and tumor tissue samples collected during this trial to correlate with PFS and OS:

* c-Met and EGFR mRNA by RT-qPCR
* plasma HGF and soluble Met receptor
* c-Met and EGFR phosphoprotein levels by IHC
* KRAS mutation status

Arms:
arm 1: None

Interventions: intervention 1: Cabozantinib 40 MG intervention 2: Erlotinib 100Mg Tab
Intervention descriptions: intervention 1: To be taken orally once daily intervention 2: To be taken orally once daily

Protocol document:
Prot_SAP_000.pdf: 
NCT03213626 
 
 
A phase II trial of cabozantinib and erlotinib for patients with EGFR 
and c-Met co-expressing metastatic pancreatic adenocarcinoma  
PROTOCOL NUMBER: 
IUSCC-0597 
STUDY DRUGS: 
Cabozantinib (XL184) 
Erlotinib 
IND NUMBER: 
134512 
SPONSOR: 
IUSCC 
PRINCIPAL INVESTIGATOR: 
Patrick Loehrer, MD 
Director, Indiana University Simon Cancer Center 
535 Barnhill Drive, Room 473 
Indianapolis, Indiana 46202 
Phone: (317) 274-3539 
Fax: 317-278-4190 
E-mail: ploehrer@iupui.edu 
CO-INVESTIGATORS:  
Safi Shahda, MD 
Murray Korc, MD 
Amikar Sehdev, MD 
STATISTICIAN: 
Susan M. Perkins, PhD 
SUPPORT PROVIDED BY: 
IUSCC & Exelixis (cabozantinib) 
VERSION DATE: 
26 March 2019 
 


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SYNOPSIS  
TITLE 
A phase II trial of cabozantinib and erlotinib for patients with EGFR and c-Met co-expressing 
metastatic pancreatic adenocarcinoma 
PROTOCOL NUMBER: IUSCC-0597  
CLINICAL PHASE 
Phase II 
RATIONALE 
This study is a trial based on the work of Dr. Murray Korc in the IUSCC, and is intended to be a 
key part of a SPORE grant for pancreatic cancer. The study looks at a novel combination of 
targeted agents in a biomarker-selected population of patients with pancreatic cancer, a group for 
whom new therapeutic options is desperately needed. 
OBJECTIVES 
Primary:  
• 
To demonstrate a radiographic response rate of 15% or greater for the combination in a selected 
population 
Secondary:  
• 
To estimate progression-free survival (PFS), objective response rate (ORR), disease control rate 
(DCR), overall survival (OS) 
• 
To assess safety and tolerability of this combination in the target patient population 
Correlative: 
The following tests will be performed on blood and tumor tissue samples collected during this trial to 
correlate with PFS and OS: 
• 
c-Met and EGFR mRNA by RT-qPCR 
• 
plasma HGF and soluble Met receptor 
• 
c-Met and EGFR phosphoprotein levels by IHC 
• 
KRAS mutation status 
 
STUDY DESIGN 
This is an open-label, single arm, phase II trial. 
NUMBER OF SUBJECTS 
Approximately 37-40 subjects will be enrolled on this trial. 
TARGET POPULATION 
1. Adenocarcinoma of the pancreas (or recurrence of previously resected disease) with metastatic 
disease; 
2. EGFR and c-Met overexpressed in tumor as determined by immunohistochemistry (IHC) test 
score of 2+ for both markers; 
3. Radiographic progression on one prior combination regimen for locally advanced or metastatic 
disease. 


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ESTIMATED LENGTH OF SUBJECT PARTICIPATION 
Subjects may continue to receive study treatment until they experience unacceptable drug-related 
toxicity, disease progression or subject withdrawal for any reason including investigator 
assessment that the risk:benefit ratio is no longer favorable. Subjects will be followed until death 
or two years (median follow-up of 8 months). 
ESTIMATED STUDY DATES 
09/2017 (first study screening visit) to 12/2020 (last study follow-up visit) 
INVESTIGATIONAL REGIMEN DOSE/ROUTE/DURATION 
Patients who meet the eligibility criteria will be treated with cabozantinib orally at 40 mg daily 
and erlotinib orally at 100 mg daily without breaks. 
Cabozantinib is supplied as 20-mg tablets; Erlotinib is supplied as 25-mg, 100-mg, and 150-mg 
tablets. 
SAFETY ASSESSMENTS 
Safety will be monitored on an ongoing basis. Laboratory testing (chemistry, hematology tests) 
will be performed every 2 weeks for the first 8 weeks followed by assessments every 4 weeks. 
Other safety evaluations including EKGs, urinalysis, coagulation and thyroid function studies will 
be performed at regular intervals. 
Adverse event seriousness, severity grade, and relationship to study treatment will be assessed by 
the investigator. Severity grade will be defined by the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. 
TUMOR ASSESSMENTS 
Tumors will be assessed by contrast enhanced CT or MRI every 8 weeks. 
Pre-treatment tissue will be obtained via archival tissue collection.  All tumor tissue from eligible 
patients will be utilized for the correlative studies which are outlined in this trial. 
BIOMARKER ASSESSMENTS 
1. c-MET and EGFR mRNA by qPCR 
2. plasma HGF and soluble c-Met receptor 
3. c-Met and EGFR phosphoprotein levels by IHC 
4. KRAS mutation status 
STATISTICAL METHODS 
The optimal two-stage design to test the null hypothesis that P ≤ 0.025 versus the alternative that P 
≥ 0.150 has an expected sample size of 17.32 and a probability of early termination of 0.757. If the 
drug is actually not effective, there is a 0.045 probability of concluding that it is (the target for this 


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value was 0.050). If the drug is actually effective, there is a 0.198 probability of concluding that it 
is not (the target for this value was 0.200). After testing the drug on 11 patients in the first stage, 
the trial will be terminated if 0 respond. If the trial goes on to the second stage, a total of 37 
patients will be studied. If the total number responding is less than or equal to 2, the combination 
is rejected. 
ORR and DCR will be estimated with 95% exact binomial confidence intervals.  PFS will be 
estimated using a 95% confidence interval based on the exponential distribution.  Safety and 
tolerability data will be tabulated.  For biomarkers, baseline levels and changes over time will be 
correlated with PFS using Cox proportional hazards regression. 
 


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TABLE OF CONTENTS 
1 
SCHEMA ..................................................................................................................13 
2 
BACKGROUND AND RATIONALE .....................................................................13 
2.1 
Background ......................................................................................................13 
2.2 
Rationale ..........................................................................................................14 
3 
STUDY OBJECTIVES AND DESIGN ...................................................................15 
3.1 
Study Objectives ..............................................................................................15 
3.1.1 
Primary Objective ................................................................................15 
3.1.2 
Secondary Objectives...........................................................................15 
3.1.3 
Correlative Objectives .........................................................................15 
3.2 
Study Design ....................................................................................................15 
3.3 
Treatment Assignment .....................................................................................16 
3.4 
Blinding and randomization .............................................................................16 
3.5 
Study Sites .......................................................................................................16 
3.6 
Withdrawals .....................................................................................................16 
4 
TREATMENTS ........................................................................................................17 
4.1 
Investigational Treatment ................................................................................17 
4.1.1 
Cabozantinib Tablets ...........................................................................17 
4.1.2 
Erlotinib Tablets...................................................................................18 
4.2 
Composition, Formulation, and Storage ..........................................................18 
4.3 
Dose, Schedule and Route ...............................................................................19 
4.3.1 
Dose Modifications, Interruptions, and Discontinuation .....................19 
4.3.2 
Dose Reinstitution and Reescalation ...................................................21 
4.4 
Warnings and Precautions and Guidelines for the Management of Adverse 
Events ...............................................................................................................22 
4.4.1 
Guidelines for Management of Potential Adverse Events ...................25 
4.4.1.1 
Gastrointestinal Disorders ...........................................................26 
4.4.1.2 
Hepatobiliary Disorders ..............................................................27 
4.4.1.3 
Hematological Disorders ............................................................28 
4.4.1.4 
Fatigue, Anorexia, and Weight Loss ...........................................28 
4.4.1.5 
Skin Disorders .............................................................................29 
4.4.1.6 
Wound Healing and Surgery .......................................................30 
4.4.1.7 
Hypertension ...............................................................................30 
4.4.1.8 
Thromboembolic Events .............................................................31 
4.4.1.9 
Proteinuria ...................................................................................32 
4.4.1.10 
Corrected QTc Prolongation .......................................................33 


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4.4.1.11 
Hypophosphatemia .....................................................................35 
4.4.1.12 
Thyroid Function Disorders ........................................................35 
4.4.1.13 
Hemorrhagic Events....................................................................35 
4.4.1.14 
GI Perforation/Fistula and Non-GI Fistula Formation................36 
4.4.1.15 
Osteonecrosis of the Jaw .............................................................36 
4.4.1.16 
Respiratory, Thoracic and Mediastinal Disorders ......................37 
4.4.1.17 
Renal Failure ...............................................................................37 
4.4.1.18 
Ocular Disorders .........................................................................37 
4.5 
Concomitant Medications and Therapies.........................................................38 
4.5.1 
Anticancer Therapy ..............................................................................38 
4.5.2 
Other Medications ................................................................................38 
4.5.3 
Allowed Therapies ...............................................................................38 
4.5.4 
Prohibited or Restricted Therapies .......................................................39 
4.5.5 
Potential Drug Interactions ..................................................................40 
4.6 
Compliance ......................................................................................................43 
4.7 
Study Drug Accountability ..............................................................................43 
5 
STUDY POPULATION ...........................................................................................44 
5.1 
Inclusion Criteria .............................................................................................44 
5.2 
Exclusion Criteria ............................................................................................46 
6 
STUDY ASSESSMENTS AND PROCEDURES ....................................................49 
6.1 
Schedule of Assessments .................................................................................50 
6.2 
Pre-Treatment Period .......................................................................................53 
6.2.1 
Administrative Procedures ...................................................................53 
6.2.1.1 
Recruitment and Registration .....................................................53 
6.2.1.2 
Informed Consent........................................................................53 
6.2.1.3 
Inclusion/Exclusion Criteria .......................................................54 
6.2.1.4 
Medical and Cancer History .......................................................54 
6.2.1.5 
Registration .................................................................................54 
6.2.1.6 
Prior and Concomitant Medications Review ..............................54 
6.3 
Treatment Period ..............................................................................................55 
6.3.1 
Clinical Procedures ..............................................................................55 
6.3.1.1 
Adverse Event Monitoring ..........................................................55 
6.3.1.2 
Physical Exam .............................................................................56 
6.3.1.3 
Vital Signs ...................................................................................56 
6.3.1.4 
Eastern Cooperative Oncology Group (ECOG) Performance 
Scale ............................................................................................56 
6.3.1.5 
Electrocardiogram (ECG) ...........................................................56 
6.3.1.6 
Laboratory Assessments .............................................................56 


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6.3.1.7 
Subject Drug Compliance ...........................................................58 
6.3.1.8 
Disease Assessment ....................................................................58 
6.4 
Post-Treatment Period .....................................................................................58 
6.4.1.1 
Safety Follow-Up ........................................................................58 
6.5 
Survival Follow-Up .........................................................................................58 
6.6 
Correlative Studies ...........................................................................................58 
7 
SAFETY ...................................................................................................................60 
7.1 
Definitions of Adverse Events .........................................................................60 
7.1.1 
Adverse Events ....................................................................................60 
7.1.2 
Suspected Adverse Reactions (SAR) ...................................................60 
7.1.3 
Adverse Reaction (AR) ........................................................................61 
7.1.4 
Serious Adverse Events .......................................................................61 
7.1.5 
Unexpected Adverse Events ................................................................62 
7.1.6 
Determining Attribution to the Investigational Agents .......................63 
7.2 
Adverse Event Reporting Requirements ..........................................................64 
7.2.1 
Reporting to the IRB ............................................................................64 
7.2.2 
Reporting to Exelixis ...........................................................................64 
7.2.2.1 
SAEs ...........................................................................................64 
7.2.2.2 
Study Initiation............................................................................65 
7.2.2.3 
Study Maintenance......................................................................65 
7.2.2.4 
Study Closure ..............................................................................65 
7.2.3 
Reporting to the FDA...........................................................................66 
7.2.3.1 
15-Day IND Reports: ..................................................................66 
7.2.3.2 
7-Day Reports: ............................................................................66 
7.2.3.3 
Report Content: ...........................................................................66 
7.2.4 
Reporting to Participating Sites ...........................................................67 
7.3 
Other Safety Considerations ............................................................................67 
7.3.1 
Laboratory Data ...................................................................................67 
7.3.2 
Pregnancy .............................................................................................67 
7.3.3 
Medication Errors/Overdose ................................................................68 
7.3.4 
Follow-Up of Adverse Events .............................................................68 
8 
STATISTICAL CONSIDERATIONS......................................................................68 
8.1 
General Considerations ....................................................................................68 
8.2 
Study Design ....................................................................................................68 
8.3 
Definition of Endpoints....................................................................................68 
8.4 
Analysis Population .........................................................................................69 
8.4.1 
Enrolled Population .............................................................................69 
8.4.2 
Safety Population .................................................................................69 


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8.4.3 
Efficacy Population ..............................................................................69 
8.5 
Sample Size, Accrual and Study Duration .......................................................69 
8.6 
Patient Characteristics ......................................................................................70 
8.7 
Significant Protocol Violations ........................................................................70 
8.8 
Safety Analysis ................................................................................................70 
8.9 
Efficacy Analysis .............................................................................................70 
8.10 
Correlative Analysis.........................................................................................70 
8.11 
Interim Analysis/Criteria for Stopping Study ..................................................71 
9 
DATA AND SAFETY MONITORING ...................................................................71 
9.1 
Data and Safety Monitoring Committee ..........................................................71 
9.2 
IND Annual Reports ........................................................................................72 
9.3 
Study Auditing and Monitoring .......................................................................72 
9.4 
Oncore Reporting Requirements ......................................................................72 
9.5 
Study Accrual Oversight ..................................................................................72 
9.6 
Oncore Safety Reporting..................................................................................72 
9.7 
Protocol Deviation Reporting ..........................................................................72 
10 
ETHICAL ASPECTS ...............................................................................................73 
10.1 
Local Regulations ............................................................................................73 
10.2 
Informed Consent.............................................................................................73 
10.3 
Institutional Review Board/Ethics Committee ................................................73 
10.4 
Compliance with Trial Registration and Results Posting Requirements .........74 
10.5 
Future Use of Subject Samples ........................................................................74 
11 
CONDITIONS FOR MODIFYING THE PROTOCOL...........................................74 
11.1 
Emergency Modifications ................................................................................74 
11.2 
Other Protocol Deviations/Violations ..............................................................74 
11.3 
Amendments ....................................................................................................74 
12 
CONDITIONS FOR TERMINATING THE STUDY .............................................75 
13 
STUDY DOCUMENTATION AND RECORD KEEPING ....................................75 
13.1 
Investigator’s Files and Retention of Documents ............................................75 
13.2 
Source Documents and Background Data .......................................................76 
13.3 
Audits and Inspections .....................................................................................76 
13.4 
Case Report Forms and Data Submission ........................................................76 


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14 
CONFIDENTIALITY OF TRIAL AND SUBJECT RECORDS .............................77 
15 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS............77 
16 
REFERENCES .........................................................................................................77 
17 
APPENDICES ..........................................................................................................80 
17.1 
Appendix A: Performance Status Criteria .......................................................80 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST 
aspartate aminotransferase 
AUC 
area under the plasma drug concentration time curve 
BP 
blood pressure 
BUN 
blood urea nitrogen 
CHF 
congestive heart failure 
CrCl 
creatinine clearance 
CRF 
case report form 
CRPC 
castration-resistant prostate cancer 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DCR 
disease control rate 
DLT 
dose-limiting toxicity 
DVT 
deep vein thrombosis 
EC 
ethics committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EKG 
electrocardiogram 
ESC 
Exelixis Safety Committee 
ESMO 
European Society of Medical Oncology 
ESR 
erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GABA 
γ-aminobutyric acid 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GGT 
γ-glutamyl transferase 
GnRH 
gonadotropin-releasing hormone 
ICH 
International Conference on Harmonisation 
IME 
important medical event 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 


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IUSCC 
Indiana University Simon Cancer Center 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LHRH 
luteinizing hormone-releasing hormone 
LMWH 
low molecular weight heparin 
LLN 
lower limit of normal 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
myocardial infarction 
MRI 
magnetic resonance imaging 
MTC 
medullary thyroid cancer 
NCI 
National Cancer Institute 
NSAID 
non-steroidal anti-inflammatory drug 
NSCLC 
non-small cell lung cancer 
NYHA 
New York Heart Association 
ORR 
objective response rate 
PD 
progressive disease 
PDAC 
pancreatic ductal adenocarcinoma 
PE 
pulmonary embolism 
PI 
principal investigator 
PFS 
progression-free survival 
PPES 
palmar-plantar erythrodysesthesia 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
qd 
once daily 
ONJ 
osteonecrosis of the jaw 
QTc 
corrected QT interval 
QTcF 
QTc calculated by the Friderica formula 
RBC 
red blood cell 
RPLS 
reversible posterior leukoencephalopathy syndrome 
RT-qPCR 
reverse-transcriptase quantitative PCR 
SAE 
serious adverse event 
SBP 
systolic blood pressure 
TCGA 
The Cancer Genome Atlas 
TFT 
thyroid function test 
TIA 
transient ischemic attack 
TSH 
thyroid stimulating hormone 
ULN 
upper limit of normal 
UPCR 
urine protein/urine creatinine ratio 


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VEGF(R) 
vascular endothelial growth factor (receptor) 
 
 
 


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1 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
2 
BACKGROUND AND RATIONALE 
2.1 
Background  
Pancreatic ductal adenocarcinoma (PDAC) is a treatment-recalcitrant cancer with an overall 5-
year survival rate of 7%. Metastatic is even more lethal, and therapeutic options remain limited. 
Based on a randomized study, the EGFR kinase inhibitor erlotinib appeared to have modest 
activity1 and was approved by the FDA. Importantly, in a subset of patients who developed 
significant rash, there appeared to be a substantial survival benefit compared to either placebo 
treated patients or erlotinib treated patients who did not experience rash. EGFR overexpression 
relative to non-malignant pancreatic tissue is common in PDAC;2 however, KRAS mutation is 
also nearly universal,3 and may mediate resistance to EGFR therapy.4 Importantly, recent 
evidence with mouse models underscores the requirement for EGFR signaling in order to allow 
oncogenic KRAS to drive pancreatic neoplastic transformation and progression.5 


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Another cell-surface signaling pathway that has been shown to have preclinical activity in 
pancreatic cancer models is the HGF/c-Met signaling axis. The c-Met receptor, as is the case for 
EGFR, is overexpressed in a majority of PDACs.6 Based on previous studies, a substantial 
fraction of PDACs co-overexpress these two 
receptors and their ligands.7-9 As early as 
2000 it was noted that cross-talk exists 
between the two pathways,7-9 and that the 
two pathways can synergize in terms of 
activation of downstream pathways. 
Importantly, investigators at our institution 
and others have documented 
heterodimerization of c-Met and EGFR 
subunits. These heterodimers result in more 
signaling that enhances pancreatic cancer 
cell invasion and p-AKT signaling, (Murray Korc, personal communication) even in the presence 
of mutated KRAS. This co-receptor signaling suggests that inhibition of both receptors 
simultaneously may be required for anti-tumor activity, and also suggests a target population of 
tumors overexpressing both molecules. Based on these preclinical findings, we propose a trial to 
test this hypothesis in patients with metastatic PDAC (mPDAC) that co-expresses c-Met and 
EGFR.  
The combination of cabozantinib and erlotinib has been studied previously in non-small cell lung 
cancer (NSCLC). The combination was considered tolerable, with adverse events consisting 
primarily of diarrhea (29% grade 3) and rash (6% grade 3).10 
2.2 
Rationale 
At present, the majority of fit patients with mPDAC are treated in the first-line with either 
FOLFIRINOX (leucovorin, fluorouracil [5-FU], irinotecan and oxaliplatin) or gemcitabine and 
nab-paclitaxel. Recently, MM-398 (irinotecan liposome injection) was approved in combination 
with 5-FU for patients failing initial gemcitabine-based chemotherapy,11 but no regimen has been 
adequately studied to be considered a standard of care for patients who have failed front-line 
treatment, and patients often have difficulty tolerating further combination chemotherapy after 
progressing on an intensive combination regimen, with hematologic toxicity and neuropathy as 
particular problems. As such, there remains a substantial unmet need for second-line therapy of 
metastatic PDAC. Based on this unmet need and the preclinical data above, we propose a phase 
II trial of the combination of erlotinib and cabozantinib for patients with EGFR+/c-Met+ 


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metastatic pancreatic cancer who have been treated with and progressed on (or within 3 months 
of stopping) front-line treatment for advanced disease. While The Cancer Genome Atlas (TCGA) 
data suggest that concomitant overexpression of EGFR and c-Met occurs in 3% of PDAC 
patients, based on our unpublished results using reverse-transcriptase quantitative PCR (RT-
qPCR), we have found that ~30% of these patients have increased levels of both EGFR and c-
Met. 
3 
STUDY OBJECTIVES AND DESIGN 
3.1 
Study Objectives 
3.1.1 
Primary Objective 
The primary objective of this trial is to demonstrate a radiographic response rate of 15% or 
greater for the combination in a selected population. 
3.1.2 
Secondary Objectives 
The secondary objectives of this trial are:  
• To estimate progression-free survival (PFS), objective response rate (ORR), disease 
control rate (DCR), overall survival (OS); and 
• To assess safety and tolerability of this combination in the target patient population. 
3.1.3 
Correlative Objectives 
The following tests will be performed on blood and tumor tissue samples collected during this 
trial to correlate with PFS and OS: 
• c-Met and EGFR mRNA by RT-qPCR 
• plasma HGF and soluble Met receptor 
• c-Met and EGFR phosphoprotein levels by IHC 
• KRAS mutation status 
3.2 
Study Design 
This is an open-label, single arm, phase II trial. 
Safety will be monitored on an ongoing basis. Laboratory testing (chemistry, hematology tests) 
will be performed every 2 weeks for the first 8 weeks followed by assessments every 4 weeks. 
Other safety evaluations including EKGs, urinalysis, coagulation and thyroid function studies will 
be performed at regular intervals. 
Adverse event seriousness, severity grade, and relationship to study treatment will be assessed by 
the investigator. Severity grade will be defined by the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. 


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Each subject’s course will consist of three periods: 
• A Pre-Treatment Period in which subjects are consented and undergo screening 
assessments to be qualified for the study (Section 6.2); 
• A Treatment Period in which subjects receive study treatment and undergo study 
assessments (Section 6.3); 
• A Post-Treatment Period in which subjects no longer receive study treatment but undergo 
follow-up study assessments and contacts (Section 6.4). 
3.3 
Treatment Assignment  
It is the responsibility of the investigator to assign a subject number before treating each subject 
with cabozantinib and erlotinib. 
3.4 
Blinding and randomization 
This is a non-randomized trial. 
3.5 
Study Sites 
This study will be conducted at the Indiana University Melvin and Bren Simon Cancer 
Center/Indiana University Health Hospital.  
3.6 
Withdrawals 
Subjects may discontinue study treatment or withdraw their consent to participate in the study at 
any time without prejudice. The investigator may withdraw a subject from study treatment or 
from the study if, in his or her clinical judgment, it is in the best interest of the subject or if the 
subject cannot comply with the protocol.  
In addition, any of the following conditions require discontinuation of the subject from study 
treatment: 
• An adverse event or intercurrent illness that in the opinion of the investigator warrants the 
subject’s withdrawal from study treatment; 
• The investigator believes it  is not in the best interest of the subject to continue on study 
• Specific conditions described in the Sections 4.4 Warnings and Precautions and 
Guidelines for the Management of Adverse Events; 
• Necessity for treatment with other anticancer treatment prohibited by protocol; 
• Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (e.g., male condom, female condom) during the course of the study and for 
4 months after discontinuation of study treatment; 
• Women who become pregnant or are breastfeeding; 


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• If the subject does not recover from his or her toxicities to tolerable Grade ≤ 2 within 6 
weeks, the subject will have study treatment discontinued unless there is unequivocal 
evidence that the subject is benefitting. In this situation, a subject may be able to restart 
therapy with a dose reduction upon resolution of the toxicity and with agreement of the 
sponsor-investigator; 
• Request by regulatory agencies for termination of treatment of an individual subject or all 
subjects under the protocol; 
• Significant noncompliance with the protocol schedule in the opinion of the investigator; 
• Progressive disease (PD) or the subject no longer experiences clinical benefit as 
determined by the investigator 
4 
TREATMENTS 
4.1 
Investigational Treatment  
4.1.1 
Cabozantinib Tablets  
Exelixis internal number: XL184 
Chemical name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate  
Cabozantinib tablets are supplied as film coated tablets containing cabozantinib malate 
equivalent to 20 mg or 60 mg of cabozantinib and contain microcrystalline cellulose, lactose 
anhydrous, hydoxypropyl cellulose, croscarmellose sodium, colloidal silicon dioxide, 
magnesium stearate and Opadry® yellow. All tablet strengths are prepared from a common 
blend and are distinguished by shape. The 20 mg tablets are round and the 60 mg tablets are oval. 
The components of the tablets are listed in Table 4-1.  Details regarding the pharmacology, 
nonclinical toxicology and clinical experience can be found in the Investigator’s Brochure for 
cabozantinib. 
 
 
 


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Table 4-1: 
Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Cabozantinib malate (25% drug load as cabozantinib) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
- 
HPMC 2910/Hypromellose 6 cp  
- 
Titanium dioxide  
- 
Triacetin  
- 
Iron Oxide Yellow 
Film Coating 
4.00 
4.1.2 
Erlotinib Tablets 
Trade name: tarceva 
Chemical name: N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)-4-quinazolinamine 
Erlotinib tablets for oral administration are available in three dosage strengths containing 
erlotinib hydrochloride (27.3 mg, 109.3 mg, and 163.9 mg) equivalent to 25 mg, 100 mg, and 
150 mg erlotininb and the following inactive ingredients: lactose monohydrate, hypromellose, 
hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, sodium starch 
glycolate, sodium lauryl sulfate, and titanium dioxide. The tablets which are round, biconvex 
face and straight sides, also contain trace amounts of color additives, including FD&C Yellow #6 
(25 mg only) for product identification.  
Details regarding the pharmacology, nonclinical toxicology and clinical experience can be found 
in the Package Insert for erlotinib.  
4.2 
Composition, Formulation, and Storage 
All study medication will be stored as described in the pharmacy manual and inventoried in 
accordance with applicable state and federal regulations. 


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4.3 
Dose, Schedule and Route 
Subjects will receive cabozantinib orally at a dose of 40 mg once daily (qd), and erlotinib orally 
at a dose of 100 mg qd.  
Both study medications must be taken on an empty stomach.  Subjects will be instructed not to 
eat for at least 2 hours before and at least 1 hour after taking cabozantinib and erlotinib.  Subjects 
should be instructed to take their study medications at approximately the same time every day.  If 
a subject misses a dose, the dose may be taken later only if it is within 12 hours of when the 
missed dose should have been taken. The missed dose should not be made up if it is within 12 
hours of the next scheduled dose.   
Cabozantinib and erlotinib tablets should be swallowed whole with at least 8 ounces of water.  
The tablets should not be crushed. Grapefruit, grapefruit juice, and Seville oranges and their 
products should be avoided by subjects taking cabozantinib.  
Avoid concomitant use of erlotinib with proton pump inhibitors if possible. If concomitant use of 
an H2-receptor antagonist such as ranitidine is required, erlotinib should be taken 10 hours after 
the H2-receptor antagonist dosing and at least 2 hours before the next dose of the H2-receptor 
antagonist. 
If concomitant antacid use is necessary, the antacid dose and erlotinib dose should be separated 
by several hours. 
In all subjects, dose reductions and delays to manage toxicity are allowed under the guidelines in 
Section 4.3.1 below. 
4.3.1 
Dose Modifications, Interruptions, and Discontinuation 
Subjects will be monitored for adverse events (AEs) from the time of first study intervention 
(i.e., biopsy, if needed, or treatment, whichever comes first) through their last follow-up visit 
(i.e., 30 days after the date of the last dose of study treatment). Subjects will be instructed to 
notify their physician immediately at the onset of any AE. Causality assessment of AEs will be 
determined by the investigator. AE severity will be graded by the investigator in accordance with 
CTCAE v.4.03.  
The following should be taken into consideration in decisions regarding dose modifications 
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• As a general approach all AEs should be managed with supportive care at the earliest 
signs of toxicity considered related to the study treatment. Should this be ineffective, 
dose interruptions and/or reductions should be considered to prevent worsening of 
toxicity.  
• Dose modification criteria are shown in Table 4-3. 
• Dose interruptions and/or reductions should be implemented for unacceptable toxicity. 
Doses may be modified at any time while a subject is on treatment. 
• The assigned starting dose for cabozantinib is 40 mg/day, and the assigned starting dose 
for erlotinib is 100 mg/day. One dose reduction level of cabozantinib and one dose 
reduction level of erlotinib are permitted (see Table 4-2). 
• Dose reductions or interruptions may also occur in the setting of lower grade toxicity than 
defined in Table 4-3 if the investigator feels it is in the interest of a subject’s safety and 
will optimize drug tolerability. 
• Interruption of treatment for treatment-related AEs may occur at any time per investigator 
discretion. If treatment is interrupted due to related AEs for more than 6 weeks, treatment 
should be discontinued unless there is unequivocal evidence that the subject is 
benefitting. In this situation, a subject may be able to restart therapy with a dose 
reduction upon resolution of the toxicity per the discretion of the investigator. 
• Dose interruptions for reason(s) other than related AEs (e.g., surgical procedures) can be 
longer than 6 weeks per the discretion of the investigator. 
• Subjects may continue on only one study drug if the other drug must be stopped 
altogether and physician believes there is clinical benefit to staying that drug. 
Guidelines for the management of specific AEs are provided in Section 4.4.1.  
 
Table 4-2: 
Dose Reductions of Cabozantinib and Erlotinib 
Assigned Starting Dose 
First Dose Level Reduction 
 
40-mg cabozantinib oral qd 20-mg cabozantinib oral qd 
(discontinue if this dose is not tolerated) 
 
100-mg erlotinib oral qd 
50-mg erlotinib oral qd (discontinue if this dose is not tolerated) 
 
See Section 4.5.5 for complete details regarding potential drug interactions. 
 
 


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Table 4-3: 
Dose Modifications for Treatment-Related AEs for Cabozantinib and 
Erlotinib 
Dose modifications should be made to both cabozantinib and erlotinib for any overlapping 
treatment-related adverse events unless the investigator suspects one drug over another to be the 
cause of unacceptable toxicity. In this case, dose modifications may be made to one drug per the 
investigator’s discretion. The most common overlapping toxicities are: diarrhea, fatigue, nausea, 
skin reactions and vomiting. 
 
CTCAE v.4.03 Grade 
Recommended Guidelines for Managementa 
Grade 1 AEs 
Add supportive care as indicated. Continue treatment at the 
current dose level if AE is manageable and tolerable. 
Grade 2 AEs which are tolerable and 
are easily managed 
 
Grade 2 AEs which are intolerable 
and cannot be adequately managed  
Continue treatment at the current dose level with supportive 
care. 
 
At the discretion of the investigator, treatment should be dose 
reduced or interrupted. 
Note: It is recommended that dose holds be as brief as 
possible.  
Grade 3 AEs (except clinically 
non-relevant laboratory abnormalities) 
Treatment should be interrupted unless the toxicity can be 
easily managed with a dose reduction and optimal medical 
care.  
Note: It is recommended that dose holds be as brief as 
possible. 
Grade 4 AEs (except clinically 
non-relevant laboratory abnormalities) 
Subjects should have treatment interrupted immediately.  
Discontinue treatment unless the following criteria are met:  
• 
Subject is deriving clear clinical benefit as determined 
by the investigator and agreed by the sponsor-
investigator 
• 
Toxicity can be managed with a dose reduction 
following recovery to Grade 1 (or baseline) and 
optimal medical care  
Note: The dose delay and modification criteria for specific medical conditions are provided in Section 4.3.1. For 
re-treatment criteria of study treatment after a dose hold see Section 4.3.2. 
a Study treatment dose adjustment is only needed if the toxicity was deemed related to treatment or had an 
unclear relationship to treatment. 
 
4.3.2 
Dose Reinstitution and Reescalation 
If the subject recovers from his or her toxicities to CTCAE v.4.03Grade ≤ 1 or to the baseline 
value (or lower) and the toxicity was unrelated to study treatment, then study treatment may be 
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If the subject recovers from his or her toxicities to Grade ≤ 1 or to the baseline value (or lower) 
the toxicity was deemed possibly related to study treatment, then study treatment may be 
restarted at a reduced dose (see Table 4-2 for the schedule of dose reductions).  
Subjects receiving the lowest trial dose (cabozantinib = 20 mg/day; erlotinib = 50 mg/day) may 
be restarted at the same dose if deemed safe at the discretion of the investigator. Subjects unable 
to tolerate the lowest trial dose should discontinue study treatment. 
Re-escalation to the previous dose, (but not higher than the trial dose [cabozantinib = 40 mg/day; 
erlotinib = 100 mg/day]) may be allowed at the discretion of the investigator and agreement of 
the PI for AEs which have resolved or recovered to Grade 1 (or baseline value) and deemed 
tolerable and easily managed by optimized supportive treatment. Dose re-escalation is not 
allowed for a drug-related dose reduction triggered by Grade 4 hematologic toxicities or by 
Grade 4 AEs affecting major organs (e.g., central nervous system, cardiac, hepatic, renal). 
4.4 
Warnings and Precautions and Guidelines for the Management of Adverse 
Events 
The most frequent adverse events experienced by ≥ 20% of subjects were: 
• Cabozantinib: diarrhea, fatigue, nausea, decreased appetite, vomiting, weight decreased, 
palmar-plantar erythrodysesthesia syndrome (PPES), constipation, hypertension, 
dysgeusia, dysphonia, and asthenia. 
• Erlotinib: rash, diarrhea, anorexia, fatigue, dyspnea, cough, nausea, and vomiting. 
Adverse events associated with laboratory abnormalities experienced by ≥ 5% of subjects 
include: 
• Cabozantinib: anemia, AST increased, ALT increased, hypothyroidism, hypokalemia, 
hypomagnesemia, thrombocytopenia, hypocalcemia, hypophosphatemia, lipase increased, 
lactate dehydrogenase (LDH) increased, neutropenia, ALP increased, hyponatremia, and 
leukopenia. Mild to moderate QTc interval prolongation (10-15ms) has also been 
observed with a QT interval calculated by the Fridericia formula (QTcF) not exceeding 
500 ms. 
Subjects may also experience medically important but less frequent adverse events including: 
• Cabozantinib: arterial and venous thrombotic AEs (e.g., deep vein thrombosis [DVT], 
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[MI]), severe hemorrhagic events, proteinuria, wound healing complications, 
gastrointestinal [GI] perforation, abscesses including intra-abdominal and pelvic abscess, 
GI and non-GI fistulae formation, osteonecrosis, and reverse posterior 
leukoencephalopathy syndrome (RPLS).  
• Erlotinib: interstitial lung disease (ILD), renal failure, hepatoxicity with or without 
hepatic impairment, GI perforation, bullous and exfoliative skin disorders, MI/ischemia, 
cerebrovascular accident (CVA), microangiopathic hemolytic anemia with 
thrombocytopenia, ocular disorders, hemorrhage in patients taking warfarin, and embryo-
fetal toxicity. Please refer to the package insert for more detailed information on 
managing these conditions.  
Treatment should be permanently discontinued for the following adverse events:  
• Cabozantinib: visceral perforation or fistula formation, severe hemorrhage, serious 
arterial thromboembolic events, nephrotic syndrome, malignant hypertension, 
hypertensive emergency, persistent uncontrolled hypertension despite optimal medical 
management, osteonecrosis of the jaw (ONJ), and serious and life-threatening RPLS. 
• Erlotinib: ILD, severe hepatic toxicity (see Section 4.4.1.2), gastrointestinal perforation, 
severe bullous, blistering, or exfoliating skin conditions, and corneal perforation or severe 
ulceration. 
The predicted effective plasma half-life of cabozantinib is 55 hours. Thus, when initiating 
therapy with cabozantinib, it will take most subjects 2 to 3 weeks to reach steady state. If AEs 
attributable to cabozantinib occur within the initial 3-week period of dosing, early intervention 
with dose modifications may be justified for AEs that, if worsened, could potentially be 
dangerous or debilitating, because without a dose adjustment, systemic exposure of cabozantinib 
might be expected to increase after the onset of the AE.  Cabozantinib-related events that 
generally have an early onset include hypocalcemia, hypokalemia, thrombocytopenia, 
hypertension, PPES, abdominal pain, mucosal inflammation, constipation, diarrhea and 
vomiting.  
A population pharmacokinetic analysis in 591 patients receiving the single-agent erlotinib 2nd/3rd 
line regimen showed a median half-life of 36.2 hours. Time to reach steady state plasma 
concentration would therefore be 7 to 8 days. No significant relationship of clearance to 
covariate of patient age, body weight, or gender were observed. Smokers had a 24% higher rate 
of erlotinib clearance. Similar results were observed in a population pharmoacokinetic analysis 


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conducted with 204 pancreatic cancer patients who receive erlotinib plus gemcitabine. Co-
administration of gemcitabine had no effect on erlotinib plasma clearance. Rash and diarrhea, the 
most common adverse reactions with erlotinib, usually occur within one month of starting 
treatment. 
 
 


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4.4.1 
Guidelines for Management of Potential Adverse Events 
Please refer to the subsections below for specific guidelines regarding the following potential 
adverse events:  
Gastrointestinal disorders (diarrhea, nausea, 
decreased appetite, vomiting, constipation, 
stomatitis and abdominal pain) 
Section 4.4.1.1 
Table 4-4: Management of Treatment-Emergent 
Diarrhea 
Hepatobiliary disorders (elevations of ALT, AST, 
bilirubin; hepatic failure, hepatorenal syndrome) 
Section 4.4.1.2 
Hematological disorders (neutropenia, 
thrombocytopenia) 
Section 4.4.1.3 
Fatigue, anorexia, and weight loss 
Section 4.4.1.4 
Skin disorders (rash [blisters, erythematous rash, 
macular rash, skin exfoliation, dermatitis 
acneiform, and papular rash], palmar-plantar 
erythrodysesthesia syndrome [PPES], pruritus, 
dry skin, erythema, pigmentary changes, alopecia) 
Section 4.4.1.5 
Table 4-5: Management of PPES 
Wound healing and surgery 
Section 4.4.1.6 
Hypertension 
Section 4.4.1.7 
Table 4-6: Management of Hypertension Related 
to Cabozantinib 
Thromboembolic events (deep vein thrombosis 
[DVT], pulmonary embolism [PE], transient 
ischemic attack [TIA], myocardial infarction, 
ischemia, cerebrovascular accident) 
Section 4.4.1.8 
 
Proteinuria 
Section 4.4.1.9 
Table 4-7: Manage of Proteinuria 
Corrected QTc prolongation 
Section 4.4.1.10 
Hypophosphatemia 
Section 4.4.1.11 
Thyroid function disorders (changes in thyroid 
function tests, hypothyroidism) 
Section 4.4.1.12 
Hemorrhagic events 
Section 4.4.1.13 
GI perforation/fistula and non-GI fistula 
Section 4.4.1.14 
Osteonecrosis of the jaw 
Section 4.4.1.15 
Respiratory, thoracic and mediastinal disorders 
(cough, dyspnea, fistula formation, pneumonia, 
interstitial lung disease [ILD]) 
Section 4.4.1.16 
Renal failure (hepatorenal syndrome, severe acute 
renal failure, renal insufficiency) 
Section 4.4.1.17 
Ocular disorders (decrease tear production, 
abnormal eyelash growth, keratoconjunctivitis 
sicca, keratitis) 
Section 4.4.1.18 
 
 
 


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4.4.1.1 
Gastrointestinal Disorders 
The most common non-hepatobiliary GI AEs reported in clinical studies with cabozantinib 
regardless of causality are diarrhea, nausea, decreased appetite, vomiting, constipation, stomatitis 
and abdominal pain. Diarrhea, nausea, and vomiting were amongst the most common adverse 
reactions experienced by ≥ 20% of subjects who took erlotinib. 
Diarrhea: Subjects should be instructed to notify their physician immediately at the first signs of 
poorly formed or loose stool or an increased frequency of bowel movements. 
Guidelines for the evaluation and management of diarrhea are shown in Table 4-4. 
Administration of antidiarrheal/antimotility agents is recommended at the first sign of diarrhea as 
initial management. Some subjects may require concomitant treatment with more than one 
antidiarrheal agent. When therapy with antidiarrheal agents does not control the diarrhea to 
tolerable levels, cabozantinib and erlotinib should be temporarily interrupted or dose reduced. 
When the diarrhea is controlled, retreatment with cabozantinib and erlotinib may be acceptable 
per investigator decision. 
In addition, general supportive measures should be implemented such as continuous oral isotonic 
hydration, correction of fluid and electrolyte abnormalities, small frequent meals, and stopping 
lactose-containing products, high-fat meals, and alcohol. 
Recurrent or prolonged diarrhea can be associated with anal or perianal skin erosions which 
increase the risk for anal abscesses, fistulas, or proctitis. Good personal hygiene should be 
emphasized. Regular examinations of the perianal region should be performed whenever diarrhea 
has occurred during treatment with cabozantinib and erlotinib. Infections of the perianal region 
should be treated per local guidelines. 
 
 


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Table 4-4: Management of Treatment-Emergent Diarrhea 
CTCAE v.4.03 Grade  
Action To Be Taken  
Tolerable Grade 1-2 
(duration < 48 h) 
• 
Continue with study treatment and consider dose reduction 
• 
Initiate treatment with an antidiarrheal agent (eg, loperamide 4 
mg followed by 2 mg after each episode of diarrhea [maximum: 
16 mg loperamide per day]) 
• 
Dietary modifications (eg, small lactose-free meals, bananas and rice) 
• 
Intake of isotonic fluids (1-1.5 L/day) 
• 
Re-assess after 24 hours: 
o 
Diarrhea resolving to baseline bowel habits: gradually add 
solid foods and discontinue or decrease antidiarrheal 
treatment after 12 h diarrhea-free interval 
o 
Diarrhea not resolving: Continue/resume antidiarrheal 
Intolerable Grade 2, 
Grade 2 > 48 h, 
or ≥ Grade 3 
• 
Interrupt study treatment 
• 
Ask subject to attend clinic 
• 
Rule out infection (eg, stool sample for culture) 
o 
Administer antibiotics as needed (eg, if fever or Grade 3-4 
neutropenia persists > 24 h) 
• 
Administer fluids (1-1.5 L/day orally or IV, as appropriate) for 
hydration or to correct electrolyte abnormalities 
• 
For Grade 3-4 or complicated lower grade diarrhea 
consider hospitalization and IV hydration 
• 
Re-assess after 24 h 
o 
Diarrhea resolving to baseline bowel habits or Grade ≤ 1: 
consider restarting study treatment at reduced dose 
o 
Diarrhea not resolving: 
• 
Start and or continue antidiarrheal treatment (eg, loperamide 4 
mg followed by 2 mg after each episode of diarrhea 
[maximum: 16 mg loperamide per day]) 
• 
Consider starting second line antidiarrheal or referral to 
gastroenterologist 
o 
If severe diarrhea cannot be resolved with the measures 
listed above, discontinue treatment. 
4.4.1.2 
Hepatobiliary Disorders 
Elevations of ALT, AST, and bilirubin have been observed during treatment with cabozantinib. 
Hepatic failure and hepatorenal syndrome, including fatal cases, can occur with erlotinib 
treatment in subjects with normal hepatic function; the risk of hapatic toxicity is increased in 
subjects with baseline hepatic impairment. Perform periodic liver testing (transaminases, 


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bilirubin, and alkaline phosphatase) during treatment. If possible, hepatotoxic concomitant 
medications should be discontinued in subjects who develop increased values of ALT, AST, or 
bilirubin.  
Subjects on this study may enter with increased ALT/AST serum levels up to 3 × ULN. Dose 
reductions of study treatment should be considered in any subject who develops drug-related 
grade 2 bilirubin lasting longer than 1 week. In subjects who develop doubling of ALT/AST 
elevations in combination with a bilirubin elevation > 2 × ULN without reasonable other 
explanation, drug-induced liver injury should be suspected and treatment interrupted. 
Reinstitution of study treatment after recovery of ALT, AST, and bilirubin to baseline level is at 
the discretion of the investigator. 
Withhold and consider discontinuing erlotinib in subjects without pre-existing hepatic 
impairment for total bilirubin levels greater than 3 x the ULN or transaminases greater than 5 x 
the ULN. Withhold and consider discontinuing erlotinib in patients with pre-existing hepatic 
impairment or biliary obstruction for doubling of bilirubin or tripling of transaminases values 
over baseline. Discontinue erlotinib in subjects whose abnormal liver tests meeting the above 
criteria do not improve significantly or resolve within 3 weeks. 
4.4.1.3 
Hematological Disorders 
Hematological toxicities (i.e., neutropenia and thrombocytopenia) and associated complications 
have been observed after administration of cabozantinib and may be managed with dose 
interruptions and/or dose reductions. Use of granulocyte colony-stimulating factor support for 
neutrophil recovery is allowed per investigator discretion and in accordance with accepted 
guidelines after the first incidence of clinically relevant cytopenia. 
Febrile neutropenia or evidence of infection associated with neutropenia should be treated 
appropriately and in a timely manner according to institutional guidelines. 
Dose reductions or dose interruptions for anemia are not mandated but can be applied as 
clinically indicated. Supportive care such as red blood cell transfusions may be managed 
according to institutional guidelines. 
4.4.1.4 
Fatigue, Anorexia, and Weight Loss 
Fatigue has been reported during treatment with cabozantinib and erlotinib. Refer to Table 4-3 
for general management guidelines. 


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Anorexia and weight loss should be managed in accordance to local standard of care including 
nutritional support. If fatigue, anorexia, or weight loss cannot be adequately managed, study 
treatment should be temporarily interrupted or dose reduced per Table 4-2 and Table 4-3.   
4.4.1.5 
Skin Disorders 
Palmar-plantar erythrodysesthesia syndrome (PPES; also known as hand-foot syndrome), skin 
rash (including blisters, erythematous rash, macular rash, skin exfoliation, dermatitis acneiform, 
and papular rash), pruritus, dry skin, erythema, pigmentary changes, and alopecia have been 
reported in cabozantinib-treated subjects. Treatment guidelines for PPES related to study 
treatment are presented in Table 4-5. 
Rash was amongst one of the most common adverse reactions experienced by ≥ 20% of subjects 
who took erlotinib. Grade 3-4 rash was reported in 5% of patients treated with erlotinib and 
gemcitabine as first-line treatment of pancreatic cancer. Rash includes PPES, acne, skin disorder, 
pigmentation disorder, erythema, skin ulcer, dermatitis exfoliative, rash popular, and skin 
desquamation. Bullous, blistering and exfoliative skin conditions, including cases suggestive of 
Stevens-Johnson syndrome/toxic epidermal necrolysis, which in some cases were fatal, can 
occur with erlotinib treatment. Discontinue treatment in subjects who develop severe bullous, 
blistering or exfoliating conditions. Please refer to the guidelines for treatment-related rash 
(except for PPES which can be found in Table 4-5 below) in Table 4-3. 
In the case of study treatment-related skin changes (e.g., rash, hand-foot syndrome), the 
investigator may request that additional assessments be conducted with the subject’s consent. 
These assessments may include digital photographs of the skin changes and/or a biopsy of the 
affected skin and may be repeated until the skin changes resolve.  
 
 


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Table 4-5: 
Management of Treatment-Emergent Hand-Foot Syndrome (PPES) 
CTCAE v.4.03 
Grade  
Action To Be Taken  
Grade 1 
Study treatment may be continued at the current dose if PPES is clinically 
insignificant and tolerable. Otherwise, study treatment should be reduced to 
the next lower dose level.a Start urea 20% cream twice daily AND clobetasol 
0.05% cream once daily. Reassess at least weekly; if PPES worsens at any 
time or does not improve after 2 weeks, proceed to the intervention guidelines 
for Grade 2. 
Grade 2  
Study treatment may be continued if PPES is tolerated. Study treatment should 
be dose reduced or interrupted if PPES is intolerable. Continue urea 20% 
cream twice daily AND clobetasol 0.05% cream once daily and add analgesics 
(e.g., non-steroidal anti-inflammatory drug (NSAID)s/gamma-aminobutyric 
acid agonists) for pain control if needed. Reassess at least weekly; if PPES 
worsens or affects self-care, proceed to the intervention guidelines for Grade 3. 
Grade 3 
Interrupt study treatment until severity decreases to Grade 1 or 0. Continue 
treatment of skin reaction with clobetasol 0.05% cream twice daily AND 
analgesics. Resume study drug at a reduced dose if PPES recovers to Grade 
≤ 1. Discontinue subject from study treatment if PPES does not improve within 
6 weeks. 
a Permitted dose levels are defined by individual protocols. 
4.4.1.6 
Wound Healing and Surgery  
Surgical and traumatic wounds must have completely healed before starting cabozantinib 
treatment and be monitored for wound dehiscence or wound infection while the subject is being 
treated with cabozantinib. If possible, cabozantinib treatment should be stopped for at least 28 
days prior to major surgery. 
4.4.1.7 
Hypertension 
Hypertension is a common class effect of drugs that inhibit VEGF pathways and has been 
reported among subjects treated with cabozantinib. 
Treatment guidelines for hypertension deemed related to cabozantinib are presented in Table 4-6. 
Blood pressure should be monitored in a constant position at each visit (either sitting or supine). 
In general, subjects with known hypertension should be optimally managed before study entry. 
Decisions to decrease or hold the dose of study treatment must be based on blood pressure 
readings taken by a medical professional and must be confirmed with a second measurement at 
least 5 minutes after the first measurement.  Other than for hypertension requiring immediate 
therapy, the presence of new or worsened hypertension should be confirmed at a second visit 
before taking therapeutic action. It is recommended that this second visit occurs within 1 week. 


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Treatment should be discontinued in subjects with hypertensive crises or hypertensive 
encephalopathy. 
Table 4-6: 
Management of Hypertension Related to Cabozantinib 
Criteria for Dose Modifications 
Treatment/Cabozantinib Dose Modification 
Subjects NOT receiving optimized anti-hypertensive therapy 
> 150 mm Hg (systolic)a and < 160 mm 
Hg 
OR 
> 100 mm Hg (diastolic) and < 110 mm 
Hg 
 
• 
Optimize antihypertensive medications by adding new 
or additional antihypertensive medications and/or 
increase dose of existing medications. 
• 
Reduce study treatment by one dose level if optimal 
antihypertensive therapy (usually to include 3 agents) 
does not result in BP <150 mm Hg systolic or 
<100 mm Hg diastolic 
• If subject is symptomatic interrupt study treatment 
≥ 160 mm Hg (systolic) 
OR 
≥ 110 mm Hg (diastolic) 
• 
Reduce cabozantinib by one dose levelb or interrupt 
study treatment per investigator discretion 
• 
Add new or additional anti-hypertensive medications 
and/or increase dose of existing medications and 
monitor subject closely for hypotension. If optimized 
antihypertensive therapy (usually to include 3 agents) 
does not result in BP < 150 mm Hg systolic or 
< 100 mm Hg diastolic, study treatment should be dose 
reduced further or interrupted 
• 
Study treatment should be dose interrupted if upper 
limits of systolic BP (≥ 160 mm Hg) are sustained and 
not adequately manageable or if systolic BP is 
> 180 mm Hg or diastolic BP > 110 mm Hg, or if 
subject is symptomatic 
• Re-start study treatment at the most tolerable dose and 
re-escalate only if BP falls to and is sustained at 
< 150 mm Hg systolic and < 100 mm Hg diastolic 
Hypertensive emergencyc 
• 
Discontinue study treatment 
a The investigator may decide to initiate or adjust antihypertensive treatment at a lower threshold than systolic 
BP >150 or diastolic BP >100 based on their clinical judgment and assessment of the individual subject. 
b Permitted dose levels are defined by individual protocols. 
c Hypertensive emergency is defined as uncontrolled elevated blood pressure with clinical evidence of 
progressive or impending end-organ damage (eg, myocardial infarction/ischemia, intracranial hemorrhage, 
cerebral ischemia, pulmonary edema, encephalopathy, kidney damage). 
4.4.1.8 
Thromboembolic Events 
Thromboembolic complications are frequent in cancer patients due to procoagulant changes 
induced by the malignancy or anticancer therapy including inhibitors of VEGF pathways. Deep 
vein thrombosis and PE have been observed in clinical studies with cabozantinib; including fatal 


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events (please refer to the Investigator’s Brochure). Subjects who develop a PE or DVT should 
have treatment held until therapeutic anticoagulation with heparins (e.g., low molecular weight 
heparin [LMWH]) is established. LMWH are the preferred management for thrombotic events, 
warfarin is not recommended although is allowed at investigator discretion. Treatment may be 
resumed in subjects who are stable and have uncomplicated PE or DVT and are deriving clinical 
benefit from treatment and that anticoagulation does not place them at a significant risk that 
outweighs the benefit of resuming treatment per discretion of the investigator/PI. During 
anticoagulation treatment, subjects need to be monitored on an ongoing basis for bleeding risk 
and signs of bleeding which may require additional or more frequent laboratory tests in 
accordance to institutional guidelines. If there are any signs of clinically significant bleedings, 
treatment should be permanently discontinued. 
Arterial thrombotic events have been observed in studies with cabozantinib (e.g., transient 
ischemic attack, myocardial infarction) and erlotinib (e.g., myocardial infarction/ischemia, 
cerebrovascular accident). Treatment should be discontinued in subjects who develop an acute 
myocardial infarction, cerebral infarction or any other clinically relevant arterial thromboembolic 
complication. 
4.4.1.9 
Proteinuria 
Proteinuria is an anticipated AE with the inhibition of VEGF pathways and has been observed in 
cabozantinib clinical studies, and nephrotic syndrome has been reported with cabozantinib and 
other inhibitors of VEGF pathways. Management guidelines are provided in Table 4-7.   
Treatment should be permanently discontinued in subjects who develop nephrotic syndrome 
(proteinuria > 3.5 grams per day in combination with hypoalbuminemia and peripheral edema 
[hyperlipidemia and thrombotic disease may also be present]) or any other relevant renal disease. 
 
 


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Table 4-7: 
Management of Treatment-emergent Proteinuria 
Severity of Proteinuria 
(UPCR) 
Management of Proteinuria 
≤ 1 mg/mg 
(≤ 113.1 mg/mmol) 
• 
No change in cabozantinib treatment or monitoring 
> 1 and < 3.5 mg/mg 
(> 113.1 and < 395.9 
mg/mmol) 
• 
Consider confirming with a 24-hour protein assessment within 7 days 
• 
No change in cabozantinib treatment required if UPCR ≤ 2 mg/mg or 
urine protein ≤ 2 g/24 hours on 24-hour urine collection. 
• 
Dose reduce or interrupt cabozantinib treatment if UPCR > 2 mg/mg 
on repeat UPCR testing or urine protein > 2 g/24 hours on 24-hour 
urine collection. Continue cabozantinib on a reduced dose if UPCR 
decreases to < 2 mg/mg. Consider holding cabozantinib treatment if 
UPCR remains > 2 mg/mg despite a dose reduction until UPCR 
decreases to < 2 mg/mg. Restart cabozantinib treatment at a reduced 
dose after a dose hold unless otherwise approved by PI. 
• 
Repeat UPCR within 7 days and once per week. If UPCR < 1 mg/mg 
on 2 consecutive readings, UPCR monitoring can revert to protocol-
specific times. (Second reading is confirmatory and can be done within 
1 week of first reading.) If UPCR remains > 1 mg/mg and < 2 mg/mg 
for 1 month or is determined to be stable (< 20% change) for 1 month, 
check urine protein/creatinine per protocol or as clinically indicated. 
≥ 3.5 mg/mg 
(≥ 395.9 mg/mmol) 
• 
Hold cabozantinib treatment pending repeat UPCR within 7 days 
and/or 24-hour urine protein.  
• 
If ≥ 3.5 mg/mg on repeat UPCR, continue to hold cabozantinib 
treatment and check UPCR every 7 days. If UPCR decreases to < 2 
mg/mg, restart cabozantinib treatment at a reduced dose and 
monitoring of urine protein/creatinine should continue weekly until the 
UPCR decreases to < 1 mg/mg. If UPCR remains > 1 mg/mg and < 2 
mg/mg for 1 month or is determined to be stable (< 20% change) for 1 
month, check urine protein/creatinine per protocol or as clinically 
indicated. 
Nephrotic syndrome 
• 
Discontinue all study treatment 
4.4.1.10 
Corrected QTc Prolongation 
The effect of orally administered cabozantinib 140 mg qd on QTc interval was evaluated in a 
placebo-controlled study in subjects with MTC. A mean increase in QTcF of 10-15 ms was 
observed after 4 weeks after initiating cabozantinib treatment. A concentration-QTc relationship 
could not be definitively established. Changes in cardiac wave form morphology or new rhythms 
were not observed. No cabozantinib-treated subjects in this study had a QTcF > 500 ms. 


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Cabozantinib should be used with caution in subjects with QT prolongation risk, a history of QT 
interval prolongation, or who are taking antiarrhythmics or drugs known to prolong the QT 
interval. Concomitant treatment with strong CYP3A4 inhibitors, which may increase 
cabozantinib plasma concentrations, should be avoided.  
If at any time on study there is an increase in QTcF to an absolute value > 500 ms or an increase 
of > 60 ms above baseline, two additional ECGs must be performed with intervals not less than 
3 min apart within 30 min after the initial ECG. 
If the average QTcF from the three ECGs is > 500 ms or increased by > 60 ms above baseline, 
the following actions must be taken: 
• Withhold study treatment 
• Immediately notify the PI 
• Hospitalize symptomatic subjects (e.g., with palpitations, dizziness, syncope, orthostatic 
hypotension, a significant ventricular arrhythmia on ECG) for a thorough cardiology 
evaluation and management 
• Consider cardiology consultation for asymptomatic subjects for evaluation and 
management 
• Check electrolytes, especially magnesium, potassium and calcium; correct abnormalities 
as clinically indicated 
• Check concomitant medications for any medication that may have contributed to QT 
prolongation, and if possible, discontinue these medications (http://www.qtdrugs.org) 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation and symptoms have resolved. Study treatment may be restarted at a reduced dose level 
if all of the following conditions are met: 
• Symptoms are determined to be unrelated to the QT interval prolongation 
• The QTcF value > 500 ms or increase of > 60 ms above baseline is not confirmed 
according to protocol procedures 
• Study treatment has been interrupted through a minimum of 1 week following the return 
of the QTcF to ≤ 500 msec or return to ≤ 60 ms above baseline. 
• QT prolongation can be unequivocally associated with an event other than cabozantinib 
administration and is treatable/has been resolved  
• PI has reviewed all available information and has agreed to the continuation of study 
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Following reinitiation of study treatment, ECGs must be repeated weekly for 2 weeks, then every 
2 weeks for 1 month, then according to the protocol-defined time points. 
All study treatment must be permanently discontinued if either of the following applies: 
• Cardiac evaluation confirms that symptoms are the consequence of QT interval 
prolongation 
• Recurrence of QTcF prolongation (confirmed by ECG lab) after reinitiation of study 
treatment at a reduced dose 
4.4.1.11 
Hypophosphatemia 
Hypophosphatemia has been reported during treatment with cabozantinib. Serum phosphorus 
should be monitored frequently while receiving cabozantinib. Other causes of hypophosphatemia 
should be ruled out and/or these causes treated in accordance to standard of care. Mild to 
moderate hypophosphatemia should be managed by oral replacement including food that are 
high in phosphate (dairy items, meats, beans) and/or oral phosphate supplements in accordance 
to standard clinical practice guidelines.  
Clinically relevant hypophosphatemia should be managed in accordance to the dose modification 
guidelines as outlined in Table 4-2 and Table 4-3 or as clinically indicated. 
4.4.1.12 
Thyroid Function Disorders 
Changes in thyroid function tests (TFTs) and hypothyroidism have been reported with 
cabozantinib therapy and other tyrosine kinase inhibitors as a result of altered thyroid hormone 
regulation by mechanisms that seem to be specific for each agent.12 Currently available data are 
insufficient to determine the mechanism of TFT alterations and its clinical relevance. Routine 
monitoring of thyroid function and assessments for signs and symptoms associated with thyroid 
dysfunction is recommended before initiation and during treatment. Management of thyroid 
dysfunction (e.g., symptomatic hypothyroidism) should follow accepted clinical practice 
guidelines and dose modification guidelines as outlined in Table 4-2 and 4-3.  
4.4.1.13 
Hemorrhagic Events 
Hemorrhagic events have been reported with cabozantinib. In order to mitigate risk of severe 
hemorrhage, subjects should be evaluated for potential bleeding risk factors before initiating 
treatment and monitored for bleeding events with serial complete blood counts and physical 
examination while on study. Risk factors for hemorrhagic events may include (but may not be 
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• Tumor of the lung with cavitary lesions or tumor lesions which invades, encases, major 
blood vessels. The anatomic location and characteristics of tumor as well as the medical 
history must be carefully reviewed in the selection of subjects for treatment; 
• Recent or concurrent radiation to the thoracic cavity; 
• Active peptic ulcer disease, inflammatory GI diseases including Crohn’s disease and 
ulcerative colitis; 
• Underlying medical conditions which affect normal hemostasis (e.g., deficiencies in 
clotting factors and/or platelet function, or thrombocytopenia); 
• Concomitant medication with anticoagulants or other drugs which affect normal 
hemostasis; 
• History of clinically significant hemoptysis. 
Treatment should be discontinued in subjects with serious and life-threatening bleeding events or 
recent hemoptysis (≥ 2.5 mL of red blood). 
4.4.1.14 
GI Perforation/Fistula and Non-GI Fistula Formation 
Gastrointestinal perforation/GI fistula: After starting treatment, subjects should be monitored for 
early signs of GI perforation such as abdominal pain, nausea, emesis, constipation, and fever 
especially if known risk factors for developing GI perforation or fistula are present.  
Discontinue treatment in subjects who have been diagnosed with GI perforation/fistula. 
Non-GI fistula formation: Complications from radiation therapy has been identified as a possible 
predisposing risk factor for fistula formation in subjects undergoing treatment with cabozantinib. 
Fistula should be ruled out as appropriate in cases of onset of severe mucositis or difficulty 
swallowing after start of therapy. Discontinue treatment and initiate appropriate management in 
subjects who have been diagnosed with a non-GI fistula. 
Discontinue treatment in subjects who have been diagnosed with non-GI fistula. 
4.4.1.15 
Osteonecrosis of the Jaw 
Osteonecrosis of the jaw (ONJ) has been reported in subjects treated with cabozantinib. 
Additional risk factors for ONJ have been identified including the use of bisphosphonates and 
denosumab, chemotherapy, corticosteroids, local radiotherapy, and dental or orofacial surgery 
procedures.   
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Invasive dental procedures should be avoided. In cases where dental procedures are unavoidable, 
treatment should be held for at least 4 weeks prior to the procedure and resumed after complete 
wound healing has occurred. Bone healing may often require a protracted time. 
4.4.1.16 
Respiratory, Thoracic and Mediastinal Disorders 
Dyspnea has been reported in clinical studies with cabozantinib and erlotinib. Cough was 
amongst one of the most common adverse reactions experienced by ≥ 20% of subjects who took 
erlotinib. Symptoms should be managed according to locally accepted clinical practice including 
an assessment for underlying causes. Pulmonary embolism should be considered as possible 
causes for new onset dyspnea given the risk of thrombosis associated with inhibition of VEGF 
signaling. Furthermore, fistula formation and pneumonia have been reported in subjects treated 
with cabozantinib and should be considered as clinically indicated in subjects presenting with 
pulmonary symptoms. 
Cases of serious ILD, including fatal cases, can occur with erlotinib treatment. Withhold 
treatment for acute onset of new or progressive unexplained pulmonary symptoms such as 
dyspnea, cough, and fever pending diagnostic evaluation. If ILD is confirmed, treatment with 
erlotinib should be permanently discontinued. 
4.4.1.17 
Renal Failure 
Hepatorenal syndrome, severe acute renal failure including fatal cases, and renal insufficiency 
can occur with erlotinib treatment. Renal failure may arise from exacerbation of underlying 
baseline hepatic impairment or severe dehydration. Withhold treatment in subjects developing 
severe renal impairment (CTCAE version 4.03 grade 3 or 4) until renal toxicity is resolved.  
4.4.1.18 
Ocular Disorders 
Decreased tear production, abnormal eyelash growth, keratoconjunctivitis sicca or keratitis can 
occur with erlotinib treatment and can lead to corneal perforation or ulceration. Discontinue 
erlotinib if subjects present with corneal perforation or sever ulceration. Withhold erlotinib for 
keratitis of NCI-CTC version 4.03 grade 3-4 or for grade 2 lasting more than 2 weeks. Withhold 
and consider discontinuing erlotinib for acute/worsening ocular disorders such as eye pain. 


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4.5 
Concomitant Medications and Therapies 
4.5.1 
Anticancer Therapy 
Local intervention is discouraged unless medically unavoidable. Subjects receiving local 
intervention (e.g., palliative radiation) are allowed to continue to receive study treatment at the 
investigator’s discretion.  
4.5.2 
Other Medications 
All concomitant medications used by the subject (including prescription and over-the-counter 
medications, transfusions, vitamins, herbal remedies, and nutritional supplements) during the 
period from 28 days before the first dose of study treatment through 30 days after the date of the 
last dose of study treatment are to be recorded in the case report forms. 
4.5.3 
Allowed Therapies  
• Antiemetics and antidiarrheal medications are allowed prophylactically in accordance to 
standard clinical practice if clinically indicated;  
• Granulocyte colony-stimulating factors (G-CSF or GM-CSF) are allowed if used per 
clinical guidelines (e.g., American Society of Clinical Oncology [ASCO] or [European 
Society for Medical Oncology] ESMO guidelines);  
• Drugs used to control bone loss (e.g., bisphosphonates and denosumab) are allowed if 
started before screening activities but may not be initiated or exchanged during the course 
of the study and require PI approval; 
• Transfusions, hormone replacement, and short term higher doses of corticosteroids 
should be utilized as indicated by standard clinical practice; 
• Individualized anticoagulation therapy with heparin is allowed if it can be provided safely 
and effectively under the following circumstances:  
o Low dose heparins for prophylactic use are allowed if clinically indicated and the 
benefit outweighs the risk per the investigator’s discretion.  
o Therapeutic doses of low molecular weight heparins (LMWH) at the time of first 
dose are allowed if the subject has been on a stable dose of LMWH for at least 6 
weeks, and has had no clinically significant hemorrhagic complications from the 
anticoagulation regimen or the tumor.  
o Therapeutic doses of low molecular weight heparins (LMWH) after first dose are 
allowed if clinically indicated (e.g., for the treatment of deep venous thrombosis), 
and the benefit outweighs the risk per the investigator’s discretion. For 


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management of thromboembolic complications while on study, refer to Section 
4.4.1.8.  
o Accepted clinical guidelines regarding appropriate management while receiving 
anticoagulation therapy with heparins must be followed. This includes, but is not 
limited to, subject education regarding potential adverse drug reactions, 
monitoring laboratory parameters, dose adjustments (e.g., due to kidney 
dysfunction);  
o For restrictions on oral anticoagulants see Section 4.5.4. 
• Administration of the PPI esomeprazole resulted in no clinically-relevant effect on 
cabozantinib plasma PK in healthy volunteers (Study XL184-018). Therefore, 
concomitant use of gastric pH modifying agents (i.e., PPIs, H2 receptor antagonists, and 
antacids) is not contraindicated in subjects administered cabozantinib. However, co-
administration of erlotinib with omeprazole decreased erlotinib AUC by 46%. Please see 
additional information regarding erlotinib and PPIs (omeprazole and ranitidine in Section 
4.5.5). Cimetidine should be avoided with cabozantinib due to potential CYP 
interactions. 
Potential drug interactions are summarized in Section 4.5.5. 
4.5.4 
Prohibited or Restricted Therapies  
The following therapies are prohibited while the subject is on study: 
• Any investigational agent or investigational medical device; 
• Therapeutic doses of oral anticoagulants (e.g., warfarin or other coumarin-related agents, 
direct thrombin or direct FXa inhibitors, or antiplatelet agents such as clopidogrel, or 
chronic use of aspirin above low dose levels for cardioprotection per local applicable 
guidelines); 
• Any other systemic anticancer treatment (e.g., chemotherapy, immunotherapy, 
radionuclides) and local anticancer treatment such as surgery, ablation, or embolization.  
The following therapies should be avoided if possible, while the subject is on study: 
• Palliative external radiation to bone metastasis for bone pain should not be performed 
while on study. Subjects who have such an intervention may be considered not evaluable 
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• Erythropoietic stimulating agents (e.g., epoetin alfa and darbepoetin alfa) should not be 
used based on a report of increased risk of tumor recurrence and/or progression 
associated with erythropoietin;13 
• Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 family 
(e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. 
John’s Wort) may significantly decrease cabozantinib and erlotinib concentrations and 
should be avoided. Selection of alternate concomitant medications with no or minimal 
CYP3A4 enzyme induction potential is recommended; 
• Caution must be used when discontinuing treatment with a strong CYP3A4 inducer in a 
subject who has been concurrently receiving a stable dose of cabozantinib or erlotinib 
because this could significantly increase the exposure to cabozantinib and erlotinib; 
• Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and 
ritonavir) may increase cabozantinib and erlotinib concentrations and should be avoided. 
Grapefruit and Seville oranges may also increase plasma concentrations of cabozantinib 
and erlotinib and should be avoided. 
Additional information on potential drug interactions with cabozantinib and erlotinib is provided 
in Section 4.5.5. 
4.5.5 
Potential Drug Interactions 
Cytochrome P450 (CYP):  
Please refer to the drug interaction tables at the following websites for lists of substrates, 
inducers, and inhibitors of selected CYP450 isozyme pathways: 
Http://medicine.iupui.edu/clinpharm/ddis/table.aspx 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractio
nsLabeling/ucm080499.htm   
Cabozantinib 
Data from a clinical drug interaction study (Study XL184-008) show that clinically relevant 
steady-state concentrations of cabozantinib appear to have no marked effect on the area under the 
plasma drug concentration time curve (AUC) of co-administered rosiglitazone, a CYP2C8 
substrate. Therefore, cabozantinib is not anticipated to markedly inhibit CYP2C8 in the clinic, 


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and by inference, is not anticipated to markedly inhibit other CYP450 isozymes that have lower 
[I]/Ki values compared with CYP2C8 (i.e., CYP2C9, CYP2C19, CYP2D6, CYP1A2, and 
CYP3A4). In vitro data indicate that cabozantinib is unlikely to induce cytochrome P450 
enzymes, except for possible induction of CYP1A1 at high cabozantinib concentrations (30 μM).  
Cabozantinib is a CYP3A4 substrate and a weak substrate for CYP2C9 (but not a CYP2D6, 
CYP2C8, CYP2C19, CYP2B6, or CYP1A2 substrate), based on data from in vitro studies. 
Results from a clinical pharmacology study, XL184-006, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an approximately 77% 
reduction in cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Chronic co-administration of cabozantinib with strong inducers of the CYP3A4 
family (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital, and St. 
John’s Wort) may significantly decrease cabozantinib concentrations. The chronic use of strong 
CYP3A4 inducers should be avoided. Other drugs that induce CYP3A4 should be used with 
caution because these drugs have the potential to decrease exposure (AUC) to cabozantinib. 
Selection of alternate concomitant medications with no or minimal CYP3A4 enzyme induction 
potential is recommended.  
Results from a clinical pharmacology study, XL184-007, showed that concurrent administration 
of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 38% increase in 
the cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy 
volunteers. Co-administration of cabozantinib with strong inhibitors of the CYP3A4 family 
(e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir) 
may increase cabozantinib concentrations. Grapefruit and Seville oranges may also increase 
plasma concentrations of cabozantinib and should be avoided. Strong CYP3A4 inhibitors should 
be avoided and other drugs that inhibit CYP3A4 should be used with caution because these drugs 
have the potential to increase exposure (AUC) to cabozantinib. Selection of alternate 
concomitant medications with no or minimal CYP3A4 enzyme inhibition potential is 
recommended. In addition, cimetidine should be avoided because of its potential to interfere with 
CYP3A4 mediated metabolism of cabozantinib. 
Erlotinib 
Erlotinib is also metabolized predominately by CYP3A4. Co-treatment with the potent CYP3A4 
inhibitor ketoconazole increased erlotinib AUC by 67%. When erlotinib was co-administered 
with ciprofloxacin, an inhibitor of both CYP3A4 and CYP1A2, the erlotinib exposure (AUC) 


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and maximum concentration increased by 39% and 17% respectively. Dose modifications are 
recommended and can be made per investigator’s discretion in subjects who require strong 
CYP3A4 inhibitors (e.g., atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, 
nefazodone, nelfinavir, ritonavir, saquinavir, telathromycin, treleandomycin [TAO], 
voriconazole, grapefruit or grapefruit juice) and CYP3A4 and CYP1A2 inhibitors (e.g., 
ciprofloxacin). See Table 4-2 for details. Avoid concomitant use if possible. However, subjects 
taking both cabozantinib and erlotinib, should follow the guidelines for cabozantinib since 
cabozantinib recommends avoiding CYP3A4 inhibitors. 
Pre-treatment by the CYP3A4 inducer rifampicin for 7-11 days prior to erlotinib decreased 
erlotinib AUC by 58% to 80%. Dose modifications are recommended and can be made per 
investigator’s discretion in subjects who require CYP3A4 inducers (e.g., rifampin, rifabutin, 
rifapentine, phenytoin, carbamazepine, phenobarbital, or St. John’s Wort). See Table 4-2 for 
details. Avoid concomitant use if possible. However, subjects taking both cabozantinib and 
erlotinib, should follow the guidelines for cabozantinib since cabozantinib recommends avoiding 
CYP3A4 inducers. 
Cigarette smoking: Cigarette smoking results in reduction in erlotinib AUC. Dose modifications 
are recommended and can be made per investigator’s discretion. See Table 4-2 for details. 
Drugs affecting gastric pH: Co-administration of erlotinib with omeprazole decreased erlotinib 
AUC by 46%, and co-administration of erlotinib with ranitidine 300 mg decreased erlotinib AUC 
by 33%. When erlotinib was administered with ranitidine 150 mg twice daily (at least 10 h after 
the previous ranitidine evening dose and 2 h before the ranitidine morning dose), erlotinib AUC 
decreased by 15%. Increasing the dose of erlitinib when co-administered with such agents is not 
likely to compensate of the loss of exposure. Dose scheduling modifications are recommended in 
subjects who require ranitidine and antacids (see Section 4.3). 
Protein Binding: Cabozantinib is highly bound (≥ 99.7%) to human plasma proteins. Therefore, 
highly protein bound drugs should be used with caution with cabozantinib because there is a 
potential displacement interaction that could increase free concentrations of cabozantinib and/or 
a co-administered highly protein-bound drug (and a corresponding increase in pharmacologic 
effect). 
Other Interactions: Food may increase exposure levels of cabozantinib by 57%, fasting 
recommendations should be followed. Subjects should fast (with the exception of water) for at 
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hour fast and before going to bed, subjects are to take cabozantinib with a full glass of water 
(minimum of 8 oz or 240 mL) with no more food intake for one hour post-dose. 
In vitro data suggest that cabozantinib is unlikely to be a substrate for P-glycoprotein, but it does 
appear to have the potential to inhibit the P-glycoprotein transport activity. Therefore, 
cabozantinib may have the potential to increase plasma concentrations of co-administered 
substrates of P-glycoprotein.  
Cabozantinib was shown to be a substrate of drug transporter MRP2 in an in vitro assay. 
Administration of MRP2 inhibitors to subjects may result in increases in cabozantinib plasma 
concentrations. 
Chronic use of modafinil should be avoided because of its potential to reduce cabozantinib 
exposure (see Investigator’s Brochure). 
Additional details regarding potential drug interactions with cabozantinib can be found in the 
Investigator’s Brochure. 
4.6 
Compliance 
Drug accountability will be assessed with drug dispensing and return records.  
4.7 
Study Drug Accountability 
The investigator will maintain accurate records of receipt of all cabozantinib, including dates of 
receipt. In addition, accurate records will be kept regarding when and how much study treatment 
is dispensed and used by each subject in the study. Reasons for deviation from the expected 
dispensing regimen must also be recorded. At completion of the study, to satisfy regulatory 
requirements regarding drug accountability, all unused study drug will be reconciled and 
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5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
A subject must fully meet all of the following criteria to be eligible for the study: 
1. The subject has a biopsy-proven diagnosis of adenocarcinoma of the pancreas (or 
recurrence of previously resected disease) with metastatic disease that is measurable per 
RECIST 1.1; 
2. The subject must have an archived tissue sample such as a prior surgical sample or 
biopsy sample that is adequate for testing; 
3. The subject must have EGFR and c-Met overexpressed in tumor as determined by 
immunohistochemistry (IHC) test score of 2+ for both markers; 
4. The subject has demonstrated radiographic progression after front-line treatment (prior 
adjuvant therapy allowed if ≥ 6 months elapsed between end of adjuvant therapy and 
metastatic relapse); 
5. The subject is ≥ 18 years old on the day of consent; 
6. The subject has an Eastern Cooperative Oncology Group (ECOG) performance status of 
0 or 1; 
7. The subject has recovery to baseline or ≤ Grade 1 CTCAE v.4.03 from toxicities related 
to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on 
supportive therapy; 
8. The subject has organ and marrow function and laboratory values as follows within 
7 days before the first dose of study treatment: 
a. The ANC ≥ 1500/mm3 without colony stimulating factor support; 
b. Platelets ≥ 100,000/mm3; 
c. Hemoglobin ≥ 9 g/dL; 
d. Bilirubin ≤ 1.5 × the ULN. For subjects with known Gilbert’s disease, bilirubin 
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e. AST/ALT ≤ 3 x the ULN; 
f. Serum albumin ≥ 2.8 g/dl; 
g. Serum creatinine ≤ 1.5 × the ULN or creatinine clearance (CrCl) ≥ 40 mL/min. 
For creatinine clearance estimation, the Cockcroft and Gault equation should be 
used: 
i. 
Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum creatinine × 72); 
ii. 
Female: Multiply above result by 0.85; 
h. UPCR ≤ 1;  
i. Serum phosphorus, calcium, magnesium and potassium ≥ LLN; 
j. Prothrombin time (PT)/INR or partial thromboplastin time (PTT) test < 1.3 × the 
ULN within 7 days before the first dose of study treatment; 
9. The subject is capable of understanding and complying with the protocol requirements 
and has signed the informed consent document; 
10. The subject has a life expectancy of 12 weeks or greater; 
11. The subject is able to tolerate oral medications and no evidence of ongoing 
malabsorption; 
12. All sexually active subjects of reproductive potential must agree to use both a medically 
accepted barrier method (e.g., male or female condom) and a second method of birth 
control during the course of the study and for 4 months after the last dose of study 
drug(s); 
13. Female subjects of childbearing potential must not be pregnant at screening. Females of 
childbearing potential are defined as premenopausal females capable of becoming 
pregnant (i.e., females who have had any evidence of menses in the past 12 months, with 
the exception of those who had prior hysterectomy or bilateral oophorectomy). However, 
women who have been amenorrheic for 12 or more months are still considered to be of 
childbearing potential if the amenorrhea is possibly due to prior chemotherapy, 
antiestrogens, low body weight, ovarian suppression or other reasons. 


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5.2 
Exclusion Criteria  
A subject who meets any of the following criteria is ineligible for the study: 
1. The subject has received cytotoxic chemotherapy or biologic agents (e.g., cytokines or 
antibodies) within 14 days, or nitrosoureas/mitomycin C within 6 weeks before the first 
dose of study treatment; 
2. Prior treatment with cabozantinib or erlotinib; 
3. Radiation therapy for bone metastasis within 2 weeks, any other external radiation 
therapy within 4 weeks before the first dose of study treatment. Systemic treatment with 
radionuclides within 6 weeks before the first dose of study treatment. Subjects with 
clinically relevant ongoing complications from prior radiation therapy are not eligible; 
4. Receipt of any type of small molecule kinase inhibitor (including investigational kinase 
inhibitor) within 14 days before the first dose of study treatment; 
5. The subject has received any other type of investigational agent within 28 days before the 
first dose of study treatment; 
6. Known brain metastases or cranial epidural disease unless adequately treated with 
radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks 
before the first dose of study treatment. Eligible subjects must be neurologically 
asymptomatic and without corticosteroid treatment at the time of the start of study 
treatment; 
7. Concomitant anticoagulation at therapeutic doses with oral anticoagulants (e.g., warfarin, 
direct thrombin and Factor Xa inhibitors) or platelet inhibitors (e.g., clopidogrel);  
Note: Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-
dose LMWH are permitted. Anticoagulation with therapeutic doses of LMWH is allowed 
in subjects who are on a stable dose of LMWH for at least 6 weeks before first dose of 
study treatment, and who have had no clinically significant hemorrhagic complications 
from the anticoagulation regimen or the tumor.  
8. The subject has experienced any of the following: 


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a. clinically-significant GI bleeding within 6 months before the first dose of study 
treatment; 
b. hemoptysis of ≥ 0.5 teaspoon (2.5ml) of red blood within 3 months before the first 
dose of study treatment; 
c. any other signs indicative of pulmonary hemorrhage within 3 months before the 
first dose of study treatment; and 
d. clinically confirmed history of interstitial lung disease (ILD). 
9. The subject has radiographic evidence of cavitating pulmonary lesion(s); 
10. The subject has tumor invading a major blood vessel (encasement of local vascular 
structures is not exclusionary). 
11. The subject has evidence of tumor invading the GI tract (esophagus, stomach, small or 
large bowel, rectum or anus), or any evidence of endotracheal or endobronchial tumor 
within 28 days before the first dose of cabozantinib which in the opinion of the 
investigator places the subject at greater risk of perforation. 
12. The subject has uncontrolled, significant intercurrent or recent illness including, but not 
limited to, the following conditions: 
a. Cardiovascular disorders including: 
i. 
Congestive heart failure (CHF): New York Heart Association (NYHA) 
Class III (moderate) or Class IV (severe) at the time of screening; 
ii. 
Concurrent uncontrolled hypertension defined as sustained blood pressure 
(BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal 
antihypertensive treatment within 7 days of the first dose of study 
treatment; 
iii. 
Any history of congenital long QT syndrome; 
iv. 
Any of the following within 6 months before the first dose of study 
treatment: 


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• unstable angina pectoris; 
• clinically-significant cardiac arrhythmias; 
• stroke (including transient ischemic attack (TIA), or other ischemic 
event); 
• myocardial infarction. 
b. GI disorders particularly those associated with a high risk of perforation or fistula 
formation including: 
i. 
Tumors invading the GI tract, active peptic ulcer disease, inflammatory 
bowel disease (e.g., Crohn’s disease), diverticulitis, cholecystitis, 
symptomatic cholangitis or appendicitis, acute pancreatitis or acute 
obstruction of the pancreatic duct or common bile duct, or gastric outlet 
obstruction 
ii. 
Abdominal fistula, GI perforation, bowel obstruction, intra-abdominal 
abscess within 6 months before first dose of study treatment 
Note: Complete healing of an intra-abdominal abscess must be confirmed 
prior first dose of study treatment 
c. Other clinically significant disorders that would preclude safe study participation; 
13. Major surgery within 12 weeks before the first dose of study treatment. Complete wound 
healing from major surgery must have occurred 1 month before the first dose of study 
treatment. Minor surgery (including uncomplicated tooth extractions) within 28 days 
before the first dose of study treatment with complete wound healing at least 10 days 
before the first dose of study treatment. Subjects with clinically relevant ongoing 
complications from prior surgery are not eligible; 
14. QTcF > 500 msec within 1 month before the first dose of study treatment: 
a. Three ECGs must be performed for eligibility determination. If the average of 
these three consecutive results for QTcF is ≤ 500 msec, the subject meets 
eligibility in this regard. 
15. Pregnant or lactating females; 


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16. Active smoker; 
17. Inability to swallow intact tablets; 
18. Previously identified allergy or hypersensitivity to components of the study treatment 
formulations; 
19. Diagnosis of another malignancy within 2 years before the first dose of study treatment, 
except for superficial skin cancers, or localized, low grade tumors deemed cured and not 
treated with systemic therapy; malignancy felt by investigator to potentially affect subject 
survival or ability to evaluate disease response. 
6 
STUDY ASSESSMENTS AND PROCEDURES 
The following schedule of assessments applies to all subjects (see Section 6.1). More frequent 
assessments should be obtained if clinically indicated. 


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6.1 
Schedule of Assessments 
 
Pre-Treatment Period 
Study Treatment Period (cycles done every 28 ± 5 days) 
Post-
Treatment 
Period 
Survival 
Follow-Up 
Within 28 days 
before 1st Dose 
of Study 
Treatment 
Within 7 days 
before 1st dose 
of Study 
Treatment 
Cycle 
1/Day 
1 
Cycle 1D15 
C2D1 
C2D15 
C3D1 and 
beyond will 
be done 
every 4 
weeks (± 5 
days) 
30 - 37 Days 
after last 
dose 
Every 3 months 
for up to 2 years 
after treatment 
discontinuation 
Administrative Procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical and cancer 
history 
X 
 
 
 
 
 
 
 
 
Registration 
X 
 
 
 
 
 
 
 
 
Prior and concomitant 
medication review 
X 
X 
X 
X 
X 
X 
X 
X 
 
Safety follow-up 
 
 
 
 
 
 
 
X 
 
Survival follow-up 
 
 
 
 
 
 
 
 
X1 
Clinical Procedures/Assessments 
Adverse 
events/patient drug 
compliance 
X2 
 
X 
X 
X 
X 
X 
X3 
 
Physical examination4 
X 
 
X 
X 
X 
X 
X 
X 
 
Vital signs5 
 
X 
X 
X 
X 
X 
X 
X 
 
ECOG performance 
status 
X 
 
X 
X 
X 
X 
X 
X 
 
12-lead ECG 
 
 
X 
X 
 
 
X 
 
X 
 
 
 
 
 


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Pre-Treatment Period 
Study Treatment Period (cycles done every 28 ± 5 days) 
Post-
Treatment 
Period 
Survival 
Follow-Up 
Within 28 days 
before 1st Dose 
of Study 
Treatment 
Within 7 days 
before 1st dose 
of Study 
Treatment 
Cycle 
1/Day 
1 
Cycle 1D15 
C2D1 
C2D15 
C3D1 and 
beyond will 
be done 
every 4 
weeks (± 5 
days) 
30 - 37 Days 
after last 
dose 
Every 3 months 
for up to 2 years 
after treatment 
discontinuation 
Laboratory Assessments 
Complete blood count 
with differential 
 
X 
 
X 
X 
X 
X 
X 
 
Comprehensive serum 
chemistry panel 
 
X 
 
X 
X 
X 
X 
X 
 
Urinalysis with UPCP 
 
X 
 
X 
X 
X 
X 
X 
 
PT/INR, PTT 
 
X 
 
X 
X 
X 
X 
 
 
TSH, free T3, free T4  
 
X 
 
X 
X 
X 
X 
 
 
CA19-9 
 
X11 
 
 
X 
 
X 
 
 
Pregnancy test (urine 
or serum)9 
 
X 
 
  
X 
 
X 
X 
 
Treatment 
Cabozantinib and 
erlotinib 
administration 
 
 
X (daily) 
 
 
Disease Assessment 
Contrast enhanced CT 
or MRI6 
X 
 
 
 
 
 
X (every 8 
weeks) 
 
 
Archival Tissue Collection/Correlative Studies 
Blood sample 
collection8 
 
 
X10 
X 
X 
 
X 
 
 
Tissue sample 
collection8 
X7 
 
 
 
 
 
 
 
 
 
 
 


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Footnotes: 
1. Follow-up may be done by medical record review or phone call to subject and/or next of kin. 
2. Subjects will be monitored for adverse events (AEs) from the time of first study intervention (i.e., biopsy, if needed, or treatment, whichever comes first). 
3. Additional follow-up will occur for subjects with AEs related to study treatment that are ongoing at the time of this visit, and for subjects with SAEs related to study treatment 
that occur after the time of this visit. 
4. A Full physical exam will be done in the pre-treatment period and on Cycle 1/Day 1. Physical exams may also be done by the investigator or qualified designee throughout 
participation in the trial as clinically indicated. 
5. Vital signs include: height (at screening only), weight, temperature, pulse, respiratory rate, and blood pressure. 
6. All sites of known disease must be assessed. 
7. Patients will be asked for archival tissue during the screening period. Archival tissue is required pre-treatment as part of study eligibility to test for EGFR and c-MET 
expression. KRAS will also be tested if previous KRAS testing was not done or results are unknown AND there is adequate tissue available from tissue collected at screening  
8. Only samples collected from eligible patients during the screening period will be utilized for the correlative studies which are outlined in this trial. Samples collected from 
ineligible patients during screening will be discarded. 
9. Only for women of childbearing potential. 
10. This sample may be collected any time after enrollment so long as it occurs before the patient takes his/her first dose of study medication on Cycle 1/Day 1. 
11. The window for this test is within 28 days of starting treatment. 


 
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6.2 
Pre-Treatment Period 
During the Pre-Treatment Period, subjects are consented and qualified (screened) for the study. 
Informed consent must be obtained before initiation of any clinical screening procedure that is 
performed solely for the purpose of determining eligibility for this study. There is a separate 
screening consent for this trial. Evaluations performed as part of routine care before informed 
consent can be considered as screening evaluations if done within the defined screening period.  
Study eligibility is based on meeting all of the study inclusion criteria and none of the exclusion 
criteria at screening and on Study Day 1 before study treatment administration. For each subject, 
the Pre-Treatment Period ends upon receipt of the first dose of study treatment or final 
determination that the subject is ineligible for the study. 
The following assessments will be conducted before subjects receive their first dose of 
cabozantinib and erlotinib on this protocol: 
6.2.1 
Administrative Procedures 
6.2.1.1 
Recruitment and Registration 
Applicable regulatory documents must be completed and on file prior to registration of any 
subjects. Potential patients will be identified in the Oncology outpatient clinics or by referrals 
from outside physicians. Patients who appear to be eligible for this trial will undergo the 
Informed Consent Process and be screened for eligibility utilizing the Eligibility Criteria.  
6.2.1.2 
Informed Consent 
The Investigator must obtain documented consent from each potential subject prior to 
participating in a clinical trial. 
Consent must be documented by the subject’s dated signature or by the subject’s legally 
acceptable representative’s dated signature on a consent form along with the dated signature of 
the person conducting the consent discussion.  
A copy of the signed and dated consent form should be given to the subject before participation 
in the trial. 
The initial informed consent form, any subsequent revised written informed consent form and 
any written information provided to the subject must receive the IRB’s approval in advance of 
use.  The subject or his/her legally acceptable representative should be informed in a timely 
manner if new information becomes available that may be relevant to the subject’s willingness to 


 
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continue participation in the trial.  The communication of this information will be provided and 
documented via a revised consent form or addendum to the original consent form that captures 
the subject’s dated signature or by the subject’s legally acceptable representative’s dated 
signature if the new information would affect the subject’s willingness to continue participation 
in the study as determined by the IRB. 
Specifics about a trial and the trial population will be added to the consent form template at the 
protocol level.   
The informed consent will adhere to IRB requirements, applicable laws and regulations and 
Sponsor requirements. 
6.2.1.3 
Inclusion/Exclusion Criteria 
The completed Eligibility Checklist will be forwarded to the Indiana University Simon Cancer 
Center (IUSCC) Clinical Trials Office (CTO) designee for eligibility verification.   
6.2.1.4 
Medical and Cancer History 
A medical history will be obtained by the investigator or qualified designee during the screening 
period.  Medical history will include all active conditions, and any condition diagnosed within 
the prior 10 years that are considered to be clinically significant by the Investigator.  Details 
regarding the disease for which the subject has enrolled in this study will be recorded separately 
and not listed as medical history.   
The investigator or qualified designee will obtain prior and current details regarding cancer 
disease status and will review all prior cancer treatments including systemic treatments, 
radiation, and surgeries.  
6.2.1.5 
Registration 
The original signed IRB approved Informed Consent Document and completed Eligibility 
Checklist will be forwarded to the IUSCC CTO designee for eligibility verification and 
registration in the OnCore® database. Notification will be sent to the Principal Investigator (PI), 
treating physician and research nurse when registration is complete to confirm registration and 
inform them of the subject ID number. 
6.2.1.6 
Prior and Concomitant Medications Review 
During the screening period, the investigator or qualified designee will review prior medication 
use (including prescription and over-the-counter medications, transfusions, vitamins, herbal 


 
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remedies, and nutritional supplements and any protocol-specified washout requirement) and 
record prior medication taken by the subject within 28 days before written informed consent. 
Treatment for the disease for which the subject has enrolled in this study will be recorded 
separately and not listed as a prior medication.  
The investigator or qualified designee will record medication, if any, taken by the subject during 
the trial. All medications related to reportable SAEs should be recorded as defined in Section 
7.1.4. 
6.3 
Treatment Period  
During the Treatment Period subjects will receive cabozantinib and erlotinib until either disease 
progression, the occurrence of unacceptable drug-related toxicity or for other reason(s) for 
subject withdrawal as described in Section 3.6.  
If the subject is unable to have a study assessment taken within the defined time window due to 
an event outside of his or her control (e.g., clinic closure, personal emergency, inclement 
weather, vacation), the assessment should be performed as close as possible to the required 
schedule.  
Regular tumor assessments should be performed in accordance to the guidelines in 
Section 6.3.1.8 to determine if PD is present.  
The Treatment Period ends when a subject receives his or her last dose of study treatment; the 
subject then enters the Post-Treatment Period. 
6.3.1 
Clinical Procedures 
6.3.1.1 
Adverse Event Monitoring 
Subjects should be instructed to immediately inform the PI of any AEs. Subjects experiencing 
dizziness, sleepiness, or other symptoms that could influence alertness or coordination should be 
advised not to drive or operate other heavy machinery. 
The investigator or qualified designee will assess each subject to evaluate for potential new or 
worsening AEs as specified in the Schedule of Assessments and more frequently if clinically 
indicated. Adverse events will be graded and recorded throughout the study and during the 
follow-up period according to NCI CTCAE Version 4.03.  Toxicities will be characterized in 
terms regarding seriousness, causality, toxicity grading, and action taken with regard to trial 
treatment.  


 
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Please refer to Section 7.1 for detailed information regarding the assessment and recording of 
AEs. 
6.3.1.2 
Physical Exam 
The investigator or qualified designee will perform a complete physical exam during the 
screening period and on Cycle 1/Day 1. Clinically significant abnormal findings should be 
recorded as medical history.  Physical exams may also be done by the investigator or qualified 
designee throughout participation in the trial as clinically indicated. 
6.3.1.3 
Vital Signs 
The investigator or qualified designee will take vital signs at screening and per the Schedule of 
Study Assessments in Section 6.1. Vital signs should include: height at screening only, weight, 
temperature, pulse, respiratory rate, and blood pressure. 
6.3.1.4 
Eastern Cooperative Oncology Group (ECOG) Performance Scale 
The investigator or qualified designee will assess ECOG status at screening and per the Schedule 
of Study Assessments in Section 6.1.   
6.3.1.5 
Electrocardiogram (ECG) 
The investigator or qualified designee will perform a 12-lead ECG at screening and every 4 
weeks beginning Cycle 2/Day 1. Up to 2 ECGs may be done during screening as one must be 
within 7 days of starting treatment. 
6.3.1.6 
Laboratory Assessments 
Abnormalities in clinical laboratory tests that lead to a change in subject management (e.g., dose 
delayed [withheld] or reduced, requirement for additional medication, treatment or monitoring) 
are considered clinically significant for the purposes of this study, and will be recorded on the 
Adverse Events Case Report Form (CRF). If laboratory values constitute part of an event that 
meets criteria defining it as serious, the event (and associated laboratory values) must be reported 
as an SAE. 
 
 


 
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Laboratory Assessments 
Hematology 
• WBC count with 
differential 
(including at 
minimum: 
neutrophils, 
basophils, 
eosinophils, 
lymphocytes, 
monocytes) 
• hematocrit 
• platelet count 
• RBC count 
• hemoglobin 
 
Serum chemistry 
• albumin 
• ALP 
• amylase 
• ALT 
• AST 
• bicarbonate 
• BUN 
• chloride 
• creatinine 
• GGT 
• glucose 
• ionized calcium or 
total and corrected calcium 
• lactate 
dehydrogenase  
• lipase 
• magnesium 
• phosphorus 
• potassium 
• sodium 
• total bilirubin 
• total protein 
 
Urinalysis 
• appearance 
• color 
• pH 
• specific gravity 
• ketones 
• protein 
• UPCR 
• glucose 
• bilirubin 
• nitrite 
• creatinine 
• urobilinogen 
 
• occult blood 
(microscopic 
examination of 
sediment will be 
performed only if 
the results of the 
urinalysis dipstick 
evaluation are 
positive) 
Other 
• TSH, Free T3 and 
T4 
• Pregnancy test 
(urine or serum) for 
women of child-
bearing potential 
• PT/INR, PTT 
• CA19-9 
 
 
 
 


 
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6.3.1.7 
Subject Drug Compliance 
Subjects will be asked about drug compliance and any adverse events he or she may experience 
during clinic visits. Any discrepancies in drug accountability will be clarified with the subject. 
6.3.1.8 
Disease Assessment 
Contrast enhanced imaging studies (CT or MRI) will be performed at screening and every 8 
weeks beginning Cycle 3/Day 1. All sites of known disease must be assessed. CT modalities 
should be done according to standard of care for the subject’s disease. 
6.4 
Post-Treatment Period 
6.4.1.1 
Safety Follow-Up 
Subjects will return to the study site 30 to 37 days after their last dose of study drugs to complete 
end-of-study safety assessments. 
Laboratory and physical examinations will be performed. Remaining study treatment will be 
returned by the subject, and treatment compliance via subject drug diaries will be documented. 
Additional follow-up will occur for subjects with AEs related to study treatment that are ongoing 
at the time of this visit, and for subjects with SAEs related to study treatment that occur after the 
time of this visit. 
6.5 
Survival Follow-Up 
Subjects will be followed every 3 months for up to 2 years after treatment discontinuation for 
survival via medical record review or phone call to the subject and/or next of kin. 
6.6 
Correlative Studies 
HGF and its receptor, c-Met (also known as Met and MET), are also overexpressed in PDAC. c-
Met also heterodimerizes with EGFR, and EGFR-Met cross-talk may contribute to 
chemoresistance. Np-1 and Np-2, which are transmembrane proteins that act as co-receptors for 
VEGF-A, HGF, and class 3–secreted semaphorins, are also overexpressed in PDAC, and Np-1 
associates with Met, enhancing HGF’s ability to promote migration and invasion in pancreatic 
cancer cells (PCCs), as previously reported by us. Np-1, which does not associate with EGFR, 
can signal via integrin beta 1 (ITG-β1) to promote PCC invasion and survival. ITG-β1, which is 
also overexpressed in PDAC, can enhance EGFR signaling. Together, these observations point to 
a previously unrecognized signaling node in PDAC that consists of Met/EGFR/Np-1/2, and ITG-
β1. In this proposal, we will test the hypothesis that it is possible to target this signaling node by 
dual inhibition of Met with cabozantinib and EGFR with erlotinib.  


 
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Based on the above, we will analyze tumor tissue to assess expression of c-Met and EGFR by 
RT-qPCR and immunohistochemistry. Immunostaining will be conducted by Indiana University 
Health Department of Pathology on baseline samples and in the Korc laboratory for samples 
collected post-treatment using the same standard operating procedures (SOPs). SOPs will include 
same antibodies and antibody titers, and same antigen exposure procedures. The advantages of 
using the RT-qPCR and immunohistochemistry approaches is that they are easy to execute 
rapidly and may yield important information for trial design and interpretation. By rapidly 
performing RT-qPCR for HGF, c-Met, and EGFR, we will be able to accurately evaluate which 
PDAC samples express high levels of all three transcripts, and consider these patients as 
candidate for the clinical trial, even before performing the more sophisticated studies on the 
tumors as outlined above. In addition, we will assess expression of Np-1, ITG-b1, p-EGFR and 
p-c-Met by immunostaining and/or immunofluorescence. 
We will perform contrast enhanced CT or MRI every 8 weeks with additional correlative studies 
on blood and tissue collected at baseline (pre-treatment) and Cycle 1/Day 15 (post-treatment) to 
measure Met and EGFR mRNA by qPCR, blood collection to assay plasma HGF and soluble 
Met receptor, and to evaluate Met and EGFR total phosphoprotein levels by electro-luminescent 
2-site immunoassays in tissue to determine if these assays can serve as predictors of response to 
therapy.  
All patients must have archival tissue for EGFR and c-Met expression testing by 
immunohistochemistry (IHC) as only patients with a test score of 2+ for both markers will be 
eligible to participate in this trial. Patients will be asked for archival tissue during the screening 
period (i.e. at baseline). It is anticipated that most patients who may be eligible for this study will 
have archival tissue available for screening. Patients without archival tissue are ineligible. Tumor 
tissue is required pre-treatment as part of study eligibility criteria to test for EGFR and c-MET 
expression. KRAS will also be tested if previous KRAS testing was not done or results are 
unknown AND there is adequate tissue available from tissue collected at screening. Archival 
tissue obtained may come from previous EUS or CT-guided biopsies or surgical resection. FNA 
cores are acceptable. Primary lesion tissue (typically obtained via EUS-guided biopsy or surgical 
resection) is preferred; however, metastatic lesion tissue may also be used (typically obtained via 
CT-guided biopsy). Only samples collected from eligible patients during the screening period 
will be utilized for the correlative studies which are outlined in this trial. Tissue samples 
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Approximately 20 ml of blood will be collected at baseline (during screening period or prior to 
first administration of study drug on Cycle 1/Day 1) and beginning Cycle 1/Day 15 and every 4 
weeks thereafter (i.e. Cycle 2/Day 1, Cycle 3/Day 1, Cycle 4/Day 1, etc.). Only samples 
collected from eligible patients during the screening period will be utilized for the correlative 
studies which are outlined in this trial. Blood samples collected from ineligible patients during 
screening will be discarded. 
Complete details regarding tissue and blood collection, processing, transfer and storage 
information for these correlative studies can be found in the Laboratory Manual for this study.  
7 
SAFETY 
7.1 
Definitions of Adverse Events 
7.1.1 
Adverse Events  
An AE is any untoward medical occurrence in a patient or clinical investigation subject who has 
been enrolled in a clinical study and who may have been given an investigational product, 
regardless of whether or not the event is assessed as related to the study treatment. An AE can 
therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, regardless 
of whether or not the event is assessed as related to the investigational product. Pre-existing 
medical conditions that worsen during a study should be recorded as AEs. Abnormal laboratory 
values, ECG findings, or vital signs are to be recorded as AEs if they meet the criteria described 
in Section 4.3 and 4.4. 
All untoward events that occur after patient begins study treatment through 30 after the decision 
to discontinue study treatment (or the date the subject is deemed to be a screen failure) are to be 
recorded by the investigational site. This requirement includes AEs from unscheduled as well as 
scheduled visits.  
7.1.2 
Suspected Adverse Reactions (SAR) 
Suspected adverse reaction is any adverse event for which there is a reasonable possibility that 
the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. Suspected adverse 
reactions are the subset of all adverse events for which there is a reasonable possibility that the 
drug caused the event. 


 
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Examples of types of evidence that would suggest a causal relationship between the drug and the 
adverse event: 
• A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome). 
• One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon 
rupture). 
• An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group. 
7.1.3 
Adverse Reaction (AR) 
An adverse reaction is any adverse event caused by a drug. Adverse reactions are a subset of all 
suspected adverse reactions where there is reason to conclude that the drug caused the event. 
7.1.4 
Serious Adverse Events  
The SAE definition and reporting requirements are in accordance with the International 
Conference of Harmonisation (ICH) Guideline for Clinical Safety Data Management: Definitions 
and Standards for Expedited Reporting, Topic E2A. 
An SAE is defined as any untoward medical occurrence that at any dose:  
• Result in death; 
• Is immediately life-threatening (i.e., in the opinion of the investigator, the AE places the 
subject at immediate risk of death; it does not include a reaction that, had it occurred in a 
more severe form, might have caused death); 
• Requires inpatient hospitalization ≥ 24 hours or prolongation of existing hospitalization 
o NOTE: Hospitalizations that are not considered SAEs are:  
 Hospitalization planned prior to first administration of study drug 
 Hospitalization for less than 24 hours 
 Hospitalization for elective treatment of a pre-existing condition unrelated 
to the study medication 
• Results in persistent or significant disability or incapacity: 


 
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o Note: The term “disability” refers to events that result in a substantial disruption 
of a subject’s ability to conduct normal life function. 
• Is a congenital anomaly or birth defect; 
• Is an important medical event (IME):  
o Note: The term “important medical event” refers to an event that, based upon 
appropriate medical judgment, may not be immediately life-threatening or result 
in death or hospitalization, but may jeopardize the subject or require intervention 
to prevent one of the other serious outcomes listed under the definition of SAE. 
Examples of IMEs include intensive treatment in an emergency room or at home 
for allergic bronchospasm; blood dyscrasias, or convulsions that do not result in 
hospitalization; or development of product dependency or product abuse. 
• Pregnancy 
o Pregnancy of a female subject during the study or within 30 days after the last 
dose of study drug should be reported via an SAE report. Additional details 
regarding pregnancy can be found in Section 6.3.3. 
7.1.5 
Unexpected Adverse Events 
An adverse event or suspected adverse reaction is considered “unexpected” if it is not listed in 
the Reference Safety Information section (Appendix K) of the Investigator’s Brochure 
(cabozantinib), Adverse Reactions section of the Package Insert (erlotinib), or is not listed at the 
specificity or severity that has been observed; or, if an investigator brochure is not required or 
available, is not consistent with the risk information described in the general investigational plan 
or elsewhere in the current application, as amended. For example, under this definition, hepatic 
necrosis would be unexpected (by virtue of greater severity) if the investigator brochure referred 
only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and cerebral 
vasculitis would be unexpected (by virtue of greater specificity) if the investigator brochure 
listed only cerebral vascular accidents. "Unexpected," as used in this definition, also refers to 
adverse events or suspected adverse reactions that are mentioned in the investigator brochure as 
occurring with a class of drugs or as anticipated from the pharmacological properties of the drug, 
but are not specifically mentioned as occurring with the particular drug under investigation.  
This definition relies entirely on the adverse events or suspected adverse reactions listed in the 
investigator brochure for the particular drug under investigation (or elsewhere in the general 
investigational plan if an investigator brochure is not required or available) as the basis for 
determining whether newly acquired information generated from clinical trials or reported from 
other sources is unexpected. This means that events not listed for the particular drug under 


 
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investigation in the investigator brochure are considered “unexpected” and those listed are 
considered “expected.” When new adverse event information is received, it is the PI’s 
responsibility to determine whether the event is “unexpected” for IND safety reporting purposes. 
In the clinical trial setting, there has been some confusion with the term “expected” as it has been 
used to mean “anticipated” for the disease being treated or population being studied rather than 
“listed in the investigator brochure.” For example, some adverse events can be anticipated to 
occur as a result of a disease or in an older population (e.g., cancer-related deaths in a cancer 
trial, strokes or acute myocardial infarctions in an older population). However, for reporting 
purposes, these anticipated events are not “expected” because they are not listed in the 
investigator brochure (i.e., the test drug is not suspected or known to cause them). 
Adverse events listed in the investigator brochure as occurring with members of the same class 
of drugs, or as anticipated from the pharmacological properties of the drug, would be considered 
unexpected until they have been observed with the drug under investigation. For example, 
although angioedema is anticipated to occur in some patients exposed to drugs in the 
angiotensin-converting enzyme (ACE) inhibitor class and angioedema would be described in the 
investigator brochure as a class effect, a case of angioedema observed with the drug under 
investigation should be considered unexpected for reporting purposes until it is included in the 
investigator brochure as occurring with the drug under investigation. 
7.1.6 
Determining Attribution to the Investigational Agents 
An assessment of the relationship between the AE and the medical intervention. CTCAE does 
not define an AE as necessarily “caused by a therapeutic intervention”. After naming and 
grading the event, the clinical investigator must assign an attribution to the AE using the 
following attribution categories: 
Relationship 
Attribution 
Description 
Unrelated to investigational 
agent/intervention 
Unrelated 
The AE is clearly NOT related 
Unlikely 
The AE is doubtfully related 
Related to investigational 
agent/intervention 
Possible 
The AE may be related 
Probable 
The AE is likely related 
Definite 
The AE is clearly related 
 


 
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7.2 
Adverse Event Reporting Requirements 
7.2.1 
Reporting to the IRB  
1. Unanticipated problems involving risks to subjects or others will be reported promptly to the 
IRB if they:  
• unexpected; 
• related or possibly related to participation in the research; and 
• suggests that the research places subjects or others at a greater risk of harm than was 
previously known or recognized.   
If the adverse event does not meet all three (3) criteria listed above, the event does not have to be 
promptly reported to the Indiana University IRB.  However, it should be reported at the time of 
continuing review. 
2. Prompt reporting of unanticipated problems to the IRB is defined as within 5 days from 
becoming aware of the event. 
7.2.2 
Reporting to Exelixis 
7.2.2.1 
SAEs 
As soon as an investigator becomes aware of an AE that meets the definition of ‘serious,’ this 
should be documented to the extent that information is available. 
• IUSCC shall notify Exelixis within twenty-four (24) hours of making such discovery by 
submitting a completed SAE report form and any other pertinent SAE information as 
indicated on the SAE reporting form; 
• The SAE reporting form must be submitted to Exelixis even if it is not felt to be drug 
related; 
• Pregnancy (for a subject or for the partner of a subject), although not itself an SAE, 
should also be reported on a pregnancy form and be followed up to determine outcome, 
including spontaneous or voluntary termination, details of birth, and the presence or 
absence of any birth defects or congenital abnormalities; 
• SAEs that must be recorded on an SAE Reporting form include the following: 
o all SAEs that occur after informed consent and through 30 days after the decision 
to discontinue study treatment (or the date the subject is deemed to be a screen 
failure); 
o any SAEs assessed as related to study treatment or study procedures, even if the 
SAE occurs more than 30 days after the decision to discontinue study treatment; 


 
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o although most hospitalizations necessitate reporting of an SAE, some 
hospitalizations do not require SAE reporting, as follows: elective or previously 
scheduled surgeries or procedures for pre-existing conditions that have not 
worsened after initiation of treatment (e.g., a previously scheduled ventral hernia 
repair); pre-specified study hospitalizations for observation; or events that result 
in hospital stays of fewer than 24 hours and that do not require admission (e.g., an 
emergency room visit for hematuria that results in a diagnosis of cystitis and 
discharge to home on oral antibiotics). SAEs must, however, be reported for any 
surgical or procedural complication resulting in prolongation of the 
hospitalization. 
IUSCC will report to Exelixis all SAEs that are sent to the FDA at the time of submission to the 
FDA. Follow-up information will be provided to Exelixis as reasonably requested. Send SAE 
reports on the MedWatch Report Form to:  
Exelixis Drug Safety 
Facsimile: (650) 837-7392 
Email: drugsafety@exelixis.com 
7.2.2.2 
Study Initiation 
IUSCC will provide the following to Exelixis prior to initiation of Exelixis support (provision of 
product and/or funding): 
• Final study protocol 
• Fully executed IST Agreement 
• Regulatory Response Documentation (IND or CTA documentation if applicable) 
• IRB/IEC approval 
7.2.2.3 
 Study Maintenance 
Throughout the study, IUSCC will provide the following to Exelixis: 
• At least one safety study status update per year, to include information on enrollment and 
study completion dates.   
• Immediate notification of any amendments made due to safety reasons.  
7.2.2.4 
Study Closure 
IUSCC will provide Exelixis a copy of the IND Annual Report. Upon study closure, IUSCC will 
certify that all safety reporting obligations were met. 


 
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7.2.3 
Reporting to the FDA 
Per CFR 312.32 (c), the investigator-sponsor of the IND must notify the Food and Drug 
Administration (FDA) and all participating investigators in a written IND safety report of any 
adverse experience.  There are two types of reports to the FDA: 7-day and 15-day reports. 
7.2.3.1 
15-Day IND Reports:  
The investigator-sponsor of the IND must notify the Food and Drug Administration (FDA) and 
all participating investigators in a written IND safety report of any: 
• suspected adverse reaction that is both  
• serious and  
• unexpected   
Each written notification shall be made as soon as possible, and no later than 15 calendar days 
after the investigator-sponsor’s initial receipt of the information.   
7.2.3.2 
7-Day Reports: 
The investigator-sponsor must notify FDA and all participating investigators in a written IND 
safety report of any adverse experience: 
• fatal or life-threatening experience that is both 
• associated with use of the drug and 
• unexpected 
The FDA will be notified as soon as possible but no later than 7 calendar days after initial 
receipt of the information. 
7.2.3.3 
Report Content: 
Each written notification may be submitted on FDA Form 3500A or in a narrative format and 
must bear prominent identification of its contents, i.e., “IND Safety Report”.  For purposes of 
this protocol, the MedWatch Report Form (FDA 3500A mandatory reporting), along with 
FDA Form 1571, and a cover letter submitted to the appropriate FDA division, will serve as 
the written IND safety report.  Follow-up information to a safety report should be submitted as 
soon as the relevant information is available. 
Submit: 
• MedWatch Report Form (FDA 3500A) 


 
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• FDA Form 1571 
• Cover Letter 
The IUSCC Protocol Development Coordinator should be contacted to assist with all FDA 
submissions and will be provided with a copy of all events that are reported to the FDA.  All 
IND submissions will be maintained in a master file in the Clinical Trials Office of the IU Simon 
Cancer Center. 
7.2.4 
Reporting to Participating Sites  
Exelixis will send IND safety reports from external studies that involve the study drug to the 
Multicenter Network Associate Administrator, or designee. The Multicenter Network Associate 
Administrator, or designee, will forward the safety reports to the sponsor-investigator, or 
designee, who will review these reports and determine if revisions are needed to the protocol or 
consent. IUSCC will forward these reports to participating sites every 2 weeks.  
For IND safety reports originating from this study, IUSCC will distribute reports which are 
serious, unexpected and associated with the study intervention (possibly, probably or definitely 
related) to all participating sites in the form of an Expedited Safety Report (external safety/IND 
safety report) within 15 calendar days from determination that the suspected adverse reaction 
qualifies for reporting. Copies of these External Safety Reports will be kept on file in the IUSCC 
CTO. Upon receipt from IUSCC, site investigators, or designees, are responsible for submitting 
these safety reports to their respective IRBs, as per their IRB policies. 
Exelixis reserves the right to upgrade the investigator assessment of an SAE based on sponsor-
investigator reporting responsibilities. 
7.3 
Other Safety Considerations 
7.3.1 
Laboratory Data 
All laboratory data required by this protocol and any other clinical investigations should be 
reviewed. Any abnormal value that leads to a change in subject management (e.g., dose 
reduction or delay or requirement for additional medication or monitoring) or that is considered 
to be of clinical significance by the investigator should be reported as an AE or SAE as 
appropriate. 
7.3.2 
Pregnancy 
If a subject becomes pregnant during the study, she will be taken off study treatment and will be 
followed through the end of her pregnancy. The investigator must inform the PI of the 


 
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pregnancy. Forms for reporting pregnancies will be provided to the study sites upon request. The 
outcome of a pregnancy (for a subject or for the partner of a subject) and the medical condition 
of any resultant offspring must be reported to Exelixis or designee. Any birth defect or 
congenital anomaly must be reported as an SAE, and any other untoward events occurring during 
the pregnancy must be reported as AEs or SAEs, as appropriate. 
7.3.3 
Medication Errors/Overdose 
Any study drug administration error or overdose that results in an AE, even if it does not meet 
the definition of serious, requires reporting within 24 hours to Exelixis or designee. 
7.3.4 
Follow-Up of Adverse Events 
Any related SAEs or any AEs assessed as related that led to treatment discontinuation, including 
clinically significant abnormal laboratory values that meet these criteria, ongoing 30 days after 
the decision to discontinue study treatment must be followed until either resolution of the event 
or determination by the investigator that the event has become stable or irreversible. This follow-
up guidance also applies to related SAEs that occur > 30 days after the decision to discontinue 
study treatment. The status of all other continuing AEs will be documented as of 30 days after 
the decision to discontinue study treatment. 
8 
STATISTICAL CONSIDERATIONS 
8.1 
General Considerations 
Statistical analysis of this study will be the responsibility of the Department of Biostatistics at 
Indiana University School of Medicine. Parameter estimates and relevant summary statistics will 
be reported for both efficacy and safety outcomes. Continuous variables will be summarized by 
means, medians, minima, maxima and standard deviations. Categorical variables will be 
summarized by frequencies and percentages. Missing data will not be imputed. Additional 
exploratory analysis will be conducted when appropriate. Changes from the analysis plan will 
not require an amendment to the protocol unless it changes a significant feature in the protocol. 
The statistical analysis methods are outline below. 
8.2 
Study Design 
This is a single arm two-stage Phase II study. No randomization or blinding is involved. 
8.3 
Definition of Endpoints 
Objective response (radiographic response) rate: proportion of all subjects with confirmed PR or 
CR according to RECIST 1.1, from the start of treatment until disease progression/recurrence 


 
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(taking as reference for progressive disease the smallest measurements recorded since the start of 
treatment) 
Disease control rate: proportion of all subjects with stable disease (SD) for 8 weeks, or partial 
response (PR), or complete response (CR) according to RECIST 1.1, from the start of treatment 
until disease progression/recurrence (taking as reference for progressive disease the smallest 
measurements recorded since the start of treatment). 
Progression-free survival: a measurement from the date of first treatment until the criteria for 
disease progression is met as defined by RECIST 1.1 or death occurs. Subjects who have not 
progressed will be right-censored at the date of the last disease evaluation.  
Overall survival (OS): a measurement from the date of first treatment until death from any cause. 
Safety: Adverse event terms recorded in the eCRFs defined by the National Cancer Institute 
(NCI) CTCAE v4.03. Seriousness, severity grade and relationship to study treatment will be 
assessed by the investigator.  
8.4 
Analysis Population 
8.4.1 
Enrolled Population 
The enrolled population comprises all patients who meet the eligibility criteria and are registered 
onto the study. 
8.4.2 
Safety Population 
The safety population comprises all patients who have received at least one dose of the study 
medication. This set will be used for safety analysis. 
8.4.3 
Efficacy Population 
The efficacy population comprises all patients who have received at least one dose of the study 
medication, have been evaluated for the primary endpoint, and have no significant protocol 
violations. This population will be used for efficacy analysis. 
8.5 
Sample Size, Accrual and Study Duration 
The optimal two-stage design to test the null hypothesis that P ≤ 0.025 versus the alternative that 
P ≥ 0.150 has an expected sample size of 17.32 and a probability of early termination of 0.757. If 
the drug is actually not effective, there is a 0.045 probability of concluding that it is (the target 
for this value was 0.050). If the drug is actually effective, there is a 0.198 probability of 


 
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concluding that it is not (the target for this value was 0.200). After testing the drug on 11 patients 
in the first stage, the trial will be terminated if 0 respond. If the trial goes on to the second stage, 
a total of 37 patients will be studied. If the total number responding is less than or equal to 2, the 
combination is rejected. To allow for a few patients being not evaluable for efficacy, up to 40 
subjects may be enrolled. It is estimated that two patients per month will meet eligibility criteria.  
As such we estimate 6 months to complete the first cohort and 15 months to complete enrollment 
to the second cohort. Average follow-up is expected to be 9 months to a year.   
8.6 
Patient Characteristics 
Baseline patient characteristics will be tabulated in the enrolled population, such as 
demographics (age, race, gender), and disease characteristics (tumor location, stage). 
8.7 
Significant Protocol Violations 
Significant protocol violations such as with respect to eligibility criteria and treatment plan will 
be tabulated. 
8.8 
Safety Analysis 
The safety population will be used for all safety analysis. All safety data will be listed. For the 
treatment-emergent AEs, namely AEs started or worsened during the on-treatment period, the 
incidence will be summarized by system organ class and/or preferred term, severity based on 
CTCAE grades, type of adverse event and the relation to the study drug. Deaths reportable as 
SAEs and non-fatal serious adverse events will be listed by patient and tabulated by type of 
adverse event. 
8.9 
Efficacy Analysis 
An exact binomial test will be used to test the hypothesis that radiographic response (ORR) is 
greater than 15%).  ORR and DCR will be estimated with 95% exact binomial confidence 
intervals.  Median PFS and OS will be estimated using 95% confidence intervals based on the 
exponential distribution.  Safety and tolerability data will be tabulated.   
8.10 
Correlative Analysis 
c-Met and EGFR levels as quantitated by RT-qPCR will be compared to c-Met and EGFR 
biomarkers as determined by IHC using Bland-Altman plots and intra-class correlation measures.  
All biomarkers, both pre-treatment and changes over time will be correlated with PFS using Cox 
proportional hazards regression. Time dependent ROC curves will be generated to assess 
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8.11 
Interim Analysis/Criteria for Stopping Study 
After testing the drug on 11 patients in the first stage, the trial will be terminated if 0 respond. If 
the trial goes on to the second stage, a total of 37 patients will be studied. If the total number 
responding is less than or equal to 2, the combination is rejected. 
9 
DATA AND SAFETY MONITORING  
This study will be conducted in accordance with the IU Simon Cancer Center Institutional 
DSMP for High Risk Trials. Investigators will conduct continuous review of data and subject 
safety. Weekly review meetings for high risk trials are required and will include the principal 
investigator, clinical research specialist and/or research nurse (other members per principal 
investigator’s discretion). Weekly meeting summaries should include review of data and subject 
safety by including for each dose level: the number of subjects, significant toxicities as described 
in the protocol, dose adjustments and responses observed. Study teams should maintain meeting 
minutes and attendance for submission to the DSMC upon request. 
9.1 
Data and Safety Monitoring Committee 
The IUSCC Data and Safety Monitoring Committee (DSMC) is responsible for oversight of 
subject safety, regulatory compliance, and data integrity for this trial. The DSMC will review 
this study semi-annually to review overall trial progress, toxicity, compliance, data integrity, and 
accrual per the Institutional DSMP. 
Furthermore, the DSMC conducts an administrative review of serious adverse events (SAEs), 
deviations, reportable events, and any other outstanding business. Major issues may require 
further DSMC review or action. 
For any increase in frequency of grade 3 or above adverse events (above the rate reported in the 
Investigator Brochure or package insert), the principal investigator will notify the DSMC Chair 
immediately. The notification will include the incidence of study adverse events, grades, and 
attributions, as well as investigator statements regarding comparison with risks per the IB/ 
package insert. 
At any time during the conduct of the trial, if it is the opinion of the investigators that the risks 
(or benefits) to the subject warrant early closure of the study, the DSMC Chair and Compliance 
Officer must be notified within 1 business day via email, and the IRB must be notified within 5 
business days. Alternatively, the DSMC may initiate suspension or early closure of the study 
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9.2 
IND Annual Reports  
For trials with an IND held locally by the IU principal investigator or university, the IND Annual 
Report will be reviewed by the DSMC. 
9.3 
Study Auditing and Monitoring 
All trials conducted at the IUSCC are subject to auditing and/or monitoring per the Institutional 
DSMP. Reports will be reviewed by the full DSMC at the time of study review. 
9.4 
Oncore Reporting Requirements 
The DSMC reviews data and study progress directly from Oncore; therefore, timely data entry 
and status updates are vital. Study data must be entered within Oncore promptly, no later than 
one week from study visit occurrence. Subject status in Oncore will be updated in real time, as 
this may affect overall trial enrollment status. Global SAEs and deviations will be reviewed on a 
monthly basis by the DSMC Chair directly from Oncore. 
9.5 
Study Accrual Oversight 
Accrual data will be entered into the IU Simon Cancer Center OnCore system. The Protocol 
Progress Committee (PPC) reviews study accrual twice per year, while the PPC coordinator 
reviews accrual quarterly. 
9.6 
Oncore Safety Reporting 
In addition to protocol- and regulatory-required safety reporting, all serious adverse events 
(SAEs) will be captured in the Oncore system within 1 business day of notification. Initial SAE 
reporting will include as much detail as available, with follow-up to provide complete 
information. 
Attributions will be assessed to study drugs, procedures, study disease, and other alternate 
etiology. 
9.7 
Protocol Deviation Reporting 
Protocol deviations will be entered into OnCore within 5 days of discovery and reviewed by the 
DSMC Chair on a monthly basis. Findings will be reported to the full DSMC at the time of study 
review. For serious or repetitive protocol deviations, additional action may be required by the 
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10 
ETHICAL ASPECTS 
10.1 
Local Regulations 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical Practice” 
(GCP) ICH E6 Tripartite Guideline (January 1997). The investigator will ensure that the conduct 
of the study complies with the basic principles of GCP as outlined in the current version of 
21 Code of Federal Regulations, subpart D, Part 312, “Responsibilities of Sponsors and 
Investigators” Part 50, “Protection of Human Subjects” and Part 56, “Institutional Review 
Boards.” 
10.2 
Informed Consent 
The site investigator will ensure the subject is given full and adequate oral and written 
information about the nature, purpose, possible risks and benefits of the study.  Subjects must 
also be notified they are free to discontinue from the study at any time. The subject should be 
given the opportunity to ask questions and allowed time to consider the information provided. 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The site investigator must store the original, signed 
informed consent form. A copy of the signed informed consent form must be given to the 
subject. 
The CRF for this study contains a section for documenting informed subject consent, and this 
must be completed appropriately. If new safety information results in significant changes in the 
risk/benefit assessment, the consent form should be reviewed and updated as necessary. All 
subjects (including those already being treated) should be informed of the new information, 
should be given a copy of the revised form, and should give their consent to continue in the 
study. 
10.3 
Institutional Review Board/Ethics Committee  
This study is being conducted under a United States Investigational New Drug application or 
other Clinical Trial Application, as appropriate. This protocol (and any modifications) and 
appropriate consent procedures must be reviewed and approved by an IRB/EC. This board must 
operate in accordance with current local, regional, and federal regulations. The investigator will 
send a letter or certificate of IRB/EC approval to Exelixis (or designee) before subject enrollment 
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10.4 
Compliance with 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-investigator of the trial 
is solely responsible for determining whether the trial and its results are subject to the 
requirements for submission to the Clinical Trials Data Bank, http://www.clinicaltrials.gov. The 
sponsor-investigator has delegated responsibility to IUSCC Clinical Trials Office for registering 
the trial and posting the results on clinicaltrials.gov. Information posted will allow subjects 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 study 
site contact information. 
10.5 
Future Use of Subject Samples 
. Samples that are being collected for research purposes will be used for this study, and they will 
not be banked for use on future, yet undetermined studies.  
11 
CONDITIONS FOR MODIFYING THE PROTOCOL 
11.1 
Emergency Modifications 
The sponsor-investigator may implement a deviation from, or a change of, the protocol to 
eliminate an immediate hazard(s) to trial subjects without prior IRB approval. As soon as 
possible after the modification has been made, the implemented deviation or change and the 
reasons for it should be submitted to the IRB for review and approval. 
11.2 
Other Protocol Deviations/Violations 
If a deviation or violation occurs, the deviation should be reported in OnCore®. Any protocol 
violation that occurs must be reported to the IRB per institutional policies and reported to IUSCC 
as soon as possible. IUSCC will determine if the violation affects the safety of the study subject 
and integrity of the data. 
11.3 
Amendments 
If it is necessary for the study protocol to be amended, the amended protocol will be generated 
by IUSCC and must be approved by the FDA (if applicable) and the IRB prior to 
implementation. Local requirements must be followed. 
The Principal Investigator is responsible for the distribution of these documents to the IRB, and 
to the study’s research staff. The distribution of these documents to the regulatory authority will 
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12 
CONDITIONS FOR TERMINATING THE STUDY 
Exelixis reserves the right to terminate the study, and investigators reserve the right to terminate 
their participation in the study, at any time. Should this be necessary, Exelixis and the 
investigator will arrange the procedures on an individual study basis after review and 
consultation. In terminating the study, Exelixis and the investigator will ensure that adequate 
consideration is given to the protection of the subjects’ interests. 
13 
STUDY DOCUMENTATION AND RECORD KEEPING 
13.1 
Investigator’s Files and Retention of Documents 
The investigator must maintain adequate and accurate records to enable the conduct of the study 
to be fully documented and the study data to be subsequently verified. These documents should 
be classified into two separate categories as follows: (1) the investigator’s study file, and 
(2) subjects’ clinical source documents. 
The investigator’s study file will contain the protocol and protocol amendments, CRFs, query 
forms, IRB/EC and governmental approvals with correspondence, sample informed consent, 
drug records, staff curriculum vitae and authorization forms, and other appropriate documents 
and correspondence. 
Subjects’ clinical source documents include the subjects’ hospital/clinic records; physicians’ and 
nurses’ notes; the appointment book; original laboratory, ECG, electroencephalogram, X-ray, 
pathology and special assessment reports; signed informed consent forms; consultant letters; and 
subject screening and enrollment logs.  
The investigator must keep these two categories of documents on file for at least the latest of 
2 years following the marketing application approval date for the study treatment in the 
indication being investigated, 2 years after the investigation is completed or discontinued, or for 
a time consistent with local regulatory requirements. After that period, the documents may be 
destroyed subject to local regulations with prior written permission from Exelixis. If the 
investigator wants to assign the study records to another party or move them to another location, 
Exelixis must be notified in advance. 
If the investigator cannot guarantee the archiving requirement at the study site for any or all of 
the documents, special arrangements must be made between the investigator and Exelixis to store 
these in a sealed container outside of the study site so that they can be returned sealed to the 


 
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investigator in case of a regulatory audit. When source documents are required for the continued 
care of the subject, appropriate copies should be made for storing outside of the study site. 
13.2 
Source Documents and Background Data 
Upon request, the investigator will supply its licensees and collaborators with any required 
background data from the study documentation or clinic records. This is particularly important 
when CRFs are illegible or when errors in data transcription are suspected. In case of special 
problems or governmental queries or requests for audit inspections, it is also necessary to have 
access to the complete study records, provided that subject confidentiality is protected. 
13.3 
Audits and Inspections 
The investigator should understand that source documents for this study should be made 
available, after appropriate notification, to qualified personnel from the Exelixis Quality 
Assurance Unit (or designee) or to health authority inspectors. The verification of the CRF data 
must be by direct inspection of source documents. 
13.4 
Case Report Forms and Data Submission 
This study will utilize electronic Case Report Form completion in the OnCore® database. A 
calendar of events and required forms are available in OnCore® at https://cancer.iu.edu/oncore. 
The OnCore® database is a comprehensive database used by the Indiana University Simon 
Cancer Center (IUSCC) Clinical Trials Office (CTO) and supported by the Indiana University 
Simon Cancer Center. Access to data through OnCore® is restricted by user accounts and 
assigned roles. Once logged into the OnCore® system with a user ID and password, OnCore® 
defines roles for each user which limits access to appropriate data.   
All source documents are to remain in the patient’s clinic file. All documents should be kept 
according to applicable federal guidelines. Clinical trial data in OnCore® are periodically 
monitored by the IUSCC per the Data Safety Monitoring Committee (DSMC) Charter (see 
Section 9.1.1).  
All paper forms should be typed or filled out using indelible ink and must be legible. Errors 
should be crossed out but not obliterated, the correction inserted, and the change initialed and 
dated by the investigator or his or her authorized delegate.  
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the data 
in the CRFs and in all required reports. 


 
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14 
CONFIDENTIALITY OF TRIAL AND SUBJECT RECORDS 
The investigator must assure that subjects’ anonymity will be maintained and that their identities 
are protected from unauthorized parties. On CRFs or other documents, subjects should be 
identified by identification codes and not by their names. The investigator should keep a subject 
enrollment log showing codes, names, and addresses. The investigator should maintain 
documents not for submission to Exelixis or designees (e.g., subjects’ written consent forms) in 
strict confidence. 
All tumor scans, research samples, photographs, and results from examinations, tests, and 
procedures may be sent to Exelixis and its partners or designees for review. 
15 
PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS 
The Principal Investigator (Protocol Chair) holds the primary responsibility for publication of the 
study results; provided that the PI will provide any such publication to Exelixis, Inc. for review 
at least sixty (60) days before submission and also comply with any provisions regarding 
publication that are agreed to between the PI’s institution (e.g., institution name) and Exelixis, 
Inc. in the Clinical Trial Agreement related to this study. The results will be made public within 
24 months of the end of data collection. However, if a report is planned to be published in a peer-
reviewed journal, then that initial release may be an abstract that meets the requirements of the 
International Committee of Medical Journal Editors. In any event, a full report of the outcomes 
should be made public no later than three (3) years after the end of data collection. Authorship 
for abstracts and manuscripts resulting from this study will be determined in accordance to 
guidelines established by the International Committee of Medical Journal Editors. 
16 
REFERENCES 
1. 
Moore MJ, Goldstein D, Hamm J, et al. Erlotinib plus gemcitabine compared with 
gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National 
Cancer Institute of Canada Clinical Trials Group. Journal of clinical oncology: official journal of 
the American Society of Clinical Oncology 2007;25:1960-6. 
2. 
Troiani T, Martinelli E, Capasso A, et al. Targeting EGFR in pancreatic cancer treatment. 
Current drug targets 2012;13:802-10. 
3. 
Bryant KL, Mancias JD, Kimmelman AC, Der CJ. KRAS: feeding pancreatic cancer 
proliferation. Trends in biochemical sciences 2014;39:91-100. 


 
CONFIDENTIAL 
Version Date: 3/26/2019 
 
 
 
 
 Page 78 of 80 
4. 
Raponi M, Winkler H, Dracopoli NC. KRAS mutations predict response to EGFR 
inhibitors. Current opinion in pharmacology 2008;8:413-8. 
5. 
Navas C, Hernandez-Porras I, Schuhmacher AJ, Sibilia M, Guerra C, Barbacid M. EGF 
receptor signaling is essential for k-ras oncogene-driven pancreatic ductal adenocarcinoma. 
Cancer cell 2012;22:318-30. 
6. 
Di Renzo MF, Poulsom R, Olivero M, Comoglio PM, Lemoine NR. Expression of the 
Met/Hepatocyte Growth Factor Receptor in Human Pancreatic Cancer. Cancer Research 
1995;55:1129-38. 
7. 
Jo M, Stolz DB, Esplen JE, Dorko K, Michalopoulos GK, Strom SC. Cross-talk between 
Epidermal Growth Factor Receptor and c-Met Signal Pathways in Transformed Cells. Journal of 
Biological Chemistry 2000;275:8806-11. 
8. 
Puri N, Salgia R. Synergism of EGFR and c-Met pathways, cross-talk and inhibition, in 
non-small cell lung cancer. Journal of carcinogenesis 2008;7:9. 
9. 
Brandes F, Schmidt K, Wagner C, et al. Targeting cMET with INC280 impairs tumour 
growth and improves efficacy of gemcitabine in a pancreatic cancer model. BMC cancer 
2015;15:1064. 
10. 
Reckamp K, Frankel P, Mack P, Gitlitz B et al. Phase II trial of XL184 (cabozantinib) 
plus erlotinib in patients (pts) with advanced EGFR-mutant non-small cell lung cancer (NSCLC) 
with progressive disease (PD) on epidermal growth factor receptor (EGFR) tyrosine kinase 
inhibitor (TKI) therapy: A California Cancer Consortium phase II trial (NCI 9303). J Clin Oncol 
(Meeting Abstracts) May 2014 vol. 32 no. 15_suppl  8014  
11. 
Wang-Gilliam A, Li C, Bodoky G et al.  Nanoliposomal irinotecan with fluorouracil and 
folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-
1): a global, randomised, open-label, phase 3 trial. Lancet. 2015 Nov 29. pii: S0140-
6736(15)00986-1. 
12. 
Torino F, Corsello SM, Longo R, Barnabei A, Gasparini G. Hypothyroidism related to 
tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. Nat Rev Clin Oncol. 
2009;6(4):219-28. 


 
CONFIDENTIAL 
Version Date: 3/26/2019 
 
 
 
 
 Page 79 of 80 
13. 
Wright JR, Ung Y, Julian J, et al. Randomized, double-blind, placebo-controlled trial of 
erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol. 
2007;25:1027-32. 
 
 
 


 
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17 
APPENDICES 
17.1 
Appendix A: 
Performance Status Criteria 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity. Fully active, able to 
carry on all predisease performance 
without restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. Restricted 
in physically strenuous activity, but 
ambulatory and able to carry out work 
of a light or sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs or 
symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed < 50% of the time. Ambulatory 
and capable of all self-care, but unable 
to carry out any work activities. Up and 
about more than 50% of waking hours. 
60 
Requires occasional assistance, but is able 
to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed > 50% of the time. Capable of 
only limited self-care, confined to bed 
or chair more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely disabled. 
Cannot carry on any self-care. Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. Death 
not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead 
0 
Dead 
ECOG, Eastern Cooperative Oncology Group