Clinical trial NCT02132598
Conditions: Non Small Cell Lung Cancer (NSCLC) Metastases to the Brain
Keywords: Lung Cancer Non Small Cell Brain metastases c-MET
Sponsor: Liza Villaruz, MD
Start date: 2015-12-01; Completion date: 2019-08-09
Enrollment: 5 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label phase II clinical trial designed to allow a preliminary assessment of the efficacy and safety of cabozantinib in unselected Non-Small Cell Lung Cancer (NSCLC) patients with metastases to the brain and in the subset of patients with c-MET amplified Non-Small Cell Lung Cancer with metastases to the brain. Previously treated patients with non-squamous NSCLC who have had brain metastases at any point in their treatment history are eligible for enrollment on this clinical trial. Patients with clinically asymptomatic untreated brain metastases will be allowed on trial at the discretion of the treating investigator. Patients who have undergone treatment for their brain metastases with Whole-Brain Radiation Therapy (WBRT), stereotactic radiosurgery (SRS) or surgery must be clinically stable and recovered from all procedures at the time of study enrollment.

Detailed description:
This is a Phase 2, single-arm, open-label study of cabozantinib in subjects with molecularly unselected Non-Small Cell Lung Cancer (NSCLC) with metastases to the brain and in patients with c-MET amplified Non-Small Cell Lung Cancer (NSCLC) with metastases to the brain.

Patients will receive cabozantinib at 60 mg orally once daily and continue on treatment until disease progression, death or unacceptable adverse events. Treatment cycles are 4 weeks in duration.

The primary endpoint is Overall Response Rate (ORR) in both the unselected NSCLC population and the molecularly selected patients on the basis of c-MET amplification.

Arms: arm 1: Patients will receive cabozantinib at 60 mg orally once daily and continue on treatment until disease progression, death or unacceptable adverse events.

Treatment cycles are 4 weeks in duration
Interventions: intervention 1: cabozantinib
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_SAP_000.pdf: 
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BIOMARKER 
ASSESSMENTS 
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4. 
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ABBREVIATIONS 
8-9 
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Immunohistochemical. 
5. 
3.2 Exclusion Criteria 
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Exclusion criterion 2 is revised to reduce the exposure interval 
of prior treatment with a small molecule kinase inhibitor or 
hormonal therapy, from 14 days to 7 days. The interval is 
shortened in order to lower the risk of pseudo-progression that 
can occur in patients with oncogene driven disease upon 
withdrawal of targeted therapy.  
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STUDIES 
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of progression. 
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10. STUDY CALENDAR 
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progression, and associated footnote 14 including information 
that subject must provide consent to undergo the tissue biopsy.  


 
1 
 
TITLE: A SINGLE-ARM PHASE II CLINICAL TRIAL OF CABOZANTINIB (XL184) IN 
PATIENTS WITH PREVIOUSLY TREATED NON-SMALL CELL LUNG CANCER 
(NSCLC) WITH BRAIN METASTASES WITH AND WITHOUT C-MET 
AMPLIFICATION 
 
UPCI #: 
13-182 
IND#: 
122255 
Phase: 
II 
Version: 
8 
Version Date: 
05/02/17 
Investigational Agent: 
Cabozantinib (XL184) 
Commercial Agent: 
N/A 
 
Sponsor-Investigator: 
Liza C. Villaruz, MD 
 
UPMC Cancer Pavilion 
 
5150 Centre Avenue, 5th Floor 
Pittsburgh, PA 15232 
 
Telephone: 412-648-6577 
 
E-mail: villaruzl@upmc.edu 
 
Biostatistician: 
Brenda Kurland, PhD 
412-383-1128 
bfk10@pitt.edu  
 
Source(s) of Support: 
Exelixis, Inc. 
 
Study Monitor: 
Education and Compliance Office for Human Subject Research 
Research Conduct and Compliance Office 
University of Pittsburgh 
3500 Fifth Avenue, Suite 205 
Pittsburgh, PA 15213 
 
 
 


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SYNOPSIS 
 
RATIONALE 
Seventeen to thirty percent of patients with newly diagnosed NSCLC will present with metastatic 
disease to the brain.1-3 Treatment options for brain metastases from NSCLC include whole–brain 
radiation therapy (WBRT), stereotactic radiosurgery (SRS), surgical resection or some combination 
of these options. The median survival time after whole-brain radiation therapy usually ranges from 3-
6 months and strongly correlates with the patient’s age, performance status, number and location of 
metastatic lesions.4-6 In addition, whole brain radiotherapy may cause devastating CNS damage. The 
majority of patients with brain metastases also suffer from active extracranial disease, and systemic 
disease progression is a common cause of death. Therefore, development of effective systemic 
treatment for control of both extracranial and brain metastases is desirable. 
  
There are an increasing number of drug trials that are specifically focusing on patients with brain 
metastases. One of possibly targetable pathways is the HGF/MET pathway. The c-MET receptor 
tyrosine kinase has been implicated in tumor cell migration, invasion, proliferation and angiogenesis 
and is the only known high affinity receptor for hepatocyte growth factor (HGF).7  Amplification of 
c-MET has been associated with poor prognosis in NSCLC, mediastinal lymph node metastases, and 
resistance, both acquired and intrinsic, to EGFR tyrosine kinase inhibitors in EGFR-mutant lung 
adenocarcinoma.8-10  c-MET expression and phosphorylation has been shown to be associated with 
the development of NSCLC brain metastases and are selectively enriched in brain metastases relative 
to paired primary lung tumors.11  Of most importance, the presence of de novo c-MET amplification 
in NSCLC has been linked to rapid and durable clinical response to single agent crizotinib, a c-MET 
receptor tyrosine kinase inhibitor. 12  
 
In a series of 200 NSCLC brain metastases collected at the University of Pittsburgh Medical Center 
(UPMC) between 2005 and 2012, 50% were of adenocarcinoma histology. To date we have 
completed FISH studies on 77 of these brain metastases. Twenty-one percent (16 of 77) of these brain 
metastases were c-MET amplified as defined by a FISH ratio > 2.0; 38% (6 of 16) of these c-MET 
amplified brain tumors also harbored a KRAS mutation (confidential unpublished data). These data 
are intriguing in its marked inconsistency with the ongoing genotyping efforts of the Lung Cancer 
Mutation Consortium (LCMC), in which c-MET amplification was present in only 5 (1%) of 733 
metastatic lung adenocarcinomas that underwent profiling for 10 oncogenic drivers. Furthermore, 
96% of the oncogenic drivers identified through the LCMC were mutually exclusive. These data 
suggest that c-MET amplification plays a critical role in the metastatic potential of NSCLC to the 
brain and implicates c-MET as a therapeutic target in NSCLC with brain metastases, in particular, the 
subset with c-MET amplification.  
  
Cabozantinib (XL184) is a potent oral inhibitor of MET, VEGFR2, and RET that produces robust 
antiangiogenic and antitumor effects in preclinical models. The efficacy of single agent cabozantinib 
was evaluated in patients with progressive glioblastoma multiforme (GBM) in a phase II open-label 
clinical trial at 140 mg daily and 100 mg daily dose levels. Cabozantinib at both dose levels was 
associated with objective responses in central nervous system disease. The objective response rates 
(ORR) in patients who were naïve to prior treatment with anti-angiogenic therapy were 21% and 
30%, at the 140 mg and 100 mg dose levels, respectively, suggesting blood-brain barrier penetration. 
In a randomized discontinuation study in molecularly unselected NSCLC patients, cabozantinib given 


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at 100 mg orally daily was associated with a 10% ORR and an overall disease control rate (DCR; 
partial response plus stable disease) of 38% at 12 weeks. This current trial is a single-arm phase II 
clinical trial evaluating the efficacy and safety of cabozantinib in NSCLC patients with brain 
metastases both in an unselected population and in a subset with c-MET amplification.   
 
STUDY DESIGN 
This is a single institution open-label phase II clinical trial designed to allow a preliminary 
assessment of the efficacy and safety of cabozantinib in unselected NSCLC patients with metastases 
to the brain and in the subset of patients with c-MET amplified NSCLC with metastases to the brain. 
Previously treated patients with non-squamous NSCLC who have had brain metastases at any point in 
their treatment history are eligible for enrollment on this clinical trial. Patients with clinically 
asymptomatic untreated brain metastases will be allowed on trial at the discretion of the treating 
investigator. Patients who have undergone treatment for their brain metastases with WBRT, SRS or 
surgery must be clinically stable and recovered from all procedures at the time of study enrollment. 
Patients will receive cabozantinib at 60 mg once daily and continue on treatment until disease 
progression, death or unacceptable adverse events.  
 
A Simon's optimal two-stage design is used to minimize the expected sample size if the treatment is 
not effective. The target enrollment is 54 evaluable patients. Patients must have adequate tumor tissue 
available to complete c-MET FISH studies as well as routine molecular profiling at the UPMC. A 
minimum of 15 evaluable patients with c-MET amplified tumors, as determined by a FISH ratio (c-
MET/CEP7) > 2.0 based on testing of the primary tumor and/or site of metastatic disease, will be 
required. 
 
OBJECTIVES 
Primary Objectives:  
• To assess the ORR in patients with NSCLC and brain metastases treated with cabozantinib. 
• To assess the ORR of cabozantinib in patients with c-MET amplified NSCLC and brain 
metastases 
 
Secondary Objectives: 
• To assess the DCR at 16 weeks, the progression-free survival (PFS), the overall survival (OS) 
and the safety and tolerability of cabozantinib in patients with NSCLC and brain metastases.  
• To assess the DCR at 16 weeks, the PFS, the OS and the safety and tolerability of 
cabozantinib in patients with c-MET amplified NSCLC with brain metastases.  
• To assess the time to progression (TTP) of intracranial disease with cabozantinib.  
 
Exploratory Objectives:  
• To perform correlative studies to identify potential biomarkers of response to cabozantinib, 
including other known oncogenic drivers in lung adenocarcinoma and HGF co-expression. 
 
 
 


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INVESTIGATIONAL REGIMEN DOSE/ ROUTE/ DURATION 
Cabozantinib is supplied as 20, 60-mg tablets. 
 
Patients will receive cabozantinib at 60 mg once daily and continue on treatment until disease 
progression, death or unacceptable adverse events. Treatment cycles are 4 weeks in duration. 
 
TUMOR ASSESSMENTS 
• 
Computed tomography scans every 8 weeks for assessment of extra-cranial disease will be 
performed.  
• 
MRI of the brain with contrast (or CT brain with contrast in patients who are unable to 
obtain an MRI, e.g., has a pacemaker) every 8 weeks to assess intracranial disease will be 
performed.  
o In patients whose first site of disease progression is extra-cranial disease, a brain 
MRI (or CT brain with contrast in patients who are unable to obtain an MRI) will be 
performed at the time of extra-cranial disease progression and every 12 weeks in the 
study follow-up period. 
 
SAFETY ASSESSMENTS 
Safety will be monitored on an ongoing basis. Laboratory testing (chemistry, hematology tests) will 
be performed every 2 weeks for the first 12 weeks followed by assessments every 4 weeks. Other 
safety evaluations including EKGs and urine protein-creatinine ratio (UPCR) 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 4.0. 
 
BIOMARKER ASSESSMENTS 
Tumor tissue will be mandated at time of study enrollment. All tumors will undergo routine 
molecular testing (as part of the standard of care) at UPMC, which includes Sanger sequencing and 
SNaPshot analysis for the detection of mutations in the EGFR exons 18-21, KRAS codons 12, 13 and 
61, BRAF codon 600 and PIK3CA codons 542, 545 and 1047, in addition to FISH for the EML4-
ALK rearrangement, ROS1 rearrangement, c-MET amplification and the KIF5B-RET translocation. 
In patients who do not have an oncogenic driver on routine mutational profiling, the tumors will 
undergo next generation sequencing using the Ion AmpliSeq™ Cancer Panel on Ion Torrent PGM 
(Life Technologies) (also standard at UPMC).  
 
Serum, plasma, and peripheral blood mononuclear cell (PBMC) samples will be collected at baseline 
(C1D1) as well on day 1 of cycles 2 and 3 and then at time of progression.   We hypothesize that 
markers of increased HGF/MET dependence (MET amplification, MET mutation, high MET 
expression, high serum HGF and/or sc-MET) at baseline will predict response to cabozantinib and an 
increase in serum HGF and/or sc-MET after treatment may predict lack of response. We will analyze 
the predictive value high serum levels of HGF and sc-MET at baseline and during treatment.  
Baseline and serial HGF and sc-MET as well as other potential biomarker serum levels will be 


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measured using ELISA. Future genetic polymorphism testing planned on PBMCs if subject agrees. 
 
c-MET expression (IHC) will also be determined utilizing the SP44 antibody and correlated with c-
MET FISH. HGF expression has been shown to be a key predictor of response to c-MET inhibition in 
both glioblastoma cell lines and xenograft models.13 HGF expression will be determined on tumors 
samples as a potential predictor of clinical response. 
 
In addition to mandatory archival or tissue from new biopsy at baseline, we will obtain optional 
research biopsies at time of progression. These samples will allow us to identify both biomarkers for 
response as well as mechanisms of acquired resistance to cabozantinib.  The tissue samples will be 
used for research purposes (immunohistochemical [IHC] biomarker studies) as well as standard 
CLIA-certified molecular testing. If a targetable alteration is identified then this may guide post-
progression therapy. A core biopsy is preferable, fine needle aspirate (FNA) is acceptable, from the 
most accessible site at which disease progression is evident. In addition to the biomarker assessments 
listed above for baseline tumor tissue, we will also perform next generation sequencing using the Ion 
AmpliSeq™ Cancer Panel on Ion Torrent PGM (Life Technologies) (also standard at UPMC). This 
50-gene cancer panel includes our standard clinical metastatic lung cancer panel (including KRAS, 
PIK3CA, BRAF, and EGFR) as well as additional genes of interest (HRAS, AKT1, PTEN, STK11, 
JAK2/3 and TP53, and CDKN2A). 
 
STATISTICAL METHODS 
This phase II trial is designed to allow preliminary assessment of the efficacy and safety of 
cabozantinib in NSCLC patients with metastases to the brain and in the subset of patients with c-
MET amplified NSCLC with metastases to the brain. 
 
The hypothesis is that cabozantinib increases ORR from 5% to 15% in patients with NSCLC with 
brain metastases. The historical ORR in the second–line setting is based on a 5.8% response rate in 
patients with recurrent NSCLC treated with docetaxel.14 In a prior study of patients with metastatic 
NSCLC, the 12-week ORR for cabozantinib was 10% (95% confidence interval 5%-20%).8 Based on 
our preliminary data, we anticipate a higher ORR in patients with brain metastases. 
 
Therefore, target enrollment is 54 evaluable patients. Simon's optimal two-stage design is used to 
minimize the expected sample size if the treatment is not effective. A stopping rule for futility is 
implemented if 1 or fewer of the first 29 evaluable patients have an objective response. (Accrual may 
continue during follow-up for these patients.)  If ≥2 responses are observed in the first 29 evaluable 
patients, an additional 25 patients will be enrolled. A promising study result would be a response rate 
of 6/54 (11%) or greater. This design has 82% power to detect a true response rate of 15% (compared 
with a null rate of 5%). A minimum of 15 evaluable patients with c-MET amplified tumors will be 
enrolled. If 1 or fewer than 29 patients in the first stage of the Simon design have an objective 
response and fewer than 15 of the 29 have c-MET amplified tumors, accrual will continue for the c-
MET amplified patients only to reach a minimum of 15 evaluable patients with c-MET amplification. 
 
The ORR will be reported for the unselected population (all evaluable patients) and for patients with 
c-MET amplification. A 90% and 95% Wilson confidence interval for the ORR will also be reported. 
With a minimum of 15 patients with c-MET amplification a promising ORR should be detectable. 
For example, the 95% Wilson confidence interval for a 3/15 ORR (20%) is (7%, 45%). 


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TABLE OF CONTENTS 
Synopsis ...........................................................................................................................................2 
1. 
OBJECTIVES ....................................................................................................................11 
1.1 
Primary Objectives.................................................................................................11 
1.2 
Secondary Objectives.............................................................................................11 
1.3 
Exploratory Objectives ..........................................................................................11 
2. 
BACKGROUND ...............................................................................................................11 
2.1 
Non-Small Cell Lung Cancer (NSCLC) ................................................................11 
2.2 
Drug Information: Cabozantinib (XL184) .............................................................12 
2.3 
Rationale for the Study, Dose and Schedule ..........................................................23 
2.4 
Study Design ..........................................................................................................24 
3. 
PATIENT SELECTION ....................................................................................................25 
3.1 
Eligibility Criteria ..................................................................................................25 
3.2 
Exclusion Criteria ..................................................................................................27 
3.3 
Inclusion of Women and Minorities ......................................................................30 
3.4 
Replacements .........................................................................................................30 
4. 
REGISTRATION PROCEDURES ...................................................................................30 
4.1 
General Guidelines.................................................................................................30 
4.2 
Registration Process ...............................................................................................31 
5. 
TREATMENT PLAN ........................................................................................................31 
5.1 
Agent Administration: Cabozantinib Tablets (XL-184) ........................................31 
5.2 
General Concomitant Medication and Potential Drug Interactions .......................32 
5.3 
Electrocardiogram (ECG) Assessment ..................................................................34 
5.4 
Study Treatment Duration......................................................................................34 
5.5 
Study Post-Treatment and Follow Up....................................................................36 
5.6 
Duration of Study ...................................................................................................36 
6. 
DOSING DELAYS/DOSE MODIFICATIONS ...............................................................37 
6.1 
Re-escalating study treatment after a dose reduction: ...........................................37 
7. 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .............................38 
7.1 
Adverse Events and Risks List for Cabozantinib ..................................................39 
7.2 
Reporting of Suspected Adverse Reactions ...........................................................55 
7.3 
Review of Safety Information: Sponsor Responsibilities ......................................55 
7.4 
IND safety reports ..................................................................................................55 
7.5 
Reporting adverse events to the responsible IRB ..................................................58 
8. 
PHARMACEUTICAL INFORMATION ..........................................................................58 
8.1 
IND Agent Cabozantinib (XL-184) .......................................................................59 
9. 
BIOMARKER STUDIES ..................................................................................................60 


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10. 
STUDY CALENDAR .......................................................................................................62 
11. 
MEASUREMENT OF EFFECT........................................................................................63 
11.1 
Measurability of Tumor at Baseline ......................................................................64 
11.2 
Specifications by Methods of Measurements ........................................................65 
11.3 
Tumor Response Evaluation ..................................................................................67 
11.4 
Response Criteria ...................................................................................................68 
12. 
DATA REPORTING / REGULATORY REQUIREMENTS ...........................................70 
12.1 
Data Safety Monitoring Plan .................................................................................70 
12.2 
Quality Control and Quality Assurance .................................................................71 
12.3 
Data Handling and Record-Keeping ......................................................................71 
12.4 
Institutional Review Board (IRB) Approval ..........................................................72 
12.5 
Ethical and Scientific Conduct of the Clinical Study ............................................72 
12.6 
Informed Consent...................................................................................................72 
12.7 
Publication of Data and Protection of Trade Secrets .............................................73 
13. 
STATISTICAL CONSIDERATIONS...............................................................................73 
13.1 
Study Design/Endpoints.........................................................................................73 
13.2 
Sample Size/Accrual Rate ......................................................................................74 
13.3 
Study and Safety Populations ................................................................................74 
13.4 
Safety Analysis ......................................................................................................74 
REFERENCES ..............................................................................................................................76 
APPENDIX A: PERFORMANCE STATUS CRITERIA .............................................................79 
APPENDIX B: EVALUATION OF LESIONS USING RECIST 1.1 CRITERIA .......................80 
 
 
 
 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
AUC 
area under the plasma drug concentration time curve 
AUC0-last 
AUC from time zero to the last quantifiable time point 
AUC0-∞ 
AUC from time zero to infinity 
BP 
blood pressure 
BUN 
blood urea nitrogen 
Cmax 
maximum plasma concentration 
CPK 
creatine phosphokinase 
cPR 
confirmed partial response 
CR 
complete response 
CrCl 
creatinine clearance 
CRF 
case report form 
CRPC 
castration-resistant prostate cancer  
CSF 
colony stimulating factor 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome P450 
DBP 
diastolic blood pressure 
DCR 
disease control rate 
DLT 
dose limiting toxicity 
DTC 
differentiated thyroid cancer 
DVT 
deep vein thrombosis 
EC 
ethics committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ED50 
dose required for 50% inhibition 
ESC 
Exelixis Safety Committee 
ESR 
erythrocyte sedimentation rate 
FDA 
Food and Drug Administration 
FNA 
Fine needle aspirate 
FLT3 
FMS-like tyrosine kinase 3 
FSH 
follicle-stimulating hormone 
GABA 
γ-aminobutyric acid 
GB 
glioblastoma 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GEJ 
gastroesophageal junction 
GnRH 
gonadotropin-releasing hormone 
HCC 
hepatocellular carcinoma 
HEENT 
head eye ear nose and throat 


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HGF 
hepatocyte growth factor 
IC50 
concentration required for 50% inhibition 
ICH 
International Conference on Harmonisation 
IHC 
Immunohistochemical 
IME 
important medical event 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
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 
mRECIST 
modified Response Evaluation Criteria in Solid Tumors 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
NSAID 
non-steroidal anti-inflammatory drug 
NSCLC 
non-small-cell lung cancer 
NYHA 
New York Heart Association 
ORR 
overall response rate 
OS 
overall survival 
PBMC 
Peripheral blood mononuclear cell 
PD 
progressive disease 
PE 
pulmonary embolism 
PFS 
progression-free survival 
PFS6 
progression-free survival at 6 months 
P-gp 
P-glycoprotein 
PI 
principal investigator 
PIB 
powder-in-bottle 
PK 
pharmacokinetic 
PO 
oral  
PPE 
palmar-plantar erythrodysesthesia 
PR 
partial response 
PT 
prothrombin time 
PTT 
partial thromboplastin time 
qd 
once daily 
QTc 
corrected QT 
QTcF 
QTc calculated by the Fridericia formula 
RBC 
red blood cell 
RCC 
renal cell carcinoma 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RPLS 
reversible posterior leukoencephalopathy syndrome 
RTK 
receptor tyrosine kinase 


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SAE 
serious adverse event 
SBP 
systolic blood pressure 
SD 
stable disease 
SCLC 
small-cell lung cancer 
t1/2, z 
terminal-phase half-life 
tmax 
time to the maximum plasma concentration 
TFT 
thyroid function test 
TIA 
transient ischemic attack 
TSH 
thyroid stimulating hormone 
TTP 
time to progression 
ULN 
upper limit of normal 
UPCR 
urine protein/urine creatinine ratio 
VEGF(R) 
vascular endothelial growth factor (receptor) 
 
 


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1. OBJECTIVES 
 
1.1 
Primary Objectives 
 To assess the overall response rate (ORR) in patients with NSCLC and brain metastases 
treated with cabozantinib. 
 To assess the ORR of cabozantinib in patients with c-MET amplified NSCLC and brain 
metastases 
 
1.2 
Secondary Objectives 
 To assess the disease control rate (DCR) at 16 weeks, the progression-free survival (PFS), 
the overall survival (OS) and the safety and tolerability of cabozantinib in patients with 
NSCLC and brain metastases.  
 To assess the DCR at 16 weeks, the PFS, the OS and the safety and tolerability of 
cabozantinib in patients with c-MET amplified NSCLC with brain metastases.  
 To assess the time to progression (TTP) of intracranial disease with cabozantinib. 
 
1.3 
Exploratory Objectives 
 To perform correlative studies to identify potential biomarkers of response to 
cabozantinib, including other known oncogenic drivers in lung adenocarcinoma and HGF 
co-expression 
 
2. 
BACKGROUND 
 
2.1 
Non-Small Cell Lung Cancer (NSCLC) 
 
Lung cancer is the leading cause of cancer mortality in the United States and worldwide.15 An 
estimated 226,160 new cases of lung cancer will be diagnosed in 2012 in the United States alone, and 
160,340 lung cancer deaths are estimated to occur. The five year survival for all lung cancer patients 
is a dismal 15%. Historically, non-small cell lung cancer (NSCLC) was treated as a single disease 
entity, and palliative chemotherapy in the metastatic setting resulted in modest survival prolongation 
and preservation of quality of life.16-20 A series of large randomized controlled phase III clinical trials 
established platinum-based doublets as the standard of care in the treatment of metastatic NSCLC 
with response rates of 20-30% and a median survival of 8-11 months.21-25  
 
Recent advances in the treatment of metastatic NSCLC have come from recognition that NSCLC is 
not a single disease entity, but rather a collection of distinct molecularly-driven neoplasms. Lynch et 
al. and Paez et al. first described a subset of patients with NSCLC harboring activating mutations in 
the EGFR gene who responded to treatment with EGFR tyrosine kinase inhibitors (TKIs).26, 27  This 
discovery permanently shifted the landscape of NSCLC therapy to a personalized approach based on 
the molecular alterations of a patient’s tumor; a paradigm typified not only by targeted therapies in 
EGFR mutant lung adenocarcinomas, but also in ALK translocation driven adenocarcinomas of the 
lung and more recently, the therapeutic advances in lung adenocarcinomas harboring ROS1 gene 
rearrangements and BRAF mutations.28-30   
 


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The MET protein is a receptor tyrosine kinase receptor which upon binding its only known 
physiologic ligand, hepatocyte growth factor/scatter factor (HGF/SF) activates a series of 
downstream processes that are critical for oncogenesis including cell proliferation, survival, 
invasion/migration and metastasis.31  Upon binding of HGF to the Sema domain of MET, 
dimerization and subsequent autophosphorylation occurs leading the activation of MET receptor and 
downstream signaling through the RAS-ERK, PI3K-AKT-mTOR and STAT pathways .31   In 
addition, activated MET has been demonstrated to have significant crosstalk with the EGFR 
pathway.31  Aberrant signaling through the MET pathway has been observed in a number of tumor 
types and can occur through mutation, amplification or overexpression of the MET or overexpression 
of HGF.32  Although mutations in the MET gene are rare in NSCLC,33 the MET gene is amplified in 
adenocarcinoma of the lung in 1% to 20% of cases examined.34-36   Recently, a large study by the 
LCMC suggested the MET gene is only amplified in about 1% of adenocarcinomas of the lung.37  
Interestingly, MET amplification is a common mechanism of acquired resistance to EGFR TKIs and 
is found in up to 20% of patients who have acquired resistance to EGFR TKIs.38,39  In addition to 
mutations or amplification of MET, the MET protein is overexpressed in a significant number of 
cases of advanced NSCLC.  
 
Given the critical role of the MET pathway in tumorigenesis, metastasis and acquired resistance to 
targeted therapy, there are more than a dozen MET targeted therapies in clinic trials which target its 
ligand HGF (rilotumumab, ficlatuzumab), the extracellular portion of the MET receptor 
(onartuzumab – MetMAb) or the intracellular kinase activity of the MET receptor (tivantinib, 
crizotinib, cabozantinib).32 Although anti-MET therapy as monotherapy or in combination in 
unselected patient populations has been disappointing to date, a recent phase II trial comparing 
onartuzumab (MetMAb) and erlotinib versus erlotinib alone in the 2nd and 3rd line setting for 
metastatic NSCLC found a significant advantage in PFS and OS for the combination in the “MET 
high” population.40   Furthermore, 54% of patient samples were defined as “MET high” (50% or 
greater cells on the diagnostic slide with a staining intensity of 2 or 3) which suggests that a 
significant fraction of patients with metastatic lung cancer may be at least partially MET dependent. 
This concept is now being tested in global Phase III randomized, multicenter, double-blind, placebo-
controlled study testing this combination vs. erlotinib only in the “MET high” population 
(NCT01456325). In addition to monoclonal antibodies targeting MET, there are several MET 
tyrosine kinase inhibitors in development and/or FDA approved agents (crizotinib), and these agents 
are being used to target the MET pathway in mutational defined subsets such as KRAS mutant 
NSCLC and in the acquired resistance to EGFR TKI therapy setting.41   Of most significance to this 
protocol, several case reports have suggested that patient tumors with MET amplification may be 
MET “addicted” and dramatic responses have been seen with MET TKI monotherapy. 42, 43 
 
2.2 
Drug Information: Cabozantinib (XL184) 
 
Cabozantinib (XL184) is an inhibitor of multiple receptor tyrosine kinases and was approved by the 
U.S. Food and Drug Administration (FDA) on 29 November 2012 for the treatment of patients with 
progressive, metastatic medullary thyroid cancer (MTC). It is commercially available as 
COMETRIQ® in the United States. 
 
 
 


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2.2.1 Pharmacology 
 
Cabozantinib inhibits receptor tyrosine kinases MET (hepatocyte growth factor [HGF] receptor), 
vascular endothelial growth factor receptor 2 (VEGFR2), and RET. These targets are important 
mediators of tumor growth and/or angiogenesis, and MET is particularly associated with tumor 
invasiveness and metastasis. In vivo pharmacodynamic activity of cabozantinib against MET, 
VEGFR2 and RET has been demonstrated in preclinical studies and has been associated with tumor 
growth inhibition and tumor regression. In preclinical studies, cabozantinib treatment has also been 
shown to inhibit tumor angiogenesis, tumor invasiveness and metastasis, and the progression of 
tumors in bone. 
 
2.2.2 Cabozantinib Nonclinical Toxicology 
 
In nonclinical toxicology studies of cabozantinib in rodents and non-rodents, histopathological 
changes associated with cabozantinib administration were observed in gastrointestinal (GI) tract, 
bone marrow, lymphoid tissues, kidney, adrenal, and reproductive tract tissues, and secondary 
changes were observed in bone and pancreas. Cabozantinib tested negative in bacterial and 
mammalian cell genotoxicity assays in vitro. In reproductive toxicity studies, cabozantinib was 
embryotoxic in rats, produced fetal soft tissue changes in rabbits, and decreased fertility in male and 
female rats. 
 
2.2.3 Clinical Experience and Summary 
 
A range of cabozantinib dose levels have been explored. In Phase 1 Study XL184-001, subjects were 
treated with cabozantinib at doses ranging from 0.064 to 9.22 mg/kg (0.08 to 11.52 mg/kg malate salt 
weight) using a powder-in-bottle (PIB) aqueous suspension formulation on an intermittent dosing 
schedule; from 140 mg (175 mg malate salt weight) to 212 mg (265 mg malate salt weight) as a PIB 
formulation on a once-daily dosing (qd) schedule; and from 140 mg to 200 mg (250 mg malate salt 
weight) in capsule form on a qd schedule. Other studies have explored doses as low as 20 mg (25 mg 
malate salt weight). In more recently initiated clinical studies, cabozantinib is being administered in a 
tablet formulation. Results from a bioequivalence study in healthy adult subjects (Study XL184-010) 
indicate that the cabozantinib 140 mg tablet formulation is bioequivalent to the 140 mg capsule 
formulation based on AUC parameters (AUC from 0 hours to the last sampling time point [AUC0-t] 
and AUC from 0 hours to infinity [AUC0-∞] geometric mean ratios: 108%; 90% confidence interval 
(CI)%: 101, 117).  
 
The single-agent maximum tolerated dose (MTD) of the capsule in a daily dosing schedule based on 
28 days of dosing in Study XL184-001 was determined to be 140 mg (175 mg malate salt weight). 
The 140 mg capsule dose level was evaluated in placebo-controlled Phase 3 Study XL184-301 in 
subjects with MTC: dose modifications (reductions or interruptions) occurred frequently in the 
cabozantinib arm of this study. 
 
Lower doses of cabozantinib have been explored in other indications, and two ongoing Phase 3 
studies in prostate cancer are evaluating a tablet dose of 60 mg qd. Common to all approaches is the 
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above 60 mg in the prostate cancer Phase 3 studies.  
 
A pooled analysis of safety data in 1311 subjects treated with cabozantinib in company-sponsored 
single-agent studies (XL184-001, XL184-008, XL184-201, XL184-203, XL184-205, and XL184-301 
[cabozantinib arm]) has been performed. The data cut-off for this analysis is 28 February 2013. 
 
2.2.4 Clinical Safety Profile 
 
2.2.4.1 
Adverse Events 
 
Across company-sponsored open-label studies with single-agent cabozantinib, the most frequently (≥ 20% 
of subjects) observed AEs, regardless of causality, are shown in Table 1-1. 
 


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2.2.4.2 
Serious Adverse Events 
 
Medically important adverse events (MIAEs) of Grade 3 and higher that may be related to 
cabozantinib, including gastrointestinal (GI) perforation (1.5%), GI fistula (0.5%) and non-GI fistula 
(0.6%) formation, intra-abdominal/pelvic abscess (0.9%), non-central nervous system (non-CNS) 
(3.1%) and CNS (0.8%) hemorrhage, venous (8.7%) and arterial (1.8%) thromboembolic events, 
wound complications (1.0%), hypertension (10.0%), osteonecrosis (0.2%), palmar-plantar 
erythrodysesthesia (PPE; 9.1%), proteinuria (1.4%), and hepatocellular toxicity (0.8%), have been 
observed in single-agent clinical studies with cabozantinib. A single event of reversible posterior 
leukoencephalopathy (RPLS) has occurred in one cabozantinib-treated subject in Study XL184-301.  
 
The most commonly reported SAEs (experienced by ≥1% of subjects), regardless of causality, are 
shown in Table 1-2. 


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No cases meeting the Hy’s law criteria have been identified as of 28 Feb 2013.  
At the 140 mg dose, a mean increase from baseline in Fridericia’s correction of QT (QTcF) of 10-15 
ms was observed at 4 weeks (Day 29) after initiating cabozantinib treatment in Study XL184-301. No 
changes in cardiac wave form morphology or new rhythms were observed. No cabozantinib-treated 
subjects had a QTcF > 500 ms. 
 
2.2.4.3 
Deaths 
 
There have been 24 deaths assessed as related to study treatment in the pooled analysis of single-
agent studies: GI hemorrhage (two subjects), pulmonary embolism (PE) (two subjects), respiratory 
failure (two subjects), hemorrhage (two subjects), death due to unknown cause (three subjects); 
reasons for death in a single subject were intestinal perforation, diverticular perforation/peritonitis, 
hemoptysis/tracheal fistula, acquired tracheo-esophageal fistula, esophageal fistula, enterocutaneous 
fistula, esophageal hemorrhage, respiratory disorder, cardiac arrest, hepatic failure, sudden death, 
bronchopneumonia and sepsis.  
 
In the Phase 1b/2 XL184-202 study evaluating combined dosing of cabozantinib/erlotinib, the MTDs 
were determined to be 40 mg (50 mg malate salt weight) of cabozantinib plus 150 mg of erlotinib 
(maximizing the erlotinib dose) and 100 mg (125 mg malate salt weight) of cabozantinib plus 50 mg 
of erlotinib (maximizing the cabozantinib dose). There was a higher incidence of diarrhea with 
combination treatment compared with single-agent cabozantinib.  
 
In the Phase 1 XL184-002 dose-finding study evaluating 40 or 60 mg doses (50 or 75 mg malate salt 
weight, respectively) of cabozantinib in combination with standard dose TMZ ± radiation therapy 
there was a higher incidence of thrombocytopenia and neutropenia with combination treatment 
compared with single-agent cabozantinib. The MTD for cabozantinib in combination with TMZ was 
determined to be 40 mg qd. 
 
2.2.5 Clinical Pharmacokinetics 
 
From a population PK (PopPK) analysis of cabozantinib, the predicted effective half-life is 
approximately 55 hours, the oral volume of distribution (V/F) is approximately 349 L, and the 
clearance (CL/F) at steady-state is estimated to be 4.4 L/h. The terminal half-life (for predicting drug 
washout) is approximately 120 hours. Following oral administration of cabozantinib, median time to 
peak cabozantinib plasma concentrations (Tmax) ranged from 2 to 5 hours post-dose. Repeat daily 
dosing of cabozantinib at 140 mg for 19 days resulted in 4- to 5-fold mean cabozantinib accumulation 
(based on area under the plasma concentration-vs-time curve [AUC]) compared with a single dose 
administration; steady state was achieved by Day 15. Cabozantinib is highly protein bound in human 
plasma (≥ 99.7%).The PK evaluation of cabozantinib in the pediatric population is ongoing. A PopPK 
analysis did not identify clinically relevant differences in clearance of cabozantinib between females 
and males or between Whites (89%) and non-Whites (11% [<4% were Asian]). Cabozantinib PK was 
not affected by age (20-86 years).  
 
Within a 48-day collection period after a single dose of 14C-cabozantinib in healthy subjects, 
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in urine. A PK study of cabozantinib in patients with renal impairment is ongoing. The results of a 
population PK analysis suggested that mild to moderate renal impairment (creatinine clearance value 
≥30 mL/min) does not have a clinically relevant effect on the clearance of cabozantinib.  
 
A high-fat meal increased maximum plasma concentration (Cmax) and AUC values by 41% and 
57%, respectively relative to fasted conditions in healthy subjects administered a single 140 mg oral 
cabozantinib dose.  
 
Cabozantinib is a substrate of cytochrome P450 (CYP) 3A4 (CYP3A4) in vitro. Inhibition of 
CYP3A4 reduced the formation of the cabozantinib N-oxide metabolite by >80%. Inhibition of 
CYP2C9 had a minimal effect on cabozantinib metabolite formation (i.e., a <20% reduction). 
Inhibition of CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C19, CYP2D6 and CYP2E1 had no 
effect on cabozantinib metabolite formation. Cabozantinib AUC was increased 38% with 
coadministration of the strong CYP3A4 inhibitor ketoconazole and decreased 77% with 
coadministration of the strong CYP3A4 inducer rifampin.  
 
Cabozantinib is a noncompetitive inhibitor of CYP2C8 (Kiapp = 4.6 μM), a mixed-type inhibitor of 
both CYP2C9 (Kiapp = 10.4 μM) and CYP2C19 (Kiapp = 28.8 μM), and a weak competitive 
inhibitor of CYP3A4 (estimated Kiapp = 282 μM) in human liver microsomal (HLM) preparations. 
Concentration associated with 50% inhibition (IC50) values >20 μM were observed for CYP1A2, 
CYP2D6, and CYP3A4 isozymes in both recombinant and HLM assay systems. Cabozantinib at 
steady-state plasma concentrations (≥100 mg/day daily for a minimum of 21 days) showed no effect 
on single-dose rosiglitazone (a CYP2C8 substrate) plasma exposure (Cmax and AUC) in patients 
with solid tumors.  
 
Cabozantinib is an inducer of CYP1A1 mRNA in human hepatocyte incubations (i.e., 75-100% of 
CYP1A1 positive control β-naphthoflavone induction), but not of CYP1A2, CYP2B6, CYP2C8, 
CYP2C9, CYP2C19 or CYP3A4 mRNA or isozyme-associated enzyme activities.  
 
Cabozantinib is an inhibitor (IC50 = 7.0 μM), but not a substrate, of P-glycoprotein (P-gp) transport 
activities in a bi-directional assay system using MDCK-MDR1 cells. 
 
Comparative Bioavailability Study of Cabozantinib Tablet and Capsule Formulations in 
Healthy Adult Subjects (Study XL184-005) 
Study XL184-005 is a Phase 1, open-label, randomized, single-dose, two-treatment, two way 
crossover comparative bioavailability study of cabozantinib tablet and capsule formulations in 
healthy volunteers. Subjects received single oral doses of the assigned treatment of Test (100 mg 
cabozantinib, dosed as one 100 mg tablet) or Reference (100 mg cabozantinib, dosed as two 50 mg 
capsules), according to a randomization scheme. Each dosing was administered under fasting 
conditions, and blood samples were collected up to 504 hours post dose for each subject after each 
treatment to assess plasma cabozantinib PK.  
 
Based on the preliminary PK data from 23 subjects who completed both treatments, after a single oral 
dose of cabozantinib at 100 mg, the terminal-phase half-life (t1/2, z) of cabozantinib appeared to be 
similar for both tablet and capsule formulations, with approximately mean values of 110 hours. The 
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5 hours for the capsule formulation. High inter-subject variability for the maximum plasma 
concentration (Cmax) and the area under the plasma drug concentration time curve (AUC) values 
were observed for both formulations (coefficient of variation [CV]% Cmax: 51% for the tablet 
formulation, 61% for the capsule formulation; CV% for the AUC from time zero to the last 
quantifiable timepoint or to infinity [AUC0-last or AUC0-inf]: 40-43% for the tablet formulation, 
43% for the capsule formulation.) The geometric mean Cmax of the tablet formulation was 
approximately 39% higher than the value observed for the capsule formulation. The geometric mean 
AUC0-last and AUC0-inf values for the tablet formulation were also higher (15% and 19%, 
respectively) than those observed for the capsule formulation. However, due to the high within-
formulation variability observed, no statistical difference in exposure between the two formulations 
was apparent. 
 
Effect of Food on the Bioavailability of Cabozantinib in Healthy Adult Subjects (Study XL184-
004) 
Study XL184-004 is a Phase 1, open-label, randomized, single-dose, two-treatment, two-way 
crossover study to assess the effect of food on the bioavailability of cabozantinib in healthy adult 
subjects. According to a randomization scheme, 56 subjects received single oral doses of the assigned 
treatment of Test (175 mg cabozantinib, dosed as one 100 mg capsule and three 25 mg capsules 30 
minutes after administration of a high fat breakfast) or Reference (175 mg cabozantinib, dosed as one 
100 mg capsule and three 25 mg capsules under fasting conditions). Blood samples were collected up 
to 504 hours post dose for each subject after each treatment to assess plasma cabozantinib 
pharmacokinetics.  
 
Based on the preliminary PK data from 46 subjects who completed both treatments, a high fat meal 
did not appear to alter the terminal t1/2, z of cabozantinib [mean t1/2, z : 131 hours (fed) vs 128 hours 
(fasted)]. The high fat meal significantly increased the median tmax to 6 hours from 4 hours (fasted). 
The high fat meal also significantly increased both the cabozantinib Cmax and AUC values by 39% 
and 56%, respectively. The geometric mean ratio of Cmax fed/fasted was 1.39 (90% CI: 1.16-1.67), 
and the geometric mean ratio of AUC0-last fed/fasted was 1.56 (90% CI: 1.34-1.80). Based on this 
result, cabozantinib must be taken on an empty stomach (fasting is required 2 hours before and 1 hour 
after each cabozantinib dose). 
 
2.2.6 Clinical Activity 
 
In addition to MTC, cabozantinib has demonstrated findings consistent with broad clinical anti-tumor 
activity in early Phase 1 and Phase 2 studies in several other tumor types. In a randomized 
discontinuation trial (RDT) XL184-203, the following disease control rates (DCR = complete 
response [CR] + partial response [PR] + stable disease [SD]) at Week 12 were observed in tumor 
types including non-small cell lung cancer (NSCLC), 38%; breast cancer, 48%; melanoma, 46%; 
ovarian cancer, 53%; hepatocellular carcinoma (HCC), 66%; and CRPC, 66%. In Study XL184-008, 
clinical activity was also observed in differentiated thyroid cancer (DTC; DCR = 73% at 24 weeks) 
and renal cell carcinoma (RCC; median progression-free survival [PFS] = 12.9 months). Observations 
of clinical activity have included decrease of soft tissue tumor lesions including visceral metastases, 
effects on metastatic lesions on bone scan (partial or complete bone scan resolution), reduction in 
serum markers of bone resorption and formation, reduction in circulating tumor cells (CTCs; subjects 
with prostate cancer), increases in hemoglobin, and improvements in bone pain and reductions in 


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narcotic use in subjects with bone metastases. Activity in MTC and CRPC subjects is described in 
more detail below. 
 
In the placebo-controlled Phase 3 study XL184-301 in 330 MTC subjects, a significant increase in 
median PFS was seen in the cabozantinib arm compared with placebo (11.2 vs 4.0 months; hazard 
ratio [HR] =0.28; 95 CIs: 0.19, 0.40). Confirmed PRs occurred in 28% of cabozantinib-treated 
subjects and none in the placebo arm; responses were durable (median duration 14.6 months). An 
unplanned administrative analysis of overall survival (OS) performed at the request of the FDA with 
a data cut-off of 15 June 2012 (75% of required deaths) showed a trend for improved duration of OS 
in the cabozantinib arm compared with placebo (26.0 months vs 20.3 months; HR = 0.83; 95% CI: 
0.60, 1.14). 
 
2.2.6.1 
XL184-001 
 
In a Phase 1 study (XL184-001), subjects with advanced tumors were enrolled in successive cohorts 
to receive cabozantinib administered orally (PO) as capsules or as a PIB aqueous suspension 
formulation. A total of 85 subjects, including 37 subjects with MTC, were enrolled in the XL184-001 
study. Among the 35 subjects with MTC and measurable disease, PR was achieved in 10 subjects 
(29%): three subjects were treated at starting dose levels other than the MTD of 140 mg (175 mg 
malate salt weight) capsule formulation and seven subjects were treated at the MTD. Five of the 10 
responders had a PR at the first radiologic assessment. The median duration of treatment for these 10 
subjects was 538.5 days (17.7 months) with a range of 145 to 2082+ days (4.8 to 68.4+ months). 
Activity was independent of both RET mutation status and prior treatment with tyrosine kinase 
inhibitors, including those known to inhibit RET (e.g., vandetanib) (Kurzrock et al. 2011). 
 
2.2.6.2 
XL184-201 
 
In a Phase 2 study (XL184-201), subjects with relapsed or recurrent GB in first or second relapse 
were enrolled to receive cabozantinib qd as a single agent. Subjects were enrolled in three successive 
cohorts, the first receiving an initial dose of 140 mg FBE weight (175 mg malate salt weight; Group 
A). To explore the tolerability and antitumor activity at a lower dose, subsequent cohorts (Groups B 
and C) received an initial dose of 100 mg (125 mg malate salt weight). Study objectives included 
assessments of safety, tolerability, and clinical activity (consisting of independent radiology facility 
[IRF]-determined response assessment and PFS), at the two dose levels.  
 
Clinical activity data are summarized in Table 1-3 for 46 subjects who received cabozantinib at a 
starting dose of 140 mg (175 mg malate salt weight) qd (Group A) and 59 subjects who received 
cabozantinib at a starting dose of 100 mg (125 mg malate salt weight) qd (Group B). In both of these 
cohorts, radiographic response was evaluated by an IRF review of MRI scans per modified 
Macdonald criteria (Macdonald et al. 1990). An additional cohort with a starting dose of 100 mg qd 
(Group C) was also enrolled, but clinical activity data have not yet been analyzed.  
 
 
 


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Table 1-3: Response Rate and Progression-Free Survival in XL-184-201 (N=105) 
 
 
2.2.6.3 
XL184-202 
 
In a Phase 1b/2 study (XL184-202), subjects with NSCLC received treatment with cabozantinib with 
or without erlotinib. The Phase 1 portion of the study followed a dose-escalation design in which 
subjects with NSCLC in whom erlotinib therapy had failed were enrolled in successive cohorts to 
receive once-daily doses of cabozantinib in combination with erlotinib. During the Phase 1 portion of 
the study, erlotinib was administered as a single agent for a 14-day run-in phase, and then 
cabozantinib and erlotinib were administered in combination for 28-day cycles. Dosing cohorts were 
assessed in two parallel arms maximizing doses of cabozantinib and erlotinib. The MTD of Arm A 
(maximizing the erlotinib dose) was determined to be 100 mg FBE weight (125 mg malate salt 
weight) of cabozantinib plus 50 mg of erlotinib. The MTD of Arm B (maximizing the cabozantinib 
dose) was determined to be 40 mg (50 mg malate salt weight) of cabozantinib plus 150 mg of 
erlotinib.  
 
In the Phase 2 portion of the study, subjects with NSCLC who had progressed after receiving clinical 
benefit from erlotinib were enrolled in two parallel arms: Arm 1 in which treatment was single-agent 
cabozantinib at a dose of 100 mg qd and Arm 2 in which treatment comprised cabozantinib in 
combination with erlotinib at a dose of cabozantinib 100 mg and erlotinib 50 mg (the MTD of Arm A 
from the Phase 1 portion). Twenty-eight subjects (15 in Arm 1 and 13 in Arm 2) received study drug 
in Phase 2. Enrollment of this study has been terminated. Clinical and safety data for this study is 
available through the database cut-off date of 02 August 2012.  
 
Sixty-four subjects were enrolled in the Phase 1 dose-escalation portion of the study examining the 
combination of cabozantinib and erlotinib in NSCLC subjects. All but two subjects had been 
previously treated with and progressed on erlotinib therapy. A PR was observed in 5 subjects (8%). 
The ORR for the Phase 1 population was 8.2% (90% CI: 3.3, 16.5). The median PFS for subjects 
(mITT Population) was 3.68 months (95% CI: 3.15, 5.49). The Kaplan-Meier estimate of the 
probability of a subject to be progression-free at 6 months was 29.4%. 


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Twenty-eight subjects were enrolled in the Phase 2 portion of the study, in which subjects who had 
received clinical benefit from erlotinib and subsequently experienced PD receive single-agent 
cabozantinib or cabozantinib in combination with erlotinib. A PR was observed in one subject who 
was treated with single-agent cabozantinib. The ORR for subjects who received cabozantinib was 
6.7% (90% CI: 0.3, 27.9). No objective responses were seen in subjects who received cabozantinib + 
erlotinib (0/13 subjects). 
 
The median PFS for subjects (mITT Population) was 1.91 months (95% CI: 1.64, 7.06) for the 
cabozantinib arm and 3.94 months (95% CI: 1.54, 7.26) for the cabozantinib + erlotinib arm. The 
Kaplan-Meier estimate of the probability of a subject to be progression-free at 6 months was 30.8% 
for the cabozantinib arm and 22.0% for the cabozantinib + erlotinib arm. 
 
2.2.6.4 
XL184-203 
 
In a Phase 2 RDT (XL184-203), subjects were enrolled into one of the nine tumor-specific cohorts: 
breast cancer, gastric/gastroesophageal junction (GEJ) cancer, HCC, melanoma, NSCLC, ovarian 
cancer, pancreatic cancer, prostate cancer, and small-cell lung cancer (SCLC). Eligible subjects with 
advanced solid tumors received open-label cabozantinib at a starting dose of 100 mg qd for 12 weeks 
(Lead-In Stage). Tumor response per mRECIST v1.0 was assessed every 6 weeks. Subjects with PR 
or CR at Week 12 continued to receive open-label cabozantinib; subjects with progressive disease 
(PD) discontinued cabozantinib. Subjects with SD at Week 12 were randomized 1:1 in a double-
blinded fashion to receive cabozantinib or placebo (Randomized Stage). Cross-over from placebo to 
cabozantinib was allowed upon PD. Primary endpoints were objective response rate (ORR) at Week 
12 and PFS in the Randomized Stage. An Independent Data Monitoring Committee (IDMC) 
monitored safety in the blinded Randomized Stage. As of October 2011, all subjects have been 
unblinded.  
 
A Study Oversight Committee (SOC) monitored efficacy during the Lead-In Stage and, based on 
periodic review of all available data, could recommend that enrollment into specific cohorts be halted, 
continued within the RDT design, or closed in favor of opening an open-label NRE cohort. Non-
randomized expansion cohorts were opened for CRPC (N=144) and ovarian cancer (N=61). Subjects 
enrolled into NRE cohorts received open-label cabozantinib qd until PD or unacceptable toxicity 
developed.  
 
A total of 205 subjects received study drug in the NRE cohorts. In the CRPC cohort subjects were 
dosed at starting levels of either 100 mg (N=93) or 40 mg (N=51). All subjects (N=61) in the ovarian 
cancer cohort were dosed at the starting level of 100 mg.  
 
In the Phase 2 study XL184-203, cabozantinib demonstrated broad clinical activity in men with 
CRPC (Smith et al. 2013). During the RDT phase, the majority of CRPC subjects with bone 
metastases and elevated total alkaline phosphatase (t-ALP) levels at baseline showed reductions in t-
ALP (Smith et al. 2013). Similarly, during the non-randomized expansion (NRE) phase, the majority 
of CRPC subjects at the 100 mg assigned dose showed reductions in circulating bone specific alkaline 
phosphatase (BSAP) (Smith et al. 2012). These effects were independent of prior or concomitant 
bisphosphonate treatment. Reductions in bone biomarkers were also evident in the 40 mg CRPC NRE 


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cohort (de Bono et al, 2012). Effects on bone scan were assessed by an independent reader, and pain 
and narcotic use were prospectively assessed using an interactive voice recording system (IVRS) and 
a diary. Subjects achieved a bone scan response (BSR) in both the 100 mg and 40 mg assigned NRE 
dose cohorts (67% and 49%, respectively). Among subjects with baseline pain of at least 4 (0-10 
scale by Brief Pain Inventory [BPI]), a majority had at least a decrease of 30% in the average daily 
worst pain compared with baseline in both cohorts (100 mg: 64% of subjects; 40 mg: 69% of 
subjects). In addition, more than half of subjects decreased narcotic use. 
 
All enrolled subjects with hepatocellular carcinoma were Child-Pugh Class A, and 30 (73%) had 
evidence of extrahepatic spread. The majority of subjects (80%) had one to two lines of prior therapy. 
More than half of the subjects (51%) had been treated previously with sorafenib. The overall DCR at 
Week 12 was 66%. Regression of measurable soft-tissue disease per mRECIST was observed in 28 of 
36 (78%) subjects with at least one post-baseline tumor assessment. Two subjects (5%) achieved PRs. 
Nine of 26 (35%) subjects who had alpha-fetoprotein (AFP) levels ≥ 20 ng/mL at baseline 
experienced ≥ 50% reduction in AFP. The overall median PFS was 4.4 months, while the sorafenib 
pre-treated group had a median PFS of 5.2 months. In an updated analysis, the median OS was 11.5 
months (95% CI: 7.3, 15.6) (data on file). Among sorafenib-pretreated subjects, the median OS was 
12.9 months (95% CI: 10.8, 16.8). Based on preliminary analysis, no apparent difference in 
cabozantinib exposure between subjects with HCC and subjects with other tumors was observed.  
 
In unselected NSCLC patients, cabozantinib given at 100 mg orally daily was associated with a 10% 
ORR, a median PFS of 4.2 months and a 38% DCR at 12 weeks. 
 
2.2.6.5 
Translational Medicine 
 
Phase 1: Study XL184-001: Exposure to cabozantinib resulted in significant changes in levels of the 
circulating biomarkers placental growth factor (PlGF), VEGF, soluble VEGFR2 (sVEGFR2), and 
erythropoietin (EPO), consistent with results observed with other anti-VEGFR2 pathway agents 
(Murukesh et al. 2010; Deprimo et al. 2007). Calcitonin (CTN) and carcinoembryonic antigen (CEA) 
levels in subjects with MTC have been found to correlate with tumor burden, and doubling times with 
risk of PD (Giraudet et al. 2007). There were clear treatment-related reductions in both markers in the 
majority of subjects with MTC treated with cabozantinib. While there was no obvious relationship 
between down-regulation of these markers and attaining a PR by investigator assessment, there was a 
weak but statistically significant correlation between best tumor response (% decrease in sum of 
longest diameter) and best calcitonin or best CEA response. It is unclear at this time whether these 
markers will have utility in monitoring response to cabozantinib in this disease setting. 
 
Phase 2: Study XL184-201 (Glioblastoma): Plasma samples were analyzed for several biomarkers 
of response to anti-angiogenic agents, including levels of VEGF-A, sVEGFR2, and PlGF. Changes in 
pharmacodynamic markers consistent with cabozantinib on-target effects were observed after 
cabozantinib administration in 40 subjects treated with a starting dose of 140 mg FBE weight (175 
mg malate salt weight). Changes in PlGF (↑), VEGF-A (↑), sVEGFR2 (↓), and soluble KIT (sKIT)(↓) 
reached statistical significance at multiple time points, particularly Days 15 and 29. Soluble MET as a 
potential biomarker of MET inhibition was modulated (↑) upon cabozantinib treatment and changes 
reached statistical significance as well, on Day 15 and Day 57 (Cycle 3 Day 1). Preliminary analysis 
of potential correlations between clinical outcome and baseline levels or changes during treatment of 


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the plasma proteins did not reveal significant correlations.  
 
Results from a similar analysis of plasma samples obtained from subjects treated with a starting dose 
of 125 mg showed statistically significant modulation of plasma biomarkers VEGF-A, PlGF, and 
sVEGFR2, as well as modulation of sKIT and sMET. 
 
Genotyping of Archival Tumor Tissue: Select genotyping analyses have been conducted on 
archival tumor tissue and clinical sites have shared their own results when available. Based on the 
preliminary analysis of 48 melanoma subjects with both tumor response and BRAF mutation data, 
clinical activity of cabozantinib appears to be independent of BRAF mutation status (Gordon et al. 
2012). Clinical activity of cabozantinib also appears to be independent of epidermal growth factor 
receptor (EGFR) and KRAS mutation status in NSCLC subjects based on the preliminary data 
(Hellerstedt et al. 2012). 
 
2.3 
Rationale for the Study, Dose and Schedule 
 
Seventeen to thirty percent of patients with newly diagnosed NSCLC will present with metastatic 
disease to the brain.1-3 Treatment options for brain metastases from NSCLC include whole–brain 
radiation therapy (WBRT), stereotactic radiosurgery (SRS), surgical resection or some combination 
of these options. The median survival time after whole-brain radiation therapy usually ranges from 3-
6 months and strongly correlates with the patient’s age, performance status, number and location of 
metastatic lesions. 4-6  In addition, whole brain radiotherapy may cause devastating CNS damage. The 
majority of patients with brain metastases also suffer from active extracranial disease, and systemic 
disease progression is a common cause of death. Therefore, development of effective systemic 
treatment for control of both extracranial and brain metastases is desirable.  
 
There are an increasing number of drug trials that are specifically focusing on patients with brain 
metastases. One of possibly targetable pathways is HGF/MET pathway. The c-MET receptor tyrosine 
kinase has been implicated in tumor cell migration, invasion, proliferation and angiogenesis and is the 
only known high affinity receptor for hepatocyte growth factor (HGF).7 Amplification of c-MET has 
been associated with poor prognosis in NSCLC, mediastinal lymph node metastases, and resistance, 
both acquired and intrinsic, to EGFR tyrosine kinase inhibitors in EGFR-mutant lung 
adenocarcinoma.8-10 c-MET expression and phosphorylation has been shown to be associated with the 
development of NSCLC brain metastases and are selectively enriched in brain metastases relative to 
paired primary lung tumors.11 Of most importance, the presence of de novo c-MET amplification in 
NSCLC has been linked to rapid and durable clinical response to single agent crizotinib, a c-MET 
receptor tyrosine kinase inhibitor.12  
 
In a series of 200 NSCLC brain metastases collected at the University of Pittsburgh Medical Center 
(UPMC) between 2005 and 2012, 50% were of adenocarcinoma histology. To date we have 
completed FISH studies on 77 of these brain metastases. Twenty-one percent (16 of 77) of these brain 
metastases were c-MET amplified as defined by a FISH ratio > 2.0; 38% (6 of 16) of these c-MET 
amplified brain tumors also harbored a KRAS mutation (confidential unpublished data). These data 
are intriguing in its marked inconsistency with the ongoing genotyping efforts of the Lung Cancer 
Mutation Consortium (LCMC), in which c-MET amplification was present in only 5 (1%) of 733 
metastatic lung adenocarcinomas that underwent profiling for 10 oncogenic drivers. Furthermore, 


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96% of the oncogenic drivers identified through the LCMC were mutually exclusive. These data 
suggest that c-MET amplification plays a critical role in the metastatic potential of NSCLC to the 
brain and implicates c-MET as a therapeutic target in NSCLC with brain metastases, in particular, the 
subset with c-MET amplification.  
 
Cabozantinib (XL184) is a potent oral inhibitor of MET, VEGFR2, and RET that produces robust 
antiangiogenic and antitumor effects in preclinical models. The efficacy of single agent cabozantinib 
was evaluated in patients with progressive glioblastoma multiforme (GBM) in a phase II open-label 
clinical trial at 140 mg daily and 100 mg daily dose levels. Cabozantinib at both dose levels was 
associated with objective responses in central nervous system disease. The objective response rates 
(ORR) in patients who were naïve to prior treatment with anti-angiogenic therapy were 21% and 
30%, at the 140 mg and 100 mg dose levels, respectively, suggesting blood-brain barrier penetration. 
In a randomized discontinuation study in unselected NSCLC patients, cabozantinib given at 100 mg 
orally daily was associated with a 10% overall response rate (ORR) and an overall disease control 
rate (partial response plus stable disease) of 40%. This current trial is a single-arm phase II clinical 
trial evaluating the efficacy and safety of cabozantinib in NSCLC patients with brain metastases both 
in an unselected population and in a subset with c-MET amplification.  
 
A starting dose of cabozantinib 60 mg daily was selected based on an expected better toxicity and 
tolerability profile. Cabozantinib 140 mg daily in GBM is most commonly associated with fatigue 
(any grade) in 74% patients (grade 3/4 fatigue in 30% patients). Adverse side effects (all grades) 
associated with dose reduction/interruptions were asthenia in 24% patients, palmar-plantar 
erythrodysesthesia in 17% patients, anorexia in 13% patients, diarrhea in 13% patients, transaminase 
elevations in 11% patients, nausea in 9% patients, and pancreatitis/pancrease enzyme increase in 9% 
patients. In total, cabozantinib 140 mg daily was associated with dose interruptions in 87% patients 
and dose reductions in 52% patients. Cabozantinib 100 mg daily is better tolerated with grade 3/4 
fatigue occurring in 16% patients (any grade, 63% patients). The most common all-grade adverse 
events were a variable cluster of symptoms consisting of fatigue, decreased appetite, taste alterations, 
nausea, diarrhea, weight loss, and palmar-plantar erythrodysesthesia, which resulted in dose 
reductions in 62% of patients. 44 However, 60 mg is the recommended phase II dose in a clinical trial 
enrolling NSCLC patients in Japan, and 60 mg is the starting dose of cabozantinib in a number of 
ongoing clinical trials for other tumor indications as well.  
 
2.4 
Study Design 
 
2.4.1 Overview of Study Design 
 
This is a Phase 2, single-arm, open-label study of cabozantinib in subjects with molecularly 
unselected NSCLC with metastases to the brain and in patients with c-MET amplified NSCLC with 
metastases to the brain. 
 
Patients will receive cabozantinib at 60 mg once daily and continue on treatment until disease 
progression, death or unacceptable adverse events. Treatment cycles are 4 weeks in duration. 
 
The primary endpoint is ORR in both the unselected NSCLC population and the molecularly selected 
patients on the basis of c-MET amplification. 


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Simon's optimal two-stage design is used to minimize the expected sample size if the treatment is not 
effective. A stopping rule for futility is implemented if 1 or fewer of the first 29 patients have an 
objective response. (Accrual may continue during follow-up for these patients.) If ≥2 responses are 
observed in the first 29 patients, an additional 25 patients will be enrolled. A promising study result 
would be a response rate of 6/54 (11%) or greater. This design has 82% power to detect a true 
response rate of 15% (compared with a null rate of 5%). A minimum of 15 evaluable patients with c-
MET amplified tumors will be enrolled. If 1 or fewer than 29 patients in the first stage of the Simon 
design have an objective response and the minimum number of c-MET amplified tumors has not been 
met, accrual will continue for the c-MET amplified subset only, until the minimum number of patients 
with c-MET amplified tumors is met. 
 
3. PATIENT SELECTION 
 
3.1 
Eligibility Criteria 
 
A subject must fully meet all of the following criteria to be eligible for enrollment as defined by the 
inclusion and exclusion criteria as follows: 
 
1. Previously treated patients with non-squamous NSCLC who have had brain metastases at any 
point in their treatment history are eligible for enrollment on this clinical trial. (Patients must 
have received at least one regimen for systemic disease which may be cytotoxic or oral 
tyrosine kinase inhibitor therapy.) 
a. Patients with clinically asymptomatic (no requirement for systemic corticosteroids) 
untreated brain metastases will be allowed on trial at the discretion of the treating 
physician 
b. Patients who have undergone treatment for their brain metastases with whole brain 
radiotherapy, stereotactic radiosurgery, or surgical resection must be clinically stable 
and recovered from all procedures at the time of study enrollment. 
2. Patients must have tumor tissue available for submission that is sufficient to complete c-MET 
FISH studies as well as routine molecular profiling at the UPMC. Patients must agree to 
submission of these specimens as defined in Section 9. 
a. c-MET amplification will be determined by FISH ratio (c-MET/CEP7) > 2.0, based on 
testing of the primary tumor and/or site of metastatic disease 
b. Patients’ tumors must undergo testing for EGFR exon 19 deletion, EGFR exon 21 
L858R substitution, and ALK rearrangements. If positive, patients must have been 
treated with an appropriate TKI prior to enrolling to the study. 
3. The subject has had an assessment of all extracranial disease sites (e.g., by computerized 
tomography (CT) scan, positron emission tomography-CT, and bone scan as appropriate) 
within 28 days before the first dose of cabozantinib. 
4. The subject must have a baseline brain MRI scan or CT scan of the head (in patients unable to 
obtain an MRI) within 14 days prior to first dose of cabozantinib. 


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a. Patients receiving glucocorticoids must be on a stable dose of glucocorticoids during 
the 5 days prior to the baseline brain imaging.  
5. Patients must have measurable disease as defined by RECIST v1.1 
a. Lesions that have previously been treated with SRS are excluded as measurable 
disease because distinction of radiation necrosis and tumor progression can be difficult 
in this setting and enlargement of the lesion may not necessarily mean progression. 
6. Subjects having undergone recent resection or biopsy of an intracranial tumor will be eligible 
as long as all of the following conditions apply:  
a. First dose of cabozantinib occurs at least 28 days after surgery, and the subject has 
recovered from the effects of surgery 
7. Age ≥18 years. Because no dosing or adverse event data are currently available on the use of 
cabozantinib in patients <18 years of age, children are excluded from this study, but will be 
eligible for future pediatric trials. 
8. ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A). 
9. Patients must have normal organ and marrow function as defined below: (within 4 days of 
beginning treatment unless noted otherwise) 
 
Hemoglobin 
≥9 g/dL 
Absolute Neutrophil Count(ANC) 
≥1,500/mm3 (no CSF support) 
Platelets 
≥100,000/mm3 
Bilirubin 
≤ 1.5 x upper limit of normal 
(ULN) 
Bilirubin (Gilbert’s Disease) 
< 3.0 mg/dL 
AST(SGOT) and ALT(SGPT) 
≤3.0 × ULN 
Serum creatinine 
OR 
Creatinine clearance (CrCl) 
For creatinine clearance estimation, the Cockcroft and 
Gault equation should be used:  
Male: CrCl (mL/min) = (140 - age) × wt (kg) / (serum 
creatinine × 72)  
Female: Multiply above result by 0.85 
≤ 1.5 x ULN 
 
≥40 mL/min 
Lipase 
no radiologic or clinical evidence of pancreatitis 
< 2.0 x ULN 
Urine protein/creatinine ratio (UPCR) 
<1 
Serum phosphorus, calcium, magnesium and potassium 
≥ Lower limit of normal (LLN) 
 
10. The subject is capable of understanding and complying with the protocol requirements and 
has signed the informed consent document. 
11. Women of childbearing potential must have a negative serum pregnancy test at screening. 
Women of childbearing potential include women who have experienced menarche and who 


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have not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy) or are not postmenopausal. Post-menopause is defined as amenorrhea 
≥ 12 consecutive months. Note: 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, anti-estrogens, ovarian suppression or any other reversible reason. 
12. The effects of cabozantinib on the developing human fetus are unknown. For this reason 
women of child-bearing potential and men must agree to use adequate contraception 
(hormonal or barrier method of birth control; abstinence) prior to study entry and for 4 months 
after the last dose of study drug, even if oral contraceptives are used. Should a woman become 
pregnant or suspect she is pregnant while she or her partner is participating in this study, she 
should inform her treating physician immediately. Men treated or enrolled on this protocol 
must also agree to use adequate contraception prior to the study, for the duration of study 
participation, and 4 months after completion of cabozantinib administration. 
 
3.2 
Exclusion Criteria 
 
1. The subject has received cytotoxic chemotherapy (including investigational cytotoxic 
chemotherapy) or biologic agents (e.g., cytokines or antibodies; including investigational 
biologic agents) within 3 weeks, or nitrosoureas/ mitomycin C within 6 weeks before the first 
dose of study treatment. 
2. The subject has received prior treatment with a small molecule kinase inhibitor or a hormonal 
therapy (including investigational kinase inhibitors or hormones) within 7 days or five half-
lives of the compound or active metabolites, whichever is longer, before the first dose of study 
treatment. 
3. Prior treatment with cabozantinib. 
4. The subject has received radiation therapy as follows:  
a. To the thoracic cavity, abdomen or pelvis within 3 months of the first dose of study 
treatment or has with ongoing complications or is without complete recovery and 
healing from prior radiation therapy 
b. To bone or brain metastasis within 14 days of the first dose of study treatment 
c. To any other site(s) within 28 days of the first dose of study treatment 
5. The subject has received radionuclide treatment within 6 weeks of the first dose of study 
treatment. 
6. The subject has evidence of acute intracranial or intratumoral hemorrhage either by MRI or 
computerized tomography (CT) scan. The subject has not recovered to baseline or CTCAE ≤ 
Grade 1 from toxicity due to all prior therapies except alopecia and other non-clinically 
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7. The subject has prothrombin time (PT)/ International Normalized Ratio (INR) or partial 
thromboplastin time (PTT) test ≥ 1.3  the laboratory ULN within 7 days before the first dose 
of study treatment. 
8. The subject is receiving concomitant anticoagulation treatment at therapeutic doses with oral 
anticoagulants (e.g., warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors 
(e.g., clopidogrel) at the time of study entry.  
Note: Low-dose aspirin for cardioprotection (per local applicable guidelines), low-dose 
warfarin (< 1 mg/day), and low dose, low molecular weight heparins (LMWH) are 
permitted. Anticoagulation with therapeutic doses of LMWH is allowed in subjects without 
radiographic evidence of brain metastasis, who are on a stable dose of LMWH for at least 12 
weeks before randomization, and who have had no complications from a thromboembolic 
event or the anticoagulation regimen.  
9. The subject has received enzyme-inducing anti-epileptic agents within 2 weeks before the first 
dose of cabozantinib (e.g., carbamazepine, phenytoin, phenobarbital, primidone). Other 
enzyme inducing agents prohibited within 2 weeks before the first dose of cabozantinib 
include rifampin, rifabutin, rifapentin, and St. John’s Wort. 
10. The subject has experienced any of the following: 
a. Clinically-significant gastrointestinal 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 
11. The subject has radiographic evidence of cavitating pulmonary lesion(s) 
12. The subject has tumor abutting, invading or encasing any major blood vessels. 
13. 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. 
14. 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 BP > 140 mm Hg 
systolic, or > 90 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: 
1. unstable angina pectoris 


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2. clinically-significant cardiac arrhythmias 
3. stroke (including TIA, or other ischemic event) 
4. myocardial infarction 
5. thromboembolic event requiring therapeutic anticoagulation (Note: 
subjects with a venous filter (e.g. vena cava filter) are not eligible for 
this study) 
b. Gastrointestinal disorders particularly those associated with a high risk of perforation 
or fistula formation including: 
i. Any of the following within 28 days before the first dose of study treatment 
1. Intra-abdominal tumor/metastases invading GI mucosa 
2. Active peptic ulcer disease, 
3. Inflammatory bowel disease (including ulcerative colitis and Crohn’s 
disease), diverticulitis, cholecystitis, symptomatic cholangitis or 
appendicitis 
4. Malabsorption syndrome 
ii. Any of the following within 6 months before the first dose of study treatment: 
1. Abdominal fistula 
2. Gastrointestinal perforation 
3. Bowel obstruction or gastric outlet obstruction 
4. Intra-abdominal abscess. Note: Complete resolution of an intra-
abdominal abscess must be confirmed prior to initiating treatment with 
cabozantinib even if the abscess occurred more than 6 months before 
the first dose of study treatment. 
c. Other disorders associated with a high risk of fistula formation including PEG tube 
placement within 3 months before the first dose of study therapy. 
d. Other clinically significant disorders such as: 
i. Serious active infection requiring systemic treatment within 28 days before the 
first dose of study treatment. 
ii. Serious non-healing wound/ulcer/bone fracture within 28 days before the first 
dose of study treatment. 
iii. History of organ transplant 
iv. Concurrent uncompensated hypothyroidism or thyroid dysfunction within 7 
days before the first dose of study treatment. 
v. History of surgery as follows: 
1. Subjects having undergone recent resection or biopsy of an intracranial 
tumor will be eligible as long as all of the following conditions apply: 
First dose of cabozantinib occurs at least 28 days after surgery, and the 
subject has recovered from the effects of surgery. 
2. Other minor surgery within 28 days of the first dose of cabozantinib if 
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wound dehiscence, subjects will be eligible for trial after a minimum of 
3 months after surgery to the first dose of cabozantinib, provided 
complete wound healing is confirmed at least 28 days before the first 
dose of cabozantinib.  
3. Other major surgery within 2 months of the first dose of cabozantinib if 
there were no wound healing complications. If there is evidence of 
wound dehiscence, subjects will be eligible for trial after a minimum of 
6 months after surgery to the first dose of cabozantinib, provided 
complete wound healing in confirmed at least 28 days before the first 
dose of cabozantinib. 
15. The subject is unable to swallow tablets. 
16. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF) >500 ms 
within 28 days before randomization. Note: if initial QTcF is found to be > 500 ms, two 
additional EKGs separated by at least 3 minutes should be performed. If the average of these 
three consecutive results for QTcF is ≤ 500 ms, the subject meets eligibility in this regard. 
17. The subject is pregnant or breastfeeding. 
18. The subject has a previously identified allergy or hypersensitivity to components of the study 
treatment formulation. 
19. The subject is unable or unwilling to abide by the study protocol or cooperate fully with the 
investigator or designee. 
20. The subject has had evidence within 2 years of the start of study treatment of another 
malignancy which required systemic treatment. Note: Subjects with a history of early stage or 
locally advanced non-metastatic prostate cancer within 2 years of the start of study treatment 
may be included in the study. 
 
3.3 
Inclusion of Women and Minorities 
 
Both men and women of all races and ethnic groups are eligible for this trial. 
 
3.4 
Replacements 
 
Subjects will not be replaced in this study 
 
4. REGISTRATION PROCEDURES 
 
4.1 
General Guidelines 
 
Eligible patients will be entered on study centrally at the Hillman Cancer Center by the Study 
Coordinator 412-623-3082.  
 
Following registration, patients should begin protocol treatment within 28 days. Additional testing 


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will take place 4 days prior to the first dose of study treatment. Issues that would cause treatment 
delays should be discussed with the Investigator. If a patient does not receive protocol therapy 
following registration within the designated time period, the patient’s registration on the study may be 
canceled. The Study Coordinator should be notified of cancellations as soon as possible. 
 
4.2 
Registration Process 
 
To register a patient, the following documents should be completed by the research nurse, the PI or a 
co-investigator and faxed to 412-623-7862 at the Hillman Cancer Center 
 Copy of required pre-study tests 
 Completed eligibility checklist 
 Signed patient consent form  
 
The research nurse or data manager at the participating site will then call or e-mail the Study 
Coordinator, 412-623-3082, to verify eligibility. To complete the registration process, the 
Coordinator will 
 Assign a patient study number 
 Register the patient on the study 
 Fax or e-mail the patient study number to the participating site 
 Call the research nurse or data manager at the participating site and verbally confirm 
registration. 
 
5. TREATMENT PLAN 
 
5.1 
Agent Administration: Cabozantinib Tablets (XL-184) 
 
Treatment will be administered on an outpatient basis. Reported adverse events and potential risks are 
described in Section 7. Appropriate dose reduction is described in Section 6. No investigational or 
commercial agents or therapies other than those described below may be administered with the intent 
to treat the patient's malignancy. 
 
Regimen Description 
Agent 
Dose 
Route 
Schedule 
Cycle 
Length 
Cabozantinib 
60mg 
orally 
7 days per 
week 
28 days  
(4 weeks) 
 
 
 
The patient will be requested to maintain a medication diary of each dose of 
medication. The medication diary will be returned to clinic staff at the end of 
each 28 day cycle. 
 


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Subjects will receive cabozantinib at 60 mg (starting dose) once daily and continue treatment until 
disease progression or death, see section 5.4, or unacceptable adverse event as defined in section 7. 
Cabozantinib is to be taken without food (subjects should not eat for at least 2 hours before and at 
least 1 hour after taking cabozantinib) with a full glass (at least 8 ounces) of water.  
 
5.2 
General Concomitant Medication and Potential Drug Interactions 
 
5.2.1 Anticancer Therapy  
 
If a subject requires additional systemic anticancer treatment, including steroid treatment for prostate 
cancer subjects, study treatment must be discontinued. 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. Subjects with prostate cancer 
currently receiving luteinizing hormone-releasing hormone (LHRH) or gonadotropin releasing 
hormone (GnRH) agonists may be maintained on these agents. 
 
5.2.2 Other Medications 
 
Subjects must be instructed to inform the investigators of the current or planned use or all other 
medications during the study (including prescription medications, vitamins, herbal and nutritional 
supplements, and over-the-counter medications). It is the responsibility of the investigator to ensure 
that details regarding all medications are documented. 
 
Bisphosphonates started prior to screening activities or initiated during the course of the study to 
control bone pain are allowed with caution. 
 
Colony stimulating factors (e.g., erythropoietin and granulocyte colony stimulating factors) and pain 
medications administered as dictated by standard practice are acceptable while the subject is enrolled 
in the study. However, colony stimulating factors should not be administered prophylactically prior to 
the first dose of study treatment.  
 
No concurrent investigational agents are permitted. 
 
5.2.3 Potential Drug Interactions 
 
Cytochrome P450: Preliminary 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 AUC of co-administered rosiglitazone, a CYP2C8 substrate. Therefore, cabozantinib is not 
anticipated to markedly inhibit CYP2C8 in the clinic, and by inference, is not anticipated to markedly 
inhibit other CYP450 isozymes that have lower [I]/Ki values compared to 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 (but not a CYP2C9 or CYP2D6 substrate), based on data from 


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in vitro studies using CYP-isozyme specific neutralizing antibodies.  
 
Preliminary results from a clinical pharmacology study, XL184-006, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inducer, rifampin, resulted in an 
approximately 80% reduction in cabozantinib exposure (AUC values) after a single dose of 
cabozantinib in healthy volunteers. Co-administration of cabozantinib with strong inducers of the 
CYP3A4 family (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
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 e.g., chronic use of modafinil should be avoided because of its potential to reduce 
cabozantinib exposure. Selection of alternate concomitant medications with no or minimal CYP3A4 
enzyme induction potential is recommended. In addition, 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, as this could significantly increase the exposure to cabozantinib.  
 
Preliminary results from a clinical pharmacology study, XL184-007, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 33-39% 
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 / grapefruit juice and Seville oranges may also 
increase plasma concentrations of cabozantinib. Strong CYP3A4 inhibitors 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.  
 
Because in vitro studies only assessed the metabolizing capacity of the CYP3A4, CYP2C9, and 
CYP2D6 pathways, the potential for drugs that inhibit/induce other CYP450 pathways (e.g., 
CYP2C8, CYP2C19, CYP2B6, CYP1A2) to alter cabozantinib exposure is not known. Therefore, 
these drugs should be used with caution when given with cabozantinib.  
Please refer to the Flockhart drug interaction tables for lists of substrates, inducers, and inhibitors of 
selected CYP450 isozyme pathways (Flockhart 2007; 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx). 
 
Protein Binding:  
Cabozantinib is highly protein bound (approximately 99.9%) 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). 
Factors that influence plasma protein binding may affect individual tolerance to cabozantinib. 
Therefore, concomitant medications that are highly protein bound (e.g., diazepam, furosemide, 
dicloxacillin, and propranolol) should be used with caution. Because warfarin is a highly protein 
bound drug with a low therapeutic index, administration of warfarin at therapeutic doses should be 
avoided in subjects receiving cabozantinib due to the potential for a protein binding displacement 
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Drugs Associated with QTc Prolongation: 
Treatment with cabozantinib has been associated with a mild prolongation of the QTc interval. 
Caution should be used when treating subjects on cabozantinib with other drugs associated with QTc 
prolongation (see http://www.qtdrugs.org). Additional QTc monitoring is suggested for subjects who 
are treated concomitantly with QTc prolonging drugs. 
 
Other Interactions:  
In a relative bioavailability study in dogs, cabozantinib exposure was not significantly affected by 
drugs that alter gastric pH. Nevertheless, drugs such as proton pump inhibitors (PPIs) and H2 
antagonists produce profound suppression of gastric acid secretion and significant increases in gastric 
pH. By elevating gastric pH, PPIs and H2 antagonists may decrease cabozantinib plasma exposure 
levels and its effectiveness in vivo, resulting in clinically significant drug interactions. The use of 
PPIs (e.g., omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole) and/or H2 
antagonists (e.g., ranitidine, famotidine, and nizatidine) is discouraged during this study. If antacids 
are not adequate, the use of H2 blockers is preferred over PPIs (Note: Cimetidine should be avoided 
because of its potential to interfere with CYP3A4 mediated metabolism of cabozantinib). Antacids, 
H2 blockers, or PPIs should be taken at least 2 hours (preferably 4 hours) after taking cabozantinib 
but at least 14 hours before the next dose of cabozantinib if possible.  
 
In vitro data suggest that cabozantinib is unlikely to be a substrate for P glycoprotein (P-gp), but it 
does appear to have the potential to inhibit the P-gp transport activity.  
 
Additional details related to these overall conclusions are provided in the Investigators Brochure. 
 
5.3 
Electrocardiogram (ECG) Assessment 
 
ECG assessments will be performed with standard 12-lead ECG equipment according to standard 
procedures. Pre-treatment ECGs should be performed at intervals specified in the study calendar, 
section 10.0.  
 
At any time point, if there is an increase in QTc interval to an absolute value > 500 msec using the 
Fridericia correction formula, two additional ECGs should be performed approximately 2 minutes 
apart, within 30 minutes. (See Section 7.1.15: Guidelines for Management of Treatment-Emergent 
Corrected QT (QTc) Prolongation). Abnormalities in the ECG that lead to a change in subject 
management (e.g., dose reduced or withheld, requirement for additional medication or monitoring) or 
result in clinical signs and symptoms are considered clinically significant for the purposes of this 
study and will be recorded on the AE CRF. If values meet criteria defining them as serious, they must 
be reported as SAEs.  
 
5.4 
Study Treatment Duration 
 
In the absence of treatment delays due to adverse event(s), treatment may continue daily, 7 days per 
week for four weeks per each treatment cycle.  
 
Subjects may discontinue study treatment or withdraw their consent to participate in the study at any 


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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 AE, unacceptable drug-related toxicity or inter-current illness that in the opinion of the 
investigator warrants the subject’s withdrawal from treatment 
• 
Specific conditions described in the Adverse Events and Risks List, Section 7.1 
• 
The investigator feels it is not in the best interest of the subject to continue on study treatment  
• 
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 following 
discontinuation of study treatment 
• 
Women who become pregnant or are breast feeding 
o 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 
sponsor of the pregnancy. Forms for reporting pregnancies will be provided to the study 
sites upon request. 
o 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. Pregnancy, 
although not itself an SAE, should also be reported on an SAE form or 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. 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. 
• 
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 
• 
Request by regulatory agencies for termination of treatment of an individual subject or all 
subjects under the protocol 
• 
Subject request to discontinue study treatment (with or without concurrent withdrawal of 
informed consent)  
• 
Significant noncompliance with the protocol schedule in the opinion of the investigator. 
• 
The minimum dose of study treatment will be 20 mg qd. Subjects who cannot tolerate 20 mg qd 
will have study treatment discontinued. 
• 
Progressive disease (PD) as determined by the investigator.  
 
The reason for study treatment discontinuation will be documented. For subjects who discontinue or 


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are withdrawn from study treatment, every effort must be made to undertake protocol-specified 
follow up procedures and end of treatment assessments, if possible, unless consent to participate in 
the study is also withdrawn. 
 
If a subject fails to return for the protocol-defined visits, an effort must be made to determine the 
reason. If the subject cannot be reached by telephone, at the minimum a registered letter should be 
sent to the subject (or the subject’s legal guardian) requesting contact with the clinic. 
 
If a subject is discontinued from study treatment because of an AE considered to be related to study 
treatment and the event is ongoing 30 days after the last dose of study treatment, the event must be 
followed until resolution or determination by the investigator that the event has become stable or 
irreversible. 
 
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. 
 
5.5 
Study Post-Treatment and Follow Up  
 
Subjects will return to the study site 30 to 37 days after their last dose of cabozantinib to complete 
end-of-study assessments. Laboratory and physical examinations will be performed (see Study 
Calendar section 10.0). Remaining cabozantinib will be returned by the subject, and treatment 
compliance 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. 
 
After disease progression, subjects will be followed for survival based upon the timing of the routine 
clinical care for their disease. Follow-up may occur every 3 months for the first 2 years, then 
approximately every 6 months x 3 years, then annually. Survival information will be obtained via 
routine standard of care visits and/or medical record review.  
 
5.6 
Duration of Study 
 
Subjects may continue to receive study treatment until they experience unacceptable drug-related 
toxicity, disease progression or death as defined in Section 5.4. The reason for study removal and the 
date the patient was removed from study must be documented in the Case Report Form. 
 
If a subject withdraws consent to participate in the study, the reason for withdrawal will be 
documented, no further study procedures or assessments will be performed, and no further study data 
will be collected for this subject, other than the determination of survival status from public records 
such as government vital statistics or obituaries. 
 
Exelixis and/or the Sponsor-Investigator reserve the right to terminate the study, and sub-
investigators reserve the right to terminate their participation in the study, at any time. Should this be 
necessary, Exelixis and the Sponsor-Investigator will arrange the procedures on an individual study 
basis after review and consultation. In terminating the study, Exelixis and the Sponsor-Investigator 


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will ensure that adequate consideration is given to the protection of the subjects’ interests. 
 
6. DOSING DELAYS/DOSE MODIFICATIONS 
 
Subjects will receive cabozantinib orally at a (starting) dose of 60 mg once daily. Treatment cycles 
are 4 weeks in duration (28 days). 
 
In all subjects, dose reductions and delays to manage toxicity are allowed under the guidelines in 
Table 6-1 below. See Section 7, for adverse events list (7.1) and reporting requirements (7.2) 
associated with dosing delays and/or dose modifications.  
 
Table 6-1: Dose Modification for Cabozantinib 
Dose Level 
Cabozantinib Dose 
0 
60 mg daily 
-1 
40 mg daily 
-2 
20 mg daily 
NOTE: In situations where the toxicity is attributable to cabozantinib requiring a dose reduction 
beyond dose level -2, cabozantinib will be discontinued, and the patient will be removed from the 
protocol therapy. 
 
6.1 
Re-escalating study treatment after a dose reduction: 
 Subjects who required a dose reduction for a related Grade 3 (unless easily managed) or any 
Grade 4 non-hematologic adverse event should not be re-escalated 
 For other related AEs, subjects may be re-escalated to the previous dose at the discretion of the 
investigator but not sooner than 2 weeks beyond the resolution to Grade ≤ 1 or to the baseline 
value of AEs. 
 If a subject has been dose-reduced more than once, dose re-escalation can only occur to the next 
higher dose level. Further dose escalation to higher well-tolerated dose levels is allowed only if 
clinically indicated per investigator’s judgment and dose escalation criteria are met with each 
escalation (e.g. a minimum 2 week interval between escalations)  
 If the AEs that previously led to dose reduction(s) recur at the same grade or higher that 
previously required a dose reduction, the dose should be reduced again and no further dose 
escalation will be permitted.  
 Dose re-escalation is not allowed for dose reduction triggered by neutropenia or 
thrombocytopenia. 
Additional information for dose delays or dose reductions: 
 Dose delays for reason(s) other than AEs related to cabozantinib, such as surgical procedures with 
no anticancer therapy intent, may be allowed with investigator approval. The acceptable length of 
interruption will be determined by the investigator. 


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 Subjects will be instructed to notify their physician immediately of any and all AEs. Subjects 
experiencing one or more AEs due to the study treatment may require a dosing delay or 
reduction(s) in their dose in order to continue with study treatment.  
 
7. ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The following 
list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will determine 
whether the event requires expedited reporting in addition to routine reporting. 
 
Adverse event terms recorded on the CRFs will be mapped to preferred terms using the Medical 
Dictionary for Regulatory Activities (MedDRA). 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) CTCAE v4.0. Listings of AEs will be provided. 
 
Subjects will be monitored continuously for AEs throughout the study. Subjects must be instructed 
to notify their physician immediately for any and all toxicities. 
 
Guidelines for the management of AEs (i.e., dose interruptions and dose reductions) are presented in 
sections 6, Table 6-1. Dose reductions or interruptions are permitted in the setting of lower grade 
toxicity than defined in the following sections at the discretion of the investigator if the investigator 
feels it is in the interest of a subject’s safety. Each dose reduction of cabozantinib should be to one 
dose level lower that the current dose. Dose reductions of more than one dose level are acceptable if 
agreed to by the Investigator. All AEs should also be managed with supportive care at the earliest 
signs of toxicity considered related to study treatment.  
 
If study treatment of cabozantinib is restarted after being withheld or interrupted, the subject should 
be instructed not to make up the missed doses of cabozantinib.  
 
The reason for treatment delay and reduced dose must be recorded on the case report form (CRF). 
Dosing may need to be interrupted for AEs considered not related to cabozantinib if this is clinically 
indicated or if causality is initially uncertain. Study treatment may be resumed at the same dose (or a 
lower dose per investigator judgment) if the AE is determined not to be related to cabozantinib once 
the investigator determines that retreatment is clinically appropriate and the subject meets the 
protocol re-treatment criteria. 
 
Subjects will be monitored continuously for AEs throughout the study and for 30 days after the last 
dose of study treatment and for any serious adverse event (SAE) assessed as related to study 
treatment or study procedures, even if the SAE occurs more than 30 days after the last dose of study 
treatment. 
 
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 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. AE’s of grade 2 or greater 


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or any that result in dose holds or reductions will be collected and reported. 
 
7.1 
Adverse Events and Risks List for Cabozantinib 
 
The general adverse event profile of cabozantinib includes GI symptoms (such as nausea, vomiting, 
and diarrhea), fatigue, anorexia, weight loss, palmar-plantar erythrodysesthesia (PPE) syndrome, skin 
rash, elevated ALT and AST, increased pancreatic enzymes with rare cases of  pancreatitis, increase 
in TSH/hypothyroidism as well as side effects associated with inhibition of VEGF signaling such as 
thrombotic events (e.g., pulmonary embolism [PE] and deep vein thrombosis [DVT]), hypertension, 
proteinuria, hemorrhagic events, and rare cases of gastrointestinal [GI] perforation, fistula formation 
and rectal/perirectal abscess. Arterial thromboembolism (transient ischemic attack [TIA], or 
myocardial infarction [MI]) have been reported rarely. Please refer to the most recent Investigator’s 
Brochure for additional details. 
 
As with all investigational products, unknown AEs may occur. Subjects should be monitored closely 
throughout their study participation for anticipated AEs related to study treatment(s) additional 
anticipated AEs potentially related to VEGFR inhibition, as well as unexpected AEs. 
 
The half-life of cabozantinib is 80-172 hours. Thus, when initiating therapy with cabozantinib, it will 
take most subjects 2-3 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, since without a dose 
adjustment, systemic exposure of cabozantinib might be expected to increase after the onset of the 
AE. 
 
7.1.1 General Guidelines for Non-Hematologic and Hematologic Adverse Events 
 
General guidelines for the management of non-hematologic and hematologic toxicities are provided 
in Table 7-1 and Table 7-2, respectively. As a general approach, it is suggested that all AEs be 
managed with supportive care when possible at the earliest signs of toxicity. Calcium, magnesium, 
potassium and phosphorus should be kept above the lower limits of the laboratory normal values. For 
more specific guidelines on gastrointestinal AEs (diarrhea, nausea/vomiting, stomatitis/mucositis), 
hepatobiliary disorders, pancreatic disorders including lipase and amylase elevations, skin disorders 
(PPE), embolism and thrombus, hypertension, proteinurea, hemorrhage, rectal and perirectal abscess, 
gastrointestinal (GI) perforation and GI fistula, non-GI fistula, wound healing and surgery, 
osteonecrosis of the jaw (ONJ),  endocrine disorders and management of treatment-emergent 
prolongation of the QTc interval, management of fatigue, anorexia, weight loss, eye disorders, 
musculoskeletal and connective tissue disorders, nervous system disorders, 
respiratory/thoracic/mediastinal disorders and congenital, familial and genetic disorders refer to 
Section 7.1.2 – Section 7.1.20 below. 
 
 
 
 
 
 


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Table 7-1: General Approach to the Management of Cabozantinib-Related Non-Hematologic 
Adverse Events 
CTCAE Version 4 Grade  
Guidelines/Intervention 
Grade 1: 
Add supportive care as indicated. Continue cabozantinib at the current dose 
level. 
Grade 2: 
Grade 2 AEs considered related to 
cabozantinib that are subjectively 
tolerable or easily managed 
Add supportive care as indicated. Continue cabozantinib at the current dose 
level.  
Grade 2 AEs considered related to 
cabozantinib that are intolerable to the 
subject or deemed unacceptable in the 
investigator’s judgment; or are not 
easily managed or corrected 
Dose reduce 
 
If the AE dose not resolve to Grade ≤ 1 or baseline in 7 to 10 days or 
worsens at any time, cabozantinib dosing should then be interrupted. 
Then upon resolution to baseline or Grade ≤ 1, the reduced dose should 
be restarted. 
 
If the AE does resolves to Grade ≤ 1 or baseline without a dose 
interruption, continue the reduced dose. 
Grade 3: 
 
Grade 3 AEs considered related to 
cabozantinib which occurred without 
optimal prophylaxis or which is easily 
managed by medical intervention or 
resolved quickly 
 
Interrupt cabozantinib and add supportive care as indicated 
 
For AEs that are easily managed (e.g., correction of electrolytes) with 
resolution to baseline or Grade ≤ 1 within 24 hours,  cabozantinib may 
be resumed at either the same dose or with a dose reduction at the 
discretion of the investigator unless this is a recurring event at which 
time the dose should be reduced 
 
For AEs that require supportive care, the dose should be held while 
supportive care is initiated and optimized. Then upon resolution of the 
AE to baseline or Grade ≤ 1,  cabozantinib may be resumed at either the 
same dose or with a dose reduction at the discretion of the investigator 
unless this is a recurring event at which time the dose should be reduced 
Grade 3 AEs considered related to 
study treatment that occurred despite 
optimal prophylaxis or is not easily 
managed by medical intervention  
Interrupt study treatment until recovery to ≤ Grade 1 or baseline, and resume 
treatment with a dose reduction 
Grade 4: 
 
Grade 4 AEs considered related to 
study treatment 
Permanently discontinue study treatment unless determined that the subject 
is unequivocally deriving clinical benefit. In this case, upon recovery to 
Grade ≤ 1 or baseline, the subject may be re-treated at a reduced dose that is 
to be determined by the investigator and sponsor but only with sponsor 
approval. 


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Dose reductions or delays may occur in the setting of lower grade toxicity than defined above if the 
investigator believes that it is in the interest of the subject’s safety.  
 
 
Table 7-2: General Approach to the Management of Cabozantinib-Related Hematologic 
Adverse Events 
CTCAE Version 4 Grade 
Intervention 
Neutropenia 
Grade 3 neutropenia with documented 
infection 
Grade 3 neutropenia ≥ 5 days 
Grade 4 neutropenia  
Interrupt cabozantinib treatment until resolution to Grade ≤ 1, and resume 
cabozantinib treatment at a reduced dose.  
Thrombocytopenia 
Grade 3 thrombocytopenia with clinically 
significant bleeding or Grade 4 
thrombocytopenia 
Interrupt cabozantinib treatment until platelet count is  ≥ 100,000/mm3, 
and resume cabozantinib treatment at a reduced dose 
Febrile Neutropenia 
Grade 3 febrile neutropenia 
Interrupt cabozantinib treatment until recovery of ANC to Grade ≤ 1 and 
temperature to ≤ 38.0°C and resume cabozantinib treatment at a reduced 
dose. 
Grade 4 febrile neutropenia 
Permanently discontinue study treatment unless determined that the 
subject is unequivocally deriving clinical benefit. In this case, upon 
recovery to Grade ≤ 1 or baseline, the subject may be re-treated at a 
reduced dose that is to be determined by the investigator and sponsor but 
only with sponsor approval. 
Other Grade 4 Hematologic Toxicities 
Grade 4 hematologic toxicities  
other than anemia 
Permanently discontinue study treatment unless determined that the 
subject is clearly deriving clinical benefit. In this case, upon recovery to 
Grade ≤ 1 or baseline, the subject may be re-treated at a reduced dose that 
is to be determined by the investigator and sponsor and only with 
approval by the sponsor. 
Grade 4 anemia 
Permanent discontinuation for Grade 4 anemia is not mandated. Dose 
reductions or dose delays for anemia should be applied as clinically 
indicated. Supportive care such as red blood cell transfusions should be 
managed according to institutional guidelines. 
ANC, absolute neutrophil count; LLN, lower limit of normal 
Neutropenia: Grade 1 (LLN ≤ ANC < 1.5  109/L; Grade 2 (1  109/L ≤ ANC <1.5 x 109/L), Grade 3 (0.5  109/L ≤ ANC < 1 
 109/L), Grade 4 (ANC < 0.5  109/L). 
Febrile Neutropenia: Grade 3 (present); Grade 4 (Life-threatening consequences; urgent intervention indicated). 
Thrombocytopenia: Grade 1 (Platelet count <LLN – 75 x 109/L); Grade 2 (Platelet count <75.0 – 50.0 x  109/L); Grade 3 (Platelet 
count ≤ 50 - 25  109/L); Grade 4 (Platelet count < 25  109/L). 


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7.1.2 Diarrhea, Nausea, Vomiting, Stomatitis, and Mucositis 
 
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. Administration of antidiarrheal agents 
is recommended at the first sign of diarrhea as initial management. Loperamide is recommended as 
standard first line therapy. Alternatively, diphenoxylate/atropine can be used. Additional agents to 
consider in subjects with diarrhea that is refractory to the above include deodorized tincture of opium 
and octreotide. 45 Some subjects may require concomitant therapy with loperamide, 
diphenoxylate/atropine, and deodorized tincture of opium to control diarrhea. The dose modification 
guidance in Table 6-1should be followed. In addition, general supportive measures should be 
implemented including continuous oral hydration, correction of fluid and electrolyte abnormalities, 
small frequent meals, and stopping lactose-containing products, high fat meals and alcohol. 
 
Nausea and Vomiting 
Anti-emetic agents along with supportive care are recommended as clinically appropriate at the first 
sign of nausea and vomiting. The dose modification guidance in Table 6-1should be followed.  
The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 receptor antagonists and 
dexamethasone (NK-1 receptor antagonists can induce or inhibit CYP3A4, and glucocorticoids 
induce CYP3A4 and thus could lower cabozantinib exposure. Caution is also recommended with the 
use of nabilone, which is a weak inhibitor of CYP3A4. 
 
Stomatitis and Mucositis 
Preventive measures may include a comprehensive dental examination to identify any potential 
complications before study treatment is initiated. Appropriate correction of local factors should be 
instituted as indicated, such as modification of ill-fitting dentures and appropriate care of gingivitis. 
During treatment with cabozantinib, good oral hygiene and standard local treatments such as non-
traumatic cleansing, and oral rinses (e.g., with a weak solution of salt and baking soda) should be 
maintained. The oral cavity should be rinsed and wiped after meals, and dentures should be cleaned 
and brushed often to remove plaque. Local treatment should be instituted at the earliest onset of 
symptoms. When stomatitis interferes with adequate nutrition and local therapy is not adequately 
effective, dose reduction or temporary withholding of cabozantinib should be considered 
 
7.1.3 Hepatobiliary Disorders 
 
Elevations of transaminases have also been observed during treatment with cabozantinib. In general, 
it is recommended that subjects with elevation of ALT, AST, and/or bilirubin have more frequent 
laboratory monitoring of these parameters. If possible, hepatotoxic concomitant medications and 
alcohol should be discontinued in subjects who develop elevated transaminases.  
 
Since subjects may enter the study with elevations of AST/ALT at baseline, the following guideline 
should be used for dose modifications: 
 
 


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Cabozantinib treatment should also be interrupted when transaminase increases are accompanied by 
progressive elevations of total bilirubin, and/or elevations of coagulation tests (e.g., International 
Normalized Ratio [INR]). Monitoring of transaminases should be intensified (2–3 times per week) 
and cabozantinib should be held until the etiology of the abnormalities is determined and these 
abnormalities are corrected or stabilize at clinically acceptable levels (INR < 1.5 x ULN, total 
bilirubin < 1.5 x ULN, aminotransferases ≤ baseline grade).  
 
Subjects must have cabozantinib permanently discontinued if transaminase elevations are 
accompanied by evidence of impaired hepatic function (bilirubin elevation >2xULN), in the absence 
Transaminase elevation 
CTCAE v4.0 
 
Intervention 
Subjects with AST and ALT less than or equal to the ULN at baseline 
Grade 1  
Continue cabozantinib with weekly monitoring of liver function tests (LFTs) for at 
least 4 weeks. Then resume the standard protocol-defined monitoring of LFTs. 
Grade 2 
Continue cabozantinib with at least twice weekly monitoring of LFTs for 2 weeks. 
Then weekly for 4 weeks. If LFTs continue to rise within Grade 2, interrupt 
cabozantinib treatment. Then continue with at least weekly LFTs until resolution to 
Grade ≤ 1. Study treatment may then be resumed at a one-dose-level reduction of 
cabozantinib 
Grade 3  
Interrupt cabozantinib treatment and monitor with at least twice weekly LFTs until 
Grade ≤ 2. Then continue with at least weekly LFTs until resolution to Grade ≤ 1. 
Cabozantinib may then be resumed at a one-dose-level reduction.  
Grade 4 
Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1. If the subject was 
unequivocally deriving clinical benefit, the subject may be able to resume treatment at 
a lower dose of cabozantinib as determined by the investigator and sponsor but only 
with sponsor approval. 
Subjects with AST or ALT above the ULN  but ≤ 3.0 x ULN (i.e., Grade 1) at  baseline   
≥ 1.5 fold increase of AST or 
ALT AND both AST and 
ALT are ≤ 5.0 x ULN 
Continue cabozantinib treatment with at least twice weekly monitoring of LFTs for 4 
weeks and weekly for 4 weeks. If LFTs continue to rise, interrupt study treatment. Then 
continue with at least weekly LFTs until resolution to Grade ≤ 1. Study treatment may 
then be resumed at a one-dose-level reduction of cabozantinib 
≥ 1.5 fold increase of AST or 
ALT and at least one of AST 
or ALT is Grade 3 (i.e. AST 
or ALT > 5.0 but ≤ 20.0 x 
ULN) 
Interrupt study treatment and monitor with at least twice weekly LFTs until Grade ≤ 2. 
Then continue with at least weekly LFTs until resolution to Grade ≤ 1. Study treatment 
may then be resumed at a one-dose-level reduction of cabozantinib. 
Grade 4  
Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1. If the subject was 
unequivocally deriving clinical benefit, the subject may be able to resume treatment at 
a lower dose as determined by the investigator and sponsor but only with sponsor 
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of evidence of biliary obstruction (i.e., significant elevation of alkaline phosphatase) or some other 
explanation of the injury (e.g., viral hepatitis, alcohol hepatitis), as the combined finding (i.e., Hy’s 
Law cases) represents a signal of a potential for the drug to cause severe liver injury. 
 
All subjects who develop isolated bilirubin elevations of Grade 3 should have study treatment held 
until recovered to Grade ≤ 1 or baseline (or lower). If this occurs within 6 weeks of the dosing delay, 
study treatment may continue at a reduced dose. In subjects without biliary obstruction and Grade 4 
bilirubin elevation, or with recurrence of Grade 3 bilirubin elevation after a dose reduction, study 
treatment must be discontinued. 
 
7.1.4 Pancreatic Conditions 
 
Amylase and lipase elevations have been observed in clinical studies with cabozantinib. The clinical 
significance of asymptomatic elevations of enzymes is not known but in general has not been 
associated with clinically apparent sequelae. It is recommended that subjects with lipase elevation 
and/or symptoms of pancreatitis have more frequent laboratory monitoring of lipase and/or amylase 
(2-3 times per week). Subjects with symptomatic pancreatitis should be treated with standard 
supportive measures. 
 
Asymptomatic Lipase or Amylase  Elevations 
Grade 1 or Grade 2 
Continue at current dose level. More frequent monitoring is recommended 
Grade 3 
 
Interrupt treatment 
 
Monitor lipase and amylase twice weekly 
 
Upon resolution to Grade ≤ 1 or baseline, cabozantinib may be restarted at the 
same dose or at a reduced dose provided that this occurs within 6 weeks. 
 
If retreatment following Grade 3 lipase or amylase elevation is at the same 
dose and Grade 3 or Grade 4 elevations recur, then treatment must be 
interrupted again until lipase and amylase  levels have resolved to Grade ≤ 1 
or baseline and retreatment must be at a reduced dose. 
Grade 4 
 
Interrupt treatment 
 
Monitor lipase and amylase twice weekly 
 
Upon resolution to Grade ≤ 1 or baseline and if resolution occurred within 4 
days, cabozantinib may be restarted at the same dose or a reduced dose. If 
resolution took more than 4 days, the dose must be reduced upon retreatment 
provided that resolution occurred within 6 weeks. 
 
If retreatment following Grade 4 lipase or amylase elevation is at the same 
dose and Grade 3 or 4 elevations recur, then treatment must be interrupted 
again until lipase and amylase have resolved to Grade ≤ 1 or baseline and 
retreatment must be at a reduced dose. 
 


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Pancreatitis 
Grade 2 and asymptomatic 
 
Continue at current dose level. More frequent monitoring of lipase and 
amylase and radiographic evaluation is recommended. 
Grade 2 symptomatic and 
Grade 3 
 
Interrupt treatment 
 
Monitor lipase and amylase twice weekly 
 
Upon resolution to Grade ≤ 1 or baseline , cabozantinib may be restarted at a 
reduced dose if resolution occurred within 6 weeks 
Grade 4 
Permanently discontinue treatment. However, if the subject was unequivocally deriving 
benefit from cabozantinib therapy, treatment may resume at a reduced at a reduced 
dose agreed to by the investigator and sponsor but only with sponsor approval. 
 
 
 
 
7.1.5 Skin Disorders 
 
Palmar-plantar erythrodysesthesia syndrome (PPE; also known as hand-foot syndrome), skin rash 
(including blister, 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. All subjects on study should be advised to use prophylactic measures 
for skin care. These measures includes the use of hypoallergenic moisturizing creams, ointment for 
dry skin, sunscreen with SPF ≥ 30; avoidance of exposure of hands and feet to hot water; protection 
of pressure-sensitive areas of hands and feet; and use of thick cotton gloves and socks to prevent 
injury and to keep the palms and soles dry. Subjects with skin disorders should be carefully 
monitored for signs of infection (e.g., abscess, cellulitis, or impetigo). 
 
Early signs of hand-foot syndrome can include tingling, numbness, and slight redness or mild 
hyperkeratosis. Early manifestations include painful, symmetrical red and swollen areas on the palms 
and soles. The lateral sides of the fingers or periungual zones may also be affected. Adequate 
interventions are required to prevent worsening of skin symptoms such as blisters, desquamations, 
ulcerations, or necrosis of affected areas. Aggressive management of symptoms is recommended, 
including early dermatology referral. 
 
Treatment guidelines for PPE related to study treatment are presented in the table below 
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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Hand-Foot Skin Reaction and Hand Foot Syndrome (PPE) 
Grade 1 
Continue cabozantinib at current dose. Start urea 20% cream twice daily AND clobetasol 0.05% cream 
once daily. Assess subject at least weekly for changes in severity. Subjects should be instructed to notify 
investigator immediately if severity worsens.  
Grade 2 
If tolerable, continue cabozantinib at current dose. If intolerable, reduce cabozantinib dose to next lower 
level and/or interrupt dosing. Start/continue urea 20% cream twice daily AND clobetasol 0.05% cream 
once daily. Add analgesics for pain control with NSAIDs/GABA agonists/narcotics if needed. Assess 
subject at least weekly for changes in severity. If treatment was interrupted (but not reduced), treatment 
may be restarted at the same dose or at one dose level lower when reaction decreases to Grade 1 or 0. If 
a treatment interruption is again required, the dose must be reduced when treatment resumes. Subjects 
should be instructed to notify investigator immediately if severity worsens. If severity worsens at any 
time, or affects self-care, proceed to the management guidelines for Grade 3 PPE.  
Grade 3 
Interrupt study treatment until severity decreases to Grade 1 or 0. Start/continue urea 20% cream twice 
daily AND clobetasol 0.05% cream once daily. Pain control with NSAIDs/GABA agonists/narcotics. 
Treatment may restart at one dose level lower when reaction decreases to Grade 1 or 0. Permanently 
discontinue subject from study if reactions worsen or do not improve within 6 weeks.  
GABA, γ-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drugs; PPE, palmar-plantar erythrodysesthesia 
 
 
7.1.6 Embolism and Thrombosis  
 
Deep vein thrombosis and PE have been observed in clinical studies with cabozantinib; including 
fatal events (please refer to the IB). Subjects who develop a PE or DVT should have study treatment 
held until therapeutic anticoagulation with heparins is established. Study treatment may be resumed 
with a one dose-level reduction in subjects who have uncomplicated PE or DVT and are deriving 
clinical benefit from study treatment. During treatment with anticoagulants, subjects need to be 
monitored on an ongoing basis for bleeding risk and signs of bleeding. Subjects with life-threatening 
PE or DVT should have study treatment discontinued unless toxicity can be managed and subject is 
deriving clear clinical benefit as determined by the investigator and agreed by the Sponsor. Venous 
filters (e.g. vena cava filters) are not recommended due to the high incidence of complications 
associated with their use. Once a subject is fully anticoagulated, treatment can be restarted per 
investigator judgment at one dose lower. Subjects should permanently discontinue after a second 
thrombotic event. Although routine prophylactic anticoagulation is not necessary for all subjects, 
prophylactic anticoagulation is allowed for individual subjects at the discretion of the investigator. 
Arterial thrombotic events (e.g., transient ischemic attack, myocardial infarction) have been observed 
rarely in studies with cabozantinib. Cabozantinib should be discontinued in subjects who develop an 
acute MI or any other clinically significant arterial thromboembolic complication. 
 
7.1.7 Hypertension 
 
Hypertension is a relatively common complication of other VEGF-pathway inhibitors and has been 
observed in cabozantinib clinical studies. 
 
Decisions to decrease or hold the dose of study treatment must be based on BP readings taken by a 
medical professional and must be confirmed with a second measurement at least 5 minutes following 


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the first measurement. Subjects with known hypertension should be optimally managed prior to study 
entry. Clinical judgment should be used in deciding whether new or worsened hypertension emerging 
during treatment with cabozantinib requires immediate therapy, or whether therapeutic intervention 
can be delayed in order to confirm the finding of new or worsened hypertension at a second visit 
before taking new therapeutic action. It is recommended that this second visit occur within 1 week. 
Blood pressure should be monitored in a constant position visit to visit, either sitting or supine. 
Cabozantinib dosing should be interrupted in subjects with severe hypertension (180 mm Hg systolic 
or 120 mm Hg diastolic; or sustained ≥ 160 mm Hg systolic or ≥ 110 diastolic) who cannot be 
controlled with medical interventions and discontinued in subjects with hypertensive crises or 
hypertensive encephalopathy (Table 7-3). 
 
 
Table 7-3: Management of Hypertension Related to Cabozantinib 
Criteria for Dose Modifications 
Treatment/cabozantinib Dose Modification 
Subjects not receiving optimized anti-hypertensive therapy 
> 140 mm Hg (systolic) and < 160 mm Hg 
OR 
> 90 mm Hg (diastolic) and < 110 mm Hg 
 
 
 Increase antihypertension therapy  (i.e., increase dose of existing 
medications and/or add new antihypertensive medications)  
 Maintain dose of cabozantinib 
 If optimal antihypertensive therapy (usually to include 3 agents) 
does not result in blood pressure < 140 systolic or < 90 diastolic, 
or if the subject is symptomatic, the dose of cabozantinib should 
be reduced. 
≥ 160 mm Hg (systolic) and < 180 mm Hg 
OR 
≥ 110 mm Hg (diastolic) and < 120 mm Hg 
 Reduce cabozantinib by one dose level. 
 Increase antihypertension therapy  (i.e., increase dose of existing 
medications and/or add new antihypertensive medications)  
 Monitor subject closely for hypotension. 
 If optimal antihypertensive therapy (usually to include 3 agents) 
does not result in blood pressure < 140 systolic or < 90 diastolic, 
dose of cabozantinib should be reduced further. 
≥ 180 mm Hg (systolic) OR 
≥ 120 mm Hg (diastolic ) 
 Interrupt treatment with cabozantinib Add new or additional anti-
hypertensive medications and/or increase dose of existing 
medications. 
 Monitor subject closely for hypotension. 
 When SBP < 140 and DBP < 90, restart cabozantinib treatment at  
one dose level lower 
 If optimal antihypertensive therapy (usually to include 3 agents) 
does not result in blood pressure < 140 systolic or < 90 diastolic, 
dose of cabozantinib should be reduced further. 
Hypertensive emergency or malignant 
hypertension 
Discontinue all study treatment 
BP, blood pressure, SBP systolic blood pressure, DBP diastolic blood pressure 
NOTE:  If SBP and DBP meet different criteria in table, manage per higher dose-modification criteria 
 


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7.1.8 Proteinuria 
 
Proteinuria has been reported with approved drugs that inhibit VEGF pathways as well as with 
cabozantinib. Proteinuria should be diagnosed and quantified by a UPCR (mg/dL protein / mg/dL 
creatinine). When a UPCR exceeds 1, a repeat UPCR or a 24-hour urine protein and creatinine should 
be performed to confirm the result. Cabozantinib should be discontinued in subjects who develop 
nephrotic syndrome (proteinuria > 3.5 grams per day in combination with hypoalbuminemia, edema 
and hyperlipidemia) or any other relevant renal disease. Also, given the nephrotoxic potential of 
bisphosphonates, these agents should be used with caution in patients receiving treatment with 
cabozantinib. Details of management are described in Table 7-4. 
 
 
Table 7-4: Management of Treatment Emergent Proteinuria 
Urine Protein/Creatinine Ratio 
Action To Be Taken 
≤ 1 
 
No change in treatment or monitoring 
> 1 and < 3.5 
 
 
No change in study treatment required  
 
Consider confirming with a 24-hour protein excretion within 7 days 
 
Repeat UPCR within 7 days and once every week. If UPCR is < 1 on 
two consecutive readings, then UPCR monitoring can revert to 
protocol specific time points. (The second reading is a confirmatory 
reading and can be done within 1 week of the first reading.). 
≥ 3.5 
 
 
Hold cabozantinib immediately and confirm with 24 hour urine protein 
excretion.  
 
Evaluate for nephrotic syndrome. If present, discontinue cabozantinib 
treatment permanently, and monitor subject for resolution of nephrotic 
syndrome.  
 
If proteinuria of ≥ 3.5 g/24 hours is confirmed without diagnosis of 
nephrotic syndrome, continue to hold cabozantinib and monitor UPCR 
weekly. If UPCR decreases to < 1.5, restart cabozantinib at a reduced 
dose. Continue monitoring UPCR once every week until two 
consecutive readings are < 1, then revert to UPCR monitoring 
frequency specified in the protocol. 
UPCR, urine protein/urine creatinine ratio 
 
7.1.9 Guidelines for the Prevention of Hemorrhagic Events 
 
Hemorrhagic events have been reported with approved drugs that inhibit VEGF pathways as well as 
with cabozantinib. As preventive measures, subjects should be evaluated for potential bleeding risk 
factors prior to initiating cabozantinib 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 limited to) the following: 
 
• 
Tumor lesions with cavitations or tumor lesions which invade, encase, or abut major blood 
vessels. The anatomic location and characteristics of primary tumors or metastases as well as 


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the medical history should be carefully reviewed in the selection of subjects for treatment 
with cabozantinib. 
• 
Recent or concurrent radiation to the thoracic cavity  
• 
Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI diseases 
• 
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 
 
Cabozantinib should be discontinued in subjects with serious and life-threatening bleeding events or 
recent hemoptysis (≥ 0.5 teaspoon (2.5ml) of red blood). Treatment with cabozantinib should be 
interrupted if less severe forms of clinically significant hemorrhage occur and may be restarted after 
the cause of hemorrhage has been identified and the risk of bleeding has subsided at a dose agreed to 
by the sponsor and the investigator. Therapy of bleeding events should include supportive care and 
standard medical interventions.  
 
Furthermore, subjects who develop tumors abutting, encasing, or invading a major blood vessel or 
who develop cavitation of their pulmonary tumors while on study treatment must be discontinued 
from cabozantinib treatment. 
 
7.1.10 Rectal and Perirectal Abscess 
 
Rectal and perirectal abscesses have been reported, sometimes in subjects with concurrent diarrhea. 
These should be treated with appropriate local care and antibiotic therapy. Cabozantinib should be 
held until adequate healing has taken place.  
 
7.1.11 Guidelines for Prevention of GI Perforation/Fistula and Non-GI Fistula Formation 
 
GI perforation/fistula and Non-GI fistula formation have been reported with approved drugs that 
inhibit VEGF pathways as well as with cabozantinib. Carefully monitor for episodes of abdominal 
pain, especially in subjects with known risk factors for developing GI perforation/fistula or non-GI 
fistula, to allow for early diagnosis. Such risk factors include (but may not be limited to) the 
following: 
 
GI-perforation/fistula: 
• 
Intra-abdominal tumor/metastases invading GI mucosa  
• 
Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, 
cholecystitis or symptomatic cholangitis, or appendicitis  
• 
History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
• 
Prior GI surgery (particularly when associated with delayed or incomplete healing). Complete 
healing following abdominal surgery or resolution of intra abdominal abscess must be 
confirmed prior to initiating treatment with cabozantinib. 
 


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Additional risk factors include concurrent chronic use of steroid treatment or non-steroidal anti- 
inflammatory drugs. Constipation indicative of bowel obstruction should be monitored and 
effectively managed.  
 
Non-GI fistula: 
• 
Radiation therapy has been identified as a possible predisposing risk factor for non-GI fistula 
formation in subjects undergoing treatment with drugs that inhibit VEGF pathways. In 
addition, subjects who have undergone extensive surgery may be at increased risk of 
developing a fistula of the involved organs Non GI fistula should be ruled out as appropriate 
in cases of onset of mucositis after start of therapy. 
 
Discontinue all study treatment in subjects who have been diagnosed with GI or non-GI 
perforation/fistula. 
 
7.1.12 Wound healing and Surgery 
 
VEGF inhibitors can cause wound healing complications and wound dehiscence which may occur 
even long after a wound has been considered healed. Therefore, surgical and traumatic wounds must 
have completely healed prior to starting cabozantinib treatment and be monitored for wound 
dehiscence or wound infection while the subject is being treated with cabozantinib.  
 
Treatment with cabozantinib must be interrupted for any wound healing complication which needs 
medical intervention. Treatment with cabozantinib can be resumed once wound healing has occurred 
unless otherwise prohibited in specific protocols. Cabozantinib should be discontinued in subjects 
with serious or chronic wound healing complications. 
 
The appropriate dose hold interval prior to elective surgery to reduce the risk for wound healing 
complications has not been determined. In general, cabozantinib should be stopped at least 3 weeks (5 
half-lives) prior to elective surgery. 
 
7.1.13 Endocrine Disorders 
 
Prospective studies of markers of thyroid functions are currently ongoing in two single-agent studies 
to characterize the effects of cabozantinib on thyroid function. Preliminary data indicate that 
cabozantinib affects thyroid function tests (TFTs) in a high number of subjects (See Cabozantinib 
Investigator’s Brochure). Routine monitoring of thyroid function and assessments for signs and 
symptoms associated with thyroid dysfunction is recommended for subjects treated with 
cabozantinib. Management of thyroid dysfunction (e.g., symptomatic hypothyroidism) should follow 
accepted clinical practice guidelines. 
 
Other endocrine disorders such as hypocalcemia and hyperglycemia, and associated laboratory 
changes, have been observed in less than 10% of subjects. Monitoring with standard laboratory tests 
for endocrine disorders and clinical examination prior to initiation and during treatment with 
cabozantinib is required. Cabozantinib should be discontinued in subjects with severe or life-
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7.1.14 Guidelines for Prevention of Osteonecrosis of the Jaw 
 
Osteonecrosis of the jaw (ONJ) has been reported with use of antiangiogenic drugs and 
bisphosphonates and denosumab in cancer patients. Additional risk factors for ONJ have been 
identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral hygiene, 
smoking, dental or orofacial surgery procedures, and cancer disease itself. Cases of osteonecrosis 
have been reported in subjects treated with cabozantinib, the details of which are provided in the 
current version of Investigator’s Brochure. As a preventive measure, invasive dental procedures 
should be avoided if possible in subjects who have previously been treated with or concomitantly 
receive bisphosphonates or denosumab. In cases where dental procedures are unavoidable, the risks 
and benefits of a dental procedure and the extent of the procedure as well as the risk of developing 
osteonecrosis of the jaw need to be considered when deciding on the duration of a temporary 
treatment interruption of cabozantinib. If clinically possible, treatment with cabozantinib should be 
held for at least 2 weeks prior to a dental procedure and resumed after complete wound healing 
occurred. 
 
Subjects with any documented case of osteonecrosis should have study treatment interrupted, and 
appropriate clinical management should be initiated. Reinitiation of study treatment must be 
discussed with and approved by the Sponsor on a case by case basis. 
 
7.1.15 Guidelines for Management of Treatment-Emergent Corrected QT (QTc) Prolongation 
 
Treatment with cabozantinib has been associated with a mild prolongation of the QTc interval. Other 
factors which may contribute to QTc prolongation include: 
 
 Treatment with other drugs associated with QTc prolongation (see http://www.qtdrugs.org) 
 Treatment with CYP3A4 inhibitors (which may increase cabozantinib drug levels) 
 Electrolyte changes (hypokalemia, hypocalcemia, hypomagnesemia) 
 Medical conditions which can alter electrolyte status e.g., severe or prolonged diarrhea 
 
Subjects having any of these additional risk factors while on cabozantinib must have ECGs 
performed approximately one week after the onset of these factors. 
 
If at any time on study there is an increase in QTc interval to an absolute value > 500 msec, two 
additional ECGs should be performed within 30 minutes after the initial ECG with intervals not less 
than 3 minutes apart. If the average QTcF from the three ECGs is > 500 msec, study treatment must 
be withheld and the following actions should be taken: 
 
• 
Check electrolytes, especially potassium, magnesium and calcium. Correct abnormalities as 
clinically indicated 
• 
If possible, discontinue any QTc-prolonging concomitant medications  
• 
Repeat ECG triplets hourly until the average QTcF is ≤ 500 msec or otherwise determined by 


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consultation with a cardiologist 
 
The Sponsor should be notified immediately of any QTc prolongation event. 
  
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc elevation has 
resolved. Cardiology consultation is recommended for evaluation and subject management. 
Symptomatic subjects must be treated according to standard clinical practice. No additional study 
treatment is to be given to the subject until after the event has resolved, the subject has been 
thoroughly evaluated, and further treatment has been agreed to by the Sponsor. If any additional study 
treatment is given (e.g., after correction of electrolyte abnormalities and normalization of QTcF), it 
will be at a reduced dose as agreed to by the investigator and the Sponsor. 
 
7.1.16 Fatigue, Anorexia and Weight Loss 
 
Fatigue 
Common causes of fatigue, such as anemia, deconditioning, emotional distress (depression and/or 
anxiety), poor nutrition, sleep disturbance, and hypothyroidism should be ruled out and treated 
according to standard of care. Pharmacological management should be considered under the direction 
of the Investigator. 
 
Anorexia and Weight Loss 
Anorexia and weight loss should be managed according to local standard of care including nutritional 
support. Pharmacologic therapy should be considered for appetite enhancement under the direction of 
the Investigator. 
 
7.1.17 Musculoskeletal and Connective Tissue Disorders 
 
Cabozantinib appears to represent minimal risk of adverse musculoskeletal effects based on 
nonclinical GLP-compliant toxicology studies. The development of new or progressive, unexplained 
musculoskeletal symptoms such as pain or weakness should be assessed for underlying causes. 
 
One event of rhabdomyolysis (CTCAE Grade 4) was reported in a subject with prostate cancer. 
Cabozantinib should be discontinued in subjects with serious and life-threatening rhabdomyolysis and 
interrupted if less severe forms occur. Reinitiation of cabozantinib treatment must be discussed with 
and approved by the sponsor.  
 
7.1.18 Nervous System Disorders 
 
Cabozantinib appears to represent minimal risk of adverse neurological effects based on nonclinical 
GLP-compliant toxicology studies. Dysphonia, dysgeusia, headache, dizziness, confusional state, 
convulsion, depression, memory impairment, hypoesthesia, peripheral neuropathy, insomnia, ataxia, 
and encephalopathy have been observed in clinical studies with cabozantinib. The development of 
any new or progressive, unexplained neurological symptoms should be assessed for underlying 
causes. 
 
One confirmed case of RPLS, a syndrome of subcortical vasogenic edema diagnosed by an MRI of 


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the brain, has been reported in one subject treated with cabozantinib. RPLS should be considered in 
any patient presenting with seizures, headache, visual disturbances, confusion or altered mental 
function. Cabozantinib treatment should be discontinued in patients with RPLS. 
 
7.1.19 Respiratory, Thoracic and Mediastinal Disorders 
 
Dyspnea has been reported in clinical studies with cabozantinib. 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 (Section 
7.1.11) and pneumonia have been reported in subjects treated with cabozantinib and should be 
considered as clinically indicated in subjects presenting with pulmonary symptoms. Subjects will 
have frequent clinical evaluations to assess for possible drug-related pulmonary changes. 
 
7.1.20 Genetic Disorders 
 
Cabozantinib was negative in an in vitro bacterial mutagenicity assay, negative in an in vitro 
chromosomal aberration assay in cultured human peripheral lymphocytes, and negative in an in vivo 
mouse micronucleus assay. 
 
Safety Definitions 
 
Adverse event: Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. 
 
Life-threatening adverse event or life-threatening suspected adverse reaction: An adverse event or 
suspected adverse reaction is considered "life-threatening" if, in the view of either the investigator or 
sponsor, its occurrence places the patient or subject at immediate risk of death. It does not include an 
adverse event or suspected adverse reaction that, had it occurred in a more severe form, might have 
caused death. 
 
Serious adverse event or serious suspected adverse reaction: An adverse event or suspected adverse 
reaction is considered "serious" if, in the view of either the investigator or sponsor, it results in any of 
the following outcomes: death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require hospitalization may be 
considered serious when, based upon appropriate medical judgment, they may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
Suspected adverse reaction: 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. 


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Suspected adverse reaction implies a lesser degree of certainty about causality than adverse reaction, 
which means any adverse event caused by a drug. 
 
Adverse reaction means 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. 
 
Unexpected adverse event or unexpected suspected adverse reaction: An adverse event or suspected 
adverse reaction is considered "unexpected" if it is not listed in the investigator brochure 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. 
 
All research subjects will be routinely questioned about adverse events at study visits.  
 
7.1.21 Recording Requirements for Adverse Events 
 
All observed or volunteered adverse events (serious or non-serious) and abnormal test findings, 
regardless of study group or suspected causal relationship to the study drug(s) will be recorded in the 
subjects’ case histories. For all adverse events, sufficient information will be pursued and/or obtained 
so as to permit 1) an adequate determination of the outcome of the event (i.e., whether the event 
should be classified as a serious adverse event) and; 2) an assessment of the casual relationship 
between the adverse event and the study drug(s). 
 
AEs or abnormal test findings felt to be associated with the investigational drug or study treatment(s) 
will be followed until the event (or its sequelae) or the abnormal test finding resolves or stabilizes at a 
level acceptable to the Sponsor-Investigator. 
 
7.1.22 Abnormal Test Findings 
 
An abnormal test finding will be classified as an adverse event if one or more of the following criteria 
are met: 
 The test finding is accompanied by clinical symptoms. 
 The test finding necessitates additional diagnostic evaluation(s) or medical/surgical 
intervention; including significant additional concomitant drug treatment or other therapy. 
 Note: simply repeating a test finding, in the absence of any of the other listed criteria, does 
not constitute an AE. 
 The test finding leads to a change in study dosing or discontinuation of subject 
participation in the clinical study. 


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 The test finding is considered an AE by the Sponsor-Investigator of the IND application. 
 
7.2 
Reporting of Suspected Adverse Reactions 
 
All events meeting the definition of a serious adverse event should be recorded on a MedWatch 
3500A Form 
(http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM048334.pdf) or 
departmental SAE form. Copies should be sent to:  
1. Investigator-Sponsor 
2. crssafetysubmissions@upmc.edu 
3. Local Institutional Review Board per institutional reporting requirements 
4. Exelixis, emailed to: drugsafety@exelixis.com or fax to 650-837-7392 
 
In addition to completing appropriate patient demographic and suspect medication information, the 
report should include as applicable the following information that is available at the time of report 
within the Event Description (section 5) of the MedWatch 3500A form: 
 
• CTCAE term(s) and grade(s) 
• Current status of study drug 
• All interventions to address the AE (testing and result, treatment and response) 
• Hospitalization and/or discharge dates 
• Event relationship to study drug 
 
Follow-up reports: 
Additional information may be added to a previously submitted report by adding to the original 
MedWatch 3500A report and submitting it as follow-up or creating supplemental summary 
information and submitting it as follow-up with the original MedWatch 3500A form 
 
7.3 
Review of Safety Information: Sponsor Responsibilities1 
 
The sponsor must promptly review all information relevant to the safety of the drug obtained or 
otherwise received by the sponsor from foreign or domestic sources, including information derived 
from any clinical or epidemiological investigations, animal or in vitro studies, reports in the scientific 
literature, and unpublished scientific papers, as well as reports from foreign regulatory authorities and 
reports of foreign commercial marketing experience for drugs that are not marketed in the United 
States. 
 
7.4 
IND safety reports 
 
The sponsor must notify FDA and all participating investigators (i.e., all investigators to whom the 
sponsor is providing drug under its INDs or under any investigator's IND) in an IND safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting under 
                                                 
1 21 CFR Sec. 312.50 


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Sections 7.5.1 to 7.5.4 below. In each IND safety report, the sponsor must identify all IND safety 
reports previously submitted to FDA concerning a similar suspected adverse reaction, and must 
analyze the significance of the suspected adverse reaction in light of previous, similar reports or any 
other relevant information. 
 
7.4.1 Serious and unexpected suspected adverse reaction 
 
The sponsor must report any suspected adverse reaction that is both serious and unexpected. The 
sponsor must report an adverse event as a suspected adverse reaction only if there is evidence to 
suggest a causal relationship between the drug and the adverse event, such as: 
 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. 
 
7.4.2 Findings from other studies 
 
The sponsor must report any findings from epidemiological studies, pooled analysis of multiple 
studies, or clinical studies (other than those reported under section 7.5.1), whether or not conducted 
under an IND, and whether or not conducted by the sponsor, that suggest a significant risk in humans 
exposed to the drug. Ordinarily, such a finding would result in a safety-related change in the protocol, 
informed consent, investigator brochure (excluding routine updates of these documents), or other 
aspects of the overall conduct of the clinical investigation. 
 
7.4.3 Findings from animal or in vitro testing 
 
The sponsor must report any findings from animal or in vitro testing, whether or not conducted by the 
sponsor, that suggest a significant risk in humans exposed to the drug, such as reports of 
mutagenicity, teratogenicity, or carcinogenicity, or reports of significant organ toxicity at or near the 
expected human exposure. Ordinarily, any such findings would result in a safety-related change in the 
protocol, informed consent, investigator brochure (excluding routine updates of these documents), or 
other aspects of the overall conduct of the clinical investigation. 
 
7.4.4 Increased rate of occurrence of serious suspected adverse reactions 
 
The sponsor must report any clinically important increase in the rate of a serious suspected adverse 
reaction over that listed in the protocol or investigator brochure. 
 
 


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Submission of IND safety reports 
 
The sponsor must submit each IND safety report in a narrative format or on FDA Form 3500A or in 
an electronic format that FDA can process, review, and archive. FDA will periodically issue guidance 
on how to provide the electronic submission (e.g., method of transmission, media, file formats, 
preparation and organization of files). The sponsor may submit foreign suspected adverse reactions 
on a Council for International Organizations of Medical Sciences (CIOMS) I Form instead of a FDA 
Form 3500A. Reports of overall findings or pooled analyses from published and unpublished in vitro, 
animal, epidemiological, or clinical studies must be submitted in a narrative format. Each notification 
to FDA must bear prominent identification of its contents, i.e., "IND Safety Report," and must be 
transmitted to the review division in the Center for Drug Evaluation and Research or in the Center for 
Biologics Evaluation and Research that has responsibility for review of the IND. Upon request from 
FDA, the sponsor must submit to FDA any additional data or information that the agency deems 
necessary, as soon as possible, but in no case later than 15 calendar days after receiving the request. 
 
7.4.4.1 
Unexpected fatal or life-threatening suspected adverse reaction reports 
 
The sponsor must also notify FDA of any unexpected fatal or life-threatening suspected adverse 
reaction as soon as possible but in no case later than 7 calendar days after the sponsor's initial receipt 
of the information. 
 
7.4.4.2 
Reporting format or frequency 
 
FDA may require a sponsor to submit IND safety reports in a format or at a frequency different than 
that required under this paragraph. The sponsor may also propose and adopt a different reporting 
format or frequency if the change is agreed to in advance by the director of the FDA review division 
that has responsibility for review of the IND. 
 
7.4.4.3 
Investigations of marketed drugs 
 
A sponsor of a clinical study of a drug marketed or approved in the United States that is conducted 
under an IND is required to submit IND safety reports for suspected adverse reactions that are 
observed in the clinical study, at domestic or foreign study sites. The sponsor must also submit safety 
information from the clinical study as prescribed by the post marketing safety reporting requirements 
(e.g., 310.305, 314.80, and 600.80 of this chapter). 
 
7.4.4.4 
Reporting study endpoints 
 
Study endpoints (e.g., mortality or major morbidity) must be reported to FDA by the sponsor as 
described in the protocol and ordinarily would not be reported under paragraph (c) of this section. 
However, if a serious and unexpected adverse event occurs for which there is evidence suggesting a 
causal relationship between the drug and the event (e.g., death from anaphylaxis), the event must be 
reported under Serious and unexpected suspected adverse reaction as a serious and unexpected 
suspected adverse reaction even if it is a component of the study endpoint (e.g., all-cause mortality). 
 


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7.4.5 Follow-up 
 
The sponsor must promptly investigate all safety information it receives. 
 
Relevant follow-up information to an IND safety report must be submitted as soon as the 
information is available and must be identified as such, i.e., "Follow-up IND Safety 
Report." 
 
If the results of a sponsor's investigation show that an adverse event not initially 
determined to be reportable under section 7.4 safety reports, is so reportable, the sponsor 
must report such suspected adverse reaction in an IND safety report as soon as possible, 
but in no case later than 15 calendar days after the determination is made. 
 
7.4.6 Disclaimer 
 
A safety report or other information submitted by a sponsor under this part (and any release by FDA 
of that report or information) does not necessarily reflect a conclusion by the sponsor or FDA that the 
report or information constitutes an admission that the drug caused or contributed to an adverse event. 
A sponsor need not admit, and may deny, that the report or information submitted by the sponsor 
constitutes an admission that the drug caused or contributed to an adverse event. 
 
7.5 
Reporting adverse events to the responsible IRB 
 
In accordance with applicable policies of the University of Pittsburgh Institutional Review Board 
(IRB), the Sponsor-Investigator will report, to the IRB, any observed or volunteered adverse event 
that is determined to be 1) associated with the investigational drug or study treatment(s); 2) serious; 
and 3) unexpected. Adverse event reports will be submitted to the IRB in accordance with the 
respective IRB procedures. 
 
Applicable adverse events will be reported to the IRB as soon as possible and, in no event, later than 
10 calendar days following the sponsor-investigator’s receipt of the respective information. Adverse 
events which are 1) associated with the investigational drug or study treatment(s); 2) fatal or life-
threatening; and 3) unexpected will be reported to the IRB within 24 hours of the Sponsor-
Investigator’s receipt of the respective information. 
Follow-up information to a reported adverse event will be submitted to the IRB as soon as the 
relevant information is available. If the results of the Sponsor-Investigator’s follow-up investigation 
show that an adverse event that was initially determined to not require reporting to the IRB does, in 
fact, meet the requirements for reporting; the Sponsor-Investigator will report the adverse event to the 
IRB as soon as possible, but in no event later than 10 calendar days, after the determination was 
made. 
 
8. PHARMACEUTICAL INFORMATION 
 
A list of the adverse events and potential risks associated with the investigational agent administered 
in this study can be found in Section 7.1. Additional information can be found in the Investigator’s 
Brochure for Cabozantinib.  
 


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8.1 
IND Agent Cabozantinib (XL-184) 
 
8.1.1 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 and 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 8-1 
 
Table 8-1: 
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 
 
8.1.2 Availability 
 
Cabozantinib is an investigational agent supplied to investigators by Exelixis; 
Exelixis internal number: XL184. 
 
8.1.3 Ordering, Accountability and Compliance 
 
The UPMC CancerCenter Investigational Drug Services (IDS) will maintain accurate records of 
receipt of all cabozantinib, including dates of receipt, lot number and expiration date, as well as 
storage criteria in accordance with UPMC CancerCenter IDS policies and procedures defined by the 
state and federal regulations. 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 or error resulting in an overdose, must be recorded and reported even if 
it does not meet the definition of serious under adverse event reporting.  
 
At completion of the study, to satisfy regulatory requirements regarding drug accountability, all 
unused cabozantinib will be reconciled and destroyed in accordance with applicable state and federal 


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regulations.  
 
9. BIOMARKER STUDIES 
 
Correlative studies will be performed to identify potential biomarkers of response to cabozantinib, 
including other known oncogenic drivers in lung adenocarcinoma and HGF co-expression. 
 
Tumor tissue will be mandated at time of study enrollment. All tumors must undergo routine 
molecular testing (as part of the standard of care) at the UPMC Presbyterian Anatomical and 
Molecular testing laboratory, which includes Sanger sequencing and SNaPshot analysis for the 
detection of mutations in the EGFR exons 18-21, KRAS codons 12, 13 and 61, BRAF codon 600 and 
PIK3CA codons 542, 545 and 1047, in addition to FISH for the EML4-ALK rearrangement, ROS1 
rearrangement, c-MET amplification and the KIF5B-RET translocation.  
 
In addition to mandatory archival or tissue from new biopsy at baseline, we will obtain optional 
research biopsies at time of progression. These samples will allow us to identify both biomarkers for 
response as well as mechanisms of acquired resistance to cabozantinib.  The tissue samples will be 
used for research purposes (IHC biomarker studies) as well as standard CLIA-certified molecular 
testing. If a targetable alteration is identified then this may guide post-progression therapy. A core 
biopsy is preferable, FNA is acceptable, from the most accessible site at which disease progression is 
evident. In addition to the biomarker assessments listed above for baseline tumor tissue, we will also 
perform next generation sequencing using the Ion AmpliSeq™ Cancer Panel on Ion Torrent PGM 
(Life Technologies) (also standard at UPMC). This 50-gene cancer panel includes our standard 
clinical metastatic lung cancer panel (including KRAS, PIK3CA, BRAF, and EGFR) as well as 
additional genes of interest (HRAS, AKT1, PTEN, STK11, JAK2/3 and TP53, and CDKN2A). 
 
In patients who do not have an oncogenic driver on routine mutational profiling, the tumors will 
undergo next generation sequencing using the Ion AmpliSeq™ Cancer Panel on Ion Torrent PGM 
(Life Technologies) (also standard at the UPMC Presbyterian Anatomical and Molecular testing 
laboratory). Additional analyses will be performed in tumors and will include c-MET expression, c-
MET mutation, and hepatocyte growth factor (HGF) expression. 
 
Serum, plasma, and peripheral blood mononuclear cell (PBMC) samples will be collected at baseline 
(C1D1) as well on day 1 of cycles 2 and 3 and then at time of progression.   Plasma samples for 
circulating tumor DNA are collected at baseline (C1D1) and time of progression. We hypothesize that 
markers of increased HGF/MET dependence (MET amplification, MET mutation, high MET 
expression, high serum HGF and/or sc-MET) at baseline will predict response to cabozantinib and an 
increase in serum HGF and/or sc-MET after treatment may predict lack of response. We will analyze 
the predictive value high serum levels of HGF and sc-MET at baseline and during treatment.  
Baseline and serial HGF and sc-MET as well as other potential biomarker serum levels will be 
measured using ELISA.  
 
In patients who have paired tumor samples from primary lesions and brain metastases, molecular 
testing will be performed on both sites of disease, i.e., patients who might have originally presented 
with early stage or loco-regionally advanced disease and subsequently present with brain metastases 
will have paired samples available.  


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The residuals and/or derivatives of samples collected and submitted for studies associated with this 
protocol will be rendered anonymous and retained at University of Pittsburgh for possible use in 
future studies. We are collecting peripheral blood mononuclear cells (PBMCs) in anticipation for 
future analysis of other genetic polymorphisms. If future use is denied or withdrawn by the patient, 
the samples will be removed from consideration for use in any future study and destroyed.  
 
Other biomarker studies may be performed as well depending on available funding and available 
scientific rationale.


 
62 
10. STUDY CALENDAR 
 
 
Within 28 
days of 1st 
Treatment 
Dose 
Within 4 
days of 1st 
Treatment 
Dose 
Day 1 of 
Cycles 1, 
2, and 3 
Daily per 
Treatment 
Cycle 
Day1, Weeks 
3,5,7,9,11,13 
then every 4 
weeks ±5 days 
Post-
Treatment12 or 
Disease 
Progression 
Informed consent 
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Medical and cancer history 
X 
 
 
 
 
 
Physical exam1 
X 
X 
 
 
X 
X 
Vital signs2 
X 
X 
 
 
X 
X 
Height 
X 
 
 
 
 
 
Weight 
X 
X 
 
 
X 
X 
ECOG Performance status 
X 
X 
 
 
X 
X 
CBC w/diff, plts 
X 
X 
 
 
X 
X 
PT/INR, PTT 
X 
X 
 
 
X5 
 
Serum chemistry3,4 
X 
X 
 
 
X 
X 
TSH, Free T3, Free T4 
X 
X 
 
 
X5 
 
Urine Protein/Urine 
Creatinine ratio (UPCR) 
X 
X 
 
 
X 
X 
Serum Pregnancy test 
(WOCBP) 
X 
X 
 
 
X5 
X 
Research Blood draw 
 
 
X6 
 
 
X6 
12-lead Electrocardiogram  
X 
X 
 
 
X5 
X 
Tumor Assessment7 
X8 
 
 
 
X9 
X10 
Concomitant Medications 
 
 
 
 
X 
X 
Archival Tissue Block11 
X 
 
 
 
 
 
Tumor Tissue Biopsy 
(Optional) 
 
 
 
 
 
X14 
Cabozantinib 
Administration 
 
 
 
X 
 
 
Pill count/collection of pill 
diary 
 
 
 
 
X13 
 
Adverse Event Evaluation 
X-------------------------------------------------------------------------------------------X 
1) A physical examination will include assessments of general appearance, skin, HEENT, thorax/lungs, 
cardiovascular, abdominal, genitourinary, musculoskeletal and neurological findings 
2) Vital signs will be conducted at regular intervals and include body temperature, respiratory rate, and blood 
pressure and pulse. Blood pressure and pulse will be measured after the subject has been sitting for at least 5 
minutes 
3) Serum Chemistry testing includes: albumin, alkaline phosphatase, ALT, amylase, AST, bicarbonate, blood urea 
nitrogen, calcium, chloride, creatinine, glucose, lactate dehydrogenase, lipase, magnesium, phosphorus, 


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potassium, sodium, total bilirubin, total protein. 
4) Lipase and/or amylase may require more frequent monitoring (2-3 times per week) if a subject has lipase 
elevation and/or symptoms of pancreatitis 
5) Testing to be performed every 4 weeks 
6) Serum, plasma, and peripheral blood mononuclear cell (PBMC) samples are collected at baseline (C1D1) and on 
day 1 of cycles 2 and 3, and then at time of progression.   Plasma samples for circulating DNA are collected at 
baseline (C1D1) and time of progression only. 
7) Regular tumor assessments should be performed according to the guidelines in Protocol Section 11 to determine 
if PD is present 
8) Includes assessment of all sites of extra-cranial disease with CT scan, PET-CT and bone scan, as appropriate. 
MRI brain with contrast (or CT head with contrast in patients who are unable to have an MRI, e.g. has a 
pacemaker) must be performed within 14 days of the 1st dose of cabozantinib while either not receiving 
glucocorticoids during the 5 days prior to the baseline brain imaging or on a stable dose of glucocorticoids during 
the 5 days prior to the baseline brain imaging. 
9) All sites of extra-cranial disease must be assessed every 8 weeks. MRI brain (or CT brain with contrast in 
patients who are unable to have an MRI) must be performed every 8 weeks. In patients whose first site of disease 
progression is extra-cranial disease, a brain MRI (or CT brain with contrast in patients who are unable to have an 
MRI) will be performed at the time of extra-cranial disease progression.  
10) MRI brain (or CT brain with contrast in patients who are unable to have an MRI) must be performed every 12 
weeks in the post-treatment period 
11) Archival tissue is mandatory for inclusion to this study. See lab manual for submission instructions. 
12) Treatment ends after last scheduled dose of cabozantinib, subject then enters post-treatment period and final 
testing is performed 30 to 37 days after last treatment dose. After disease progression, subjects will be followed 
for survival based upon the timing of the routine clinical care for their disease. 
13) Starting day 1 of cycle 2 and continuing on day 1 of all subsequent cycles, pills will be counted and the pill diary 
will be collected to evaluate patient compliance.  
14) Optional: In addition to tumor tissue for baseline routine molecular testing, additional fresh biopsy of a lesion 
amenable to safe biopsy from a primary lesion or metastatic site will be requested for molecular biomarker 
studies at disease progression. Subjects must provide consent to undergo this procedure. See lab manual for 
submission instructions. 
 
There is a window of ± 1 week available for rescheduling treatment and/or procedures at the 
discretion of the Sub-investigator, and as discussed with the Investigator if a course is missed or a 
subject's treatment and/or testing day(s) need to be rescheduled due to the subject’s inability to 
comply with the study calendar (i.e., hospitalizations, business, vacation plans, travel from long 
distances for study treatment, in advance of the scheduled date to allow ready access to the result(s), 
reduce financial burden on the subject or reduce travel inconvenience, illness, transportation issues, 
holidays, family emergencies, etc.). 
 
11. MEASUREMENT OF EFFECT 
 
For this study, computed tomography scans will be performed every 8 weeks for assessment of extra-
cranial disease. An MRI of the brain with contrast (or CT brain with contrast in patients who are 
unable to obtain an MRI, e.g., has a pacemaker) will be performed every 8 weeks to assess 
intracranial disease.  
 
In patients whose first site of disease progression is extra-cranial disease, a brain MRI (or CT brain 
with contrast in patients who are unable to obtain an MRI) will be performed at the time of extra-
cranial disease progression and every 12 weeks in the study follow-up period. 


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Subjects continuing to show benefit, (complete response [CR], partial response [PR], or stable disease 
[SD]) as defined by RECIST v1.1 may continue on study. Subjects with PD as defined by RECIST 
v1.1 should have their treatment discontinued, and they should enter the post-treatment phase of the 
study. The same method for tumor assessment should be employed at every assessment. 
 
11.1 
Measurability of Tumor at Baseline 
 
At baseline, tumor lesions will be categorized measurable or non-measurable as follows: 
 
11.1.1 Measurable Tumor Lesions 
 
Tumor lesions: must be accurately measured in at least one dimension (longest diameter in the plane 
of measurement is to be recorded) with a minimum size of: 
 
• 
10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 
10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured 
with calipers should be recorded as non-measurable). 
• 
20 mm by chest X-ray. 
 
Malignant Lymph Nodes: To be considered pathologically enlarged and measurable, a lymph node 
must be ≥15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be 
no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and 
followed. See also section below on ‘Baseline documentation of target and non-target lesions’ for 
information on lymph node measurement. 
 
11.1.2 Non-Measurable Tumor Lesions 
 
Non-measurable tumor lesions encompass small lesions (longest diameter < 10 mm or pathological 
lymph nodes with ≥ 10 to < 15 mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: leptomeningeal disease; ascites; pleural or pericardial 
effusion; inflammatory breast disease; lymphangitic involvement of skin or lung; peritoneal spread; 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques. 
 
11.1.3 Special Consideration Regarding Lesion Measurability 
 
Bone lesions, cystic lesions, and lesions previously treated with local therapy require particular 
comment: 
 
Bone Lesions 
 Bone scan, PET scan or plain films are not considered adequate imaging techniques to measure 
bone lesions. However, these techniques can be used to confirm the presence or disappearance of 
bone lesions. 
 Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, that can 


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be evaluated by cross sectional imaging techniques such as CT or MRI can be considered as 
measurable lesions if the soft tissue component meets the definition of measurability described 
above. 
 Blastic bone lesions are non-measurable. 
 
Cystic Lesions 
 Cystic lesions that meet the criteria for radiographically defined simple cysts should not be 
considered as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts. 
 ‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable lesions, if 
they meet the definition of measurability described above. However, if non-cystic lesions are 
present in the same patient, these are preferred for selection as target lesions. 
 
Lesions with Prior Local Treatment 
 Tumor lesions situated in a previously irradiated area, or in an area subjected to other loco-
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion. Study protocols should detail the conditions under which such lesions 
would be considered measurable. 
 
11.2 
Specifications by Methods of Measurements 
 
11.2.1 Measurement of Lesions 
 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never more 
than 4 weeks before the beginning of the treatment. 
 
11.2.2 Method of Assessment 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging-based evaluation is preferred 
to evaluation by clinical examination unless the lesion(s) being followed cannot be imaged but are 
assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial and ≥ 
10 mm diameter as assessed using calipers (e.g. skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is suggested. 
As noted above, when lesions can be evaluated by both clinical exam and imaging, imaging 
evaluation should be undertaken since it is more objective and may also be reviewed at the end of the 
study. 
 
Chest x-ray: Chest CT is preferred over chest X-ray, particularly when progression is an important 
endpoint, since CT is more sensitive than X-ray, particularly in identifying new lesions. However, 


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lesions on chest X-ray may be considered measurable if they are clearly defined and surrounded by 
aerated lung. Still, non-contrast CT is preferred over chest X-ray. 
 
CT and MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based on the 
assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness greater than 
5 mm, the minimum size for a measurable lesion should be twice the slice thickness. MRI is also 
acceptable in certain situations (e.g. for body scans). 
 
If prior to enrolment it is known that a patient is not able to undergo CT scans with IV contrast due to 
allergy or renal insufficiency, the decision as to whether a non-contrast CT or MRI (with or without 
IV contrast) will be used to evaluate the patient at baseline and follow-up, should be guided by the 
tumor type under investigation and the anatomic location of the disease. For patients who develop 
contraindications to contrast after baseline contrast CT is done, the decision as to whether non-
contrast CT or MRI (enhanced or non-enhanced) will be performed, should also be based on the 
tumor type, anatomic location of the disease and should be optimized to allow for comparison to the 
prior studies if possible. 
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a method 
of measurement. Ultrasound examinations cannot be reproduced in their entirety for independent 
review at a later date and, because they are operator dependent, it cannot be guaranteed that the same 
technique and measurements will be taken from one assessment to the next. If new lesions are 
identified by ultrasound in the course of the study, confirmation by CT or MRI is advised. If there is 
concern about radiation exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies are 
obtained or to determine relapse in trials where recurrence following complete response or surgical 
resection is an endpoint. 
 
Tumor Markers: Tumor markers alone cannot be used to assess objective tumor response. If markers 
are initially above the upper normal limit, however, they must normalize for a patient to be 
considered in complete response. Because tumor markers are disease specific, instructions for their 
measurement should be incorporated into protocols on a disease specific basis. Specific guidelines for 
both CA-125 response (in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer), 
have been published. In addition, the Gynecologic Cancer Intergroup has developed CA125 
progression criteria which are to be integrated with objective tumor assessment for use in first-line 
trials in ovarian cancer. For NSCLC and for this study no tumor markers can be used for response 
assessment. 
 
Cytology, Histology: These techniques can be used to differentiate between PR and CR in rare cases 
if required by protocol (for example, residual lesions in tumor types such as germ cell tumors, where 
known residual benign tumors can remain). When effusions are known to be a potential adverse effect 
of treatment (e.g. with certain taxane compounds or angiogenesis inhibitors), the cytological 
confirmation of the neoplastic origin of any effusion that appears or worsens during treatment can be 
considered if the measurable tumor has met criteria for response or stable disease in order to 


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differentiate between response (or stable disease) and progressive disease. 
 
11.3 
Tumor Response Evaluation 
 
11.3.1 Assessment of Overall Tumor Burden and Measurable Disease 
 
To assess objective response or future progression, it is necessary to estimate the overall tumor 
burden at baseline and use this as a comparator for subsequent measurements. Only patients with 
measurable disease at baseline should be included in protocols where objective tumor response is the 
primary endpoint. Measurable disease is defined by the presence of at least one measurable lesion. 
 
11.3.2 Baseline Documentation of “Target” and “Non-Target” Lesions 
 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs should 
be identified as target lesions and will be recorded and measured at baseline. 
 
This means that in instances where patients have only one or two organ sites involved a maximum of 
two (one site) and four lesions (two sites), respectively, will be recorded. Other lesions in that organ 
will be recorded as non-measurable lesions (even if size is greater than 10mm by CT scan). 
 
Target Lesions 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be 
representative of all involved organs, but in addition should be those that lend themselves to 
reproducible repeated measurements. It may be the case that, on occasion, the largest lesion does not 
lend itself to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected. 
 
Lymph Nodes  
Lymph nodes merit special mention since they are normal anatomical structures which may be visible 
by imaging even if not involved by tumor. Pathological nodes which are defined as measurable and 
may be identified as target lesions must meet the criterion of a short axis of ≥ 15 mm by CT scan. 
Only the short axis of these nodes will contribute to the baseline sum. The short axis of the node is 
the diameter normally used by radiologists to judge if a node is involved by solid tumor. Nodal size is 
normally reported as two dimensions in the plane in which the image is obtained (for CT scan this is 
almost always the axial plane; for MRI the plane of acquisition may be axial, saggital or coronal). 
The smaller of these measures is the short axis. For example, an abdominal node which is reported as 
being 20 mm x 30 mm has a short axis of 20 mm and qualifies as a malignant, measurable node. In 
this example, 20 mm should be recorded as the node measurement. All other pathological nodes 
(those with short axis ≥ 10 mm but <15 mm) should be considered non-target lesions. Nodes that 
have a short axis <10 mm are considered non-pathological and should not be recorded or followed. 
 
A sum of the diameters (longest for non-nodal lesions, short axis for nodal lesions) for all target 
lesions will be calculated and reported as the baseline sum diameters. If lymph nodes are to be 
included in the sum, then as noted above, only the short axis is added into the sum. The baseline sum 
diameters will be used as reference to further characterize any objective tumor regression in the 


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measurable dimension of the disease. 
 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as non-
target lesions and should also be recorded at baseline. Measurements are not required and these 
lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression.’ In 
addition, it is possible to record multiple nontarget lesions involving the same organ as a single item 
on the case report form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
 
11.4 
Response Criteria 
 
This section provides the definitions of the criteria used to determine objective tumor response for 
target lesions. Objective response is defined as meeting criteria for either complete response or partial 
response. 
 
11.4.1 Evaluation of Target Lesions 
 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 mm. 
 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking as 
reference the baseline sum diameters. 
 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at 
least 5 mm. (Note: the appearance of one or more new lesions is also considered progression). 
 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD, taking as reference the smallest sum diameters while on study. 
 
11.4.2 Special Consideration on the Assessment of Target Lesions 
 
Lymph nodes:  
Lymph nodes identified as target lesions should always have the actual short axis measurement 
recorded (measured in the same anatomical plane as the baseline examination), even if the nodes 
regress to below 10 mm on study. This means that when lymph nodes are included as target lesions, 
the ‘sum’ of lesions may not be zero even if complete response criteria are met, since a normal lymph 
node is defined as having a short axis of < 10 mm. Case report forms or other data collection methods 
may therefore be designed to have target nodal lesions recorded in a separate section where, in order 
to qualify for CR, each node must achieve a short axis <10 mm. For PR, SD and PD, the actual short 
axis measurement of the nodes is to be included in the sum of target lesions. 
 
Target Lesions that Become ‘Too Small to Measure’  
While on study, all lesions (nodal and non-nodal) recorded at baseline should have their actual 
measurements recorded at each subsequent evaluation, even when very small (e.g. 2 mm). However, 
sometimes lesions or lymph nodes which are recorded as target lesions at baseline become so faint on 


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CT scan that the radiologist/physician investigator may not feel comfortable assigning an exact 
measure and may report them as being ‘too small to measure’. When this occurs it is important that a 
value be recorded on the case report form. If it is the opinion of the radiologist/physician investigator 
that the lesion has likely disappeared, the measurement should be recorded as 0 mm. If the lesion is 
believed to be present and is faintly seen but too small to measure, a default value of 5 mm should be 
assigned and BML (below measurable limit ) should be ticked (Note: It is less likely that this rule will 
be used for lymph nodes since they usually have a definable size when normal and are frequently 
surrounded by fat such as in the retroperitoneum; however, if a lymph node is believed to be present 
and is faintly seen but too small to measure, a default value of 5 mm should be assigned in this 
circumstance as well and BML should also be ticked). This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness). The measurement of 
these lesions is potentially non-reproducible; therefore providing this default value will prevent false 
responses or progressions based upon measurement error. 
 
To reiterate, however, if the radiologist/physician investigator is able to provide an actual 
measure, that should be recorded, even if it is below 5 mm and in that case BML should not be 
ticked. (BML is equivalent to a less than sign <) 
 
Lesions that Split or Coalesce on Treatment  
When non-nodal lesions ‘fragment’, the longest diameters of the fragmented portions should be 
added together to calculate the target lesion sum. Similarly, as lesions coalesce, a plane between them 
may be maintained that would aid in obtaining maximal diameter measurements of each individual 
lesion. If the lesions have truly coalesced such that they are no longer separable, the vector of the 
longest diameter in this instance should be the maximal longest diameter for the ‘coalesced lesion’. 
 
11.4.3 Evaluation of Non-Target Lesions 
 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. While some non-target lesions may actually be measurable, they need not 
be measured and instead should be assessed only qualitatively at the time points specified in the 
protocol. 
 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor marker 
level (tumor markers are not applicable to assessing response in this study). All lymph nodes must be 
non-pathological in size (<10 mm short axis). 
 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits (tumor markers are not applicable to assessing response in this 
study). 
 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
 
11.4.4 Special considerations on assessment of progression of non-target disease 
 
When the Patient also has Measurable Disease  
In this setting, to achieve ‘unequivocal progression’ on the basis of the non-target disease, there must 


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be an overall level of substantial worsening in non-target disease in a magnitude that, even in 
presence of SD or PR in target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy. A modest ‘increase’ in the size of one or more non-target lesions is 
usually not sufficient to qualify for unequivocal progression status. The designation of overall 
progression solely on the basis of change in non-target disease in the face of SD or PR of target 
disease will therefore be extremely rare. 
 
When the Patient has only Non-Measurable Disease  
This circumstance arises in some Phase III trials when it is not a criterion of study entry to have 
measurable disease. The same general concepts apply here as noted above, however, in this instance 
there is no measurable disease assessment to factor into the interpretation of an increase in 
nonmeasurable disease burden. Because worsening in non-target disease cannot be easily quantified 
(by definition: if all lesions are truly non-measurable) a useful test that can be applied when assessing 
patients for unequivocal progression is to consider if the increase in overall disease burden based on 
the change in non-measurable disease is comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. an increase in tumor burden representing an 
additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable 
lesion). Examples include an increase in a pleural effusion from ‘trace’ to ‘large’, an increase in 
lymphangitic disease from localized to widespread, or may be described in protocols as ‘sufficient to 
require a change in therapy’. If ‘unequivocal progression’ is seen, the patient should be considered 
to have had overall PD at that point. While it would be ideal to have objective criteria to apply to non-
measurable disease, the very nature of that disease makes it impossible to do so; therefore the 
increase must be substantial. 
 
12. DATA REPORTING / REGULATORY REQUIREMENTS 
 
12.1 
Data Safety Monitoring Plan 
 
Investigator/Sub-investigators, regulatory, CRS management, clinical research coordinators, clinical 
research associates, data managers, and clinic staff meet monthly in disease center Data Safety 
Monitoring Boards (DSMB) to review and discuss study data to include, but not limited to, the 
following: 
 serious adverse events 
 subject safety issues 
 recruitment issues 
 accrual 
 protocol deviations 
 unanticipated problems 
 breaches of confidentiality 
 
All toxicities encountered during the study will be evaluated on an ongoing basis according to the 
NCI Common Toxicity Criteria version 4. All study treatment associated adverse events that are 
serious, at least possibly related and unexpected will be reported to the IRB. Any modifications 
necessary to ensure subject safety and decisions to continue, or close the trial to accrual are also 


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discussed during these meetings. If any literature becomes available which changes the risk/benefit 
ratio or suggests that conducting the trial is no longer ethical, the IRB will be notified in the form of 
an Unanticipated Problem submission and the study may be terminated. 
 
All study data reviewed and discussed during these meetings will be kept confidential. Any breach in 
subject confidentiality will be reported to the IRB in the form of an Unanticipated Problem 
submission. The summaries of these meetings are forwarded to the UPCI DSMC which also meets 
monthly following a designated format. 
 
For all research protocols, there will be a commitment to comply with the IRB’s policies for reporting 
unanticipated problems involving risk to subjects or others (including adverse events). DSMC 
progress reports, to include a summary of all serious adverse events and modifications, and approval 
will be submitted to the IRB at the time of renewal. 
 
Protocols with subjects in long-term (survival) follow-up or protocols in data analysis only, will be 
reviewed twice a year rather than monthly by the disease center DSMB. 
 
Both the UPCI DSMC as well as the individual disease center DSMB have the authority to suspend 
accrual or further investigate treatment on any trial based on information discussed at these meetings. 
 
All records related to this research study will be stored in a locked environment. Only the researchers 
affiliated with the research study and their staff will have access to the research records. 
 
12.2 
Quality Control and Quality Assurance 
 
Independent monitoring of the clinical study for protocol and Guidelines on Good Clinical Practice 
compliance will be conducted periodically (i.e., at a minimum of annually) by qualified staff of the 
Education and Compliance Office – Human Subject Research, Research Conduct and Compliance 
Office, University of Pittsburgh. 
 
The Investigator (i.e., the study site principal investigator) and the University of Pittsburgh and 
University of Pittsburgh Medical Center will permit direct access of the study monitors and 
appropriate regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
12.3 
Data Handling and Record-Keeping 
 
The Investigator (i.e., the study site principal investigator) will maintain records in accordance with 
Good Clinical Practice. 
 
The investigator will retain the specified records and reports for up to 2 years after the marketing 
application is approved for the investigational drug; or, if a marketing application is not submitted or 
approved for the investigational drug, until 2 years after investigations under the IND have been 
discontinued and the FDA so notified. 
 


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12.4 
Institutional Review Board (IRB) Approval 
 
The investigator (i.e., the study site principal investigator) will obtain, from the University of 
Pittsburgh Institutional Review Board (IRB), prospective approval of the clinical protocol and 
corresponding informed consent form(s); modifications to the clinical protocol and corresponding 
informed consent forms, and advertisements (i.e., directed at potential research subjects) for study 
recruitment, if applicable. 
 
The only circumstance in which a deviation from the current IRB-approved clinical protocol/consent 
form(s) may be initiated in the absence of prospective IRB approval is to eliminate an apparent 
immediate hazard to the research subject(s). In such circumstances, the investigator will promptly 
notify the University of Pittsburgh IRB of the deviation. 
 
The University of Pittsburgh IRB operates in compliance with FDA regulations at 21 CFR Parts 50 
and 21 CFR 56, and in conformance with applicable International Conference on Harmonization 
(ICH) Guidelines on Good Clinical Practice. 
 
In the event that the University of Pittsburgh IRB requires, as a condition of approval, substantial 
changes to a clinical protocol submitted under an FDA-accepted IND application, or in the event of 
an sponsor’s decision to modify the previously accepted clinical protocol, the sponsor will submit 
(i.e., in advance of implementing the change) a Protocol Amendment to the IND describing any 
change that significantly affects the safety of subjects, the scope of the investigation, or the scientific 
quality of the study. Examples of protocol changes requiring the submission of a Protocol 
Amendment include: 
 
 
Any increase in drug dosage or duration of exposure of individual subjects to the 
investigational drug beyond that described in the current protocol, or any significant 
increase in the number of subjects under study. 
 
Any significant change in the design of the protocol (such as the addition or deletion of a 
control group). 
 
The addition of a new test or procedure that is intended to improve monitoring for, or 
reduce the risk of, a side effect or AE; or the dropping of a test intended to monitor the 
safety of the investigational drug. 
 
12.5 
Ethical and Scientific Conduct of the Clinical Study 
 
The clinical study will be conducted in accordance with the current IRB-approved clinical protocol; 
ICH Guidelines on Guidelines on Good Clinical Practice; and relevant policies, requirements, and 
regulations of the University of Pittsburgh IRB, University of Pittsburgh and University of Pittsburgh 
Medical Center, Commonwealth of Pennsylvania, and applicable federal agencies. 
 
12.6 
Informed Consent 
 
The investigator (i.e., the study site principal investigator) will make certain that an appropriate 


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informed consent process is in place to ensure that potential research subjects, or their authorized 
representatives, are fully informed about the nature and objectives of the clinical study, the potential 
risks and benefits of study participation, and their rights as research subjects. The investigator, or a 
sub-investigator(s) designated by the sponsor, will obtain the written, signed informed consent of 
each subject, or the subject’s authorized representative, prior to performing any study-specific 
procedures on the subject. The date and time that the subject or the subject’s authorized 
representative, signs the informed consent form and a narrative of the issues discussed during the 
informed consent process will be documented in the subject’s case history. The investigator or sub-
investigator will retain the original copy of the signed informed consent form, and a copy will be 
provided to the subject, or to the subject’s authorized representative. 
 
The investigator will make certain that appropriate processes and procedures are in place to ensure 
that ongoing questions and concerns of enrolled subjects are adequately addressed and that the 
subjects are informed of any new information that may affect their decision to continue participation 
in the clinical study. In the event of substantial changes to the clinical study or the risk-to-benefit 
ratio of study participation, the investigator will obtain the informed consent of enrolled subjects for 
continued participation in the clinical study. 
 
12.7 
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 prior to submission and also comply with any provisions regarding publication as 
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 according to guidelines established by the International Committee 
of Medical Journal Editors. 
 
13. STATISTICAL CONSIDERATIONS 
 
13.1 
Study Design/Endpoints 
 
This is a single institution open-label phase II clinical trial designed to allow a preliminary 
assessment of the efficacy and safety of cabozantinib in unselected NSCLC patients with metastases 
to the brain and in the subset of patients with c-MET amplified NSCLC with metastases to the brain. 
 
The hypothesis is that cabozantinib increases ORR from 5% to 15% in patients with NSCLC with 
brain metastases. The historical ORR in the second–line setting is based on a 5.8% response rate in 
patients with recurrent NSCLC treated with docetaxel.14 In a prior study of patients with metastatic 
NSCLC, the 12-week ORR for cabozantinib was 10% (95% confidence interval 5%-20%).8 Based on 
our preliminary data, we anticipate a higher ORR in patients with brain metastases. 


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Therefore, target enrollment is 54 evaluable patients (defined below). Simon's optimal two-stage 
design is used to minimize the expected sample size if the treatment is not effective. A stopping rule 
for futility is implemented if 1 or fewer of the first 29 evaluable patients have an objective response. 
(Accrual may continue during follow-up for these patients.)  If ≥2 responses are observed in the first 
29 evaluable patients, an additional 25 patients will be enrolled. A promising study result would be a 
response rate of 6/54 (11%) or greater. This design has 82% power to detect a true response rate of 
15% (compared with a null rate of 5%). A minimum of 15 evaluable patients with c-MET amplified 
tumors will be enrolled. If 1 or fewer than 29 patients in the first stage of the Simon design have an 
objective response and fewer than 15 of the 29 have c-MET amplified tumors, accrual will continue 
for the c-MET amplified patients only to reach a minimum of 15 evaluable patients with c-MET 
amplification. 
 
The ORR will be reported for the unselected population (all evaluable patients) and for patients with 
c-MET amplification. A 90% and 95% Wilson confidence interval for the ORR will also be reported. 
With a minimum of 15 patients with c-MET amplification, a promising ORR should be detectable. 
For example, the 95% Wilson confidence interval for a 3/15 ORR (20%) is (7%, 45%). 
 
13.2 
Sample Size/Accrual Rate 
 
Approximately 54 subjects will be enrolled in the study. A minimum of 15 patients with c-MET 
amplified tumors is required. Accrual rate and completion through last study follow-up visit is 
estimated at 3 years.  
 
13.3 
Study and Safety Populations 
 
The efficacy population will consist of all subjects who receive any amount of study treatment and 
are evaluable for response. Response will follow RECIST 1.1 criteria (Appendix B) when at least one 
follow-up scan has been performed. A subject who withdraws from the study before a follow-up scan 
for disease progression will may be counted as evaluable without an objective response or omitted 
from analysis (not evaluable): 
 
 
No follow-up scans for RECIST 1.1, no objective response (evaluable): 
 
Progressive disease 
 
Withdraw due to treatment toxicity 
 
No follow-up scans for RECIST 1.1, omit from analysis (not evaluable) 
 
Withdraw consent for reasons other than progressive disease or toxicity 
 
Belatedly discovered to be ineligible for enrollment 
 
13.4 
Safety Analysis 
 
All safety analyses will be performed using the safety population.  
 
Adverse events will be graded using the Cancer Therapy Evaluation Program (CTEP) Common 
Terminology Criteria for Adverse Events version 4.0. Adverse events of grade 2 or greater, or that 


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result in dose holds or reductions, will be collected and reported. The number and percent of subjects 
reporting adverse events will be summarized by category (i.e., “Blood and lymphatic system 
disorders”), for the most common adverse event subcategories (i.e., “anemia”), and for serious 
adverse events (defined in section 7.2). Narratives of all serious adverse events and deaths on-study 
will be provided. 
 
 


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42. Ou SH. Activity of crizotinib (PF02341066), a dual mesenchymal-epithelial transition (MET) and 
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MET amplification. J Thorac Oncol 2011; 6: 942-46. 
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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 pre-disease 
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. 
 
 
 


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APPENDIX B: EVALUATION OF LESIONS USING RECIST 1.1 CRITERIA 
 
Evaluation of Target Lesions using RECIST 1.1 Criteria 
 
Complete response (CR): Disappearance of all target lesions. Any pathological lymph node (LN) 
target or no must have decreased in short axis to <10mm. 
 
Partial response (PR): At least a 30% decrease in the sum of the LD of the target lesions taking as 
reference the baseline sum LD. 
 
Progressive Disease (PD): At least a 20% increase in the sum of the LD of the target lesions taking 
as reference the smallest sum LD recorded since the treatment started including baseline if that is the 
smallest on study. In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5mm. The appearance of one or more new lesions also constitutes PD. 
 
Stable disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD taking as references the smallest sum LD since the treatment started. 
 
 Evaluation of Non-Target Lesions using RECIST 1.1 Criteria 
 
Complete response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker levels. All LN must be non-pathological in size (<10mm short axis). 
Non-complete response (non-CR)/non-progression (non-PD): Persistence of one or more non-
target lesion(s) or/and maintenance of tumor marker level above the normal limits. 
Progressive disease (PD): Appearance of one or more new lesions and/or unequivocal progression of 
existing non-target lesions. 
 
Evaluation of Response at each Time-Point using RECIST 1.1 Criteria 
Target lesions 
Non Target lesion 
New lesion 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not 
evaluated 
No 
PR 
SD 
Non-PD or not 
evaluated 
No 
SD 
Not evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
CR=complete response; PR=partial response; SD=stable disease; and PD=progressive 
disease. 
Evaluation of Best Overall Response using RECIST 1.1 Criteria 
 
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progression (for example, a patient who has SD at first assessment, PR at second assessment, and PD 
on last assessment has a best overall response of PR). See Eisenhauer EA, Therasse P, Bogaerts J, et 
al. Eur Cancer.2009;22:228-248 for full publication of RECIST 1.1. 
 
Other Efficacy Parameters 
PFS is defined as the time from the start of treatment until documented disease progression as defined 
via RECIST 1.1 or death. Overall survival is defined as the time from the start of treatment until 
death due to any cause.