Clinical trial NCT01812668
Conditions: Adenocarcinoma of the Prostate Hormone-resistant Prostate Cancer Recurrent Prostate Cancer Stage IV Prostate Cancer
Sponsor: Barbara Ann Karmanos Cancer Institute
Start date: 2013-03-01; Completion date: 2019-06-18
Enrollment: 20 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This pilot clinical trial studies cabozantinib-s-malate in treating patients with hormone-resistant metastatic prostate cancer. Cabozantinib-s-malate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth

Detailed description:
PRIMARY OBJECTIVES:

I. To evaluate the timing, pathophysiology, and magnitude of changes in tumor imaging and pharmacodynamic markers with XL184 (cabozantinib-s-malate) treatment in metastatic castrate resistant prostate cancer.

SECONDARY OBJECTIVES:

I. To estimate the progression-free survival (PFS) achieved with XL184 in metastatic castrate resistant prostate cancer (CRPC) patients.

II. To evaluate the feasibility of the therapy, and the toxicities associated. III. To evaluate overall survival (OS) in metastatic CRPC patients post androgen deprivation therapy (ADT) treated with XL-184.

OUTLINE:

Patients receive cabozantinib-s-malate orally (PO) daily in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks and then periodically thereafter.

Arms: arm 1: Patients receive cabozantinib-s-malate PO daily in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: cabozantinib-s-malate intervention 2: fluorine F 18 d-FMAU intervention 3: positron emission tomography intervention 4: pharmacological study intervention 5: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given PO intervention 2: Undergo 18F PET/FMAU PET scan intervention 3: Undergo 18F PET/FMAU PET scan intervention 4: Correlative studies intervention 5: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
Protocol version date Nov 17, 2011, Dec 29, 2011, Mar 19, 2012, June 28, 2012, Sept 6, 2012 Aug 16, 
2013, June 25, 2014, Aug 14, 2014 
1
 
KCI Protocol # 2011-185 
 
Pilot Trial of oral cabozantinib/ XL184 in metastatic castrate resistant prostate 
cancer to explore the changes in bone and tumor imaging related pathways 
Version date: Nov 17 2011, Dec 29, 2011, Mar 19, 2012, June 28, 2012, Sept 6, 2012, 
Aug 16 2013, June 25, 2014, Aug 14, 2014  
Sponsor- NOMIC grant Dept of Defense. 
Cabozantinib/XL184 and grant support will be provided by Exelixis Inc.  
IND#: 114758 
 
Principal Investigator:  
Ulka Vaishampayan M.D. 
 
 
 
Karmanos Cancer Institute 
 
 
 
4100 John R, HW04HO 
 
 
Detroit, MI 48201 
Tel #  313-576-8715 
Fax # 313-576-8487.  
E-mail vaishamu@karmanos.org 
 
Co-Investigators:                  
Elisabeth Heath M.D.    
Karmanos Cancer Institute 
 
 
 
4100 John R, HW04HO 
 
 
Detroit, MI 48201 
Tel# 313-576-8715 
Fax # 313-576-8767 


Protocol version date Nov 17, 2011, Dec 29, 2011, Mar 19, 2012, June 28, 2012, Sept 6, 2012 Aug 16, 
2013, June 25, 2014, Aug 14, 2014 
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E mail heathe@karmanos.org 
 
 
Anthony Shields, MD, PhD 
Associate Cancer Center Director for Clinical Sciences 
Professor of Oncology 
Karmanos Cancer Institute 
 
 
 
4100 John R, HW04HO 
 
 
Detroit, MI 48201 
Office: 313 576 8735 
Fax: 313 576 8767 
Email: shieldsa@karmanos.org 
 
Joseph Fontana M.D. 
VA Medical Center 
Oncology 11M-HO 
Room C3687 
4646 John R 
Detroit MI 48201. 
Tel# 313-576-3659 
E mail Joseph.Fontana@med.va.gov 
 
 
Lance Heilbrun Ph.D.  
Biostatistics Unit 
Karmanos Cancer Institute 
 
 
 
4100 John R, MM05BI 
 
 
Detroit, MI 48201 
Detroit, MI 48201. 
Tel# 313-576-8652 
E mail heilbrun@karmanos.org


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2013, June 25, 2014, Aug 14, 2014 
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Izabela Podgorski, PhD 
Assistant Professor 
Department of Pharmacology 
Karmanos Cancer Institute, Wayne State University 
Lab: 313 577 0941  
Office: 313 577 0514  
E Mail ipodgors@med.wayne.edu 
 
 
Susan Land PhD  
Applied Genomics Technology Center 
CS Mott Center Bldg. 
275 East Hancock St. 
Detroit MI 48201 
313-577-9605 (office phone) 
313-577-0024 (lab phone) 
 
 
 
 
E mail Sland@med.Wayne.edu 
 
Aliccia Bollig-Fischer, Ph.D. 
Applied Genomics Technology Center 
Karmanos Cancer Institute 
Wayne State University 
275 E. Hancock 
Detroit, MI 48201 
Tel 313-577-9605 
E mail bollig@karmanos.org 
 
 
 
 
 


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Study Coordinator 
 
Brenda Dickow, RN 
                                        
Clinical Trials Office  
 
 
 
 
 
 
4100 John R, MM03CT 
 
 
Detroit, MI 48201 
Tel #  313-576-9372 
E mail: dickowb@karmanos.org 
 
 
 
 
  
 
Grants and Contracts: 
Mary Jo O’Loughlin 
 
 
 
 
Karmanos Cancer Institute 
4100 John R, MM00RA 
Detroit, MI 48201 
Tel # 313-578-4405 
Fax # 313-578-4419 
e-mail: oloughli@karmanos.org 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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Pilot Trial of oral cabozantinib/XL184 in metastatic castrate resistant prostate 
cancer to explore the changes in bone and tumor imaging related pathways 
 
1.0 Background .......................................................................................................................... 12 
 
2.0 Study Objectives and Design ............................................................................................... 28 
 
2.3 Study calendar ...................................................................................................................... 30 
 
2.11 Treatment Plan and Dose Modifications ............................................................................ 33 
 
3.0 Study Population .................................................................................................................. 58 
 
4.0 Study Assessments ............................................................................................................... 63 
 
5.0 Adverse Events Reporting ................................................................................................... 68 
 
6.0 Correlative Studies ............................................................................................................... 72 
 
7.0 Statistical Considerations ..................................................................................................... 77 
 
8.0 Ethical Aspects ..................................................................................................................... 79 
 
9.0 Study Documentation........................................................................................................... 81 
 
10.0 Publication of Data ............................................................................................................ 84 
 
11.0 References .......................................................................................................................... 85  
 
12.0 Data and Safety Monitoring ............................................................................................... 89 
 
13.0 Appendices ......................................................................................................................... 91 


 
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SYNOPSIS  
Pilot trial of oral cabozantinib/ XL184 in metastatic castrate resistant prostate cancer to 
explore the changes in bone and tumor imaging related pathways 
 
 Primary Objective:  
  
To conduct a pilot clinical trial to evaluate the timing, physiology, and magnitude of changes 
in tumor imaging, and pharmacodynamic markers with XL184 treatment in metastatic 
castrate resistant prostate cancer.  
 
.  
 Secondary Objectives:  
 
1) To estimate the progression-free survival (PFS) achieved with XL184 in metastatic 
CRPC patients. 
2) To evaluate the safety and tolerability of the therapy, and the toxicities associated. 
3) To evaluate OS in chemotherapy naïve metastatic CRPC patients 
 
 
Study Treatment 
XL184 at a starting dose of 60 mg orally daily taken after fasting 2 hours prior and one 
hour after administration. 
 
Dose modifications for treatment related severe or intolerable adverse events. 
-1, and -2 Dose levels will be 40 mg and 20 mg respectively. 
 
Study Assessments 
Pretherapy CT, standard methylene diphosphonate (99mTc-MDP) bone scan, sodium 18F-
fluoride (18F-fluoride) PET bone scan, and FMAU {[2’-18F]-1-(2’-deoxy-2'-fluoro-beta-


 
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D-arabinofuranosyl)thymine} PET scan. Pretherapy bone biopsy and correlative 
pharmacodynamic sample collection (Blood and urine).  The FMAU and 18F-fluoride 
PET scans will be done under separately approved imaging protocols. 
Start XL184, monitor for toxicity every 2 weeks for the first 3 months, then once every 4 
weeks.  
At 2 -3 weeks post therapy repeat 18F-flouride PET / FMAU PET scans, bone scans and 
tumor biopsy. The timing of the scan maybe further changed depending on the optimal 
time to detect changes as determined from the first 5 patients enrolled. At 6 weeks, 20 
weeks and then every 12 weeks thereafter until patient continues on cabozantinib,  CT 
and 99Tc-MDP bone scan will be done  to evaluate tumor status.  
The week 4 timepoint scan will be discontinued for all present and future patients.    
We will also review each patients baseline scan to see if there is disease detectable.  If no 
readily visible cancer is found then the 2nd scan with FMAU PET will be eliminated for 
that patient.  So far of the 6 patients imaging, only patient 1 had no easily visible tumor 
on the baseline scan. Longer follow up of the patients has revealed that it remains a 
challenge to determine if the patients are continuing to derive clinical benefit. The PSA 
level is frequently discordant with response. Hence we will obtain an additional 18F-
flouride PET scan and a FMAU scan (if the patient had <3 FMAU scans prior) at week 
32 (+/- 10 weeks) for the patients continuing on study therapy at that timepoint. For the 
patients who discontinue therapy, prior to the 32 weeks timepoint,, the scan/s will be 
done at the time of treatment discontinuation (+/- 2 weeks).  This timepoint was chosen to 
capture the maximum number of patients currently on the study for this scan, and since 
conventional CT scan and bone scan is also conducted at the same timepoint for 
comparison. 
 
 
 
 
Tissue, Blood and Urine collection:   
 
Tumor tissue biopsy will be obtained within 2 weeks prior to and within 2-3 weeks post 
XL184 therapy.  Part of each tissue sample will be fresh-frozen for genomic analysis and 
the rest will be decalcified, fixed and embedded in paraffin for histological and 
immuhistochemical analyses. Blood and urine samples will be collected from each 
patient for correlative studies.  For the first 5 patients, samples will be taken at 
pretherapy, 1, 2 and 4 weeks after treatment begins.  Timeline for additional 15 patients 
will be adjusted based on results obtained in first 5 patients and will be correlated with 
the imaging schedule.  For instance if no changes are seen at a particular time point in all 


 
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5 patients, then that timepoint maybe excluded. Blood sample collection will be 
performed using Vacutainer CPT tubes. This method will generate serum samples for the 
analysis of biochemical markers, and mononuclear cells for future analyses of DNA and 
RNA.  All isolated samples will be stored at -80° C until use. 
 
Clinical Monitoring and testing 
 
Patients will be monitored for response (measurable disease, PSA levels, clinical 
response and bone scans) progression, survival and toxicity. 


 
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LIST OF TABLES 
Table 1-1: 
XL184 IC50 Values in Biochemical, Enzymatic Assays ........................... 16 
Table 1-2: 
XL184 ED50 Values in Tumor Models ..................................................... 17 
Table 1-3: 
Summary of XL184 In Vivo Target Modulation Studies in Mice ............ 18 
 
LIST OF APPENDICES 
Appendix A: Performance Status Criteria ...................................................................... 94 
Appendix B: Dose and Capsule Strength Nomenclature, Dosing Based on 
Weight of L-malate Salt ................................................................................  
Appendix C: Blood and Tissue Processing…………………………………………….69 
 


 
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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 
Cmax 
maximum plasma concentration 
cPR 
confirmed partial response 
CR 
complete response 
CRF 
case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DVT 
deep vein thrombosis 
EC 
ethics committee 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ED50 
dose required for 50% inhibition 
ESC 
Exelixis Safety Committee 
FDA 
Food and Drug Administration 
FMAU 
[2’-18F]-1-(2’-deoxy-2'-fluoro-beta-D-arabinofuranosyl)thymine 
FLT3 
FMS-like tyrosine kinase 3 
FSH 
follicle-stimulating hormone 
GB 
glioblastoma 
GCP 
Good Clinical Practice 
GI 
gastrointestinal 
GEJ 
gastroesophageal junction 
GnRH 
gonadotropin-releasing hormone 


 
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HCC 
hepatocellular carcinoma 
HGF 
hepatocyte growth factor 
IC50 
concentration required for 50% inhibition 
ICH 
International Conference on Harmonisation 
IME 
important medical event 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
LHRH 
luteinizing hormone-releasing hormone 
MDP 
methylene diphosphonate (99mTc-MDP) bone scan 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTC 
medullary thyroid cancer 
MTD 
maximum tolerated dose 
NCI 
National Cancer Institute 
PET 
Positron Emission Tomography 


 
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LIST OF ABBREVIATIONS (continued) 
 
NSCLC 
non-small-cell lung cancer 
PD 
progressive disease 
PE 
pulmonary embolism 
PFS 
progression-free survival 
PFS6 
progression-free survival at 6 months 
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 
RPLS 
reversible posterior leukoencephalopathy syndrome 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SD 
stable disease 
SCLC 
small-cell lung cancer 
t1/2, z 
terminal-phase half-life 
ULN 
upper limit of normal 
VEGF(R) 
vascular endothelial growth factor (receptor) 


 
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1 
BACKGROUND AND RATIONALE 
1.1 
Hypothesis:  
XL-184 is a cmet inhibitor that results in abrupt clinical changes in bone metabolism 
represented as an abrogation of 99mTc-MDP uptake on bone scan. This is likely due to 
inhibition of osteoclast function and decrease in osteoblast activity. We hypothesize that 
XL-184 uniquely targets the cross talk between cMet and VEGFR axis, downstream 
cathepsin K driven pathways and novel recetor tyrosine kinases (such as DDR-1 and 
DDR-2) in bone tumor microenvironment. Hence we propose a pilot trial designed to 
study the pathophysiology and genomic changes in bone metastases and correlate these 
with response and clinical outcome data in metastatic CRPC patients treated with XL-184 
therapy. 
1.2 
Study Objectives 
The objectives of this study are as follows: 
 Primary Objective:  
  
To conduct a pilot clinical trial to evaluate the timing, pathophysiology, and 
magnitude of changes in tumor imaging and pharmacodynamic markers with XL184 
treatment in metastatic castrate resistant prostate cancer.  
 
.  
 Secondary Objectives:  
 
1) To estimate the progression-free survival (PFS) achieved with XL184 in metastatic 
CRPC patients. 
  2) To evaluate the feasibility of the therapy, and the toxicities associated. 
  3) To evaluate OS in metastatic CRPC patients post ADT treated with XL-184. 
 
1.3 
Background: Prostate Cancer and Targeted Therapy 
Cancer is a worldwide clinical and economic problem. The American Cancer Society 
estimates that there will be nearly 1.5 million cancer diagnoses and 


 
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566,000 cancer-related deaths in the United States in 2008 (American Cancer Society 
2008). The estimated overall cost of cancer in 2006 (reflecting, for example, clinical 
treatment, lost work time and productivity for patients and families, and mortality) was 
$206.3 billion. Conventional approaches to treating cancer include surgery, radiotherapy, 
and cytotoxic chemotherapy as single modalities or as combined therapies. Recently, 
targeted therapies including antibodies and small molecule inhibitors have also 
demonstrated clinical benefit. Further studies into the pathways and mechanisms of 
action of these novel agents will help guide patient selection for future therapies and 
determine resistance mechanisms. 
Bone metastases in prostate cancer are primarily osteoblastic with evidence of deposition 
of new bone. The increased osteoblastic activity results in incorporation of Tc99-labeled 
methylene-diphosphonate allowing visualization of the lesions on bone scan. Met and its 
ligand, hepatocyte growth factor (HGF) have demonstrated increased expression after 
androgen ablation as well as with disease progression to lymph nodes and soft tissue. 
XL184 is a VEGF and c-met inhibitor that has demonstrated promising clinical efficacy 
in metastatic CRPC. Not only did the agent produce 89% aggregate response and stable 
disease rate in measurable disease, but marked improvement of bone scans was noted 
(Smith DC et al. GU ASCO symposium 2011). This is an unusual phenomenon, not seen 
even with any of the other agents that produce high levels of anti-tumor efficacy such as 
ADT. The physiologic changes occurring with the rapid normalization of bone scans 
(within the first 6 weeks) are unknown to date. We propose a pilot trial to study the 
changes occurring in bone metastases and in tumor tissue and to correlate with clinical 
outcome, with XL184 therapy. We hypothesize that XL184 uniquely targets the crosstalk 
between cMet and VEGFR axis, downstream cathepsin K-driven pathways and novel 
RTKs (e.g., DDR-1, DDR-2) in the bone tumor microenvironment. XL184 action leads to 
abrupt changes in bone metabolism and abrogation of 99mTc-MDP uptake due to the 
inhibition of osteoclast activity and subsequent decrease in osteoblast function.   
1.3.1 
Signal Pathways 
The MET receptor tyrosine kinase (RTK) (receptor for hepatocyte growth factor [HGF]) 
has been implicated as a mediator in many important aspects of tumor pathobiology, 


 
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including tumor survival, growth, angiogenesis, invasion, and dissemination (Sattler et al. 
2004; Jiang et al. 2005), and several MET RTKs have been reported to show activity in 
cell lines and animal models (Sattler et al. 2004). Recently, inhibitors of MET including 
XL880 and ARQ 197 have shown signs of antitumor activity in Phase 1 studies (Eder et 
al. 2007; Garcia et al. 2007; Ross et al. 2007). The vascular endothelial growth factor 
receptor 2 (VEGFR2 [KDR]) is a central mediator of tumor angiogenesis, and several 
small molecule and protein therapeutics targeting this receptor are currently in clinical 
development. Recently, bevacizumab (Avastin®), a monoclonal antibody directed against 
VEGF, has been shown to improve overall survival (OS) when combined with 
chemotherapy in patients with metastatic colorectal cancer (Hurwitz et al. 2004) and in 
lung cancer (Sandler et al. 2005). In addition to their individual roles in tumor 
pathobiology, nonclinical data suggest that Met and VEGFR2 play synergistic roles in 
promoting tumor angiogenesis and subsequent dissemination (Bottaro and Liotta 2003).  
Compounds that simultaneously inhibit VEGF and MET RTKs may be more effective 
anticancer agents than agents that target each of these receptors individually 
(Pennacchietti et al. 2003). The investigational drug in this study, XL184, is a potent 
RTK inhibitor that targets primarily MET and VEGFR2 RTKs. XL184 has activity 
against other RTKs that have been implicated in tumor pathobiology, including KIT, 
FMS-like tyrosine kinase 3 (FLT3), and Tie-2. In addition, XL184 is known to inhibit 
RET, a RTK known to be causative for malignancy in the setting of hereditary medullary 
thyroid cancer (MTC). 
1.4 
XL184 Background 
A summary of XL184 clinical and nonclinical experience is contained in the 
Investigator’s Brochure supplied by Exelixis (or designee). The Investigator’s Brochure 
should be reviewed in conjunction with this study protocol. 
1.4.1 
Spectrum of XL184 Activity 
XL184 is a new chemical entity that inhibits multiple RTKs with growth-promoting and 
angiogenic properties. The primary biochemical targets of XL184 are MET, VEGFR2, 
RET, and KIT (Table 1-1). 


 
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Table 1-1: 
XL184 IC50 Values in Biochemical, Enzymatic Assays  
Kinase 
IC50 (biochemical) [nM] 
MET 
1.8 
VEGFR2 
0.035 
RET 
3.8 
KIT 
4.6 
IC50, concentration required for 50% target inhibition; VEGFR2, vascular endothelial 
growth factor receptor 2. 
 
XL184 is orally bioavailable as demonstrated by pharmacokinetic (PK) experiments in 
rodent and nonrodent models. Target modulation studies show that the administration of 
XL184 in mouse models causes dose-dependent inhibition of MET, VEGFR2, a 
mutationally activated form of RET, and multiple mutationally activated forms of KIT. 
Immunohistochemical studies demonstrate rapid effects on the tumor endothelium, 
resulting in breakdown of the vasculature and tumor cell death within 8 hours after 
administration of XL184. These effects translate into significant tumor growth inhibition 
after XL184 treatment in multiple tumor models (Table 1-2). In addition, in all of the 
models examined (human breast cancer, human lung carcinoma, human MTC, and rat 
glioblastoma [GB]), marked tumor regression and excellent tolerability were observed .  


 
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Table 1-2: 
XL184 ED50 Values in Tumor Models 
Tumor Line 
Species 
Tumor Type 
ED50 
(mg/kg/day) 
Treatment 
Duration 
C6 
Rat 
Glioblastoma 
< 1 
qd  12 
MDA-MB-231 
Human 
Breast 
2 
qd  14 
H441 
Human 
NSCLC 
3 
qd  14 
TT 
Human 
Medullary thyroid 
carcinoma 
11 
qd  21 
U87 
Human 
Glioblastoma 
≤ 30 
qd  14 
ED50, dose associated with 50% tumor growth inhibition; NSCLC, non-small-cell lung 
cancer; qd, once daily. 
 
Data from pharmacodynamic experiments show that in vivo XL184 inhibits key RTKs 
that promote tumor cell proliferation and/or angiogenesis (MET, VEGFR2, and RET) 
(Table 1-3). XL184 inhibited RTKs MET in the liver, and xenograft tumors and 
VEGFR2 in lung tissue, with ED50 (dose required for 50% inhibition of receptor 
phosphorylation) values of 5, 9, and 26 mg/kg, respectively. Durations of action were 
sustained with > 50% inhibition 10-24 hours post-dose at a dose level of 100 mg/kg. 
Immunohistochemical evaluations indicated that XL184 inhibited angiogenesis and cell 
proliferation and stimulated necrosis in tumor tissue in vivo.  


 
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Table 1-3: 
Summary of XL184 In Vivo Target Modulation Studies in Mice 
Target 
Model 
Dose Response 
Duration of Action 
Maximum
Inhibition
(%) 
Estimated
ED50 
(mg/kg) 
Estimated
IC50 
(µM) 
Dose 
(mg/kg) 
Maximum 
Inhibition 
(%) 
Sustained
Inhibition 
> 50% 
(hours) 
MET 
Liver 
(+ HGF) 
97 
5 
2 
100 
99 
10 
H441 
96 
9 
7 
100 
92 
10 
VEGFR2 
Lung 
(+ VEGF) 
98 
26 
2 
100 
99 
10 
RET 
TT 
89 
11.1 
7.4 
100 
84 
4a 
ED50, dose associated with 50% inhibition of receptor phosphorylation; HGF, hepatocyte 
growth factor; IC50, plasma concentration associated with 50% inhibition of receptor 
phosphorylation; VEGF, vascular endothelial growth factor. 
a 44% inhibition after 24h, no intermediate timepoint between 4h and 24h was tested. 
 
Nonclinical experiments in nude mice demonstrated that XL184 crosses the blood-brain-
barrier in healthy animals. Four hours after drug administration at 10 mg/kg, XL184 brain 
exposure was approximately 16% (1.3 µM) of the XL184 concentration in plasma (8.2 
µM).  
Overall, the data generated in vivo demonstrate that the target profile of XL184 translates 
to potent anti-angiogenic activity and potent antitumor efficacy. The anti-VEGFR2 
activity of XL184, combined with additional growth-inhibitory properties mediated by its 
activity against MET, may result in enhanced antitumor activity in GB. Phase 1 and 2 
clinical data suggest that XL184 has robust clinical activity in several tumor types, 
including MTC and GB. 


 
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More extensive summaries of XL184 pharmacology are contained in the Investigator’s 
Brochure supplied by Exelixis (or designee). This document should be reviewed in 
conjunction with this study protocol. 
1.4.2 
XL184 Nonclinical Toxicology 
In nonclinical toxicity studies in rodents and nonrodents, histopathological changes 
associated with XL184 administration were observed in gastrointestinal (GI) tract, bone 
marrow, lymphoid tissues, kidney, adrenal and reproductive tract tissues. 
Histopathological changes present in bone and pancreas were considered secondary to 
XL184 administration. XL184 was negative in in vitro bacterial, in vitro mammalian cell, 
and in vivo mammalian genotoxicity bioassays. In reproductive toxicity studies, XL184 
was embryotoxic in rats, produced fetal soft tissue changes in rabbits, and decreased 
fertility in male and female rats. 
Safety pharmacology studies of XL184 administration did not demonstrate adverse 
effects on neurobehavioral or respiratory-system function in rats; furthermore, no 
significant changes in electrocardiographic parameters (including corrected QT [QTc] 
interval) were observed in telemeterized dogs. 
XL184 was not an inhibitor of cytochrome P450 (CYP) 3A4 in vitro and is not predicted 
to have significant effects on CYP3A4 induction. XL184 was shown to be an inhibitor of 
CYP2C8, CYP2C9*3, and CYP2C19 isozymes in vitro and was also a substrate of 
CYP3A4-mediated metabolism. The mean plasma protein binding by XL184 in vitro was 
greater than 98%. 
Additional toxicology information may be found in the Investigator’s Brochure. 
1.4.3 
Clinical Experience (Detailed and current clinical information is available in 
current version of the Investigators brochure) 
1.4.3.1 
Clinical Summary 
There are nine ongoing studies for XL184, including four Phase 1 studies, one Phase 1b/2 
study, three Phase 2 studies, and one Phase 3 study. As of 01 June 2010, there have been 
747 subjects enrolled across all nine studies. The single-agent maximum tolerated dose 


 
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(MTD) on the once daily (qd) oral (PO) dosing schedule has been determined to be 
175 mg. Details of all studies may be found in the Investigator’s Brochure. 
1.4.3.2 
Clinical Safety Profile 
The adverse event (AE) and serious adverse event (SAE) data summarized in the 
following section include those reported and entered in the clinical database and safety 
database as of 01 June 2010. The clinical studies with XL184 are ongoing, thus the AE 
data from the clinical database do not yet include all SAEs. Data from double-blinded 
studies are not presented. The severity of AEs was assessed using the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0.  
1.4.3.2.1 Adverse Events 
As of 01 June 2010, more than 561 subjects have been studied in open-label clinical trials 
with XL184, including treatment with XL184 as a single agent, as well as XL184 in 
combination with temozolomide and radiation therapy, and XL184 in combination with 
erlotinib. The available pooled data in this database include 483 subjects who received 
open-label XL184 in Studies XL184-001, XL184-002, XL184-201, XL184-202, and 
XL184-203 (lead-in stage only). The most frequently observed AEs (> 15%), regardless 
of the relationship to XL184, were fatigue, diarrhea, decreased appetite, nausea, 
constipation, vomiting, dysphonia, hypertension, rash, aspartate aminotransferase (AST) 
increased, alanine aminotransferase (ALT) increased, palmar-plantar erythrodysesthesia 
(PPE) syndrome, headache, dyspnea, cough, and weight decrease. Some of these events, 
including fatigue, diarrhea, nausea, dysphonia, hypertension, rash, AST increased, ALT 
increased, and PPE syndrome, resulted in permanent study drug discontinuation,. Effects 
that may be related to inhibition of VEGF, including hypertension, thromboembolic 
events, GI perforation and hemorrhage, wound dehiscence, and proteinuria, have been 
observed in clinical studies with XL184.  
1.4.3.2.2 Serious Adverse Events 
Of the 561 subjects enrolled in open-label clinical trials with XL184, 223 subjects (40%) 
experienced one or more SAEs recorded in the Argus safety database, and 95 subjects 
experienced one or more SAEs that were assessed to be related to treatment with XL184. 


 
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The most commonly reported SAEs assessed as drug related were pulmonary embolism 
(PE) (in 14 subjects), diarrhea (in nine subjects), deep vein thrombosis (DVT) (in seven 
subjects), nausea (in seven subjects), hypertension (in five subjects), thrombocytopenia 
(in five subjects), dehydration (in four subjects), vomiting (in four subjects), abdominal 
pain (in three subjects), and perirectal abscess (in three subjects). In addition, one late-
breaking case of reversible posterior leukoencephalopathy syndrome (RPLS) was 
reported after the data cut-off in the double-blind placebo-controlled Study XL184-301. 
Fifty-two deaths were reported within 30 days of the last dose of study drug; the majority 
was due to disease progression, and five deaths were assessed to be related to XL184. 
They were the result of GI hemorrhage (in one subject), PE (in two subjects), respiratory 
failure (in one subject), and hemoptysis (in one subject).  
Detailed information regarding the safety profile of XL184 from all studies may be found 
in the Investigator’s Brochure.  
1.4.3.3 
Clinical Pharmacokinetics 
Pharmacokinetic analysis showed dose proportional increases in maximum plasma 
concentration (Cmax) and area under the plasma concentrationtime curve (AUC) both for 
the powder-in-bottle (PIB) formulation (dose range: 0.08 to 11.52 mg/kg) and the capsule 
formulation (dose range: 125 to 175 mg). Terminal-phase half-life (t1/2, z) values were 
59.1 to 136 hours. More detailed information regarding XL184 PK from all studies and 
product metabolism in humans may be found in the Investigator’s Brochure. 
1.4.3.4 
Clinical Activity 
Preliminary clinical activity data are available for Studies XL184-001, XL184-201, 
XL184-202, and XL184-203.  
Eighty-five subjects with advanced solid tumors were enrolled in the XL184-001 study. 
Of the 85 subjects, 18 subjects experienced a tumor shrinkage of ≥ 30%, including 
17 (49%) of 35 subjects with MTC with measurable disease. In the response evaluable 
subset of subjects with MTC, 10 (29%) of 35 subjects had confirmed partial responses 
(cPRs). In addition, 15 subjects with MTC had stable disease (SD) for at least 6 months. 


 
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In Study XL184-201, 196 subjects with relapsed GB have been enrolled. At the dose of 
125 mg qd, cPRs were observed in 11 of 37 (30%) subjects who had not received prior 
anti-angiogenic therapy, with a median duration of response of 5.1 months (range, 0.9+ to 
6.7+). In subjects who had not received prior anti-angiogenic therapy, the 6-month PFS 
rate (PFS6) assessed by Kaplan-Meier estimate was 25%, with a 30% rate of censoring at 
the time of analysis. The median PFS was 16.0 and 7.9 weeks for anti-angiogenic naïve 
and anti-angiogenic pretreated subjects, respectively. At the dose of 175 mg qd, cPRs 
were observed in 7 of 34 (21%) subjects without prior anti-angiogenic therapy, with a 
median duration of response of 2.9 months (range,1.9 to12.8). In subjects who had not 
received prior anti-angiogenic therapy, the Kaplan-Meier estimate of  PFS6 was 10%. 
The median PFS was 15.9 and 14.3 weeks for anti-angiogenic naïve and anti-angiogenic 
pretreated subjects, respectively.  
In Study XL184-202, 65 subjects with non-small-cell lung cancer (NSCLC) have been 
enrolled. As of 01 June 2010, the MTD of the combination of XL184 and erlotinib in the 
Phase 1 portion has not been determined. To date, 8 of 53 evaluable subjects treated in 
Phase 1 have experienced a ≥ 30% decrease in the sum of tumor measurements as 
compared to baseline measurements. Confirmed partial response was achieved in 4 of 53 
(8%) evaluable subjects. 
In Study XL184-203, 198 subjects with advanced solid tumors have been enrolled. Six 
subjects achieved a cPR during the 12-week open-label lead-in stage, two with 
hepatocellular carcinoma [HCC], two with NSCLC, one with melanoma, one with 
prostate cancer). Of the 105 evaluable subjects (with minimum 12 weeks of follow-up), 
43 achieved SD (11 with melanoma, eight with NSCLC, five with pancreatic cancer, five 
with prostate cancer, five with HCC, four with gastric/ gastroesophageal junction [GEJ] 
adenocarcinoma, four with ovarian cancer, and one with small-cell lung cancer [SCLC]). 
The overall disease control rates (partial response [PR] + SD) at Week 12 were 88% in 
the HCC cohort, 86% in the ovarian cancer cohort, 67% in the prostate cancer cohort, 
50% in the melanoma cohort, and 50% in the NSCLC cohort. 


 
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Genotyping data in the XL184-001 study suggest the absence of a correlation between 
RET mutations and either clinical response or time on study. In an ongoing analysis in 
the XL184-201 study, genotyping analysis of several genomic alterations frequently 
found in GB revealed that none appear to confer resistance to XL184. 
Data from subjects enrolled in ongoing clinical studies demonstrated statistically 
significant changes in plasma biomarkers such as sMET and sKIT. Analysis of serial hair 
and/or skin samples revealed substantial inhibition of the phosphorylation of XL184 
targets such as MET, RET, and KIT, as well as of downstream signaling molecules AKT 
and ERK, following administration of XL184. 
1.5 
RATIONALE 
Presence of disease progression by PSA, clinical symptoms, or on scans, despite 
androgen deprivation therapy (ADT), signals the onset of castration resistant prostate 
cancer (CRPC). At this stage, the expected median survival is 18-20 months, despite 
treatment with docetaxel based chemotherapy (Petrylak et al. N Engl J Med 2004 and 
Tannock et al. N Engl J Med 2004). Although novel therapies are showing promising 
efficacy, this disease remains incurable, and development of novel therapies that are 
likely to induce complete remissions is important. Also avoiding the side effects of 
chemotherapy is a worthy goal in the patient population with prostate cancer, that is 
frequently elderly or with significant comorbidities (Oh W et al. Urology 2006 and 
Berthold DR et al. J Clin Oncol 2005). Given the limited life expectancy and the 
significant morbidity of metastatic prostate cancer (MPC), the development of novel 
therapies to improve outcomes is an “unmet need”. We propose to conduct a pilot trial in 
the metastatic CRPC patient population to explore the bone effects and tumor tissue 
effects of XL184. As this is a pilot study with exploratory endpoints, and prior treatment 
with standard of therapy is allowed, a single arm study design is reasonable. 
 
Bone metastases in prostate cancer are primarily osteoblastic with evidence of deposition 
of new bone. The increased osteoblastic activity results in incorporation of Tc99-labeled 
methylene-diphosphonate allowing visualization of the lesions on bone scan. Met and its 
ligand, hepatocyte growth factor (HGF) have demonstrated increased expression after 


 
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androgen ablation as well as with disease progression to lymph nodes and soft tissue. 
XL184 is a VEGF and c-met inhibitor that has demonstrated promising clinical efficacy 
in metastatic CRPC. Not only does the agent produce promising response rates in 
measurable disease, but a marked change in  bone scans is noted (Smith D. et al. ASCO 
GU Symposium 2011 Abstract #127). This is an unusual phenomenon, not seen even 
with any of the other agents that produce high levels of anti-tumor efficacy such as ADT. 
The physiologic changes occurring with the rapid normalization of bone scans (within the 
first 6 weeks) are unknown to date. We propose a pilot trial to study the changes 
occurring in bone metastases and in tumor tissue and to correlate with clinical outcome, 
with XL184 therapy. We hypothesize that XL184 uniquely targets the crosstalk between 
cMet/VEGFR2 axis, downstream cathepsin K-driven pathways and novel RTKs (e.g., 
DDR-1, DDR-2) in the bone tumor microenvironment. XL184 action leads to abrupt 
changes in bone metabolism and abrogation of 99mTc-MDP uptake due to the inhibition of 
osteoclast activity and subsequent decrease in osteoblast function.   
 
Proposed Model for XL 184 Mechanism of Action in Prostate Cancer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Proposed Mechanism of Action of XL 184 in Prostate Cancer.  
XL184 predominantly targets RTKs involved in tumor-induced bone resorption. 
Inhibition of osteoclast activity by XL184 results in reduced levels of the key osteoclast 
collagenase CTSK and overall inhibition of bone turnover. Inhibition of DDR-1, and -2 
directly by XL184 and indirectly by reduced availability of resorbed collagen abrogates 
collagen-induced osteoblast differentiation and woven bone deposition.  Abbreviations: 
RANKL ((Receptor Activator of NF-κB ligand), VEGF (Vascular Endothelial Growth 
Factor), VEGFR1-, 2- (VEGF Receptors), HGF (Hepatocyte Growth Factor), cMet 
(HGF Receptor), MCSF (Macrophage Colony Stimulating Factor), c-fms (MCSF 
Receptor), SCF (Stem Cell Factor), c-kit (SCF Receptor), FLt3 (FMS-like Tyrosine 
Kinase 3), DDR-1,2 (Discoidin Domain Receptor), PIGF (Placental Growth Factor), 
CTSK (Cathepsin K), TRAcP (Tartrate Resistant Acid Phosphatase), NTx (N-
Telopeptide), CTx (C-Telopeptide), ET-1 (Endothelin-1). 


 
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Imaging Studies 
 
99mTc-MDP bone scan is a most widely used, standard of care method for evaluating 
skeletal metastases of prostate cancer.  The 99mTc-MDP accumulates in new (woven) 
bone and is an indicator of changes in bone metabolism associated with prostate cancer-
induced osteoblastic response. However, 99mTc-MDP scan findings are not specific in 
determining the cause of increased or decreased uptake and are indirect markers of 
response to treatment [Schoder H, et al. Semin Nucl Med 2004]. 18F-flouride PET scans 
have improved anatomic detail over 99mTc-MDP scans, a higher accuracy in detecting 
both osteolytic and osteoblastic metastases and allow quantification of the extent of 
metastatic lesion [Shreve PD et al. Radiology 1996].  This imaging modality may be 
superior to 18F-FDG PET for prostate cancer, since the bone metastases in prostate 
cancer are primary osteoblastic. Osteoblastic metastases tend to exhibit a high rate of 
fluoride incorporation (Schoder H, et al. Semin Nuc Med 2004) and may have low FDG 
uptake (Shreve PD et al. radiology 1996). Additionally, 18F-flouride PET has improved 
sensitivity and specificity when compared to standard 99mTc-MDP bone scintigraphy, and 
importantly, PET offers the ability for rigorous quantification.(Heicappell R et al. Eur 
Urol 1999, Yeh SD, et al. Nuc Med Biol 1996 and Schirrmeister H, et al. J Clin Oncol 
1999). It is currently being evaluated in association with other therapeutic trials in 
prostate cancer (American College of Radiology Network, ACRIN Trial # 6687) to detect 
pharmacodynamic effects of novel agents. We will utilize the 18F-flouride PET in this 
study to trace the absorption of fluoride ion by bone tissue and quantify bone response. 
 
PET obtained with the thymidine analog 18F-FMAU scan then be used to image tumor 
metabolism and it is based on incorporation of the tracer by mitochondrial thymidine 
kinase 2 (TK2) [Shields EF, et al. J Nucl Med 1998 and Tehtani OS, et al. Eur J Nucl 
Med Mol Imaging 2008].  The three modalities complement each other in distinguishing 
bone changes vs. tumor response to XL184. Distribution of 18F-FMAU is useful in 
measuring cellular metabolism. Measurements of metabolism made during or after 
therapy would be far more sensitive measures of anti tumor effects than the more 


 
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conventional approach of observing the tumor for changes in size or just detecting 
location of the bone turnover as seen with 99mTc-MDP conventional bone scans. A 
decrease in mean SUV by 20% is considered a PET response and will be used as the 
threshold to detect changes. We have previously reported on the use of FMAU scans for 
detection of prostate cancer bone metastases from a study conducted at our institution 
[Sun H et al. Eur J Nucl Med Mol Imaging 2005].  We will utilize the18F-FMAU PET to 
detect and quantify changes in tumor metabolism due to incorporation by mitochondrial 
thymidine kinase. 
 
 
This study will utilize standard of care 99mTc-MDP bone scan, high resolution 18F-
flouride PET to measure effects of XL184 treatment on bone tissue, and 18F-FMAU PET 
to measure changes in tumor metabolism in response to therapy. Imaging will be 
performed using a gamma camera and PET/CT scanners. 99mTc-MDP bone scans, 18F-
flouride PET and 18F-FMAU PET is already approved for NOMIC-funded study (C-
2335, Shields, AF; PI). We propose evaluating patients with 18F-flouride imaging pre and 
post XL184 therapy to determine the optimal timing when bone scan normalization 
occurs. So approximately 5 patients will be evaluated with 18F-flouride imaging pre and 
within 2-3 weeks post XL184. Then we will determine the optimal timepoint to perform 
imaging with FMAU PET scans to evaluate for anti tumor effect, as well as the possible 
osteoclast and osteoblast inhibition resulting from the medication, and the mechanisms 
underlying it.  
 
Serum, Urine and tumor Tissue Correlates 
 
XL184 uniquely targets osteoclast-driven events in the bone tumor microenvironment 
that ultimately affect osteoblast differentiation and new bone formation. Gene expression 
profiling analyses will validate novel molecular signatures with therapeutic potential 
identified by gene expression analysis. We propose to perform aCGH (array comparative 
genomic hybridization), expression profiling of human bone biopsy samples to determine 
molecular signatures prior to and in response to XL184 treatment. 


 
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This study will generate precious bone biopsy samples from bone lesions identified by 
imaging. These samples offer unique opportunity for analysis of changes in gene 
expression profiles in response to treatment.  Particularly, imaging-guided assessment of 
early bone/tumor responses can potentially lead to identification of novel targets that 
distinguish responsive lesions from ones that progress.    
 
We will also examine the effects of XL184 treatment on bone turnover and tumor growth 
and survival via histological, immunohistochemical and serum bone marker analyses in 
human bone biopsy samples. We will utilize established protocols and procedures for 
aCGH, expression profiling, as well as histological and serum marker analyses. 
Performing aCGH will allow us to identify genetic translocation such as TMPRSS2-
ERG.   In addition, archival tissue will be collected and c-met and VEGF expression will 
be evaluated pre and post therapy. Pre and post therapy CTC counts and phenotype will 
be tested. Post therapy biopsies will be obtained for checking for VEGF and c-met 
expression, and pre and post therapy serum and urine bone markers to assess bone 
turnover will be examined.  Baseline tumor tissue will be evaluated for oncogene 
mutations and correlated with response and clinical outcome. Although there are no 
common point mutations in oncogenes, we have the capability (such as the 
pyrosequencer and sequenom) to perform mutational assays on any gene discovered in 
the future.  
 
The clinical response and outcome will be correlated with changes noted in tumor 
imaging and tissue changes to explore the pathways influencing antitumor efficacy of this 
novel agent. 
 
 
Based on prior clinical trial enrollment, about 40% of the patient population is 
expected to be of African American ancestry. This will enable evaluation of XL184 
effects in a population where it has not been systematically studied. Given the likely 
differences in prostate cancer disease course and biology, and associated comorbidities 
such as hypertension, this experience would broaden the safety and efficacy data 
regarding XL184. 


 
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1.3.1 Rationale for Cabozantinib Dose Selection 
A cabozantinib starting dose of 100 mg daily has been studied in 171 CRPC subjects 
enrolled to the Phase 2 XL184-203 RDT. Despite relatively high rates of cabozantinib 
dose reductions to the next lowest dose of 60 mg daily within the first 12 weeks of 
therapy (51%), this starting dose resulted in high rates of pain relief, bone scan 
improvement, and overall disease control.  
Preliminary data from a separate and ongoing dose-ranging study looking at lower doses 
of cabozantinib in CRPC coupled with results from a retrospective review of the Phase 2 
XL184-203 RDT indicate that lower doses below 100 mg daily are likely to retain 
efficacy while improving upon tolerability: 
Preliminary results from an ongoing dose-ranging study: To date, 9 subjects with 
metastatic CRPC enrolled to the first cohort (starting dose of 40 mg qd) are evaluable for 
bone scan response. All 9 subjects exhibit evidence of response on bone scan including 
two complete responses. Although most subjects did not have pain at baseline, one 
subject reported pain at baseline which resolved by Week 6. No dose reductions or 
interruptions have been reported to date, although one subject discontinued study 
treatment for fatigue that was present at baseline and another subject discontinued 
because of a pathologic fracture. This provides preliminary evidence that lower doses are 
pharmacologically active in a patient population with advanced CRPC.  
 
Retrospective review of Phase 2 XL184-203 RDT: While the overall rate of dose 
reduction from 100 mg to 60 mg was 51%, only 14% required an additional reduction in 
dose from 60 mg to the next lowest dose of 40 mg, which is consistent with an overall 
improvement in tolerability profile at the 60-mg dose level. The majority (69%) of 
subjects with pain at baseline who experienced early dose reduction (before Week 6) to 
60 mg went on to report pain improvement at Week 6. Moreover, 80% of these subjects 
remained progression-free and continued to report pain relief at the Week 12 time point. 
Thus the dose of 60 mg qd appears to offer improved tolerability while maintaining 
efficacy in a patient population with advanced CRPC and cancer-related pain at baseline.  
 
Further analysis of the timing of AEs that led to dose reductions or interruptions was 
conducted. The median time to first AE triggering a dose reduction or interruption at 100 
mg qd was 29 days, with very few subjects experiencing significant toxicity in the first 2 
weeks of study treatment. 
 
As such this study will adopt a starting cabozantinib dose of 60 mg qd. The goal of this 
regimen is to improve the overall tolerability of cabozantinib while maintaining efficacy 
in this patient population. 
  
 


 
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2 
STUDY DESIGN 
2.1 STUDY DESIGN  
2.1.1 
Overview of Study Design 
The study consists of open label daily, oral administration of XL184 or cabozantinib at a 
starting dose of 60mg to eligible patients.  
Administration  
 
Subjects will be provided with a sufficient supply of study treatment and instructions for 
taking the study treatment on days without scheduled clinic visits. After fasting (with 
exception of water) for 2 hours, subjects will take study treatment daily with a full glass 
of water (minimum of 8 oz/ 240 mL) and continue to fast for 1 hour after each dose of 
study treatment. Subjects should record dosing time and doses taken in a study drug 
dosing diary while on study treatment. If doses are withheld, the original schedule of 
assessments should be maintained when XL184 is restarted. The subject should be 
instructed to not make up the missed doses and to maintain the planned dosing schedule. 
Subjects must be instructed to not make up missed doses that are vomited.  
This study consists of the following: (1) a Study Treatment Period consisting of 
continued treatment with XL184, and (2) a Post-Treatment Period.  
 
2.1.2 
Study Treatment Period  
The Study Treatment Period will consist of continued treatment during which time 
subjects will receive XL184 until either disease progression or the occurrence of 
unacceptable drug-related toxicity. Subjects will be assessed for safety at least every 2 
 weeks for the first 3 months and then at least every 4 weeks thereafter.  Adverse events 
will be collected throughout the study and recorded in the subject’s clinical records  
Subjects’ tumors will be objectively assessed by PET scans and CT scans and bone scans. 
The purpose of these assessments is to allow the investigator to determine if the subject is   
benefiting from XL184 and to explore the mechanisms of changes occurring in bone and 


 
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tumors. The response will be assessed by PSA working group criteria and by RECIST 1.1 
criteria for measurable disease. Karmanos Cancer institute purchases clinical services 
(i.e. CT scans, PET/CT scans, pulmonary function test, etc.) from the Detroit Medical 
Center (DMC), a clinical services provider on the medical campus.  The consent form 
language informs the subjects that they may receive services in a DMC facility. 
 
 
 
 


 
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2.3 STUDY CALENDAR: 
Prestudy labs should be done within 21 days of day 1. Day 1 labs can be done within 3 
days of day 1. A time period of +/- 3 days is permitted for each of the days listed in the 
calendar 
Testing 
Prestudy 
Day 
1 
Wk 1 
wk 2 
wk 4 
wk 6 
Wks 
8, 10 
12 
Q 4 
wks 
post 
wk 12 
Q12 
wks 
post 
wk 810   
H and P 
X 
X 
X 
X 
X 
X 
X 
X 
 
VS, Wt 
X 
X 
X 
X 
X 
X 
X 
X 
 
PS 
X 
X 
 
X 
X 
X 
X 
X 
 
Tox 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBCdiff,plt 
X 
X 
X 
X 
X 
X 
X 
X 
 
Lytes,glu1 
X 
X 
X 
X 
X 
X 
X 
X 
 
Labs/LFTs2 
X 
X 
 
X 
X 
X 
X 
X 
 
PSA 
X 
X 
X 
X 
X 
X 
X 
X 
 
Testosterone, 
PT/PTT/INR 
 
X 
 
 
 
 
 
 
 
 
TSH, free T4 
X 
 
 
 
 
X 
 
 
X 
UA/UPC 
X 
 
X 
 
X 
X 
X 
X 
 
ECG,3 
X 
 
 
 
X 
 
X3 
X3 
X3 
Biopsy 
X 
 
 
X 
 
 
 
 
 
CT/CXR4,5 
X 
 
 
 
 
X 
 
 
X 
MDP-Bone 
scan5 
X 
 
 
X 
 
X 
 
 
X 
 18F-flouride-
PET6 
X 
 
 
X 
 
 
 
 
X 
XL184 
 
X 
X 
X 
X 
X 
X 
X 
X 
FMAU PET7 
X 
 
 
X 
 
 
 
 
 
CTC8 
X 
 
 
X 
 
 
 
 
 
PD/Bone 
markers9 
X 
 
X 
X 
X 
 
 
 
 


 
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1. Lytes include lytes, BUN and creatinine assessment. Fasting glucose should be 
measured. 
2. Labs include: Amylase, lipase, Albumin, alkaline phosphatase, total bilirubin, calcium, 
chloride, magnesium, γ-GT, LDH, inorganic phosphorus, total protein, SGOT, SGPT. If 
the total bilirubin concentration is increased above 1.5 times the upper normal limit 
(UNL), total bilirubin should be differentiated into the direct and indirect reacting 
bilirubin. 
3. ECG assessments prestudy, once every 4 weeks through week 12 and then every 8 
weeks beyond week 12. 
4. CXR is required pretherapy unless pulmonary metastases are noted. If pulmonary 
metastases, then chest CT is needed at baseline and for subsequent tumor assessment. If 
CT chest is done pretherapy, then CXR is not needed  
5. All tumor evaluation/measurement scans must be within 42 days prior to treatment. CT 
abdomen /pelvis is required for pretreatment and subsequent tumor assessments. 
6. FMAU scans are done under a separate protocol and patients will have to sign consent 
for those studies separately. Repeat bone scans and PET scans will be done during week 
2 on first 5 patients and the schedule will be re–evaluated based on findings. 18F-flouride 
PET scans should preferably be done before the bone scan in week 2. At week 32+/- 10 
weeks or at the time of discontinuing study therapyif this occurs prior to week 32, a 18F-
flouride PET scan will be done. A FMAU scan will also be done at the same time period 
if patient has had <3 FMAU scans in his lifetime. 
7. The schedule for FMAU PET will also be determined based on the timeline of changes 
observed in bone scans and PET scans in the first 5 patients. 
8.  CTC samples will be drawn at pretherapy, week 2 (post therapy) and at progression. 
9. PD samples and bone markers ; blood samples and urine will be collected per 
schedule; pretherapy day 8 (week 1), day 15 (week 2) and day 29 (week 4). For bone 
markers, 4cc of blood should be collected in a tiger top tube and the urine NTx requires a 
24 hour urine collection. 
10. End of treatment and follow up within 4 weeks of discontinuing therapy: End of 
treatment visit- EKG, urine analysis and CBC, multiphasic and PSA. Repeat tumor 


 
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assessment if not performed within the last 6 weeks. At week 32+/- 10 weeks or at the 
time of discontinuing study therapy if this occurs prior to week 32, a 18F-flouride PET 
scan and /or FMAU scan (only if patient has had <3 FMAU scans in his lifetime) will be 
done. 
All study bottles and diaries will be collected and submitted.  Patients will be followed 
for a maximum of 5 years after end of treatment. Follow up will be for survival, 
progression and next line of therapy.  
 
2.1.3 
Post-Treatment Period 
Subjects will return to the study site to complete end-of-study assessments 4 weeks 
(± 2 week) after their last dose of XL184. Patients will be followed for progression free 
survival and overall survival. 
2.4 
Treatment Assignment  
It is the responsibility of the investigator to assign a subject number prior to treating each 
subject with XL184. 
2.5 
Study Sites 
This study will be conducted at Karmanos Cancer Center, Detroit MI. 
2.6 
Withdrawals 
Subjects may discontinue study treatment or withdraw their consent to participate in the 
study at any time without prejudice. The investigator may withdraw a subject from study 
treatment or from the study if, in his or her clinical judgment, it is in the best interest of 
the subject or if the subject cannot comply with the protocol.  
In addition, any of the following conditions require withdrawal of the subject from study 
treatment: 
 An AE or intercurrent illness that in the opinion of the investigator warrants the 
subject’s withdrawal from treatment 


 
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 Necessity for treatment with other investigational drug or other anticancer 
medications prohibited by protocol 
 Participation in another clinical study using an investigational agent 
 Request by regulatory agencies for termination of treatment of an individual subject 
or all subjects under this protocol 
 Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (eg, male condom, or diaphragm with spermicidal gel) during the 
course of the study and for 3 months following discontinuation of study treatment. 
 Inability to tolerate XL184 
 XL184 treatment delays > 3 weeks 
 Progressive disease (PD) as determined by the investigator.  
 
The reason for study treatment discontinuation will be documented. For subjects who 
discontinue or 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. 
If a subject withdraws consent to participate in the study, the reason for withdrawal will 
be documented, no 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. 


 
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2.7 TREATMENT PLAN AND DOSE MODIFICATIONS 
Composition, Formulation, and Storage 
At study site, all study medication will be stored as described in the pharmacy manual 
and inventoried in accordance with applicable state and federal regulations. 
2.7.1 Investigational Treatment  
 
XL184 Tablets  
Investigational Treatment: Cabozantinib tablets 
Chemical Name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-(4-
fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate 
Exelixis internal number: XL184 
Exelexis will provide each investigator with adequate supplies of cabozantinib, which 
will be supplied as 60-mg, and 20-mg yellow film-coated tablets. The 60-mg tablets are 
oval, and the 20-mg tablets are round. The components of the tablets are listed below. 


 
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Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Cabozantinib Drug Substance (25% drug load as free base) 
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 
 
Dose, Schedule and Route 
Subjects will receive XL184 orally at a (starting) dose of 60 mg once daily (3 Tabs of 20 
mg each or 1 Tab of 60 mg each). The study consists of open label daily, oral 
administration of XL184 or cabozantinib at a starting dose of 60 mg (dose level 1) to 
eligible patients. Dose adjustment levels are given in table below: 
 
 
Dose Level 
Agent 
Dose 
Route 
Frequency 
Starting 
XL 184 
60 mg 
PO 
Daily 
-1 
XL 184 
40 mg 
PO 
Daily 
-2 
XL 184 
20 mg 
PO 
Daily 
 
Administration  
Subjects will be provided with a sufficient supply of study treatment and instructions for 
taking the study treatment on days without scheduled clinic visits. After fasting (with 


 
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exception of water) for 2 hours, subjects will take study treatment daily with a full glass 
of water (minimum of 8 oz/ 240 mL) and continue to fast for 1 hour after each dose of 
study treatment. Subjects should record dosing time and doses taken in a study drug 
dosing diary while on study treatment. If doses are withheld, the original schedule of 
assessments should be maintained when XL184 is restarted. The subject should be 
instructed to not make up the missed doses and to maintain the planned dosing schedule. 
Subjects must be instructed to not make up missed doses that are vomited.  
2.7.2General Guidelines for Treatment Delay, Dose Reduction, or Study Drug 
Discontinuation for Toxicity 
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. 
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.  
Re-escalating study treatment after a dose reduction: 
 Subjects who required a dose reduction for Grade 3 or 4 non-hematologic toxicity 
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 upon re-escalation, 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.  
 
Discontinuation from study treatment: 
 If the subject does not recover from his or her toxicities to tolerable Grade ≤ 2 within 
3 weeks, the subject will have study treatment discontinued unless there is 


 
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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. 
. 
 The minimum dose of study treatment will be 20 mg daily. Subjects who cannot 
tolerate 20 mg daily dose, will have study treatment discontinued. 
 
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. 
 
2.8 Warnings, Precautions, and Management of Anticipated Adverse Events 
The general adverse event profile of cabozantinib includes GI symptoms (such as nausea, 
vomiting, and diarrhea), fatigue, anorexia, palmar-plantar erythrodysesthesia (PPE) 
syndrome, skin rash, elevated ALT and AST, increased pancreatic enzymes with rare 
cases of  pancreatitis, as well as side effects associated with inhibition of VEGF signaling 
such as thrombotic events (eg, pulmonary embolism [PE] and deep vein thrombosis 
[DVT]), hypertension, proteinuria, hemorrhagic events, and rare cases of gastrointestinal 
[GI] perforation and rectal/perirectal abscess. Arterial thromboembolism (transient 
ischemic attack [TIA], myocardial infarction [MI]) have been reported rarely.   
2.9 Management of Adverse Events 
In the absence of an unacceptable cabozantinib-related toxicity and/or clinical signs of 
disease progression, subjects may continue treatment at the discretion of the investigator. 
Subjects must be instructed to notify their physician immediately for any and all 
toxicities. 
Guidelines for the management of AEs (ie, dose interruptions and dose reductions) are 
presented in the next sections. 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. 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). 


 
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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. 
2.10 General Guidelines for Non-Hematologic and Hematologic Adverse Events 
General guidelines for the management of non-hematologic and hematologic toxicities 
are provided in Table 3-2 and Table 3-3, respectively. As a general approach, it is 
suggested that all AEs be managed with supportive care when possible at the earliest 
signs of toxicity. 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 
perforation and gastrointestinal fistula, wound healing and surgery, and endocrine 
disorders, refer to Section 3.4.1.2 – Section 3.4.1.13 below.  Guidance for the 
management of fatigue, anorexia, weight loss, non-gastrointestinal fistula, osteonecrosis 
of the jaw, eye disorders, musculoskeletal and connective tissue disorders, nervous 
system disorders, respiratory/thoracic/mediastinal disorders and congenital, familial and 
genetic disorders can be found in the Investigators Brochure.  
 
 
 
2.11 Dose Modification Criteria and Management of Adverse Events 
 Dose Modification levels: 
Table 1 
Dose Level 
Agent 
Dose 
Route 
Frequency 
Starting 
XL 184 
60 mg 
PO 
Daily 
-1 
XL 184 
40 mg 
PO 
Daily 


 
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-2 
XL 184 
20 mg 
PO 
Daily 
 
 
  
 


 
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General Approach to the Management of Study Treatment-Related Non-
Hematologic Toxicities 
CTCAE Version 4 Grade  
Guidelines/Intervention 
Grade 1: 
Add supportive care as indicated.  Continue study treatment at the 
current dose levels. 
Grade 2: 
Grade 2 AEs considered related to 
study treatment that are subjectively 
tolerable or easily managed 
Add supportive care as indicated.  Continue study treatment at the 
current dose levels.  
Grade 2 AEs considered related to 
study treatment 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 resolves to Grade ≤ 1 or baseline 
without a dose interruption, continue the reduced dose. 
Grade 3: 
 
Grade 3 AEs considered related to 
study treatment which occurred 
without optimal prophylaxis or 
which is easily managed by medical 
intervention or resolved quickly 
 
Interrupt study treatment 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,  treatment 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, treatment 
should be restarted with a dose reduction.  Note: if the 
investigator believes the likelihood of a reoccurrence of the 
same Grade 3 AE is small due to continued prophylaxis or 
other effective intervention, treatment may be resumed 
without a dose reduction and with very careful monitoring of 
the subject.   
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. 


 
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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 0-1 General Approach to the Management of Hematologic Toxicities 
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 resolution to ≤ Grade 1, 
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. 
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 (<LLN – 75 x 109/L); Grade 2  (<75.0 – 50.0 x  109/L);   
Grade 3 (Platelet count ≤ 50 - 25  109/L); Grade 4 (Platelet count < 25  109/L). 
 
2.11.1Diarrhea, 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. 


 
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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 (Benson et al. 2004). Some subjects may require concomitant therapy with 
loperamide, diphenoxylate/atropine, and deodorized tincture of opium to control diarrhea. 
When combination therapy with antidiarrheal agents does not control the diarrhea to 
tolerable levels, a dose reduction and/or dose interruption of cabozantinib should be 
implemented as described.  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.  A dose reductions and/or dose interruption of 
cabozantinib may be required as described in Table if antiemetic treatment and/or 
prophylaxis alone is not adequate.  
Agents classified as having a high therapeutic index (such as 5-HT3 receptor antagonists, 
or NK-1 receptor antagonists) per ASCO or MASCC/ESMO guidelines for anti-emetics 
in oncology or dexamethasone are recommended (Hesketh et al. 2008, ASCO 2006; 
Roila et al, Annals of Oncology, 2010). Caution is recommended with the use of 
aprepitant or fosaprepitant and nabilone as cabozantinib exposure may be affected by 
concomitant administration because aprepitant and fosaprepitant are both inhibitors and 
inducers of CYP3A4, and nabilone 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 (eg, 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. 


 
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When stomatitis interferes with adequate nutrition and local therapy is not adequately 
effective, dose reduction or temporary withholding of cabozantinib should be considered. 
2.11.2 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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Transaminase elevation 
CTCAE v4.0 
 
Intervention 
Subjects with AST and ALT less than or equal to the ULN at baseline 
Grade 1  
Continue study treatment 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 study treatment 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 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 
Grade 3  
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 
Subjects with AST or ALT above the ULN  but ≤ 3.0 x ULN (i.e., Grade 1) at  baseline   
≥ 1.5 fold transaminases 
increase (at least one of 
AST or ALT) and still 
Grade 1 or Grade 2 
Continue study treatment with at least twice weekly monitoring of LFTs 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 transaminases 
increase (at least one of 
AST or ALT) and Grade 
3 
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. 
Subjects  AST or ALT > 3.0 but ≤ 5.0 x ULN at  baseline   
≥ 1.5 fold transaminases 
increase (at least one of 
AST or ALT) and still 
Grade 2 or Grade 3 
Interrupt study treatment and monitor with at least twice weekly LFTs until 
LFTs resolve to baseline and Grade ≤ 2.  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. 


 
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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 (eg, 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  ULN, total bilirubin < 1.5  ULN, aminotransferases < 2.5 
 ULN or baseline).  
Subjects must have cabozantinib permanently discontinued if transaminase elevations are 
accompanied by evidence of impaired hepatic function (bilirubin elevation >2xULN), in the 
absence of evidence of biliary obstruction (i.e., significant elevation of alkaline phosphatase 
[ALP]) 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.  
2.11.3 Pancreatic Conditions 
Amylase and lipase elevations have been observed in clinical studies with cabozantinib. 
The clinical significance of asymptomatic elevations of enzymes is not know but in 
general have 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. 


 
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Asymptomatic Lipase or Amylase Elevations 
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 elevations recur, then treatment must be 
interrupted again and till 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. 
Symptomatic Pancreatitis 
Pancreatitis 
Grade 1  
Continue at current dose level.  More frequent monitoring of lipase and 
amylase and radiographically  is recommended 
Grade 2 
 
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 2 pancreatitis is at the same dose and 
Grade 2 pancreatitis recurs, then treatment must be interrupted 
again and till resolution to Grade ≤ 1 or baseline and retreatment 
must be at a reduced dose. 
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 dose per investigator judgment. 


 
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2.11.4 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 with cabozantinib. All subjects on study should be advised 
on prophylactic measures including the use of emollients, removal of calluses, avoidance 
of exposure of hands and feet to hot water leading to vasodilatation, protection of 
pressure-sensitive areas of hands and feet, and use of cotton gloves and socks to prevent 
injury and keep the palms and soles dry. 
The onset of PPE is variable with paraesthesia (tingling, numbness) being the 
characteristic initial manifestation, which can be accompanied by slight redness or mild 
hyperkeratosis. PPE advances with symmetrical painful erythema and swollen areas 
(edema) 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. Subjects with skin disorders should be carefully monitored for signs of infection 
(eg, abscess, cellulitis, or impetigo). 
In the case of study treatment-related skin changes (eg, 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) 
No apparent toxicity 
Prophylaxis with Ammonium lactate 12% cream (Amlactin®) twice daily 
OR heavy moisturizer (e.g. Vaseline) twice daily 
Grade 1 
Continue treatment at current dose if tolerable or reduce to the next lower 
dose if intolerable. 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.  If severity worsens at any time or if there is no improvement after 
2 weeks, proceed to the management guidelines for Grade 2 PPE 
Grade 2 
Reduce study treatment to next lower level and/or interrupt dosing. 
Start/continue urea 20% cream twice daily AND clobetasol 0.05% cream 
once daily. Pain control with NSAIDs/GABA agonists/narcotics. Assess 
subject at least weekly for changes in severity.  Subjects should be instructed 
to notify investigator immediately if severity worsens.  If severity worsens at 
any time (eg, peeling, blisters, bleeding, edema, or hyperkeratosis or affects 
self-care) or if there is no improvement after 2 weeks, proceed to the 
management guidelines for Grade 3 PPE.  If the dose was reduced, then 
upon resolution to Grade 0 or Grade 1, treatment may continue at the 
reduced dose.  If the dose was only interrupted but not reduced, then 
treatment may be restarted at one dose level lower. 
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 
2.11.5 Embolism and Thrombosis  
In clinical studies with cabozantinib, venous thrombotic events (DVT and PE) have been 
observed in less than 10% of subjects, and arterial thromboembolic events (MI and TIA) 
have been reported rarely. In addition, subjects with cancer have a significantly increased 
likelihood of developing thromboembolic complications (Agnelli et al, 2009).  
Subjects who develop a PE and/or DVT should have study treatment interrupted until full 
anticoagulation is established with low molecular weight heparin (LMWH)  (Full 
anticoagulation with warfarin is not permitted). 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 


 
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subjects, prophylactic anticoagulation is allowed for individual subjects at the discretion 
of the investigator. 
Cabozantinib should be discontinued in subjects who develop an acute MI or any other 
clinically significant arterial thromboembolic complication. 
2.11.6 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 the first measurement. Other than for hypertension requiring 
immediate therapy, the presence of new or worsened hypertension should be confirmed at 
a second visit before taking new therapeutic action. 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. 


 
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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, 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. 
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 
 
2.11.7 Proteinuria 
Proteinuria has been reported with approved drugs that inhibit VEGF pathways as well as 
with cabozantinib. Development and worsening of proteinuria should be monitored by 
serial urinalysis (qualitative/semiquantitative assessment by dipstick; quantitative 
assessment by urine protein/urine creatinine ratio [UPCR], or 24-hour urine protein 
excretion). When a UPCR exceeds 1 (mg/dL protein / mg/dL creatinine), 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 


 
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(proteinuria > 3.5 grams per day in combination with low blood protein levels, high 
cholesterol levels, high triglyceride levels, and edema) 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 below: 
Management of Treatment Emergent Proteinuria 
 Urine Protein/Creatinine Ratio 
Action To Be Taken 
≤ 1 
 
No change in treatment or monitoring 
> 1 and < 3.5 
 
 
Confirm with a 24 hour urine protein excretion within 7 days 
 
If proteinuria of > 1 g/24 hours is confirmed, hold 
cabozantinib and continue with UPCR monitoring. When 
UPCR returns to < 1, 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. 
≥ 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, 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 
2.11.8 Hemorrhage 
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 of the lung with cavitations or tumor lesions which invade, encase, or 
abut any major blood vessels; non-small cell lung cancer (NSCLC) with squamous 
cell differentiation is known for significant lung cavitations and centrally located 


 
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tumors that may invade major blood vessels. The anatomic location and 
characteristics of tumor as well as 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 (eg, deficiencies in 
clotting factors and/or platelet function, or thrombocytopenia) 
 Concomitant medication with anticoagulants or other drugs which affect normal 
hemostasis 
 
Based on the described predisposing risk factors for hemoptysis, many studies with 
antiangiogenic drugs exclude subjects with NSCLC and squamous cell differentiation. 
Although enrollment of subjects with NSCLC with squamous cell differentiation has 
been allowed on cabozantinib studies, cabozantinib studies exclude NSCLC subjects with 
any of the following: tumors abutting, encasing, or invading a major blood vessel; 
cavitating lesions; history of clinically significant hemoptysis; or recent (within 
3 months) radiation therapy to the thoracic cavity including brachytherapy unless 
radiation therapy targets bone metastasis. 
Cabozantinib should be discontinued in subjects with serious and life-threatening 
bleeding events or recent hemoptysis (≥ ½ tablespoon 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. 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. 
2.11.9 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. 


 
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2.11.10Gastrointestinal perforation and GI fistula  
Gastrointestinal perforation and GI fistula have been reported with approved drugs that 
inhibit VEGF pathways as well as with cabozantinib. To allow for early diagnosis, 
subjects should be monitored for episodes of abdominal pain, especially if known risk 
factors for developing GI perforation or fistula (Turnage et al. 2008) are present. Such 
risk factors include (but may not be limited to) the following: 
 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.  
Additional risk factors include concurrent use of steroid treatment or non-steroidal 
anti-inflammatory drugs (Rodriguez et al. 2001, Straube et al. 2009). Constipation, 
consistent with symptoms of bowel obstruction, should be monitored and effectively 
managed. Discontinue cabozantinib and initiate appropriate management in subjects who 
have been diagnosed with GI perforation or fistula. 
2.11.12 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. 


 
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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.  
2.11.13 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. In Study XL184-203, 17 of 34 (50%) euthyroid subjects with castration-
resistant prostate cancer (CRPC) developed abnormal thyroid-stimulating hormone 
(TSH) levels 6 weeks after initiation of cabozantinib treatment (6% showed TSH levels 
between 5 and 7 mU/L, 44% had TSH > 7 mU/L). The median TSH level at week 6 was 
5.2 mU/L (range, 0.02-29.7 mU/L). In a Phase 1 combination study  of rosiglitazone and 
cabozantinib (XL184-008) to determine the potential for a clinically significant drug-drug 
interaction of cabozantinib on the CYP isozyme CYP2C8, subjects with advanced solid 
tumors (particularly renal cell carcinoma [RCC] and differentiated thyroid cancer [DTC]) 
are enrolled. Among 11 evaluable subjects, the AE of hypothyroidism was reported in 
55% of subjects. Currently available data are insufficient to determine the cause of TFT 
alterations and its clinical relevance. 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 
(eg, 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 recommended. Cabozantinib should 
be discontinued in subjects with severe or life-threatening endocrine dysfunction. 
2.11.14  Guidelines for Management of Treatment-Emergent Corrected QT (QTc) 
Prolongation 
In preclinical studies, high doses of cabozantinib (up to 1000 mg/kg) in dogs had no 
effect on electrocardiographic parameters, including QT and QTc intervals. However, the 
current clinical safety profile of cabozantinib indicates a mild to moderate prolongation 
effect upon QT and QTc intervals at clinically relevant exposures. Other factors which 
may contribute to QTc prolongation include 


 
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 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 should have 
ECGs performed approximately one week after the onset of these factors. 
A very recent analysis of ECG data from the XL184-301 study, An International, 
Randomized, Double-Blinded, Phase 3 Efficacy Study of XL184 versus Placebo in 
Subjects with Unresectable, Locally Advanced, or Metastatic Medullary Thyroid Cancer 
,in which 214 subjects were randomized to cabozantinib and 109 subjects randomized to 
placebo, demonstrates a mild to moderate prolongation of the QTcF in cabozantinib-
treated subjects vs placebo-treated subjects. Although subjects were treated with a higher 
dose in that study, we believe it is appropriate to monitor patients for QTc prolongation.  
No subject had a QTcF greater that 500 msec.   
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 consultation with a cardiologist 
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 and the subject has been thoroughly evaluated. If any additional study 
treatment is given (eg, after correction of electrolyte abnormalities and normalization of 
QTcF), it will be at a reduced dose per protocol dose levels. 
 
2.12 Concomitant Medications and Therapies 
2.12.1 Anticancer Therapy 
If a subject requires additional systemic anticancer treatment, including steroid treatment 
for prostate cancer therapy, study treatment must be discontinued. Local intervention is 


 
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discouraged unless medically unavoidable. Subjects receiving local intervention 
(eg, 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. 
2.12.2 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. 
Anti-emetics and anti-diarrheal medications should not be administered prophylactically 
prior to the first dose of cabozantinib. After the first dose of study treatment, at the 
discretion of the investigator or after the onset of symptoms, treatment (or prophylaxis) 
with anti-emetic and anti-diarrheal medications may be undertaken per standard clinical 
practice. Bisphosphonates are allowed if started prior to screening activities or may be 
initiated during the course of the study to control bone pain. 
Colony stimulating factors (eg, 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. 
2.12.3 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 (ie, 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).  


 
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Cabozantinib is a CYP3A4 substrate (but not a CYP2C9 or CYP2D6 substrate), based on 
data from 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 (eg, 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. 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 (eg, 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 (eg, CYP2C8, CYP2C19, CYP2B6, CYP1A2) to alter cabozantinib 
exposure is not known. Therefore, these drugs should be used with caution when given 
with cabozantinib.  


 
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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 (eg, 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 interaction.  
Other Interactions: A relative bioavailability study in dogs suggests that cabozantinib is 
unlikely to be affected by drugs that alter gastric pH. 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 
2.13 Compliance 
Drug accountability and subject compliance will be assessed with drug dispensing and 
return records.  
2.14 Study Drug Accountability 
The investigator will maintain accurate records of receipt of all cabozantinib, including 
dates of receipt. In addition, accurate records will be kept regarding when and how much 
study treatment is dispensed and used by each subject in the study. Reasons for deviation 
from the expected dispensing regimen must also be recorded. At completion of the study, 
to satisfy regulatory requirements regarding drug accountability, all unused cabozantinib 
will be reconciled and destroyed in accordance with applicable state and federal 
regulations. 
 


 
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3 
STUDY POPULATION 
3.1 
Target Population  
Inclusion Criteria: 
A subject must meet the following criteria to be eligible for the study: 
1. The subject has histologically confirmed prostate adenocarcinoma with 
radiologic evidence of metastases. 
2. If patient are on anti-androgens, these should be discontinued, at least 4 weeks 
prior for flutamide and at least 6 weeks for bicalutmide or nilutamide. 
3. At least 14 days should have elapsed from prior radiation therapy to bone 
metastases from prostate cancer (see details in exclusion criterion # 3 for other 
sites of RT). 
4. The subject is ≥ 18 years old. 
5. The patient has received a maximum of one prior chemotherapy regimen for 
metastatic prostate cancer. 
6. Patients must demonstrate disease progression on or after most recent 
systemic therapy, either by PSA (minimum PSA has to be > 2.0 ng/ml if no 
measurable disease present and for PSA only progression, an increase in PSA 
levels done at least one week apart is required), new bone metastases or by 
measurable disease criteria per RECIST 1.1 guidelines.  
7. Patients should have received either orchiectomy, or be on LHRH analogue or 
LHRH antagonist for metastatic prostate cancer and have a testosterone level 
<50 ng/dL. 
8. The patient has an Eastern Cooperative Oncology Group (ECOG) 
performance status of 0 or 1. 
9. Bisphosphonate therapy can be continued if started prior to protocol 
enrollment. 


 
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10. Patients must have BP readings <150/90 prior to enrollment. 
11. The subject has organ and marrow function as follows: 
a. Absolute neutrophil count (ANC) ≥ 1500/mm3without colony stimulating 
factor support 
b. Platelets ≥ 100,000/mm3 
c. Hemoglobin ≥ 9 g/dL 
d. Bilirubin ≤ 1.5  the upper limit of normal (ULN). For subjects with 
known Gilbert’s disease, bilirubin ≤ 3.0 mg/dL 
e. Serum albumin ≥ 2.8 g/dl 
f. Serum creatinine ≤ 1.5  ULN or creatinine clearance (CrCl) 
≥ 50 mL/min. 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 
g. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤ 2.5  ULN if no liver involvement, or ≤ 5  ULN with liver involvement 
h. Lipase < 1.5 x the upper limit of normal (except for subjects with 
adenocarcinoma of the pancreas) 
i. Urine protein/creatinine ratio (UPCR) ≤ 1 
j. Serum phosphorus ≥ LLN 
 
12. The subject is capable of understanding and complying with the protocol 
requirements and has signed the informed consent document. 
13. Patients participating in this trial must also be eligible and willing to sign 
consent for participation in FMAU scan done under separate protocol. 
14. Sexually active subjects (men ) must agree to use medically accepted barrier 
methods of contraception (eg, male condom, or diaphragm with spermicidal 
gel) during the course of the study and for 4 months after the last dose of 
study drug(s), even if oral contraceptives are also used by the female partner. 
All subjects of reproductive potential must agree to use both a barrier method 
and a second method of birth control. 
15. Projected life expectancy of at least 6 months. 


 
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16. No prior history of other malignancies in the last 3 years, except for squamous 
and basal cell skin cancer. 
 
 
3.2 
Exclusion Criteria  
A subject who meets any of the following criteria is ineligible for the study: 
1. The subject has received cytotoxic chemotherapy (including investigational 
cytotoxic chemotherapy) or biologic agents (eg, cytokines or antibodies) 
within 3 weeks, or nitrosoureas/ mitomycin C within 6 weeks before the first 
dose of study treatment. 
2. Prior treatment with cabozantinib 
3. The subject has received radiation therapy: 
a. to the thoracic cavity  or gastrointestinal tract within 3 months of the first 
dose of study treatment. 
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 
4. The subject has received radionuclide treatment within 6 weeks of the first 
dose of study treatment 
5. The subject has received prior treatment with a small molecule kinase 
inhibitor or a hormonal therapy (including investigational kinase inhibitors or 
hormones) within 14 days before the first dose of study treatment. Patients  
receiving LHRH or GnRH agonists to maintain castrate levels of testosterone 
or patients on bisphosphonate/denosumab, may be maintained on these agents. 
6. The subject has received any other type of investigational agent within 
28 days before the first dose of study treatment.  
7. The subject has not recovered to baseline or CTCAE ≤ Grade 1 from toxicity 
due to all prior therapies except alopecia and other non-clinically significant 
AEs. 
8. The subject has a primary brain tumor. 
9. The subject has active brain metastases or epidural disease (Note: Subjects 
with brain metastases previously treated with whole brain radiation or 
radiosurgery or subjects with epidural disease previously treated with 
radiation or surgery who are asymptomatic and do not require steroid 
treatment for at least 2 weeks before starting study treatment are eligible. 
Neurosurgical resection of brain metastases or brain biopsy is permitted if 


 
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completed at least 3 months before starting study treatment. Baseline brain 
scans are not required to confirm eligibility.) 
10. The subject has prothrombin time (PT)/ International Normalized Ratio (INR) 
or partial thromboplastin time (PTT) test results at screening ≥ 1.3  the 
laboratory ULN. 
11. The subject requires concomitant treatment, in therapeutic doses, with 
anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin 
or Factor Xa inhibitors, or antiplatelet agents (eg, clopidogrel). Low dose 
aspirin (≤ 81 mg/day), low-dose warfarin (≤ 1 mg/day), and prophylactic low 
molecular weight heparin (LMWH) are permitted. 
12. The subject has experienced any of the following within 3 months before the 
first dose of study treatment: 
a. clinically-significant hematemesis or gastrointestinal bleeding 
b. hemoptysis of > 0.5 teaspoon (2.5ml) of red blood 
c. any other signs indicative of pulmonary hemorrhage  
13. The subject has radiographic evidence of cavitating pulmonary lesion(s) 
14. The subject has tumor in contact with, invading or encasing major blood 
vessels 
15. 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 
> 150 mm Hg systolic, or > 90 mm Hg diastolic despite optimal 
antihypertensive treatment (BP must be controlled at screening) 
iii. Any of the following within 6 months before the first  dose of study 
treatment: 
 unstable angina pectoris 
 clinically-significant cardiac arrhythmias 
 stroke (including TIA, or other ischemic event) 
 myocardial infarction 
 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 at the time of screening 


 
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 intra-abdominal tumor/metastases invading GI mucosa 
 active peptic ulcer disease, 
 active inflammatory bowel disease (including ulcerative colitis and 
Crohn’s disease), diverticulitis, cholecystitis, symptomatic 
cholangitis or appendicitis 
ii. Any of the following within 6 months before the first dose of study 
treatment: 
(1)  history of 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 that 6 months 
ago. 
iii. GI surgery (particularly when associated with delayed or incomplete 
healing) within 28 days.  Note: Complete healing following abdominal 
surgery must be confirmed prior to initiating treatment with 
cabozantinib even if surgery occurred more that 28 days ago. 
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 
or concurrent evidence of intraluminal tumor involving the trachea and 
esophagus. 
d. Other clinically significant disorders such as: 
i. active infection requiring systemic treatment 
ii. serious non-healing wound/ulcer/bone fracture 
iii. history of organ transplant 
iv. concurrent uncompensated hypothyroidism or thyroid dysfunction 
v. history of major surgery within 4 weeks or minor surgical procedures 
within 1 week before randomization 
16. The subject is unable to swallow tablets 
17. The subject has a corrected QT interval calculated by the Fridericia formula 
(QTcF) >470 ms within 21 days of treatment. 
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. 


 
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20. The subject has had evidence within 2 years of the start of study treatment of 
another malignancy, which required  systemic treatment 
 
4 
STUDY ASSESSMENTS AND PROCEDURES 
4.1 
Pre-Treatment Period 
During the Pre-Treatment Period, subjects are consented and qualified (screened) for the 
study. Informed consent must be obtained before initiation of any clinical screening 
procedure that is performed solely for the purpose of determining eligibility for this 
study. Evaluations performed as part of routine care before informed consent can be 
considered as screening evaluations if done within the defined screening period, and if 
permitted by the site’s institutional review board (IRB)/ ethics committee (EC) policies. 
Informed consent may be obtained within 42 days prior to first dose of study treatment. 
At informed consent, subjects will be assigned a subject identifier. Subject identifiers are 
not to be re-assigned if a subject is determined to be ineligible, and subjects are to 
maintain their original identifier if rescreening is required. 
For each subject, the Pre-Treatment Period ends upon receipt of the first dose of study 
treatment or final determination that the subject is ineligible for the study. 
4.2 
Study Treatment Period  
Subjects are defined as enrolled upon receipt of the first dose of study treatment.  
If the subject is unable to have a study assessment taken within the defined time window 
due to an event outside of his or her control (eg, clinic closure, personal emergency, 
inclement weather, vacation), the assessment should be performed as close as possible to 
the required schedule.  
Subjects should be instructed to 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. 


 
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Subjects may receive study treatment until the earlier of PD or unacceptable toxicity. 
Regular tumor assessments should be performed according to the guidelines in 
Section 4.5 to determine if PD is present.  
The Treatment Period ends when a subject receives his or her last dose of study 
treatment; the subject then enters the Post-Treatment Period. 
 The week 4 timepoint scan will be discontinued for all present and future patients.    
We will also review each patients baseline scan to see if there is disease detectable.  If no 
readily visible cancer is found then the 2nd scan with FMAU PET will be eliminated for 
that patient.  So far of the 6 patients imaging, only patient 1 had no easily visible tumor 
on the baseline scan. Longer follow up of the patients has revealed that it remains a 
challenge to determine if the patients are continuing to derive clinical benefit. The PSA 
level is frequently discordant with response. Hence we will obtain an additional 18F-
flouride PET scan and a FMAU PET scan (if <3 lifetime FMAU scans done on the 
patient)  at week 32 (+/- 10 weeks) For the patients who discontinue therapy. prior to the 
32 weeks timepoint, the scan will be done at the time of treatment discontinuation (+/- 2 
weeks).  This timepoint was chosen to capture the maximum number of patients currently 
on the study for this scan, and since conventional CT scan and bone scan is also 
conducted at the same timepoint for comparison. 
 
4.3 
Post-Treatment Period 
Subjects will return to the study site 4 weeks (± 2 weeks) after the last dose of XL184 for 
an end-of-treatment assessment. Laboratory and physical examinations will be 
performed. Remaining study treatment 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. 
4.4 
Laboratory Assessments 
Local laboratories will perform all laboratory tests. Blood and urine samples for standard 
hematology, serum chemistry, and urinalysis panels will be prepared using standard 
procedures.  
Abnormalities in clinical laboratory tests that lead to a change in subject management 
(eg, dose delayed, withheld, or reduced; additional medication or monitoring required) or 
that are considered to be clinically significant by the investigator are to be recorded on 
the AE case report form (CRF). If laboratory values constitute part of an event that meets 


 
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criteria for an SAE, the event (and associated laboratory values) must be reported as an 
SAE (Section 5.1.2). 
4.5 
Tumor Assessment 
4.5.1 
Routine Tumor Assessment 
Tumor response should be assessed per the study schedule and until the medication is 
continuing to show benefit, (complete response [CR], PR, or SD) may continue on study. 
Subjects with disease progression 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.  
 
4.6 Response criteria:  
For measurable disease response RECIST criteria 1.1 will be used [Eisenhauer E, et al. Eur 
J Cancer 2009]. The Prostate Cancer Clinical Trials Working Group (PCWG2) criteria will 
be used to determine a response [Scher H, et al. J Clin Oncol 2008]. PCWG2 recommends 
a two-objective paradigm in metastatic CRPC: (1) controlling, relieving, or eliminating 
disease manifestations that are present when treatment is initiated and (2) preventing or 
delaying disease manifestations expected to occur. PSA decline and changes in imaging 
will also be reported. The progression for measurable disease will be per RECIST criteria, 
and for bone metastases will be defined as given below:  
4.6.1 THE RECIST 1.1 CRITERIA WITH UNIDIMENSIONAL MEASUREMENT 
ARE TO BE USED FOR MEASURABLE DISEASE RESPONSE EVALUATION 
 Methods 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.CT is the best currently available and reproducible method to measure lesions 
selected for response assessment. MRI is also acceptable in certain situations 
(e.g., for body scans but not for lung).Lesions on a chest X-ray may be considered 
measurable lesions if they are clearly defined and surrounded by aerated lung. 
However, CT is preferable. 
Clinical lesions will only be considered measurable when they are superficial and 
≥10 mm in diameter as assessed using calipers. For the case of skin lesions, 
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lesion, is recommended.Ultrasound (US) should not be used to measure tumor 
lesions. 
 
 Baseline Disease Assessment 
All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 42 days before the beginning of the 
treatment. 
Measurable 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; when CT 
scans have slice thickness >5 mm, the minimum size should be twice the slice 
thickness). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be 
accurately measured with calipers should be recorded as nonmeasurable). 
• 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 is recommended to be no greater than 5 mm). At 
baseline and in follow-up, only the short axis will be measured and followed. 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue  
components 
that can be evaluated by cross-sectional imaging techniques such as CT or MRI 
can be considered measurable if the soft tissue component meets the definition of 
measurability described above. 
• ‘Cystic lesions’ thought to represent cystic metastases can be considered 
measurable 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. 
 
Non-measurable lesions 
Non-measurable lesions are all other lesions, including small lesions (longest 
diameter <10 mm or pathological lymph nodes with 10 to <15 mm short axis), as 
well as truly non-measurable lesions.  
• Blastic bone lesions are non-measurable. 
• Lesions with prior local treatment, such as those 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.  
Target Lesions 
• All measurable lesions up to a maximum of two lesions per organ and five 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline. 
• Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and be representative of all involved organs, as well as their 
suitability for reproducible repeated measurements. 


 
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• All measurements should be recorded in metric notation using calipers if 
clinically assessed. A sum of the diameters (longest for non-nodal lesions, short 
axis for nodal lesions) for all target lesions 
Non-target Lesions 
All lesions (or sites of disease) not identified as target lesions, including 
pathological lymph nodes and all non-measurable lesions, should be identified as 
non-target lesions and be recorded at baseline. Measurements of these lesions are 
not required and they should be followed as ‘present’, ‘absent’ or in rare cases, 
‘unequivocal progression’. 
 
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 of 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 may include the baseline sum). The sum 
must also demonstrate an absolute increase of at least 5 mm. 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for 
PD. 
 
Confirmation 
In non-randomized trials where response is the primary endpoint, confirmation of 
PR and CR is required to ensure responses identified are not the result of 
measurement error. This will also permit appropriate interpretation of results in 
the context of historical data where response has traditionally required 
confirmation in such trials. 
However, in all other circumstances, (i.e., in randomized phase II or III trials or 
studies where stable disease or progression are the primary endpoints), 
confirmation of response is not required since it will not add value to the 
interpretation of trial results. However, elimination of the requirement for 
response confirmation may increase the importance of central review to protect 
against bias, in particular in studies which are not blinded. 
In the case of SD, measurements must have met the SD criteria at least once after 
study entry at a minimum interval (in general not less than 6–8 weeks) that is 
defined in the 
study protocol. 
 
4.6.2 Progression in patients with bone metastases 
Majority of the patients with prostate cancer have bone metastases which are not 
considered measurable sites of disease. Progression in patients with bone metastases will 


 
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be defined as either the appearance of a minimum of 2 new lesions on bone scan which are 
related to metastatic disease per the judgement of the treating physician, or the occurrence 
of a new skeletal related event. Skeletal-related event is defined as occurrence of new 
pathologic bone fractures (vertebral or nonvertebral), spinal cord compression, requirement 
of surgery or radiation therapy to bone metastases (including the use of radioisotopes), or a 
requirement to change antineoplastic therapy to treat bone pain or other related symptoms.  
 
4.6.3 Response Evaluable Patients 
All patients registered on the protocol and completing a minimum of 7 days of therapy 
followed by clinical, or radiologic or PSA assessment of disease status. 
 
4.6.4 Toxicity- Evaluable patients 
All patients registered on the protocol and starting therapy with protocol medication, will 
be considered toxicity evaluable. 
 
4.6.5 Progression-free survival (PFS)  
PFS will be measured from date of registration to date of first documented disease 
progression, or death from any cause, whichever occurs first.   After treatment is 
discontinued for any reason patients will be followed every 3 months for progression and 
survival. 
 
4.6.6 Overall survival (OS) 
OS will be measured from date of registration to death or last follow up.   After treatment 
is discontinued for any reason patients will be followed every 3 months for progression 
and survival. 
 
 


 
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5 
ADVERSE EVENT REPORTING AND SAFETY 
5.1 
Adverse Events and Laboratory Abnormalities 
5.1.1 
Adverse Events  
Toxicity will be graded per CTCAE version 4.0. An AE is any untoward medical 
occurrence in a patient or clinical investigation subject who has been enrolled in a clinical 
study and who may have been given an investigational product, regardless of whether or 
not the event is assessed as related to the study treatment. An AE can therefore be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of an investigational product, regardless of 
whether or not the event is assessed as related to the investigational product. Pre-existing 
medical conditions that worsen during a study should be recorded as AEs. Abnormal 
laboratory values, electrocardiogram (ECG) findings, or vital signs are to be recorded as 
AEs if they meet the criteria described in Section 5.2.1. 
All untoward events that occur after start of therapy through 30 days after the last dose of 
study treatment are to be recorded by the investigational site. This requirement includes 
AEs from unscheduled as well as scheduled visits. 
Assessment of the relationship of the AE to the study treatment by the investigator is 
based on the following two definitions: 
 
Not Related: A not-related AE is defined as an AE that is not associated with the 
study treatment and is attributable to another cause. 
 
Related: A related AE is defined as an AE where a causal relationship between 
the event and the study treatment is a reasonable possibility. A reasonable causal 
relationship is meant to convey that there are facts (eg, evidence such as 
dechallenge/ rechallenge) or other clinical arguments to suggest a causal 
relationship between the AE and study treatment. 
 


 
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5.1.2 
Serious Adverse Events  
The SAE definition and reporting requirements are in accordance with the International 
Conference of Harmonisation (ICH) Guideline for Clinical Safety Data Management: 
Definitions and Standards for Expedited Reporting, Topic E2A. 
An SAE is defined as any untoward medical occurrence that at any dose: 
1. Results in death. 
2. Is immediately life-threatening (ie, in the opinion of the investigator, the AE 
places the subject at immediate risk of death; it does not include a reaction 
that, had it occurred in a more severe form, might have caused death). 
3. Requires inpatient hospitalization or results in prolongation of an existing 
hospitalization. 
4. Results in persistent or significant disability or incapacity. 
Note: The term “disability” refers to events that result in a substantial 
disruption of a subject’s ability to conduct normal life function. 
5. Is a congenital anomaly or birth defect. 
6. Is an important medical event (IME). Note: The term “important medical 
event” refers to an event that, based upon appropriate medical judgment, may 
not be immediately life-threatening or result in death or hospitalization, but 
may jeopardize the subject or require intervention to prevent one of the other 
serious outcomes listed under the definition of Serious Adverse Event. 
Examples of IMEs include intensive treatment in an emergency room or at 
home for allergic bronchospasm; blood dyscrasias, or convulsions that do not 
result in hospitalization; or development of product dependency or product 
abuse. 
 


 
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5.1.3 
Serious Adverse Event Reporting 
As soon as an investigator becomes aware of an AE that meets the definition of ‘serious,’ 
this should be documented to the extent that information is available. 
 This report must be submitted by the study site to Exelixis or designee within 
24 hours, even if it is not felt to be drug related.  
 Email: drugsafety@exelixis.com; Fax 650-837-7392 
 The investigator agrees to provide supplementary information requested by the 
Exelixis Drug Safety personnel 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. 
 
5.1.4 
Regulatory Reporting 
All serious unexpected adverse drug reactions (unexpected related SAEs) must be 
reported to the Food and Drug Administration (FDA) by the investigator as required by 
21 CFR 312.32. 
 These reports are to be filed utilizing the Form FDA 3500A (MedWatch Form). 
The final MedWatch Form must be submitted by the study site to Exelixis at the time of 
submission to the FDA to allow Exelixis time to cross-report to Exelixis’ IND. Email: 
drugsafety@exelixis.com; Fax 650-837-7392 
 
5.2 
Other Safety Considerations 
5.2.1 
Laboratory Data 
All laboratory data required by this protocol and any other clinical investigations should 
be reviewed. Any abnormal value that leads to a change in subject management (eg, dose 
reduction or delay or requirement for additional medication or monitoring) or that is 


 
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considered to be of clinical significance by the investigator should be reported as an AE 
or SAE as appropriate. 
5.2.2 
Pregnancy 
Forms for reporting pregnancies will be provided to the study sites upon request. The 
outcome of a pregnancy (for the partner of a subject) and the medical condition of any 
resultant offspring must be reported to Exelixis or designee. Any birth defect or 
congenital anomaly must be reported as an SAE, and any other untoward events 
occurring during the pregnancy must be reported as AEs or SAEs, as appropriate. 
5.2.3 
Medication Errors/ Overdose 
Any study drug administration error or overdose that results in an AE, even if it does not 
meet the definition of serious, requires reporting within 24 hours to Exelixis or designee. 
5.2.4 
Follow-Up of Adverse Events 
Any related SAEs or any AEs assessed as related that led to treatment discontinuation, 
including clinically significant abnormal laboratory values that meet these criteria, 
ongoing 30 days after the last dose of study treatment must be followed until either 
resolution of the event or determination by the investigator that the event has become 
stable or irreversible. This follow-up guidance also applies to related SAEs that occur 
> 30 days after the last dose of study treatment. The status of all other continuing AEs 
will be documented as of 30 days after the last dose of study treatment.  
  6.0     CORRELATIVE STUDIES/PHARMACODYNAMIC STUDIES:  
 
Serum and urine markers 
Serum bone markers will be assessed pre and post XL184 therapy. These will include 
serum bone specific alkaline phosphatase (BSAP) and N-terminal telopeptide of collagen 
type I (NTx). High levels of these markers (>146u/Lfor BSAP and > 100nmol/mmol for 
NTx) were noted to be significantly predictive of higher incidence of skeletal 
complications (relative risk of 3.32, p< 0.001), prostate cancer progression (RR 2.02, 
p<0.001) and death (RR of 4.59, p<0.001) [Lara PN Jr et al. Clin Cancer Res 2006].  


 
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A number of other bone turnover markers such as osteocalcin, pyridinoline, 
deoxypyridinoline, etc have been implicated to be predictive of therapeutic response. A 
study evaluating the efficacy of matrix metalloproteinase inhibitors in prostate cancer 
reported that decline of the bone resorption markers including NTx, procollagen I NH2-
terminal propeptide, osteocalcin and deoxypyridinoline correlated with improved 
progression free survival and overall survival outcome [Lara PN et al. Clin Cancer Res 
2006 and Coleman RE et al. J Clin Oncol 2005]. This supported the fact that changes in 
bone turnover could act as surrogates of therapeutic effect in prostate cancer bone 
metastases. 
 
For the purposes of our pilot trial, we have selected the serum NTx and BSAP and urine 
NTx as the bone turnover markers due to the validation of these markers in prior large 
studies specifically utilizing zoledronate therapy [Coleman RE et al. J Clin Oncol 2005]. 
Decline in the levels was predictive of lower incidence of skeletal events as well as 
progression free and overall survival. Hence the measurement of these markers (NTx and 
BSAP) pre and post therapy will be correlated with PET scan findings and clinical 
outcomes.   
Bone markers: Serum and urine (Timeline: Pretherapy, week 1, week 2 and week 4) 
 
Urine N-telopeptide will be assessed from 24-hour urine collection sample using the 
Vitros ECI Immunodiagnostic System competitive assay (Johnson & Johnson Ortho-
Clinical Diagnostics, Raritan, NJ). Urinary marker levels will be normalized relative to 
urinary creatinine levels, and samples will be required to contain  5 mg/dL creatinine to 
ensure validity of the sample. This test will be performed at a local CLIA certified 
laboratory. 
Serum bone-specific alkaline phosphatase levels will be assessed using a chemical 
inhibition and differential inactivation assay (12). 4cc of blood will be collected in a tiger 
top tube pre and post therapy for assessment of serum BSAP. This test will be 
performed at a local CLIA certified laboratory. 
Serum N-telopeptide will be assessed from serum collection  sample using the Vitros ECI 
Immunodiagnostic System competitive assay (Johnson & Johnson Ortho-Clinical 


 
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Diagnostics, Raritan, NJ) (Chestnut CH 3rd, et al. Am J Med 1997). This test will be 
performed at a local CLIA certified laboratory. 
 
For the first 5 patients, samples will be taken at pretherapy and weeks 1, 2 and 4 after 
treatment begins.  Timeline for additional 15 patients will be adjusted based on results of 
PET scans in first 5 patients to guide the sampling schedule in next 15 patients.  The 
goal is to have the same schedule for imaging and sample collection so we can 
correlate the results. 
 
 
Additional blood samples will be collected at baseline and designated time points using 
BD Vacutainer CPT tubes for serum and DNA/RNA samples (Appendix B) in Podgorski 
lab according to protocol described below.   Total RNA isolation from blood will be 
performed using the PAXgene™ Blood RNA System (PreAnalytiX). This method requires 
specific sample collection tubes available from PreAnalytiX that contain a proprietary 
reagent that immediately stabilizes intracellular RNA. All isolated samples will be stored at -
80° C until use. TRACP 5 protein level and cathepsin K assessment in serum. We will 
use the Human TRAPTM Assays to measure the TRACP 5 proteins in serum. TRACP 5b 
is considered to be essential for clinical assessment of bone metabolism. Quantitative 
assessment of Cathepsin K levels in serum, an additional indicator of increased bone 
turnover, will be done using Cathepsin K ELISA kits from ALPCO Immunoassays, 
Salem, NH. To measure changes in osteoblast function, levels of serum bone serum 
alkaline phosphatase will be assessed using Human Alkaline Phosphatase ELISA kits 
from USCN, Lifesciences. The NTx (procollagen I NH2), a predictive marker of 
therapeutic response in prostate cancer patients will be assessed from 24-hour urine 
collection sample using the Vitros ECI Immunodiagnostic System competitive assay 
(Johnson& Johnson). 
 
 Circulating tumor cell (CTC) counts have revealed prognostic and predictive value in 
conjuction with chemotherapy in metastatic CRPC [DeBono J et al. J Clin Oncol]. We 
will examine the effects of XL184 on CTC counts. These will be performed pretherapy, 


 
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week 2 and at progression. 7.5 ml of blood will be collected in a cell save tube at these 
timepoints for CTC. The CTC counts would be performed by the KCI 
pharmacokinetics core. 
 
 
 
TUMOR/BONE BIOPSY SAMPLES: 
 
Tumor/Bone biopsy samples will be collected pre and post XL184 therapy. Part of each 
tissue sample will be fresh-frozen for aCGH and genomic expression analysis, and rest 
will be decalcified, fixed and embedded in paraffin for histological and 
immuhistochemical analyses. The biopsy samples will be picked up by Mackenzie 
Herroon or Izabela Podgorski (contact info below).  Tissues for histology will be fixed 
and decalcified (Podgorski lab) and embedded in paraffin. All immunostaining will be 
performed in Podgorski lab.  
Contact information for blood and biopsy tissue pickup: 
Mackenzie Herroon (313) 577-0941 (lab); (937) 214-1819 (cell) 
Izabela Podgorski (313) 577- 0514 (office); (586) 864-4914 (cell) 
 
Gene Expression profiling 
Tissue collected for RNA isolation will be preserved in RNAlater™ RNA Stabilization 
Reagent. Tissue approximately 0.5 cm x 0.5 cm x 0.5 cm in size will be stored in a 
nuclease-free vessel appropriate to accommodate the required 500ul volume of 
RNAlater™ preservative. Samples will be submerged and incubated in 
RNAlater™ overnight at 2-8 C.  Then the tissue will be removed from the reagent and 
stored at -80 C until RNA is extracted. 
 
The CGH analysis will be performed using comparative genomic hybridization 
microarrays with an average resolution of 35 kb (Agilent 44K). Normal human male 
DNA will be used as a reference sample and experiments will be performed with dye-
reversed replicates. For gene expression microarray experiments the 60-mer 
oligonucleotide arrays (Agilent 44K), which have the most complete coverage of the 


 
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whole human transcriptome will be used. Two color hybridizations will interrogate the 
cancer cells from the collected specimens against a common standardized reference 
sample (Universal Human Reference RNA, Stratagene) which will permit the comparison 
of our results to transcriptional profiles generated by other researchers. Alexa dyes 
(Alexa647-red and Alexa555-green) will be used for fluorescent labeling since these dyes 
are more resistant to oxidation and do not quench as easily as traditional Cy dyes.  
Labeled targets will be synthesized from the purified RNA using linear amplification and 
indirect labeling by incorporation of aminoallyl-labeled nucleotide, which will 
subsequently be modified by the covalent addition of Alexa dye (Epicentre 
Technologies). The combined analysis of gene expression and chromosomal aberration 
will be performed as devised by Oncogenomics Lab at Karmanos Cancer Institute. This 
statistical analysis will be carried out with two Bioconductor libraries, globalTest and 
Gene Set Enrichment Analysis (GSEA).  These methods will be applied to multiple 
samples with similar amplicons and will provide a basis for determining the fold change 
threshold required for an individual human tumor biopsy to indicate meaningful over-
expression harboring unique genetic amplification events. 
 
Immunohistochemistry 
The immunohistochemical analyses will be performed on bone on pre- and post treatment 
biopsy samples to assess: tumor cell proliferation (Ki67 staining), apoptosis (TUNEL), 
tumor vasculature (CD31, VEGFR2), cMet, DDR-1 and DDR-2 expression. For 
determination of osteoclast numbers, tartrate-resistant acid phosphatase (TRAcP) and 
cathepsin K staining will performed on multiple non-serial sections. Positively stained 
osteoclasts in each section will be counted and expressed as osteoclast number/mm2. For 
Ki67, VEGFR2 and cMet, DDR-1, and -2 expression the specimens will be evaluated 
independently by two investigators in a blind fashion and the results will be arbitrarily 
classified into four scores dependent on the intensity of immunoreactivity: (a) −, negative 
immunostaining; (b) ±, very weak immunostaining; (c) +, medium positive 
immunostaining; and (d) ++, strongly positive immunostaining.  The CD31-positive 
blood vessels will be counted in multiple fields and expressed as blood vessel 
number/field. To quantify apoptosis, TUNEL positive (red) and negative (blue) cells will 


 
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be counted in multiple non-serial sections and expressed as a ratio of numbers of red 
apoptotic cells to blue non-apoptotic cells.  Additional tumor and bone targets may be 
added based on results from gene expression analyses. 
 
Gene expression microarray experiments will be performed using 60-mer oligonucleotide 
arrays (Agilent 44K), which have the most complete coverage of the whole human 
transcriptome. The histomorphometric and histological approaches will be used to 
quantitatively assess changes in the bone resorption and bone-to-tumor ratio in response 
to XL184 treatment.  In addition immunohistochemical analyses will be performed to 
examine changes in tumor cell proliferation (Ki67) and apoptosis (TUNEL), tumor 
vasculature (CD31) and expression of targets of XL184 action: cMet, VEGFR2, DDR-1 
and DDR-2, Additional targets for immunohistochemical analyses may be also included 
based on the results of gene expression analyses. 
 
 
7       STATISTICAL CONSIDERATIONS 
7.1 Objectives: 
7.1.1 Primary Objective:   To conduct a pilot clinical trial to evaluate the timing, 
physiology, and magnitude of changes in tumor imaging, and pharmacodynamic markers 
with XL184 treatment in metastatic castrate resistant prostate cancer.  
  
7.1.2  Secondary Objectives: 
1) To estimate the progression-free survival (PFS) achieved with XL184 in chemotherapy 
naïve metastatic CRPC patients. 
2) To evaluate the feasibility of the therapy, and the toxicities associated. 
3) To evaluate overall survival (OS) in metastatic CRPC patients post ADT. 
4) To estimate the mean level of all continuously distributed correlatives, and to tabulate 
the distribution of all categorical correlatives. 
7.2 Endpoints: 


 
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7.2.1 Primary:  PET SUV levels pre- and post-treatment with XL184, bone scan 
parameters.   Refer to the Study Schema in Section 2.3. 
7.2.2 Secondary:  TTP, the type and grade of toxicities, clinical response, PSA response, 
and PET response. 
7.2.3 Correlative:  Serum markers, urinary markers, bone markers, gene expression 
levels, IHC parameters.   A detailed description of them is given in Section 6. 
 
7.3 Design:   This is a prospective pilot adaptive design study to obtain preliminary data.   
Each patient will undergo up to 4 PET scans, using different radiotracers.   It is desired to 
estimate the mean SUV at any time point to approximately one-third of a standard 
deviation (SD) with 80% confidence.   With N=15 patients, the mean SUV can be 
estimated to within 0.347 SD units of the true mean with 80% confidence.   These 
preliminary estimates will be of sufficient precision for use in designing a subsequent 
larger study.  Since not all patients will agree to undergo all  PET scans, the mean SUV 
may be less precisely estimated at some time points. 
 
 7.4 Analysis: 
7.4.1    For the 15 patients imaged on a common schedule (see Section 7.5.1), the 
continuous endpoints (e.g., SUV, bone scan measurements, and all continuously 
distributed correlatives) will be summarized with standard descriptive statistics, 
separately at each measurement time point.     This will include point and 80% 
confidence interval (CI) estimates.   The mean SUV levels over time will be displayed 
graphically as a line plot (with separate curves for the different radiotracers).   Gene 
expression levels will be transformed on a log 2 scale. 
 
7.4.2  The categorical endpoints (e.g., toxicities, the 3 types of response, IHC expression 
levels, etc.) will be summarized via their frequency distribution, point estimate of the 
proportion, and the Wilson type 80%  CI. 
 
7.4.3   The distribution of censored PFS will be summarized via the Kaplan-Meier (K-M) 
survivorship estimate.   Summary statistics (e.g., median, 6-month and 12-month 


 
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progression-free rates, etc.) will be calculated from the K-M life table.   Similar analyses 
will be performed for OS as well. 
 
7.5 Expected accrual rate, accrual duration, and study duration 
7.5.1    We seek to enroll 20 evaluable patients  (maximum of 25 screened to account for 
screen failures and non evaluable patients ) with clinical evidence of metastases, and 
castrate-resistant disease who will agree to undergo the various imaging studies, 
additional bone biopsy, and bone scans specified in the Study Schema of Section 2.3.   To 
monitor early bone and tumor responses to XL184 treatment, for the first 5 patients 
recruited we will perform imaging with Na18F PET as early as 2 days after beginning of 
XL184 regimen. Each patient will receive up to 4 scans.  The initial proposed timeline is: 
baseline, and 2-3 weeks post start of therapy;  however, time points selected for imaging 
may be adjusted based on results of scans and the timing of changes noted in first 5 
patients.  After the timeline indicative of measurable changes in bone and/or tumor in 
response to treatment is established, an additional 15 patients will be recruited for the 
imaging/biopsy studies on a common schedule.   Those next 15 patients will be utilized 
for statistical estimation purposes, as planned in the study design described in Section 
7.3. If the pretherapy PET scans do not show any detectable uptake in metastatic sites, the 
post therapy scan may not be conducted.  
 
7.5.2    We expect an accrual rate of 12 patients/year, but we also expect that up to one-
third of them would not complete the trial due to the required number of PET scans, bone 
scans, and the additional bone biopsy.   Allowing for up to 33% attrition, we anticipate a 
net accrual rate of about 8 patients/year who complete the trial.   Thus, it would take 
about 30 months (i.e., about 2.5 years) of accrual to enroll the needed 20 patients who 
complete all the various testing. About 25-30 patients will need to be screened to get 20 
evaluable patients on the study. 
   
7.5.3   An additional 2-3 months is required to obtain the various imaging and laboratory 
endpoints on the last patient(s) enrolled, hence the total study duration is expected to be 
32-33 months. 


 
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8     ETHICAL ASPECTS 
8.1  Local Regulations 
The study must fully adhere to the principles outlined in “Guideline for Good Clinical 
Practice” (GCP) ICH E6 Tripartite Guideline (January 1997). The investigator will 
ensure that the conduct of the study complies with the basic principles of GCP as outlined 
in the current version of 21 Code of Federal Regulations, subpart D, Part 312, 
“Responsibilities of Sponsors and Investigators” Part 50, “Protection of Human Subjects” 
and Part 56, “Institutional Review Boards.” 
8.2  Informed Consent 
It is the responsibility of the investigator, or a person designated by the investigator, to 
obtain written informed consent from each subject participating in this study after 
adequate explanation of the aims, methods, anticipated benefits, and potential hazards of 
the study. In the case where the subject is unable to read, an impartial witness should be 
present during the entire informed consent discussion. After the subject has orally 
consented to participation in the trial, the witness’s signature on the form will attest that 
the information in the consent form was accurately explained and understood. 
The CRF for this study contains a section for documenting informed subject consent, and 
this must be completed appropriately. If new safety information results in significant 
changes in the risk/ benefit assessment, the consent form should be reviewed and updated 
as necessary. All subjects (including those already being treated) should be informed of 
the new information, should be given a copy of the revised form, and should give their 
consent to continue in the study. 
8.3  Institutional Review Board/ Ethics Committee  
This study is being conducted under a United States Investigational New Drug 
application or other Clinical Trial Application, as appropriate. This protocol (and any 
modifications) and appropriate consent procedures must be reviewed and approved by an 
IRB/ EC. This board must operate in accordance with current local, regional, and federal 


 
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regulations. The investigator will send a letter or certificate of IRB/ EC approval to 
Exelixis (or designee) before subject enrollment and whenever subsequent modifications 
to the protocol are made. 
 
 
8.4   Conditions for Modifying the Protocol 
Protocol modifications may be made and will be prepared, reviewed, and approved by 
representatives of the investigator. 
All protocol modifications must be submitted to the IRB/ EC for information and 
approval in accordance with local requirements and to regulatory agencies if required. 
Approval must be obtained before any changes can be implemented, except for changes 
necessary to eliminate an immediate hazard to study subjects or those that involve only 
logistical or administrative aspects of the trial (eg, change in data monitor or change of 
telephone number). 
8.5   Conditions for Terminating the Study 
Exelixis reserves the right to terminate the study, and investigators reserve the right to 
terminate their participation in the study, at any time. Should this be necessary, Exelixis 
and the investigator will arrange the procedures on an individual study basis after review 
and consultation. In terminating the study, Exelixis and the investigator will ensure that 
adequate consideration is given to the protection of the subjects’ interests. 
 
9 STUDY DOCUMENTATION 
9.1 Department of Defense guidelines: 
a)  Accurate and complete study records will be maintained and made available 
to representatives of the U.S. Army Medical Research and Materiel 
Command. These representatives are authorized to review research records 


 
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as part of their responsibility to protect human research volunteers. Research 
records will be stored in a confidential manner so as to protect the 
confidentiality of subject information.  
 
b) Representatives of the U.S. Army Medical Research and Materiel Command 
are authorized to review research records as part of their responsibility to 
protect human research volunteers. Research records will be stored in a 
confidential manner so as to protect the confidentiality of your information.    
 
c) All unanticipated problems involving risk to subjects or others related to 
participation in the study should be promptly reported by phone (301-619-
2165), by email (hsrrb@det.amedd.army.mil), or by facsimile (301-619-
7803) to the USAMRMC, Office of Research Protections, Human Research 
Protection Office.  A complete written report will follow the initial 
notification.  In addition to the methods above, the complete report will be 
sent to the U.S. Army Medical Research and Materiel Command, ATTN: 
MCMR-ZB-PH, 504 Scott Street, Fort Detrick, Maryland 21702-5012. 
 
 
9.2  Investigator’s Files and Required Documents 
The investigator must maintain adequate and accurate records to enable the conduct of 
the study to be fully documented and the study data to be subsequently verified. These 
documents should be classified into two separate categories as follows: (1) the 
investigator’s study file, and (2) subjects’ clinical source documents. 
The investigator’s study file will contain the protocol and protocol amendments, CRFs, 
query forms, IRB/ EC and governmental approvals with correspondence, sample 
informed consent, drug records, staff curriculum vitae and authorization forms, and other 
appropriate documents and correspondence. 


 
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Subjects’ clinical source documents include the subjects’ hospital/ clinic records; 
physicians’ and nurses’ notes; the appointment book; original laboratory, ECG, 
electroencephalogram, X-ray, pathology and special assessment reports; signed informed 
consent forms; consultant letters; and subject screening and enrollment logs.  
The investigator must keep these documents on file for at least 2 years after the 
marketing application approval date for the study treatment and for the indication being 
investigated or for 2 years after the investigation is discontinued and the FDA is notified. 
After that period, the documents may be destroyed subject to local regulations with prior 
written permission from Exelixis. If the investigator wants to assign the study records to 
another party or move them to another location, Exelixis must be notified in advance. 
If the investigator cannot guarantee the archiving requirement at the study site for any or 
all of the documents, special arrangements must be made between the investigator and 
Exelixis to store these in a sealed container outside of the study site so that they can be 
returned sealed to the investigator in case of a regulatory audit. When source documents 
are required for the continued care of the subject, appropriate copies should be made for 
storing outside of the study site. 
9.3    Source Documents and Background Data 
Upon request, the investigator will supply its licensees and collaborators with any 
required background data from the study documentation or clinic records. This is 
particularly important when CRFs are illegible or when errors in data transcription are 
suspected. In case of special problems or governmental queries or requests for audit 
inspections, it is also necessary to have access to the complete study records, provided 
that subject confidentiality is protected. 
9.4   Case Report Forms  
For enrolled subjects, all and only data from the procedures and assessments specified in 
this protocol and required by the CRFs should be submitted on the appropriate CRF 
(unless source data are transmitted to Exelixis or a designee electronically, eg, central 
laboratory data). Data from some procedures required by the protocol, such as physical 
examinations and laboratory results, will be recorded only on the source documents and 


 
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will not be transcribed to CRFs. Additional procedures and assessments may be 
performed as part of the investigator’s institution or medical practice standard of care and 
may not be required for CRF entry.  
For each subject enrolled, the CRF (paper or electronic) must be completed and signed by 
the PI or authorized delegate from the study staff. 
All paper forms should be typed or filled out using indelible ink and must be legible. 
Errors should be crossed out but not obliterated, the correction inserted, and the change 
initialed and dated by the investigator or his or her authorized delegate.  
The investigator should ensure the accuracy, completeness, legibility, and timeliness of 
the data reported to Exelixis in the CRF and in all required reports. 
 
9.5   Confidentiality of Trial Documents and Subject Records 
The investigator must assure that subjects’ anonymity will be maintained and that their 
identities are protected from unauthorized parties. On CRFs or other documents 
submitted to Exelixis or designees, subjects should be identified by identification codes 
and not by their names. The investigator should keep a subject enrollment log showing 
codes, names, and addresses. The investigator should maintain documents not for 
submission to Exelixis or designees (eg, subjects’ written consent forms) in strict 
confidence. 
All tumor scans, research samples, photographs, and results from examinations, tests, and 
procedures may be sent to Exelixis and its partners or designees for review. 
 
10    PUBLICATION OF DATA  
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 


 
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withy any provisions regarding publication as are agreed to between the PI’s institution 
(eg, 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. 


 
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11     REFERENCES 
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Eder JP, Heath E, Appleman L, Shapiro G, Wang D, Malburg L, et al. Phase I experience 
with c-MET inhibitor XL880 administered orally to patients (pts) with solid 
tumors. 2007 ASCO Annual Meeting Proceedings Part I. J Clin Oncol. 
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Garcia A, Rosen L, Cunningham CC, Nemunaitis J, Li C, Rulewski N, et al. Phase 1 
study of ARQ 197, a selective inhibitor of the c-Met RTK in patients with 
metastatic solid tumors reaches recommended phase 2 dose. 2007 ASCO 
Annual Meeting Proceedings Part I. J Clin Oncol. 2007;25:18S (June 20 
Supplement) (Abstract 3525). 
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, et al. 
Bevacizumab plus Irinotecan, Fluorouracil, and Leucovorin for metastatic 
colorectal cancer. New Engl J Med. 2004;350(23):2335-42. 
Jiang WG, Martin TA, Parr C, Davies G, Matsumoto K, Nakamura T. Hepatocyte growth 
factor, its receptor, and their potential value in cancer therapies, Crit Rev 
Oncol Hematol. 2005;53(1):35-69. 
Pennacchietti S, Michieli P, Galluzzo M, Mazzone M, Giordano S, Comoglio PM. 
Hypoxia promotes invasive growth by transcriptional activation of the Met 
protooncogene. Cancer Cell. 2003;3:347-61. 
Ross RW, Stein M, Sarantopoulos J, Eisenberg P, Logan T, Srinivas S, et al. A phase II 
study of the c-Met RTK inhibitor XL880 in patients (pts) with papillary renal-
cell carcinoma (PRC). 2007 ASCO Annual Meeting Proceedings Part I. J Clin 
Oncol. 2007;25:18S (June 20 Supplement) (Abstract 15601). 


 
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Sandler AB, Gray R, Brahmer J, Dowlati A, Schiller JH, Perry MC, et al, Randomized 
phase II/III Trial of paclitaxel (P) plus carboplatin (C) with or without 
bevacizumab (NSC #704865) in patients with advanced non-squamous 
non-small cell lung cancer (NSCLC): An Eastern Cooperative Oncology 
Group (ECOG) Trial - E4599. ASCO 2005 Annual Meeting (Abstract LBA4). 
Sattler M, Ma PC, Salgia R. Therapeutic targeting of the receptor tyrosine kinase Met. 
Cancer Treat Res. 2004;119:121-38. 
Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, et al. Randomized, 
double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung 
cancer with disease-related anemia. J Clin Oncol. 2007;25:1027-32. 
D.P. Petrylak, C.M. Tangen and M.H. Hussain et al., Docetaxel and estramustine 
compared with mitoxantrone and prednisone for advanced refractory prostate cancer, N 
Engl J Med 351 (2004), pp. 1513–1520 
 
Tannock IF, Wit R, Berry WR, et al. Docetaxel plus prednisone or mitoxantrone plus 
prednisone for advanced prostate cancer.N Engl J Med. 2004 Oct 7;351(15):1502-12. 
 
Oh W, Manola J, Babcic V, et al. Response to second-line chemotherapy in patients with 
hormone refractory prostate cancer receiving two sequences of mitoxantrone and 
taxanes.Urology. 2006 Jun;67(6):1235-40. PMID: 16765185 
 
Berthold DR, Sternberg C, Tannock I. Management of advanced prostate cancer after 
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16278480. 
 
D. C. Smith, M. R. Smith, E. J. Small, et al. Phase II study of XL184 in a cohort of 
patients (pts) with castration-resistant prostate cancer (CRPC) and measurable soft tissue 
disease. GU ASCO Symposium 2011, abstract # 127. 
  


 
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Schoder H, Larson SM. Positron emission tomography for prostate, bladder, and renal 
cancer. Semin Nucl Med 2004;34(4):274-292. 
 
Shreve PD, Grossman HB, Gross MD, Wahl RL. Metastatic prostate cancer: initial 
findings of PET with 2-deoxy-2-[F-18]fluoro-D-glucose. Radiology 1996;199(3):751-
756. 
 
Heicappell R, Muller-Mattheis V, Reinhardt M, et al. Staging of pelvic lymph nodes in 
neoplasms of the bladder and prostate by positron emission tomography with 2-[(18)F]-2-
deoxy-D-glucose. EurUrol 1999;36(6):582-587. 
 
Yeh SD, Imbriaco M, Larson SM, et al. Detection of bony metastases of androgen-
independent prostate cancer by PET-FDG. Nucl Med Biol 1996;23(6):693-697. 
 
Schirrmeister H, Guhlmann A, Kotzerke J, et al. Early detection and accurate description 
of extent of metastatic bone disease in breast cancer with fluoride ion and positron 
emission tomography. J Clin Oncol 1999;17(8):2381-2389. 
 
Shields AF, Mankoff DA, Link JM,  et al. [11C]Thymidine and FDG to measure therapy 
response.  J Nucl Med  39:1757-1762, 1998. 
 
Tehrani OS, Douglas KA, Lawhorn-Crews JM, Shields AF.  Tracking cellular stress with 
labeled FMAU reflects changes in mitochondrial TK2. Eur J Nucl Med Mol Imaging. 
35:1480-8, 2008.  
 
Sun H, Sloan A, Mangner TJ, Vaishampayan U, Muzik O, Collins JM, Douglas K, 
Shields AF..Imaging DNA synthesis with [18F]FMAU and positron emission 
tomography in patients with cancer. Eur J Nucl Med Mol Imaging. 2005;32:15-22. 
 
E.A. Eisenhauer,*, P. Therasse, J. Bogaertsc, et al. New response evaluation criteria in 
solid tumours: Revised RECIST guideline (version 1.1) Eur J Cancer 2009; 45:228-247. 


 
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Howard I. Scher, Susan Halabi, Ian Tannock, et al. Design and End Points of Clinical 
Trials for Patients With Progressive Prostate Cancer and Castrate Levels of Testosterone: 
Recommendations of the Prostate Cancer Clinical Trials Working Group. Journal of 
Clinical Oncology, Vol 26, No 7 (March 1), 2008: pp. 1148-1159.  
 
Lara, P. N. Jr., Stadler, W. M., Longmate, J., et al. A Randomized Phase II Trial of the 
MatrixMetalloproteinase Inhibitor BMS-275291 in Hormone-Refractory Prostate Cancer 
Patients with Bone Metastases. Clin Cancer Res 2006, 12: 1556-1566. 
 
Coleman, R. E., Major, P., Lipton, A., et al. Predictive Value of Bone Resorption and 
Formation Markers in Cancer Patients With Bone Metastases Receiving the 
Bisphosphonate  Zoledronic Acid. J Clin Oncol, 2005, 23: 4925-4935. 
 
Chestnut CH 3rd, Bell NH, Clark GS, et al. Hormone replacement therapy in 
postmenopausal women: urinary N-telopeptide of type I collagen monitors therapeutic 
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Moss DW. Alkaline phosphatase isoenzymes. Clin Chem 1982;28:2007–2016. 
24.  
 
D. Olmos H.-T. Arkenau, J. E. Ang, et al.Circulating tumour cell (CTC) counts as 
intermediate end points in castration-resistant prostate cancer (CRPC): a single-centre 
experience. Annals of Oncol, 2008; 20:27-33. 
 
 
 
 
 


 
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12.0    DATA AND SAFETY MONITORING 
12.1     Scheduled meetings will be held monthly or more frequently depending on the 
activity of the protocol.  These meetings will include the protocol 
investigators and data managers involved with the conduct of the protocol. 
The Research Monitor for this protocol is designated to be Dr Lois Ayash 
M.D. the chair of the Data and Safety Monitoring committee who will 
independently review and oversee the protocol conduct and monitoring along 
with the Data and Safety monitoring committee at Karmanos Cancer Center. 
During these meetings the investigators will discuss matters related to: 
 
 
Safety of protocol participants (Adverse Event reporting) 
 
Validity and integrity of the data 
 
Enrollment rate relative to expectation of target accrual, characteristics of 
 
participants 
 
Retention of participants, adherence to the protocol (potential or real 
protocol violations) 
 
Data completeness on case report forms and complete source 
documentation 
 
12.2 
 Completed Data and Safety Monitoring Reports of these regular investigator  
meetings will be kept on file in the office of the Clinical Trials Core (see form in 
appendix IV). The data manager assigned to the clinical trial will be responsible for 
completing the report form.  The completed reports will be reviewed and signed off by 
the Principle Investigator (PI) or by one of the Co-PI’s in the absence of the PI.  The 
signed off forms will then be forwarded to the Director, Clinical Trials Core for review of 
completeness and processing with the Data and Safety Monitoring Committee. 
 
12.3 
The Barbara Ann KARMANOS Cancer Institute, Data and Safety Monitoring 
Committee will meet on a monthly basis to review the prior month Serious 


 
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Adverse Event forms and Data and Safety Monitoring study specific reports that 
have been filed. 


 
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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 predisease 
performance without 
restriction. 
100 
Normal, no complaints, no 
evidence of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or sedentary 
nature (eg, 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 
20 
Very sick, hospitalization 
indicated. Death not imminent. 


 
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self-care. Totally confined to 
bed or chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead 
0 
Dead 
ECOG = Eastern Cooperative Oncology Group. 


 
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Appendix B  BLOOD PROCESSING 
 
 
1. The Vacutainer CPT tube with Sodium Citrate should be at room temperature (18-
25  C) 
2. Collect 8 ml of blood into the Tube 
3. Store Tube upright at room temperature until centrifugation.  Centrifugation 
should be performed within 2 hours of blood collection 
4. Centrifuge at room temperature in a horizontal rotor (swing-out head) for a 
minimum of 20 minutes at 1500 to 1800 RCF 
 
NOTE: Mix blood sample immediately prior to centrifugation by gently inverting the 
Tube 8 to 10 times 
 
5. After centrifugation, mononuclear cells and platelets will be in a whitish layer just 
under serum layer 
6. Collect serum without disturbing the cell layer.  Store at -80 C for future 
analysis. 
7.  Collect the cell layer with a Pasteur pipette and transfer to a 15 ml size conical 
centrifuge tube with cap. Collection of cells immediately following centrifugation 
will yield best results. 
 
SUGGESTED CELL WASHING STEP: 
 
8. Add PBS to bring volume to 15 ml. Cap tube, mix by inverting the tube 5 times 
9. Centrifuge for 15 minutes at 300 RCF.  Aspirate as much supernatant as possible 
without disturbing the pellet 
10. Add PBS to bring volume to 10 ml. Cap tube, mix by inverting the tube 5 times, 
centrifuge for 10 minutes at 300 RCF and aspirate supernatant without disturbing 
the pellet 
11. Re-suspend the cell pellet in 1 ml PBS.  Transfer cell suspension into Eppendorf 
tube, centrifuge and aspirate as much supernatant as possible without disturbing 
the pellet (lymphocytes). 
12.  Store lymphocytes as pellet, do not add any solution.  For buffy coat/DNA 
analysis, add 1 ml 1% SDS/1mM EDTA/50 mM mannitol/20 mM Tris, pH 7.4 
over the cell pellet and vortex. Freeze at -80 C for future analysis. 
13.  For RNA later, resuspend the pellet in 100 ul of RNA later solution, then freeza 
at -80 C.