A Phase II Study of MRI Based Functional Imaging for the Evaluation of Bone Metastasis in Men With Castrate Resistant Prostate Cancer Receiving XL184
Phase: PHASE2
Conditions: Bone Metastases, Castrate-resistant Prostate Cancer, Recurrent Prostate Cancer, Stage IV Prostate Cancer
Sponsor: University of Chicago

TITLE: A Phase II study of MRI based functional imaging for the evaluation of 
bone metastasis in men with castrate resistant prostate cancer receiving XL184 
 
Coordinating Center: 
 
 
University of Chicago 
 
*Principal Investigator: 
Russell Szmulewitz, MD 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
773-702-7609 
 
773-702-3163 
 
rszmulew@medicine.bsd.uchicago.edu 
 
Co-Investigators: 
Oto Aytekin 
 
University of Chicago, Department of Radiology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
 
 
Walter M. Stadler 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
 
Peter Odonnell 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
 
David VanderWeele 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
 
 
Daniel Shevrin 
 
NorthShore University Health Systems 
 
2100 Pfingstein Rd 
 
Glenview, IL 60026 
 
Radiology: 
Gregory Karczmar 
 
University of Chicago, Department of Radiology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
 
 

 
ii 
 
MilicaMedved 
 
University of Chicago, Department of Radiology 
 
5841 S. Maryland Ave. MC2115 
 
Chicago, IL 60637 
 
 
 
 
 
Statistician: 
Theodore Karrison 
Dept. of Health Studies, MC2007 
5841 S. Maryland Avenue 
Chicago, IL 60637 
tkarrison@health.bsd.uchicago.edu 
 
Responsible Research Nurse: Elia Martinez, R.N. 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
773-702-4135 
 
emartinez1@medicine.bsd.uchicago.edu 
 
Responsible Data Manager/Study Coordinator: 
 
Andrea Cowhy 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
acowhy@medicine.bsd.uchicago.edu 
 
 
 
Protocol Type / Version # / Version Date: 
___08/13/2013 
 

 
iii 
SUMMARY 
 
Study Design:  In this single arm, open label phase II study, 25 patients with metastatic to the 
bone, castrate resistant prostate cancer will be treated with 60mg XL184 daily, p.o.  Patients will 
undergo two baseline screening MRI of the abdomen and pelvis prior to initiating study, and 
have a third set of MRI at 2 weeks on study.  Subsequently, patients will be followed with MRI 
of the abdomen/pelvis along with CT scan of the chest every 12 weeks for disease monitoring.  
In addition, circulating tumor cells, standard laboratories, and pain assessments will be collected 
according to the schema below. 
 
Eligible Patients:  Patients must have histologically confirmed prostate cancer with evidence of 
castration resistance defined as rising PSA or clinical/radiographic progression following 
androgen deprivation, as well as anti-androgen therapy and anti-androgen withdrawal.  Patients 
must have bone metastases identifiable on screening MRI studies.  Patients must have an ECOG 
performance status of 0 or 1 and have adequate bone marrow, liver and renal function. 
 
Primary Objective: To determine the effect of XL184 on the functional MRI metrics Ktrans and 
apparent diffusion coefficient (ADC) within castrate resistant prostate cancer bone metastases.  
Specifically, we will use dynamic contrast MRI (DCE-MRI) to measure the volume transfer 
constant of the MRI contrast reagent, Ktrans, and diffusion weighted imaging (DWI) to calculate 
the ADC at baseline and while on therapy with the hypothesis that XL184 will inhibit bone 
marrow vascular permeability and stroma proliferation, causing early changes in Ktrans and ADC. 
 
Secondary Objectives:  In addition to characterizing the change in the functional MRI metrics, 
we will be correlating the pre-treatment ADC/Ktrans values, at baseline and according to change 
over time, with standard disease metrics including RECIST tumor measurement criteria, PSA, 
circulating tumor cell numbers (CTC, CellSearch), and pain (Pain questionnaire and analgesic 
log).  As such, these metrics will be secondary objectives of the study.  We will also be 
performing an exploratory analysis of c-MET expression within circulating tumor cells. 
 

 
iv
TABLE OF CONTENTS 
 
Page 
SUMMARY .................................................................................................................................. iii 
 
TABLE OF CONTENTS ............................................................................................................ iv 
 
1. 
BACKGROUND ................................................................................................................1 
1.1. Castrate Resistant Prostate Cancer (CRPC) .........................................................................1 
1.2. MET and CRPC bone metastases ........................................................................................1 
1.3. XL184 (Cabozantinib) .........................................................................................................1 
1.4. Functional MRI ....................................................................................................................3 
1.5. Circulating Tumor Cells ......................................................................................................3 
1.6. Rationale ..............................................................................................................................4 
 
2. 
OBJECTIVES ....................................................................................................................4 
2.1. Primary Objective ................................................................................................................4 
2.2. Secondary Objectives...........................................................................................................4 
 
3. 
PATIENT SELECTION ...................................................................................................5 
3.1. Eligibility Criteria ................................................................................................................5 
3.2. Exclusion Criteria ................................................................................................................6 
3.3. Inclusion of Minorities .........................................................................................................8 
 
4. 
REGISTRATION AND DATA COLLECTION/MANAGEMENT .............................8 
 
5. 
CLINICAL ASSESSMENTS ..........................................................................................10 
5.1. Screening Assessments ......................................................................................................10 
5.2. Baseline (Day 1) Assessments ...........................................................................................11 
5.3. On-Study Assessments.......................................................................................................11 
5.4. Off Study Assessments ......................................................................................................11 
5.5. Study Calendar ...................................................................................................................12 
 
6. 
TREATMENT PLAN ......................................................................................................12 
6.1. Agent Administration.........................................................................................................12 
6.2. Description of Drug/Pharmaceutical Information .............................................................13 
6.3. Dose Reductions or Treatment Delay for Toxicity ............................................................14 
6.4. Concomitant Medication and Treatment ...........................................................................26 
6.5. Potential Drug Interactions ................................................................................................26 
 
7. 
SAFETY ............................................................................................................................28 
7.1. Adverse Events ..................................................................................................................28 
7.2. Serious Adverse Events .....................................................................................................29 
7.3. Serious and Unexpected Suspected Adverse Reactions (SUSAR) ....................................29 
7.4. Serious Adverse Event Reporting to Exelixis ....................................................................30 
7.5. Other Reporting Requirements ..........................................................................................31 
7.6. Other Safety Considerations ..............................................................................................33 
 

 
v
8. 
CORRELATIVE/SPECIAL STUDIES .........................................................................34 
8.1. Functional MRI ..................................................................................................................34 
8.2. Circulating Tumor Cell Characterization...........................................................................36 
8.3. Pain Questionnaire and Analgesic Inventory .....................................................................39 
 
9. 
MEASUREMENT OF EFFECT ....................................................................................39 
9.1. Outcome Measures based on PSA Decline ........................................................................39 
9.2. Radiographic Tumor Response ..........................................................................................39 
9.3. Duration of Response .........................................................................................................40 
9.4. Progression-Free Survival ..................................................................................................40 
 
10. 
STATISTICAL CONSIDERATIONS ...........................................................................40 
10.1. Sample Size/Primary Endpoint ..........................................................................................40 
10.2. Analysis of Secondary Endpoints ......................................................................................40 
 
11. 
PUBLICATION PLAN ...................................................................................................41 
 
APPENDIX A 
Performance Status Criteria ........................................................................................................42 
 
APPENDIX B 
Sample Data Capture Forms .......................................................................................................43 
 
APPENDIX C 
Analgesic Intake: ........................................................................................................................46 
 
Appendix D 
PROSTATE-SPECIFIC ANTIGEN WORKING GROUP    CRITERIA23 ...............................48 
 
Appendix E 
RESPONSE EVALUATION CRITERIA in SOLID TUMORS (RECIST 1.1) 42, 46 ................49 
 
REFERENCES: ...........................................................................................................................53 
 
 

 
 
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1. BACKGROUND 
 
1.1. Castrate Resistant Prostate Cancer (CRPC) 
 
Although most men are diagnosed with early stage, curable prostate cancer, unfortunately, 
prostate cancer recurrence is seen in ~40% of patients over time1. Although typically effective 
initially, in most cases hormone responsiveness is finite and patients typically fail first line 
androgen deprivation within 2-3 years, progressing to CRPC. This transition represents an 
important clinical landmark of an evolving disease that correlates with an increased risk of death 
and morbidity2.   This year ~32,000 men are projected to die from prostate cancer, the vast 
majority of whom will die from metastatic castration resistant disease (mCRPC) with bone 
metastases3.  The effective therapies for progressive CRPC are limited with docetaxel and 
cabazitxel chemotherapies along with the novel immunotherapy sipuleucel-T as the only currently 
FDA approved therapies shown to improve patient survival in the CRPC setting 4, 5, 6, 7.  The 
approximate survival after standard therapies in this setting is bleak and in the order of months.  In 
addition to death from the disease, CRPC, especially when metastatic to the bones, leads to 
substantial disability in men who suffer from the disease with a high incidence of pain, bone 
fractures, abnormal blood counts and fatigue.  There are no targeted therapies proven to be 
effective for CRPC, as the precise biology of castration resistance remains elusive.  There is thus a 
desperate need for novel therapies focused on new targets implicated in bone metastasis biology. 
 
1.2. MET and CRPC bone metastases 
 
Although the androgen receptor (AR) remains a critical driver of prostate cancer, even in the 
setting of castration resistance, and novel therapies targeting the AR are showing promise in the 
mCRPC setting8-10, disease progression despite the most formidable androgen axis inhibition is 
eventual. Multiple therapies that target castrate resistant biology beyond the AR are in 
development.  One of the most exciting targets implicated in CRPC progression is the tyrosine 
kinase c-MET.  c-Met protein is over-expressed or mutated in many tumor cell types and plays 
key roles in tumor cell proliferation, survival, invasion, metastasis, and angiogenesis11, 12.  In 
prostate cancer, c-MET expression is variable and over-expressed in 40-80% of prostate cancer 
tissues13, 14.   c-MET was found to be expressed in particularly high levels (86%) of lymph node 
and bone metastases15.  Furthermore, c-MET expression was found to be upregulated in prostate 
cancer models following castration implicating a mechanistic role in castration resistance13, 16.  In 
addition to potentially regulating prostate cancer cell survival and proliferation, c-Met and its 
ligand HGF are reported to stimulate osteoblast and osteoclast proliferation17-19.  Given c-MET’s 
potential stimulatory effects on prostate cancer and bone stroma, and prostate cancer’s 
predilection for bone metastases, c-MET is an intriguing molecule to target in mCRPC.   
 
1.3. XL184 (Cabozantinib) 
 
XL184 is an orally bioavailable small molecule inhibitor of several receptor tyrosine kinases, most 
notably 
c-MET,VEGFR2 
and 
RET 
with 
IC50 
of 
1.8 
nM, 
0.035nM 
and 
3.8 
nMrespecvitvely.XL184 caused tumor regression in multiple in vivo tumor models. Treatment 
with XL184 shows rapid effects on the tumor endothelium, resulting in breakdown of the 
vasculature beginning 24 hours after administration of XL184, thus suggesting potent anti-

 
 
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angiogenic effects of XL184. These effects translate into significant tumor growth inhibition after 
XL184 treatment in multiple tumor models including human MTC, human breast cancer, human 
lung carcinoma, and rat glioblastoma (Table 1). Overall, the data generated in vivo demonstrate 
that the target profile of XL184 translates to potent anti-angiogenic activity and potent antitumor 
efficacy. 
 
Table1: 
XL184 ED50 Values in Tumor Models 
Tumor Line 
Species 
Tissue of Origin 
ED50a 
(mg/kg/day) 
Treatment 
Duration 
TT 
Human 
Medullary thyroid carcinoma 
11 
qd 21 
MDA-MB-231 
Human 
Breast 
2 
qd 14 
H441 
Human 
Lung 
3 
qd 14 
C6 
Rat 
Brain 
<1 
qd 12 
ED50, dose associated with 50% tumor growth inhibition; qd, once daily. 
a AUC0-inf or AUC0-24 h values are about 5.16 µg∙h/mL for 3 mg/kg/day in mice, 23.3 µg∙h /mL for 1 mg/kg/day in rats, and 38.9 
µg∙h/mL for 175 mg/day in humans. 
 
Over 1000 patients to date have been treated at various doses, in multiple clinical trials with 
XL184.  With the capsule formulation, the maximum tolerated dose was 175mg daily with 
reported dose limiting toxicities of plantar/palmar erythema, elevated lipase, elevations in 
AST/ALT and mucositis.  The most common AEs considered either possibly or probably related 
to XL184 (frequency ≥ 15% of subjects, N=483 patients from pooled studies) consisted of fatigue 
(46%), diarrhea (42%), decreased appetite (27%), nausea (28%), vomiting (17%), palmar-plantar 
eryhtrodysaesthesia syndrome (17%) increased AST/ALT (16%), hypertension (16%), and rash 
(15. Most AEs (80%, regardless of relation) were of Grade 1 or 2. These events were generally 
reversible or manageable with dose interruptions or reductions. A complete description of the 
adverse event profile associated with XL184 is available within the investigator’s brochure20, 21 
 
Recently, 171 patients with metastatic castrate resistant prostate cancer were treated with XL184 
at 100mg (free base) oral daily dosing in the context of a phase II randomized discontinuation trial 
conducted in multiple tumor types, with an expanded prostate cancer cohort (NCT00940225). 
XL184 was shown to have a remarkable impact on bone metastases with 82/108 (76%) of patients 
with evaluable bone scans showing a partial or complete response, and the majority a concomitant 
improvement in bone pain20, 22.  Significant and lasting changes in measures of bone turnover were 
also observed.  Many of these patients achieved concomitant improvements in their PSA and 
hemoglobin.  There was a much more modest change in measurable disease, with only 3/34 (9%) 
confirmed responses according to RECIST criteria22.   
 
Upon review of the data from NCT00940225, it was noted that 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 daily appears to offer improved tolerability while 
maintaining efficacy in a patient population with advanced CRPC and cancer-related pain at 

 
 
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baseline.  As such, this study, as well as the pending phase III studies in CRPC, will adopt a 
starting cabozantinib dose of 60 mg daily.  
 
Based on the preliminary PK data from 46 subjects participating in a phase I open-label, single-
dose crossover study to assess the effect of food on the bioavailability of XL184 (study XL184-
004), a high-fat meal did not appear to alter the terminal t1/2, z of XL184 [mean t1/2, z : 131 hours 
(fed) vs 128 hours (fasted)]. The high-fat meal significantly increased the median tmaxto 6 hours 
from 4 hours (fasted). The high-fat meal also significantly increased both the XL184 Cmaxand 
AUC values by 39% and 56%, respectively. The geometric mean ratio of Cmax fed/fasted was 1.39 
(90% CI: 1.16-1.67), and the geometric mean ratio of AUC0-last fed/fasted was 1.56 (90% CI: 1.34-
1.80). Based on this result, XL184 should be taken on an empty stomach (fasting is required 2 
hours before and 1 hour after each dose). 
 
1.4. Functional MRI 
 
The current standard bone imaging employed in mCRPC is technitium based nuclear medicine 
bone scintigraphy, based on uptake of the radionuclide in metabolically active bone.  It is not 
specific for tumor induced changes, and is not quantitative at the lesion level.   In fact, according 
to Prostate Cancer Working Group Criteria 2.023, bone scans should only be evaluated for 
presence or lack of new lesions.  State of the art MRI technologies have several advantages over 
traditional bone scintigraphy and CT.  MRI is not hampered by X-ray attenuation by sclerotic 
bone and can thus allow accurate and precise measurement of intra-bone lesions that can be 
measured over time.   For prostate cancer bone metastases, 65% of patients will have reproducibly 
measurable bone lesions according to RECIST criteria when imaged with standard MRI, 
compared to <30% with standard CT scan24, 25. Thus a higher percentage of bone lesions can be 
assessed over time in the context of therapy and measured for response.  Functional MRI imaging 
has the additional benefit of allowing biologic characterization of the bone metastases.  Diffusion 
weighted imaging measures waters movement within the imaged region.  It can be used to 
accurately measure cellularity, proliferation, apoptosis and early responses to treatment26.  More 
specifically, by measuring the apparent diffusion coefficient (ADC), it is possible to characterize 
biologic changes within a tumor before any apparent change in size of the tumor is appreciated26, 
27.   The other functional MRI pharmacodynamic marker that has particular relevance in studies of 
anti-angiogenic agents is Ktrans, obtained using DCE-MRI.  Ktrans is a measurement calculating the 
volume transfer constant of the contrast reagent and essentially is a measurement of vascular 
perfusion.  Investigators at the University of Chicago and others have shown that VEGF targeted 
agents that alter angiogenesis are known to significantly decrease Ktrans28.  Importantly, our group 
has demonstrated that Ktrans can be reliably and reproducibly measured in CRPC bone 
metastases29.  
 
1.5. Circulating Tumor Cells 
 
Recently, many technologies have been investigated for detection and isolation of circulating 
tumor cells (CTC) from the peripheral blood30-39.  The most commonly used technology, 
immunomagnetic cell separation (CellSearch (Veridex, LLC)), has been utilized to enumerate 
CTC from men with CRPC and is an FDA approved device.  Several investigators have shown 
that absolute and change in CTC number can be prognostic and predictive of patient outcome40, 41. 
Using cutting edge resources available at the University of Chicago, the Szmulewitz laboratory 

 
 
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has successfully used fluorescence activated cell sorting (FACS) followed by multiplex IF to 
isolate and interrogate CTC from men with CRPC.  Seven out of fifteen patients in the first cohort 
had >200 presumptive CTC events by flow cytometry. All of these patients with >200 events had 
at least 10 CTC identified by imaging with the median of 22 (range 10-25) and an average of 19.4 
(+/- 5.1).  With these techniques, it is possible to probe CTC from patients with mCRPC for c-
MET and phospho-c-MET (activated c-MET) in real-time.  
 
1.6. Rationale 
 
XL184 is an inhibitor of c-MET and VEGFR2 with potent anti-angiogenesis properties in 
preclinical models.  An ongoing multi-tumor phase II clinical trial has shown a tremendous impact 
on nuclear medicine bone scan, however the biology underpinning these changes is unknown.  To 
understand the changes within the bone indicated by the initial XL184 study, more sensitive and 
precise bone imaging is necessary.  MRI based imaging, both traditional and functional, is an 
exciting tool that can potentially illuminate the mechanism of affect of XL184 on mCRPC to the 
bones by allowing sensitive interrogation of bone lesion biology. This study proposes to utilize 
functional bone imaging to test the hypothesis that XL184, through inhibition of c-MET and 
VEGFR2 in the tumor cells and stromal cells, will have a potent affect on the microenvironment, 
causing an early inhibition of angiogenesis and subsequent intra-tumoral cell death and tumor 
shrinkage.  To confirm this hypothesis, potent changes in Ktrans should be seen at 2 weeks, a very 
early time point, followed next by intra-tumoral cellular changes, characterized by ADC changes 
at 12 weeks, finally followed by tumor shrinkage at subsequent imaging. 
 
1.7 Interim Safety Analysis 
 
After the first 13 patients (approximately 50% accrual) were treated on this trial, an unplanned 
safety analysis was performed to review XL184 tolerability at the current dose and schedule, due 
to concern for frequent toxicity requiring dose modification.  Although largely well tolerated at 
60mg/day up to week 4, nearly all patients required subsequent dose reduction (12/13, with 1 
patient dose reduced at week 12) before their first on study disease evaluation at 12 weeks.  On 
average patients were either held or dose reduced for toxicity between weeks 4-6.  The most 
commonly reported toxicity requiring dose reductions were fatigue, decreased appetite, hand-foot 
syndrome, and hypertention.  The vast majority of these were persistent moderate toxicities (grade 
2) that interfered with patient quality of life.  As such, the dosing schema has been modified to 
include a scheduled dose reduction after 4 weeks on study.  As the primary endpoint of the study 
is MRI changes at 2 weeks, this change will not affect the primary scientific endpoint. 
 
2. OBJECTIVES 
 
2.1. Primary Objective 
 
The primary objective of the study is to determine effect of XL184 on the functional MRI 
metrics Ktrans and apparent diffusion coefficient (ADC) within castrate resistant prostate 
cancer bone metastases.   
 
2.2. Secondary Objectives 
 
To quantify progression free survival in men with CRPC treated with XL184 according to 
Prostate Cancer Working Group criteria23 

 
 
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 
To correlate and changes in MRI based functional metrics with bone scan, PSA, RECIST 
response criteria, CTC number and with changes in pain. 
 
To explore c-MET, phospho-c-MET staining on circulating tumor cells as a predictive 
biomarker for response and duration of response to XL-184. 
 
3. PATIENT SELECTION 
 
3.1. Eligibility Criteria 
 
3.1.1. 
Histologically or cytologically confirmed prostate cancer with progressive disease 
defined as either: 
 
 
Bone scan: 2 or more new lesions 
 
Nodal/visceral:  According to RECIST criteria (20% increase in sum of diameters)42 
 
Rising PSA: PSA evidence for progressive prostate cancer consists of a PSA level of at 
least 2 ng/ml which has risen on at least 2 successive occasions, at least 2 weeks apart. 
If the confirmatory PSA (Fig 1 #3) value is less (Fig 1 #3b) than the screening PSA 
(Fig 1 #2) value, then an additional test for rising PSA (Fig 3 #4) will be required to 
document progression.  
 
Figure 1: Eligibility Based on PSA 
 
3.1.2. 
Evidence of castration resistance defined as disease progression despite a testosterone 
level <50ng/dL (or surgical castration) 
 
3.1.2.1. 
Antiandrogen withdrawal:  
 
 
Patients who are receiving an antiandrogen (e.g. bicalutamide, nilutamide, flutamide) as 
part of primary androgen ablation must demonstrate disease progression following 
discontinuation of antiandrogen.  
 
Disease progression after antiandrogen withdrawal is defined as 2 consecutive rising 
PSA values, obtained at least 2 weeks apart, or documented osseous or soft tissue 
progression.  
 
For patients receiving flutamide, at least one of the PSA values must be obtained 4 
weeks or more after flutamide discontinuation. 

 
 
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 
For patients receiving bicalutamide or nilutamide, at least one of the PSA values must 
be obtained 6 weeks or more after antiandrogen discontinuation. 
 
No antiandrogen withdrawal response is expected in patients in whom antiandrogen 
therapy did NOT result in a decline in PSA or in those patients in whom the response to 
antiandrogens was <3 months. Therefore, it is not necessary to wait for AAWD in pts 
w/out PSA decline on an anti-androgen or in those in whom a PSA response lasted <3 
months.  In this instance, progression after withdrawal is not necessary. A 4 week wash 
out alone is sufficient. 
 
3.1.3. 
Evidence of metastatic disease to the bones within the lumbar spine, sacrum, or pelvic 
bones that is identifiable on screening pelvic MRI. 
 
 
If patient has had prior pelvis RT, then bone metastases must be out of radiated port 
(e.g. lubar or sarcral spine). 
 
3.1.4. 
Any prior therapy for castrate disease acceptable other than prior XL184 with a 
minimum washout of 2 weeks for any other anticancer therapy. 
 
 
Prior palliative radiotherapy to the pelvis must be documented and requires a minimum 
of 6-week washout. Any other radiotherapy or radionuclide requires a 2 week washout. 
 
Denosumab or zoledronic acid are allowed provided they are initiated prior to study 
initiation. 
 
3.1.5. 
ECOG performance status <2 (Appendix A). 
 
3.1.6. 
Patients must have normal organ and marrow function as defined below: 
 
 
Absolute neutrophil count  
 
 
>1,500/mcL 
 
platelets 
 
 
 
 
 
 
 
>100,000/mcL 
 
Hemoglobin  
 
 
 
 
 
 
>9.0g/dL  
 
Total bilirubin  
 
 
 
 
 
<1.5 x the upper limit of normal.  (<3 if 
known Gilbert’s) 
 
AST(SGOT)/ALT(SGPT)  
  
<2.5 X institutional upper limit of normal 
 
Creatinine clearance  
 
 
Calculated (traditional Cockroft-Gault) GFR 
>60ml/min. 
 
Lipase  
 
 
 
 
 
 
<1.5 x the upper limit of normal 
 
Urine protein/creatinine ration  
≤1 
 
Serum phosphorus  
 
 
 
>lower limit of normal 
 
3.1.7. 
Patients who are capable of sexual intercourse that may lead to fertilization must agree 
to avoid insemination either by abstinence or with an adequate form of contraception. 
 
3.1.8. 
Ability to understand and the willingness to sign a written informed consent document. 
 
3.2. Exclusion Criteria 
 
3.2.1. 
Patients who have had chemotherapy or radiotherapy within 2weeks prior to entering 

 
 
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the study or those who have not recovered from adverse events due to agents 
administered more than 2weeks earlier. 
 
 
Patients on LHRH-Agonists/antagonists should be maintained on these agents. 
 
Concomitant bone strengtheners (e.g. zoledronic acid, denosumab) are allowed 
provided they have been started prior to study initiation. 
 
3.2.2. 
Patients who are receiving herbal supplements known to increase bleeding risk 
including fish oil, flaxseed oil, clove, red clover, ginger, ginkgo biloba, St. John’s Wart 
and tumeric. 
3.2.3. 
Patients who are receiving any other investigational agents. 
 
3.2.4. 
Prior treatment with other c-MET targeted therapies. 
 
3.2.5. 
Patients with known untreated brain metastases are excluded from this clinical trial 
because of their poor prognosis and because of the unknown cerebral bleeding risk 
associated with XL184 angiogenesis inhibition. 
 
3.2.6. 
The patient has experienced any of the following within 3 months of 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  
 
3.2.7. 
Patients with documented bladder invasion with prostate cancer and active gross 
hematuria are excluded due to the increased risk of bleeding due to the study 
medication XL 184. 
 
3.2.8. 
The patients has radiographic evidence of cavitating pulmonary lesion or encasing a 
major blood vessel. 
 
3.2.9. 
The subject has uncontrolled or significant inercurrent illness including, but not limited 
to: 
 
1) Cardiovascular disorders: Decompensated congestive heart failure, uncontrolled 
hypertension (>150mm Hg systolic or >100mm Hg diastolic), unstable angina, 
myocardial infarction within 6 months, cerebrovascular event within 6 months. 
2) 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 
 intra-abdominal tumor/metastases invading GI mucosa 
 active pepticulcerdisease not controlled with antacids, 
 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 

 
 
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(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. 
3) 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. 
3) Other clinically significant disorders such as: 
i) active infection requiring systemic treatment 
(1) Chronic, but inactive hepatitis C or HIV are allowed, however an 
undetectable viral load must be documented. 
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 initiation of study 
 
3.2.10. Inability to swallow tablets. 
 
3.2.11. The patient has a corrected QT interval of >500ms. 
 
3.2.12. History of other active second malignancies. 
 
3.2.13. The patient requires concomitant treatment, in therapeutic doses, with anticoagulants 
such as warfarin or warfarin-related agents, heparin, thrombin or Factor Xa inhibitors, 
or antiplatelet agents (e.g.,clopidogrel).  
 
Low dose aspirin (≤ 81 mg/day), and prophylactic low molecular weight heparin 
(LMWH) are permitted. 
 
3.3. Inclusion of Minorities 
 
Men of all races and ethnic groups are eligible for this trial.   
 
4. REGISTRATION AND DATA COLLECTION/MANAGEMENT 
 
The University of Chicago Comprehensive Cancer Center maintains a secure, password protected, 
and regularly backed up commercial clinical trials database called “Velos.” All patients on the 
trial will be enrolled at a single institution, the University of Chicago, and will be subsequently 
entered into the Velos clinical trial database.  Data will be entered by the study coordinator and 
stored within the database using a unique identifier number. 
 
Study Coordinator: 

 
 
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Comprehensive Cancer Center 
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Andrea Cowhy 
 
University of Chicago, Department of Medicine 
 
Section of Hematology/Oncology 
 
5841 S. Maryland Ave. MC2115 
 
773-834-3095 
 
773-702-4889 
 
acowhy@medicine.bsd.uchicago.edu 
 
Eligible patients will be entered on study centrally at the University of Chicago by the Study 
Coordinator. Forms are available to NorthShore co-investigator on the University of Chicago 
Cancer Research Center website.   
 
http://cancer.uchicago.edu 
 
Click on the Intranet (top right corner). 
 
Enter your site specific user name and password 
 
Click on Phase II Website 
 
Click on Forms 
 
The following baseline clinical variables will be collected and stored in the database using data 
entry forms all available in the Velos database (Appendix B): 
 
 
Demographics 
 
Age 
 
Race 
 
Performance status 
 
Primary tumor data 
 
Diagnosis date 
 
Baseline staging 
 
Baseline PSA  
 
Gleason grade  
 
Primary tumor treatment 
 
Systemic therapy administered 
 
Date of androgen ablation start 
 
Dates of anti-androgen therapy, and withdrawal 
 
Dates and types of other systemic therapy 
 
Dates and types of systemic radiotherapy 
 
Sites of metastatic disease 
 
The pain assessment questionnaire and analgesic usage forms (Appendix C) will be collected and 
stored within each patient’s research chart along with all source documentation.  Research charts 
will be stored in a locked room at the University of Chicago only accessible by members of the 
research team. All imaging data will be collected and annotated by Dr. Oto within the HIRO 
radiology database at the University of Chicago. 
 
Patients can be registered only after the initial IRB approval for the participating site has been 
forwarded to the Coordinating Center, University of Chicago.  
 
All patients must be registered with the University of Chicago Study Coordinator.The following 

 
 
University of Chicago 
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documents should be completed by the research nurse or data manager and faxed to (773) 702-
4889 or emailed to the study coordinatora minimum of 48 hours prior to expected study med start 
date: 
 
 
Provider of information 
 
Treating Physician (NCI investigator number) 
 
Patient name and hospital ID number 
 
Patient's zip code of residence 
 
Date & copy of signed informed consent 
 
Race, gender, date of birth of patient 
 
Diagnosis and date of initial diagnosis 
 
Complete Phase II Consortium Affiliate Clinical Trial Patient Registration Form 
 
Source documentation for eligibility and pre-study procedures 
 
Prior authorization and documentation of abiraterone availability 
 
The research nurse or data manager at the participating site will then call the study coordinator to 
confirm all selection criteria listed in Section 3.   
 
To complete the registration process, the UCMC Coordinator will: 
 
 
Assign a patient study number 
 
Register the patient on the study 
 
Fax or e-mail the patient study number to the participating site 
 
Fax or e-mail, within 28 hours of completed registration, the assigned treatment arm 
 
Call the research nurse or data manager at the participating site and verbally confirm 
registration. 
 
5. CLINICAL ASSESSMENTS 
 
5.1. Screening Assessments 
 
Patients who sign informed consent and are being considered for study participation will undergo 
pre-study screening evaluations within 28 days of initiation of study drug. Tumor assessment 
including CT of the chest or chest x-ray, MRI of the abdomen and pelvis with contrast (including 
research related images-see section 8), and nuclear medicine bone scan should be performed 
within this period.  In addition, to confirm eligibility, patients should have screening CBC (white 
blood cell count, hemoglobin, platelet count, white blood cell differential), serum chemistries 
(sodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, calcium, 
alanine aminotransferase, aspartate aminotransferase, total bilirubin, total protein, alkaline 
phophatase, albumin, lipase, amylase, phosphorus), thyroid function tests (TSH, free T4), creatine 
kinase (CK), INR and Urine Protein/Creatinine ratio.  As described in the correlative section 
(Section 8.2), an additional 15 mL of blood will also be collected during screening for CTC 
analysis by the Szmulewitz laboratory (for University of Chicago patients only).  The ECOG 
performance status and concomitant medications will also be noted during screening for eligibility 
purposes. 
 

 
 
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5.2. Baseline (Day 1-Cycle 1, week 0) Assessments 
 
Eligible patients who have signed informed consent and have had eligibility confirmed will be 
seen in the outpatient clinic on Day 1of study.  They will undergo a history and physical 
examination, have ECOG performance status, concomitant medications, and baseline toxicity 
documented at this visit.  The subject will also complete the pain assessment questionnaire and 
analgesic intake log at this visit.  In addition to CBC and chemistries (phosphorus, amylase, lipase 
not required), and PSAwill also be recorded at baseline.  Subjects will subsequently receive their 
first 30 day supply of study drug (refer to Section 6 for further treatment plan information).  A 
second baseline CTC sample for the Szmulewitz laboratory will also be obtained (for University 
of Chicago patients only). Finally, as described in the correlative section (Section 8.1), a second 
baseline MRI of the pelvis will be obtained at the Day 1 visit (or within 72hours prior) 
 
5.3. On-Study Assessments 
 
Clinical visits will occur every two weeks for the first three months and then every 4 weeks 
thereafter.  Cycles are 4 weeks long and each 4 week visit will be the start of a new cycle.  A three 
day grace period will be allowed for each visit, however, every attempt should be made to 
prescribe to the study calendar.  At each of these visits, subjects will undergo a history and 
physical examination, have ECOG performance status, concomitant medications, and toxicity 
documented at each visit.  The subject will also complete the pain assessment questionnaire and 
analgesic intake log at these visits.  All screening chemistries, CBC, thyroid studies and urine 
studies, will be performed at all on study visits.  An EKG will be checked at week 4 visit to assess 
for prolongation of QTc prolongation once the study drug is at steady state.  The final CTC 
sample for the Szmulewitz lab will be collected at the week 2 visit. A pelvis MRI and bone scan 
will be performed at the week 2 visit, otherwise all radiologic examinations with bone scan, chest 
imaging, MRI abdomen/pelvis will be performed at 12 week intervals. Likewise, PSA as 
measureof disease burden will be measured every 12 weeks. 
 
5.4. Off Study Assessments 
 
Patients will be followed with these assessments until taken off study (Section 7.3 for duration of 
therapy details).  Within 30 days of study medication discontinuation, subjects will undergo a 
complete evaluation with a history and physical examination, ECOG performance status, 
concomitant medications, and baseline toxicity documented at this visit.  The subject will also 
complete the Present Pain Intensity and analgesic intake log, have CBC, chemistries, Urine 
studies, PSA, and have radiologic tumor assessments performed, unless already performed within 
two weeks of being taken off study.  Study participant refusal or inability to undergo these 
evaluations should be noted.  
 
 

 
 
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5.5. Study Calendar 
 
Evaluations 
Screening 
(w/in 4 
weeks) 
Cycle 1,  
Day 1 of 
study 
 
(Week 0) 
Cycle1, 
D15(Week 
2) 
 
Each Cycle start 
(Week 4, 8, 12, 
16, 20, etc.)  
 
Cycle 2, 
D15(Week 6) 
Cycle 3 Day 15, 
(Week 10) 
Week 
12, 
then 
every 
12 
weeks 
Off study 
History& Physical exam 
(w/vitals) 
 
X 
X 
X 
 
X 
Informed Consent 
X 
 
 
 
 
 
ECOG Performance status 
X 
X 
X 
X 
 
X 
Concomitant medications 
X 
X 
X 
X 
 
X 
Adverse Events & Toxicity  
 
X 
X 
X 
 
X 
Pain Assessmenta 
 
X 
X 
X 
 
X 
Tumor Assessments 
 
 
 
 
 
 
Chest imagingb 
X 
 
 
 
X 
X 
Bone Scan 
X 
 
X 
 
Xc 
X 
MRI Pelvis w/contrast-
Researchimages 
X 
X 
X 
 
X 
X 
MRI Abd/Pelvis w/contrast 
X 
 
 
 
X 
X 
Laboratory Assessments 
 
 
 
 
 
 
CBC with platelets and 
differential 
X 
X 
X 
X 
 
X 
Serum chemistriesd 
X 
Xf 
X 
X 
 
X 
INR 
X 
 
 
 
 
 
TSH, free T4 
X 
 
X 
X 
 
X 
EKGe 
X 
 
 
X 
 
 
Urine protein/creatinine 
X 
 
X 
X 
 
X 
PSA 
 
X 
 
 
X 
X 
CTC-Szmulewitz labg 
X 
X 
X 
 
 
 
 
aPresent Pain Intensity Score and analgesic intake log (Appendix C) 
b Either chest x-ray or CT of the chest are acceptable 
cIf new lesions seen on 12 week bone scan in absence of other metrics of progression, bone scan should be repeated 
6 week later to rule out bone scan flare. 
dSodium, potassium, chloride, bicarbonate, blood urea nitrogen, creatinine, glucose, calcium, alanine 
aminotransferase, aspartate aminotransferase, total bilirubin, total protein, alkaline phophatase, albumin, phosphorus, 
amylase, lipase, creatine kinase (CK) 
eEKG should be performed during screening period and at week 4 only, then as clinically indicated 
f Phosphorus, amylase, lipase not to be repeated at day 1 of study 
gUniversity of Chicago Patients only 
 
 
6. TREATMENT PLAN 
 
6.1. Agent Administration 
 
Treatment will be administered on an outpatient basis.  Reported adverse events and potential 
risks are described in Section 8.  All patients will be treated with XL184 at a starting dose of 

 
 
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60mg oral daily dosing.  Due to observed toxicity (see Section 1.6 above) after 4 weeks of 
treatment at 60mg/day, the dose will be decreased for all patients to 40mg/day for subsequent 
dosing.  Patients dose reduced to 40mg prior to week for will stay at this dose level.  Appropriate 
further dose modifications are described in Section 6.3.  No investigational or commercial agents 
or therapies other than those described below may be administered with the intent to treat the 
patient's malignancy with the exception of patients who are chemically castrated who should 
continue to receive their LHRH agonist while on this clinical trial.  Medications for bone health 
(e.g. zoledronic acid or denosumab) should likewise be continued (Section 3.1.5). 
 
A supply of doses will be administered at the clinical site at each 4 week visit during the On-Study 
Treatment period. Subjects should fast (with exception to water) 2 hours before through 1 hour 
after each dose.  Subjects will be provided with sufficient study treatment and instructions for 
self-administration. Any unused study treatment must be returned to the study site for drug 
accountability and disposal.  
 
6.2. Description of Drug/Pharmaceutical Information 
 
XL184 
Chemical Name: Cyclopropane-1,1-dicarboxylic 
acid 
[4-(6,7-dimethoxy-quinolin-4-yloxy)-
phenyl]-amide (4-fluoro-phenyl)-amide, (l)-malate salt 
 
How Supplied: 
Exelixis 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 in table 2. 
 
Storage and Disposal:  All study drug will be shipped and stored at room temperature (15-30 
degrees Celsius.  Inventories of XL184 will be kept by the investigational pharmacy at the 
University of Chicago.  Any unused, previously dispensed XL184 will be returned to the 
investigational pharmacy and discarded at the discretion of the pharmacist in a manner that 
prevents accidental ingestion.  At completion of the study, to satisfy regulatory requirements 
regarding drug accountability, all unused study treatment will be reconciled and destroyed 
according to applicable state, federal, and local regulations. 
 
Agent Accountability/Ordering:  The investigational pharmacist will keep a careful log of 
XL184 supply and maintain the drug accountability log.  When a patient is enrolled, the 
pharmacist will enter into the log: the subject identification number, the number of the pill bottle 
dispensed and the date.  The research nurse will retrieve pill-bottles from the investigational 
pharmacy, dispense the bottle to the patient, and collect used bottles.  The nurse will also keep a 
careful record of unused capsules and return unused drug to the investigational pharmacy for 
dispensing.  The investigational pharmacy will procure XL184 directly from Exelixis and will 
ensure that adequate supplies are maintained. 
 
Table 2: XL184 Tablet Components 
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 

 
 
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6.3.  Dose Reductions or Treatment Delay for Toxicity 
 
Subjects will be monitored for adverse events (AE’s) continuously throughout the study and for 
30 days after the last dose of study medication.  Subjects will have treatment withheld if they 
develop unacceptable toxicity defined as: 
 
Intolerable Grade 2 toxicity that cannot be adequately managed 
 
Grade 3 or greater non-hematological toxicity (including nausea, vomiting, or diarrhea 
despite optimal management) 
 
Urine protein/creatinine ratio > 2 
 
Grade 4 hematological toxicity  
 
If a subject experiences unacceptable study treatment related “unacceptable toxicity” (per the criteria 
above), study treatment may be withheld at the investigator’s discretion if clinically necessary. XL 
184 therapy will be permanently discontinued for any patient who experiences any XL184-related 
“unacceptable toxicity” who do not recover from the XL184 related toxicity to  1 Grade within four 
weeks (one cycle).  Any patient who requires more than two weeks to recover from an XL-184 related 
unacceptable toxicity will have the dose reduced one level [table 3, Section 6.3] to 40mg. If the 
patient was at 40mg already, then the appropriate dose reduction would be to 20mg.  Dose reductions 
are at the discretion of the investigator for drug holds <2 weeks.  Dose escalation from 40mg to 60mg 
is not permitted for safety reasons.  If apatient at 20mg/day does not experience further toxicity after 
completing one cycle (4 weeks) at the reduced dose, the XL184 dose may be re-escalated and the 
patient monitored at two weeks and one month for recurrence of unacceptable toxicity.Upon dose re-
escalation, if the increased dose is not tolerated, the patient should be maintained at the lower, 
tolerated dose.If study treatment is withheld, the subject should be instructed not to “shift” or make up 
the withheld doses unless the missed dose can be taken within 12 hours of the normal dosing time.  
 
 
For example, if doses are withheld on Days 11-15 of a 28-day daily-dosing cycle, dosing 
would resume (if indicated) on Day 16 and the cycle would end as scheduled on Day 28. 
 
If doses are withheld on Days 1-4 of a 28-day cycle, dosing would resume (if indicated) on 
Day 5 and the cycle would end as scheduled on Day 28. (Except for Cycle 1, wherein the 
first day of Cycle 1 is defined as the date the first dose of study treatment is administered). 
 
Table 3: Dose Reductions 
First Dose Level Reduction 
Second Dose Level Reduction 
XL184 40 mg oral daily 
XL184 20 mg oral daily 
 
 
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 

 
 
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Comprehensive Cancer Center 
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6.2.1. 
Warnings and Precautions 
 
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 
(e.g., 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. A complete description of the adverse event profile associated with 
XL184 is available within the investigator’s brochure20, 21. 
 
Subjects with severe diarrhea who are unresponsive to anti-diarrheals such as loperamide or who 
become dehydrated may require temporary interruption of therapy followed by dose reduction. 
Subjects with nausea can be managed according to accepted practice (e.g., with prochlorperazine).  
 
Adverse events potentially related to inhibition of VEGFR should be carefully monitored. 
Subjects who develop GI perforation, wound dehiscence requiring medical intervention, serious 
bleeding, nephrotic syndrome, hypertensive crisis, or thromboembolic events must be 
discontinued from the study. 
 
6.2.2. 
General Guidelines for Non-Hematologic and Hematologic Adverse Events 
 
General guidelines for the management of non-hematologic and hematologic toxicities are 
provided in Table 5 and Table 6, respectively. As a general approach, it is suggested that all AEs 
be managed with supportive care when possible at the earliest signs of toxicity.  
 
Table 5. General Approach to the Management of 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 

 
 
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Table 6. 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). 
 
 
6.2.3. 
Treatment-Emergent Hypertension 
Hypertension is a relatively common complication of other VEGF-pathway inhibitors and has 
been observed in cabozantinib clinical studies. 
 
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. 
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.  

 
 
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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 (Table 7). 
 
Table 7. Management of Hypertension Related to Cabozantinib 
 
6.2.4. 
Treatment-Emergent Proteinuria 
Proteinuria has been reported with approved drugs that inhibit VEGF pathways as well as with 
cabozantinib. Table 8 provides a recommended algorithm for treatment-emergent proteinuria 
management. 
 
Table 8: Management of Treatment-Emergent Proteinuria 
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 
Urine Protein/Creatinine Ratio 
Treatment/Dose Modification 
≤ 1 
 No change in treatment or monitoring 
> 1 and < 2 
 Repeat urine protein/creatinine within 7 days 
 If > 1 and < 2 on repeat, decrease study treatment dose to 
125 mg. Check urine protein/creatinine every 2 weeks. If 

 
 
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6.2.5. 
Pancreatic Conditions 
 
Amylase and lipase elevations have been observed in clinical studies with cabozantinib. The 
clinical significance of asymptomatic elevations of enzymes is not known but in general 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. 
 
urine protein/creatinine remains > 1 and < 2 for 1 month, 
continue reduced dose of study treatment and check urine 
protein/creatinine per protocol. If urine protein/creatinine is 
< 1 on 2 consecutive readings resume treatment with full 
dose study treatment (the second reading is a confirmatory 
reading and can be done within a week of the first reading). 
≥ 2 
 Repeat urine protein/creatinine ratio within 7 days 
 If > 2 on repeat, hold treatment and check urine 
protein/creatinine ratio every 14 days. If urine 
protein/creatinine remains > 2 and stable (≤ 20% change) 
for 1 month, can monitor per protocol. Resume treatment if 
urine protein/creatinine ratio is < 2 on 2 consecutive 
readings (the second reading is a confirmatory reading can 
be done within a week of the first reading). Restart full 
dose if urine P/C decreases to < 1. Restart study treatment 
at 75 mg if urine P/C decreases to > 1 but < 2 (dose level -
1, Table 4). 
 If urine protein/creatinine remains > 2 for 5weeks (>4 
weeks after holding XL 184), subject must come off study 
treatment. 

 
 
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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 
radiographic evaluation  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. 
 
 
 
 
6.2.6. 
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 

 
 
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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 paresthesia (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 (e.g., abscess, 
cellulitis, or impetigo). 
 
In the case of study treatment-related skin changes (e.g., rash, hand-foot syndrome), the 
investigator may request that additional assessments be conducted with the subject’s consent. 
These assessments may include digital photographs of the skin changes and/or a biopsy of the 
affected skin and may be repeated until the skin changes resolve.  
 
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 (e.g., 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 
 
6.2.7. 
Diarrhea, Nausea, Vomiting, Stomatitis and Mucositis 
 
Diarrhea 
Subjects should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements. Administration of 
antidiarrheal agents is recommended at the first sign of diarrhea as initial management. 

 
 
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Loperamide is recommended as standard first line therapy. Alternatively, diphenoxylate/atropine 
can be used. Additional agents to consider in subjects with diarrhea that is refractory to the above 
include deodorized tincture of opium and octreotide (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 Table 3 (dose reduction table). 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 3 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 (e.g., with a weak solution of salt and baking 
soda) should be maintained. The oral cavity should be rinsed and wiped after meals, and dentures 
should be cleaned and brushed often to remove plaque. Local treatment should be instituted at the 
earliest onset of symptoms. When stomatitis interferes with adequate nutrition and local therapy is 
not adequately effective, dose reduction or temporary withholding of cabozantinib should be 
considered. 
 
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: 
 
Transaminase elevation 
CTCAE v4.0 
 
Intervention 

 
 
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Cabozantinib treatment should also be interrupted when transaminase increases are accompanied 
by progressive elevations of total bilirubin, and/or elevations of coagulation tests 
(e.g., International Normalized Ratio [INR]). Should elevated transaminases be observed (grade 1 
or higher), the INR should be checked.  Should an elevated transaminase level be accompanied by 
bilirubin and/or 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 
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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[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.  
 
6.2.8. 
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 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 (e.g., 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 (≥ 0.5 teaspoon (2.5ml) of red blood). Treatment with cabozantinib should 
be interrupted if less severe forms of clinically significant hemorrhage occur and may be restarted 
after the cause of hemorrhage has been identified and the risk of bleeding has subsided. Therapy 
of bleeding events should include supportive care and standard medical interventions.  
 

 
 
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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. 
 
6.2.9. 
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. 
 
6.2.10. Guidelines for Prevention of GI Perforation/Fistula and Non-GI Fistula 
Formation 
 
GI perforation/fistula and Non-GI fistula formation have been reported with approved drugs that 
inhibit VEGF pathways as well as with cabozantinib. Carefully monitor for episodes of abdominal 
pain, especially in subjects with known risk factors for developing GI perforation/fistula or non-
GI fistula, to allow for early diagnosis. Such risk factors include (but may not be limited to) the 
following: 
 
GI-perforation/fistula: 
 Intra-abdominal tumor/metastases invading GI mucosa  
 Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, 
cholecystitis or symptomatic cholangitis, or appendicitis  
 History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess 
 Prior GI surgery (particularly when associated with delayed or incomplete healing). 
Complete healing following abdominal surgery or resolution of intra-abdominal abscess 
must be confirmed prior to initiating treatment with cabozantinib. 
 
Additional risk factors include concurrent chronic use of steroid treatment or non-steroidal 
anti-inflammatory drugs. Constipation indicative of bowel obstruction should be monitored and 
effectively managed.  
 
Non-GI fistula: 
 Radiation therapy has been identified as a possible predisposing risk factor for non-GI fistula 
formation in subjects undergoing treatment with such agents (e.g., bevacizumab). Radiation 
therapy to the thoracic cavity (including mediastinum) should be avoided within 3 months of 
starting treatment with cabozantinib. Non-GI fistula should be ruled out as appropriate in 
cases of onset of mucositis after start of therapy. 
 
Discontinue all study treatment in subjects who have been diagnosed with GI or non-GI 
perforation/fistula. 
 
6.2.11.  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 

 
 
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must have completely healed prior to starting cabozantinib treatment and be monitored for wound 
dehiscence or wound infection while the subject is being treated with cabozantinib.  
Treatment with cabozantinib must be interrupted for any wound healing complication which needs 
medical intervention. Treatment with cabozantinib can be resumed once wound healing has 
occurred unless otherwise prohibited in specific protocols. Cabozantinib should be discontinued in 
subjects with serious or chronic wound healing complications. 
The appropriate dose hold interval prior to elective surgery to reduce the risk for wound healing 
complications has not been determined. In general, cabozantinib should be stopped at least 
3 weeks (5 half lives) prior to elective surgery.  
 
6.2.12. 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 (e.g., symptomatic hypothyroidism) should 
follow accepted clinical practice guidelines. 
 
Other endocrine disorders such as hypocalcemia and hyperglycemia, and associated laboratory 
changes, have been observed in less than 10% of subjects. Monitoring with standard laboratory 
tests for endocrine disorders and clinical examination prior to initiation and during treatment with 
cabozantinib is recommended. Cabozantinib should be discontinued in subjects with severe or 
life-threatening endocrine dysfunction. 
 
6.2.13. Guidelines for Prevention of Osteonecrosis of the Jaw 
 
Osteonecrosis of the jaw (ONJ) has been reported with use of antiangiogenic drugs and 
bisphosphonates and denosumab in cancer patients. Additional risk factors for ONJ have been 
identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral hygiene, 
smoking, dental or orofacial surgery procedures, and cancer disease itself. Three cases of 
osteonecrosis have been reported in subjects treated with cabozantinib, the details of which are 
provided in the current version of IB. As a preventive measure, invasive dental procedures should 
be avoided if possible in subjects who have previously been treated with or concomitantly receive 
bisphosphonates or denosumab. In cases where dental procedures are unavoidable, the risks and 
benefits of a dental procedure and the extent of the procedure as well as the risk of developing 
osteonecrosis of the jaw need to be considered when deciding on the duration of a temporary 

 
 
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treatment interruption of cabozantinib. If clinically possible, treatment with cabozantinib should 
be held for at least 2 weeks prior to a dental procedure and resumed after complete wound healing 
occurred.  Subjects with any documented case of osteonecrosis should have study treatment 
interrupted, and appropriate clinical management should be initiated. Reinitiation of study 
treatment must be discussed with and approved by the Sponsor on a case by case  
 
6.3. Concomitant Medication and Treatment 
 
If the subject must use a concomitant medication during the study, it is the responsibility of the 
investigator to ensure that details regarding the medication are recorded.  
 
Chemotherapy and Radiotherapy 
If possible, alternative anticancer treatment should not be initiated until PD has been observed by 
standard guidelines and study treatment has been discontinued. If a subject requires additional 
systemic anticancer treatment, study treatment must be discontinued. Local intervention (e.g. 
nephrostomy tube placement, TURP) is discouraged unless medically unavoidable. Subjects 
receiving local intervention are allowed to continue to receive study treatment at the investigator’s 
discretion as long as they continue to meet study eligibility criteria. 
 
Other Medications 
Anti-emetics and anti-diarrheal medications should not be administered prophylactically prior to 
the first dose of study drug. After the first dose of study drug, at the discretion of the investigator 
and after the onset of symptoms, treatment (or prophylaxis) with anti-emetic and anti-diarrheal 
medications may be undertaken per standard clinical practice. 
 
Pain medications administered as dictated by standard practice are acceptable while the subject is 
enrolled in the study.  Colony stimulating factors (e.g. granulocyte colony-stimulating factors) 
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 before the 
first dose of study treatment. Erythropoietin should not be used based on a recent report of 
increased risk of tumor recurrence/progression associated with erythropoietin43. 
 
No concurrent investigational agents will be permitted. 
 
6.4. 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).  
 
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 

 
 
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a clinical pharmacology study, XL184-006, showed that concurrent administration of cabozantinib 
with the strong CYP3A4 inducer, rifampin, resulted in an approximately 80% reduction in 
cabozantinib exposure (AUC values) after a single dose of cabozantinib in healthy volunteers. Co-
administration of cabozantinib with strong inducers of the CYP3A4 family (e.g., dexamethasone, 
phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, phenobarbital, and St. John’s Wort) may 
significantly decrease cabozantinib concentrations. The chronic use of strong CYP3A4 inducers 
should be avoided. Other drugs that induce CYP3A4 should be used with caution because these 
drugs have the potential to decrease exposure (AUC) to cabozantinib. Selection of alternate 
concomitant medications with no or minimal CYP3A4 enzyme induction potential is 
recommended. In addition, caution must be used when discontinuing treatment with a strong 
CYP3A4 inducer in a subject who has been concurrently receiving a stable dose of cabozantinib, 
as this could significantly increase the exposure to cabozantinib.  
 
Preliminary results from a clinical pharmacology study, XL184-007, showed that concurrent 
administration of cabozantinib with the strong CYP3A4 inhibitor, ketoconazole, resulted in a 33-
39% increase in the cabozantinib exposure (AUC values) after a single dose of cabozantinib in 
healthy volunteers. Co-administration of cabozantinib with strong inhibitors of the CYP3A4 
family (e.g., ketoconazole, itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and 
ritonavir) may increase cabozantinib concentrations. Grapefruit / grapefruit juice and Seville 
oranges may also increase plasma concentrations of cabozantinib. Strong CYP3A4 inhibitors and 
other drugs that inhibit CYP3A4 should be used with caution because these drugs have the 
potential to increase exposure (AUC) to cabozantinib. Selection of alternate concomitant 
medications with no or minimal CYP3A4 enzyme inhibition potential is recommended.  
Because in vitro studies only assessed the metabolizing capacity of the CYP3A4, CYP2C9, and 
CYP2D6 pathways, the potential for drugs that inhibit/induce other CYP450 pathways (e.g., 
CYP2C8, CYP2C19, CYP2B6, CYP1A2) to alter cabozantinib exposure is not known. Therefore, 
these drugs should be used with caution when given with cabozantinib.  
 
Please refer to the Flockhart drug interaction tables for lists of substrates, inducers, and inhibitors 
of selected CYP450 isozyme pathways (Flockhart 2007; 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx).  
 
Protein Binding: Cabozantinib is highly protein bound (approximately 99.9%) to human plasma 
proteins. Therefore, highly protein bound drugs should be used with caution with cabozantinib 
because there is a potential displacement interaction that could increase free concentrations of 
cabozantinib and/or a co-administered highly protein-bound drug (and a corresponding increase in 
pharmacologic effect). Factors that influence plasma protein binding may affect individual 
tolerance to cabozantinib. Therefore, concomitant medications that are highly protein bound (e.g., 
diazepam, furosemide, dicloxacillin, and propranolol) should be used with caution. Because 
warfarin is a highly protein bound drug with a low therapeutic index, administration of warfarin at 
therapeutic doses should be avoided in subjects receiving cabozantinib due to the potential for a 
protein binding displacement interaction.  
 
Other Interactions: In a relative bioavailability study in dogs cabozantinib exposure was not 
significantly affected by drugs that alter gastric pH. Nevertheless, drugs such as proton pump 
inhibitors (PPIs) and H2-antagonists produce profound suppression of gastric acid secretion and 
significant increases in gastric pH. By elevating gastric pH, PPIs and H2-antagonists may decrease 

 
 
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cabozantinib plasma exposure levels and its effectiveness in vivo, resulting in clinically significant 
drug interactions. The use of PPIs (e.g., omeprazole, lansoprazole, rabeprazole, pantoprazole, and 
esomeprazole) and/or H2-antagonists (e.g., ranitidine, famotidine, and nizatidine) is discouraged 
during this study. If antacids are not adequate, the use of H2 blockers is preferred over PPIs (Note: 
Cimetidine should be avoided because of its potential to interfere with CYP3A4 mediated 
metabolism of cabozantinib). Antacids, H2 blockers, or PPIs should be taken at least 2 hours 
(preferably 4 hours) after taking cabozantinib but at least 14 hours before the next dose of 
cabozantinib if possible.  
 
In vitro data suggest that cabozantinib is unlikely to be a substrate for P glycoprotein (P-gp), but it 
does appear to have the potential to inhibit the P-gp transport activity.  
 
Additional details related to these overall conclusions are provided in the Investigators Brochure 
 
7. SAFETY 
 
7.1. Adverse Events 
 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical investigation of 
a subject who has been enrolled in a clinical study and who may have been administered an 
investigational product, regardless of whether or not the event is assessed as related to the study 
drug 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. Abnormal laboratory values, ECG findings, or vital signs that are 
considered clinically significant by the investigator, and pre-existing medical conditions that 
worsen during a study, should be recorded as AEs. 
 
For the purpose of data collection, all AEs that occur after informed consent through 30 days after 
last dose of study treatment (or until a subject is determined to be a screening failure) 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 will be based 
on the following two definitions: 
 
 
Definite – The AE is clearly related to the study treatment. 
 
Probable – The AE is likely related to the study treatment. 
 
Possible – The AE may be related to the study treatment. 
 
Unlikely – The AE is doubtfully related to the study treatment. 
 
Unrelated – The AE is clearly NOT related to the study treatment. 
 
Assessment of toxicities and adverse events will be graded according to the Common Toxicity 
Criteria (CTC), version 4.03:  
 
 
V4.03 (CTCAE): publish date June 14, 2010:  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-

 
 
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14_QuickReference_8.5x11.pdf 
 
7.2.  Serious Adverse Events 
 
The serious adverse event (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. 
 
ALL Serious Adverse Events, whether or not they are considered related to the study 
treatment MUST be reported to the sponsor-investigator and to the University of Chicago 
Comprehensive Cancer Center (UCCCC).  Refer to Section 7.5 for reporting guidelines. 
 
7.3. Serious and Unexpected Suspected Adverse Reactions (SUSAR) 
 
A serious adverse event is considered to be a suspected adverse reaction if there evidence to 
suggest a causal relationship to the adverse event.  This may include a single occurrence of an 
event strongly associated with drug exposure (e.g. Stevens-Johnson Syndrome), one or more 
occurrence of an event that is not commonly associated with drug exposure, but is otherwise 
uncommon in the study population, or an aggregate analysis of specific events occurring at greater 
frequency than expected from historical controls. 
 
Unexpected events are those not listed at the observed specificity or severity in the protocol, 
consent, FDA-approved package insert, or elsewhere in the current IND application.  This includes 
adverse events listed in the protocol, consent or IND as occurring within the class of drugs or 
otherwise expected from the drug’s pharmacological properties but which have not been 
previously observed with this investigational agent. 
 
ALL SUSARS occurring on this clinical trial must be reported to the FDA.  Refer to Section 

 
 
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7.5.3 for reporting guidelines. 
 
7.4. Serious Adverse Event Reporting to Exelixis 
 
As soon as an investigator becomes aware of an adverse event 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 the event is not felt 
to be drug related. 
 
Email: drugsafety@exelixis.com;  
Fax: 650-837-7392 
 
This study will be using Form FDA 3500A (MedWatch form) for SAE reporting.  
 
MedWatch forms and information:  
http://www.fda.gov/medwatch/getforms.htm 
 
The minimum information required for SAE reporting includes identity of investigator, site 
number, patient number, an event description, SAE term(s), onset date, the reason why the event 
is considered to be serious (ie the seriousness criteria) and the investigator’s assessment of the 
relationship of the event to study treatment. Additional SAE information including medications or 
other therapeutic measures used to treat the event, action taken with the study treatment due to the 
event, and the outcome/resolution of the event will be recorded on the SAE form.  
 
In all cases, the investigator should continue to monitor the clinical situation and report all 
material facts relating to the progression or outcome of the SAE. Furthermore, the investigator 
may be required to provide supplementary information as requested by the Exelixis Drug Safety 
personnel or designee. 
 
When reporting serious adverse events, the following additional points should be noted: 
 
When the diagnosis of an SAE is known or suspected, the investigator should report the 
diagnosis or syndrome as the primary SAE term, rather than as signs or symptoms. Signs 
and symptoms may then be described in the event description.  
 
Death should not be reported as an SAE, but as an outcome of a specific SAE, unless the 
event preceding the death is unknown. In the exceptional case where the events leading to 
death are unknown, then Death may be used as an event term and should be reported as 
“death, cause unknown”. If an autopsy was performed, the autopsy report should be 
provided.  
 
While most hospitalizations necessitate reporting of an SAE, some hospitalizations do not 
require SAE reporting, as follows:  
 
Elective or previously scheduled surgery, e.g., a previously scheduled ventral 
hernia repair. 
 
Procedures for pre-existing conditions that have not worsened after initiation of 
treatment. 
 
Pre-specified study hospitalizations for observation. 
 
Events that result in hospital stays of less than 24 hours and that do not require 
admission, e.g., an emergency room visit for hematuria that results in a 
diagnosis of cystitis and discharge to home on oral antibiotics. 

 
 
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 
SAEs must, however, be reported for any surgical or procedural complication resulting in 
prolongation of the hospitalization. 
 
All serious unexpected adverse drug reactions (unexpected related SAEs) must be reported 
to the FDA by the investigator as required by 21 CFR 312.32 (See Section 7.4.2 below). 
 These reports are to be filed utilizing the Form FDA 3500A (MedWatch Form). 
 The final MedWatch must be submitted by the study site to Exelixis within 1-2 business 
days of submisison to the FDA to allow Exelixis time to cross-report to Exelixis’ IND. 
Email: drugsafety@exelixis.com; Fax 650-837-7392 
 
7.5. Other Reporting Requirements 
 
7.5.1. 
University of Chicago Comprehensive Cancer Center (UCCCC) 
 
7.5.1.1. Events Occurring at the University of Chicago 
 
All serious adverse events and protocol deviations must also be reported to the University of 
Chicago Comprehensive Cancer Center (UCCCC) Cancer Clinical Trials Office (CCTO). 
 
The Research Nurse or other designated individual should report the SAE/deviation to the 
UCCCC Quality Assurance (QA) Coordinator by the end of the business day when s/he becomes 
aware of the event.  Events occurring after business hours will be reported to the CCTO by 12pm 
(noon) the next business day.  Each event report must indicate where the event meets the IRB’s 
Unanticipated Problem reporting criteria. 
 
7.5.1.2. Events Occurring at Participating Site(s)  
 
For serious and unexpected adverse events occurring at a participating site it is the responsibility 
of the research nurse, study coordinator, or other designated individual at the site where the 
event occurs to notify the UCCCC of the adverse event.  Events should be reported to the 
UCCCC QA Coordinator at: (773) 834 2461 or qaccto@bsd.uchicago.edu. 
 
For unexpected and serious suspected adverse reactions which FDA require reporting as a single 
occurrence, Form 3500A (MedWatch) must be completed by the designated site personnel and 
returned to the UCCCC QA Coordinator according to the timeframes in Section 2.4. 
 
7.5.2. 
The Institutional Review Board 
 
When appropriate, the IRB’s Unanticipated Problem electronic submission form must be 
completed by the research nurse or other designated individual and submitted by the investigator 
via the IRB’s electronic submission system within the IRB’s designated reporting 
timeframes.  Details of the IRB’s current policy can be found on their website at: 
http://bsdirb.bsd.uchicago.edu/forms-guidelines/up.html 
 
Events occurring at a participating site should be reported to the local IRB of record according 
to their policies and procedures and may be reported to the University of Chicago IRB if they 
meet current reporting criteria. 
 

 
 
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7.5.3. 
FDA 
 
This study will be conducted under an IND held by Dr. Russell Szmulewitz at the University of 
Chicago.   
 
Per 21 CFR 312.32, the sponsor-investigator is required to notify the FDA and all participating 
investigators of potential serious risks within 15 calendar days of determining the information 
meets FDA reporting requirements.  Unexpected fatal or life-threatening suspected adverse 
events must be reported to the FDA by the sponsor-investigator via phone or fax within 7 
calendar days.   
 
Current FDA regulations require that all SUSARs (see definition in section 7.3) occurring on 
this trial, other findings that suggest a significant risk to humans exposed to the investigational 
drug (e.g. information from pooled analysis of multiple studies), and any clinically significant 
increase in the rate of an expected serious adverse reaction be reported as an IND Safety Report. 
 
In order to meet these requirements, the sponsor-investigator will review all reported serious 
adverse events as they occur and will conduct a literature search to seek new safety information 
and review and analyze all safety information from this clinical trial at least annually and more 
frequently as appropriate. 
 
Table A:  Reporting Requirements 
 
Report Type 
Method of Report 
Responsible 
Party 
Timeline1 
Fatal/Life-Threatening Event 
Yes 
No 
Individual Report 
Form 3500A 
(MedWatch)7 
RN/CRA 
4 calendar days5 
10 calendar days5 
Other Findings that 
Suggest Significant Risk2 
Narrative3 
PI 
4 calendar day6 
10 calendar days6 
Clinically Significant 
Increased Frequency of 
Suspected Adverse 
Reactions4 
Narrative 
PI 
4 calendar days6 
10 calendar days6 

 
 
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1: Report Due to CCTO IND Coordinator regardless of whether or not all information regarding the event is 
available.  If applicable, a follow-up report should be provided to the IND Coordinator once additional 
information on the event is available. 
2: An IND Protocol Amendment is also required to describe any changes to the protocol, consent, or overall 
conduct of the study made as a result of this information.  All revised documents should be made available to 
the CCTO IND Coordinator at the time of IRB submission. 
3: Copy of relevant publication(s) should be included if applicable. 
4: Details of individual cases should be included as appropriate 
5: From date event was reported to the sponsor-investigator 
6: After information is received by the investigator and determined to meet reporting criteria 
7: Copy should be maintained in the subject research chart and master IND file in the CCTO. 
 
All other events (e.g. protocol deviations or other safety concerns) not meeting the requirements 
for IND Safety Reporting (per 21 CFR 312.32) but which require reporting to the IRB as an 
Unanticipated Problem will be reported to the FDA as an informational amendment or with the 
annual report as appropriate.   
 
The CCTO IND coordinator will report all reportable events to the FDA within the designated 
timelines and provide a copy of the final report to Exelixis at the time of submission to the FDA. 
(Section 7.3). 
 
7.5.4. 
Reports to Participating Institution(s) 
 
It is the responsibility of the designated Regulatory Manager on behalf of the sponsor-
investigator to notify all participating sites of all unexpected and serious suspected adverse 
reactions that occur on this clinical trial and which are reported to the FDA as an IND Safety 
Report (21 CFR 312.32).  A copy of the completed Form 3500A (MedWatch) and/or IND 
Safety Report Narrative will be provided to the responsible Regulatory Manager by the IND 
Coordinator for distribution to all participating sites. 
 
7.6. Other Safety Considerations 
 
7.6.1. 
Laboratory Data 
 
All laboratory data obtained during the course of the study should be reviewed. Any abnormal 
value that leads to a change in subject management (e.g., dose reduction or delay, requirement 
for additional medication or monitoring) or is considered to be of clinical significance by the 
investigator should be reported as an adverse event or serious adverse event as appropriate, 
unless this value is consistent with the patient’s present disease state or is consistent with values 
obtained prior to entry into the study. 
 
7.6.2. 
Pregnancy 
 
Use of medically accepted methods of contraception is very important during the study and up 
to 3 months post-study treatment. If a subject’s partner becomes pregnant during the study, she 
will be followed through the end of her pregnancy and the infant should have a follow-up at 
least 6 months after birth. If a female partner of a male subject becomes pregnant during the 
study,  the pregnant female partner will be asked to be followed through the end of her 
pregnancy. The outcome of a pregnancy (for a subject or for the partner of a subject) and the 

 
 
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medical condition of any resultant offspring must be reported to Exelixis or designee. Any birth 
defect or congenital anomaly must be reported as a serious adverse event and any other 
untoward events occurring during the pregnancy must be reported as adverse events or serious 
adverse events, as appropriate. 
 
7.6.3. 
Medication Errors 
 
Any medication error that results in an adverse event, even if it does not meet the definition of 
serious, requires reporting within 24 hours to Exelixis or designee. 
 
7.6.4. 
Follow-Up of Adverse Events 
 
Any SAE or AE assessed as possibly related that led to treatment discontinuation (including 
clinically significant abnormal laboratory values that meet these criteria) and is ongoing 30 days 
after 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 possibly-related serious adverse events that occur greater than 30 days 
after last dose of study treatment. The status of all other continuing adverse events will be 
documented as of 30 days after last dose of study treatment. 
 
7.6.5. 
Safety Monitoring 
 
According to University of Chicago Cancer Center Guidelines, this protocol will be classified as 
moderate risk.  Data and Safety Monitoring (DSM) will occur at the weekly University of 
Chicago Genitourinary Oncology DSM meeting.  At each meeting, the study will be reviewed 
for safety and progress toward completion.  Toxicities and adverse events will also be reviewed 
and a DSM form will be completed at each meeting.  Twenty percent of research charts will be 
audited annually for protocol compliance items including eligibility, completion of procedures, 
administration of treatment, reporting of toxicities, documentation of response, follow-up, data-
collection, record keeping, and the collection of correlative studies. 
 
8. CORRELATIVE/SPECIAL STUDIES 
 
8.1. Functional MRI 
 
8.1.1. 
Axial free-breathing images will be collected with 3mm thickness utilizing a 1.5T 
phased array surface coil using a field-of view 30-35 cm for all acquisitions. 
 
8.1.2. 
Screening MRI (MRI #1) will be within 14 days prior to initiating therapy with second 
baseline MRI (MRI #2) performed at least 1 week since MRI #1 and within 24 hours 
of study initiation. 
 
8.1.3. 
Bone lesions adequate for analysis must be a minimum of 2 x 2 cm. 
 
8.1.4. 
Lesions must be free of MR artifacts (e.g. metal). 
 
8.1.5. 
If more than one lesion meets all imaging criteria, the ADC and Ktrans for each lesion 

 
 
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will be recorded.  
 
8.1.6. 
Dynamic Contrast Images 
 
Imaged lesions must be in an area where the scanning plane will contain a low 
blood flow tissue (e.g. muscle) and/or a high blood flow area (e.g. kidney, liver, 
spleen) as a tissue control. 
 
The sequences that will be used for image acquisition are as follows: 
 
A scout scan to determine optimal plane of scanning through the lesion (axial, 
coronal, or sagital) will be obtained.  This plane will be used for all subsequent 
scans. 
 
A pre-infusion T1-weighted scan through the entire anatomical region will be 
obtained with the following parameters:  2D fast SPGR, TR 100 ms, TE 1.7 ms, 
flip angle 60, bandwidth 15.63 MHz, slice thickness 8 mm, slice spacing 1 mm, 
acquisition matrix 256 x 128.  Scan duration is approximately 1 min. 
 
A pre-infusion T2-weighted scan through the entire anatomical region will be 
obtained with the following parameters:  2D FSE, TR 3500 ms, TE 85 ms, echo 
train length 12, bandwidth 20.83 MHz, and acquisition matrix 192 x 160.  Scan 
duration is approximately 2.5 min. 
 
Pre-infusion T1-weighted limited scans through the center of the lesion and a 
reference tissue will be obtained with the following parameters:  2D fast SPGR, 
multiphase, TR 8 ms, TE 1.7ms, flip angle 60, bandwidth 15.63 MHz, slice 
thickness 8 mm, slice spacing 1 mm, acquisition matrix 256 x 160, 60 
acquisitions, 2 slices per acquisition.  Scan duration 125 s. 
 
Dynamic infused T1-weighted limited scans through the center of the lesion and 
a reference tissue will be obtained using the following parameters:Breath-hold T1 
3D TFE (e-thrive), 400x338x200 mm FOV, 2x2x4/2 (acquired/reconstructed) 
mm voxel size (200x169 matrix), SENSE factor 2, 10 flip angle, TR/TE 7.8/2.5 
ms, partial Fourier, 432 Hz/pixel bandwidth, SPAI).   The gadolinium-based 
contrast agent (0.1 mM/kg of patient weight of OmniscanTM(GE Healthcare) or 
0.05mM/kg MultihanceTM(Bracco, Italy) will be injected 60 s after scanning 
begins at a rate such that the total duration of injection is 10 s.  Total scan 
duration 9 min. 
 
Post-infusion T1-weighted scan through the entire lesion.  2D fast SPGR, TR 100 
ms, TE 1.7 ms, flip angle 60, bandwidth 15.63 MHz, slice thickness 8 mm, slice 
spacing 1 mm, acquisition matrix 256 x 128.  Scan duration approximately 1 min. 
 
In some instances, contrast washout may be assessed by a return to the slower 
multiple slice T1-weighted imaging (TR ~ 175 ms, TE ~ 3.1 ms).  These images, 
which allow a larger volume of tissue to be examined, will be acquired from 
several minutes after contrast media injection. 
 
Ktrans will be calculated from DCE-MRI images using the multiple tissue 
reference method as we have described28, 29 
 
8.1.7. 
Diffusion Weighted Images (ADC) 
 
DWI sequence parameters  will be as follows:Navigated 2D single shot spin 
echo EPI, 400x400x255 mm FOV, 2x2 mm acquired voxel size (reconstructed 
1.25 mm), 32 x7 mm slices, SENSE factor 2, spectrally selective fat 

 
 
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suppression (SPAIR), inversion time 100 ms, partial Fourier (0.6), b factors 0, 
800 s/mm2, TR/TE 3578/67 ms, 13.4 Hz/pixel bandwidth, 4 averages, nominal 
scan duration 3:27 min (without counting respiratory navigator triggering).  
 
ADC maps will be generated from DW images using diffusion-analysis 
software (Philips view forum, Philips Healthcare).  A region of interest (ROI) 
covering the entire lesion with as large as possible diameter, will be drawn on 
magnified images for each visualized bone metastases as determined by Dr. 
Oto.  The average ADC for within each ROI will be calculated.   
 
8.1.8. 
The intra-patient within lesion mean ADC and Ktransvalues will be determined by 
averaging the values from the two baseline examinations. 
 
8.1.9. 
The overall intra-patient and inter-patient variability will be calculated using a 
components of variance model in conjunction with the biostatistics core at the 
University of Chicago.  The investigators have used these models previously to 
describe the variability in Ktrans for mCRPC to the bone29. 
 
8.1.10. The first post therapy MRI evaluation will occur after 14 days of therapy (Section 5.5).  
72 hours (3 days) of latitude will be allowed for this evaluation.  Patients who do not 
have a completed day 14 MRI will not be evaluable for the primary endpoint of the 
study (Section2.1).  All subsequent functional MRI capture will occur at 12 week 
intervals±7 days (Section 5.5). 
 
8.1.11. Changes in ADC and Ktransvalues over time will be calculated by subtracting 
subsequent values from the baseline lesion means.  Each evaluable bone metastasis 
will be analyzed with respect to these metrics separately. 
 
8.1.12. All imaging data will be collected by Dr. Oto within the HIRO radiology database at 
the University of Chicago.  Imaging data collected at participating institutions will be 
captured according to the above guidelines, saved as DICOM images on a transferable 
medium (e.g. CD-ROM, DVD, jump drive) and mailed to the study coordinator at the 
University of Chicago.  The outside images will be anonymized within HIRO for 
analysis by Dr. Oto and his team. 
 
8.2. Circulating Tumor Cell Characterization 
 
As discussed in Section 1.5, the Szmulewitz laboratory has developed methodologies to isolate 
and interrogate CTC from patients with mCRPC.  As a secondary objective to this study, these 
methodologies will be utilized to isolate CTC before and after XL184 administration and 
characterize those CTC for c-MET and phospho (active) c-MET expression. Given the limitations 
of the procedure, with respect to the necessity for immediate processing, this correlative will only 
be collected and performed on samples collected at the University of Chicago. 
 
Sample Acquisition 
Circulating tumor cells will be isolated from the following: 
 

 
 
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1. 
Peripheral venous blood (15ml per collection) will be collected in 2BD 
VacutainerCPT® tubes (Becton Dickenson, Franklin Lakes, NJ) as described in the 
study calendar (Section 5.5).   
 
2. 
Upon collection, samples will be taken to the Szmulewitz laboratory within 30 minutes 
of blood draw for subsequent mononuclear cell isolation 
 
 
 

 
 
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Mononuclear Cell Isolation 
CTC’s- CPT tubes will be centrifuged at 1500g for 20minutes at room temperature.  Following 
centrifugation, the uppermost plasma layer will be removed and discarded.  Mononuclear cell 
layer will be then transferred from both tubes into one new 15ml conical tube.  Phosphate buffered 
saline (PBS) will be added to a total volume of 15ml.  The cells will be centrifuged at 450g for 5 
minutes at room temperature. The supernatant will be discarded and the washed mononuclear cells 
will be resuspended in 10ml of PBS for further processing.  
 
CTC Identification and Characterization 
Once mononuclear cell fraction isolated, prostate cancer cells will be identified and further 
characterized using Fluorescence Activated Cell Sorting (FACS).  The pellet of cells will be 
resuspended in cell separation buffer (PBS with 2mM EDTA, 0.5% serum albumin), FcR blocking 
buffer (Miltenyi), EpCAM (to bind epithelial cells) and CD45 (to bind white blood cells) primary 
antibodies conjugated to specific fluorescent markers (Miltenyi and Invitrogen, repectively).  Cells 
will then by analyzed in conjunction with the flow cytometry core facility gating and sorting the 
EpCAM positive, CD45 negative population. 
 
Once isolated, the cells will be characterized using multiplex fllourescentImmunocytochemistry 
(ICC).  According to the data gathered in the initial patient cohort, visualization of CTC’s with 
immunofluorescnence is optimally feasible for patients with a minimum of 100 events detected in 
the EpCAM+/CD45- gate. Therefore, only these samples will be utilized for ICC studies.  Cells 
are directly FACS sorted onto charged glass chamber slides, and then fixed with 3% formalin and 
stained with the following antibodies for multiplex fluorescence along with DAPI nuclear 
counterstain: 
 
Total c-Met: 
eBioscience Cat. # 14-8858-80 
1:100 Overnight 
Phospho c-MET Invitrogen Cat.# 44888-G 
 
1:50 Overnight 
Anti-Rat Secondary-Texas Red Conjugated  
Santa Cruz Biotech 1:100 1 hour 
Anti-Rabbit Secondat-Alexa 633 Conjugated  
Invitrogen 
 
1:100 1 hour 
 
The slides will be imaged using Axiovert 200 microscope.  Captured images will be analyzed for 
fluorescence intensity and digitally scored using ImageJ software.  Positive and negative control 
cells stained concomitantly will also be digitally analyzed and will provide the reference for 
staining intensity analysis.  
 
 

 
 
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8.3. Pain Questionnaire and Analgesic Inventory 
 
Pain assessments will consist of subject-reported responses to a questionnaire (see Appendix C) 
in which subjects will be asked to rate their pain and degree of interference in daily activities due 
to pain at its worst over the prior 24 hours (adapted from the MD Anderson Symptom Assessment 
Inventory)44, as well as their pain relative to their prior assessment (adapted from the Subjective 
Significance Question)45. The subject will complete this pain questionnaire and analgesic log at 
the study visits according to the study calendar (Section 5.5). 
 
9. MEASUREMENT OF EFFECT 
 
Although response is not the primary endpoint of this trial, patients with measurable disease will 
be assessed by standard criteria23, 42, 46 (Appendix D).  For the purposes of this study, patients 
should be re-evaluated every 12 weeks.   
 
9.1. Outcome Measures based on PSA Decline 
 
The following parameters will be recorded after the initial 12 weeks of therapy and at 12-week 
intervals thereafter.  
 
PSA decline will be measured according to PCWG-2 (2008) criteria23. 
 
PSA changes from baseline will be calculated for all patients. 
 
Time to progression (TTP) based on revised PSA Working Group-2 criteria (2008 
version).  
 
PSA progression free survival: PSA measurements will be taken at screening (baseline) 
and subsequently at time points as indicated in the schedule of visits. Any unscheduled 
PSA measurement will be utilized in the periodic assessment of PSA progression.  
 
The maximal decline in PSA for each patient will be recorded for each patient. 
 
The date of the maximal PSA decline (nadir date) will be recorded for each patient, as will 
the duration from the start of therapy to the nadir PSA.  
 
9.2.  Radiographic Tumor Response 
 
Change in measurable disease, when applicable, will be determined according to RECIST 1.1 and 
PSAWG-2 criteria (Appendix E)23, 42. For the purposes of this study, imaging will be repeated 
according to the study calendar (Section 5.5) every 12 weeks unless otherwise indicated clinically. 
 
Lymph nodes46: To be considered pathologically enlarged and measurable, a lymph node must be 
at least 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be not greater than 5 mm). Lymph nodes that are at least 10 mm but less than 15 mm in short axis 
may be pathologic and can be considered non-measurable/non-target lesions (that are not 
measured). At baseline and in follow-up, only the short axis will be measured and followed. 
 
Bone lesions:  Bone lesions are by definition non-measurable.  If bone lesions are identified on 
MRI that have soft tissue components that are identifiable and accurately measurable,  the bi-
dimensional measurements of these lesions will be recorded as soft tissue measurable disease.  Of 
note, progression based on bone scan will be assessed according to PCWG-2 criteria23.  Isolated 

 
 
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new lesions on bone scan at the 12-week scan will be confirmed with a repeat bone scan at 6 
weeks to rule out bone scan flair.  If no new lesions are seen at the 6-week confirmation, it will be 
considered flair.  All subsequent bone scans will follow standard criteria with regards to 
progression (two new lesions necessary for progression). 
 
9.3. Duration of Response 
 
The duration of overall response is measured from the time measurement criteria are met for 
complete or partial response until the first date that recurrent or progressive disease is objectively 
documented (taking as reference for progressive disease the smallest measurements recorded since 
the treatment started). 
 
Stable disease is measured from the start of the treatment until the criteria for progression are met, 
taking as reference the smallest measurements recorded since the treatment started, including the 
baseline measurements.  
 
9.4. Progression-Free Survival 
 
Time to progression or progression-free survival (PFS) is defined as the duration of time from 
start of treatment to time of progression or death, whichever occurs first. 
 
10. STATISTICAL CONSIDERATIONS 
 
10.1. Sample Size/Primary Endpoint 
 
The primary endpoint statistically will be vascular permeability as captured by the Ktrans parameter 
at the two week time-point, as we have already established the intra and inter-patient variability of 
this metric.  The effect of treatment with XL184 will be tested by subtracting the average of the 
two baseline Ktransmeasurements from the post-two week treatment value and performing a paired 
t-test.  A 95% confidence interval for the magnitude of the mean change will also be generated. In 
our previous study29, the mean Ktrans was estimated to be 0.088 (min-1) with a coefficient of 
variation of approximately 15%, corresponding to a standard deviation (SD) of the within-patient 
differences of 0.018.  To allow for additional variability due to heterogeneity of the treatment 
effect, we assume a 50% greater SD of 0.027.  In order to have 80% power to detect a 20% 
reduction in Ktrans (from 0.088 to 0.070), which has been observed with VEGF pathway directed 
agents in other malignancies, n=20 patients will be required for a two-sided test at the alpha=0.05 
significance level.  Allowing for 20% of the patients to be non-evaluable, n=25 subjects will be 
enrolled in the study.  Patients in whom there are incomplete data for week 2, week 12 MRI time 
points will be considered non-evaluable for the primary endpoint and replacement patients will be 
enrolled. 
 
10.2. Analysis of Secondary Endpoints 
 
Correlation of Functional MRI Changes with Standard Response Metrics 
Ktransand ADC will be calculated as described Section 8.1.  In addition, tumor measurements will 
be recorded at baseline and over the course of therapy. Pain will be monitored with the pain 
assessment questionnaire (Appendix C) and analgesic intake score and the scores analyzed per 

 
 
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patient over time as well as for the entire population using standard comparative statistics.  CTC 
have recently been shown to be a sensitive predictive marker of treatment response in mCRPC47.  
Thus, CTC will be enumerated centrally by Quest diagnostics using the FDA approved CellSearch 
platform.  In addition, standard prognostic laboratory studies including hemoglobin, and PSA, will 
be collected as per the schema above.  PSA PFS and overall PFS will be calculated (Section 9).  
The association of PFS with Ktrans and ADC will be established using the Cox proportional 
hazards approach using standard progression criteria23.  In addition percent change in the 
functional MRI metrics will be correlated to changes in bone scan, RECIST tumor measurements, 
PSA, CTC and pain scale changes using a non-parametric Pearson correlation coefficient, all in 
conjunction with the biostatistics core at the University of Chicago. 
 
c-MET and phospho-c-MET CTC staining 
The expression of c-MET and phospho c-MET within each CTC within one patient sample will be 
averaged and the cumulative expression will be scored as low if at or below that of the negative 
control, intermediate if between negative and positive control and high if at or above positive 
control level. The percentage of CTC with low, intermediate, high expression level will be 
calculated. Standard comparative statistics (median/range, mean/standard deviation) will be used 
to describe c-MET and phospho c-MET staining within each patient and for the entire cohort 
based on the numeric staining intensity after background subtraction (Section 8.2).  The 
association of c-MET and phospho-c-MET staining with PFS will be established using the Cox 
proportional hazards approach if possible based on sample size with adequate staining.  In 
addition, c-MET and phospho-c-staining will be correlated with the PSA and RECIST response 
rates using a non-parametric Pearson correlation coefficient to explore the role of these CTC 
metrics as predictive biomarkers. 
 
 
Safety Evaluation and Analysis 
Safety analysis will be conducted on the full analysis set. All AEs occurring on study will be listed 
by subject in a data listing. The type of adverse events (AEs), intensity and incidence rates will be 
presented in all treated subjects.”  
 
11. PUBLICATION PLAN 
 
The Principal Investigator (Protocol Chair) holds the primary responsibility for publication of the 
study results; provided that the Principal Investigator will provide any such publication to 
Exelixis, Inc. for review at least sixty (60) days prior to submission and also comply with any 
provisions regarding publication as are agreed to between the Principal Investigator’s institution 
(e.g., University of Chicago.) and Exelixis, Inc. in the Clinical Trial Agreement related to this 
study.  The results will be made public within 12 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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APPENDIX A 
 
Performance Status Criteria 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to carry on all pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able 
to carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of all 
self-care, but unable to carry out 
any work activities.  Up and about 
more than 50% of waking hours. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any 
self-care.  Totally confined to bed 
or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 
 

 
 
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APPENDIX B 
 
Sample Data Capture Forms 
 
 
 
 

 
 
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Treatment History 
 
 
 

 
 
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APPENDIX C 
 
Analgesic Intake: 
Please list each medication you have used to treat pain over the last twenty-four hours including 
the dose and the number of pills taken over the twenty-four hour period.  For transdermal patches, 
please list the dose of patch and frequency of changing the patch. 
 
Medication 
Dose 
Times taken 
Example 1: 
Morphine sulfate IR 
30mg 
6 
Example 2: 
Fentanyl patch 
50mcg/h 
Every 72 hours 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Pain Questionnaire : 
1.   People with cancer frequently have symptoms that are caused by their disease or by their 
treatment. We ask you to rate how severe the following symptoms have been in the last 24 hours. 
Please fill in the circle below from 0 (symptom has not been present) to 10 (the symptom was as bad 
as you can imagine it could be) for each item.   
 
Not 
Present 
As Bad As You 
Can Imagine 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
a. Your pain at its WORST? 
○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 
b. Your disturbed sleep at its   
WORST?  
○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 
 
2.   Symptoms frequently interfere with how we feel and function. How much have your symptoms 
interfered with the following items in the last 24 hours: 
 
Did Not 
Interfere 
Interfered 
Completely 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
a. General activity? 
○ ○ ○ ○ ○ ○ ○ ○ ○ ○ ○ 
 
3. Compared to the last time I completed this questionnaire, my painin the last 24 hours was 
A. Very much worse 
B. Moderately worse 
C. A little worse 
D. About the same 
E. A little better 
F. Moderately better 
G. Very much better 
 
 
 

 
 
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Appendix D 
 
PROSTATE-SPECIFIC ANTIGEN WORKING GROUP    CRITERIA23 
 
Progressive Disease after Androgen Deprivation Eligibility Criteria: 
 
PSA evidence for progressive prostate cancer consists of a PSA level of at least 5 ng/ml which 
has risen on at least 2 successive occasions, at least 2 weeks apart. If the confirmatory PSA (#3 
below) value is less (i.e., #3b) than the screening PSA (#2) value, then an additional test for 
rising PSA (#4) will be required to document progression. 
 
Procedures for Assessing PSA Progression Post Study Treatment 
PSA measurements will be taken on a monthly basis.  PSA increases and decreases will be 
tracked in order to assess disease response.  
PSA partial response is defined by at least a 50% decline from screening (baseline) PSA value.  
The declined must be confirmed by a second PSA value obtained 4 or more weeks later.   
PSA progressive disease may be defined in both patients who have not shown a decrease in 
their PSA and those who have.  For patients who have not shown a decrease, progressive 
disease is defined as an increase of 25% over the screening (baseline) PSA value and in 
increase in the absolute-value PSA level by at least 5ng/mL.  This increase should be 
confirmed by a second value.   
For those patients whose PSA have decreased but has not reached response criteria, 
progressive disease is defined as 25% increase over the nadir PSA value provided that the 
increase is at least 5ng/mL and is confirmed. 
 
Duration of PSA Response  
Duration of PSA Response is measured from the time when the PSA value first declines by at 
least 50% of the screening (baseline) and that was eventually confirmed by a second value.  It 
is calculated until the time at which there is an increase of 50% of PSA nadir, provided the 
absolute increase is at least 5 ng/mL. The increase must be confirmed by a second consecutive 
measurement that is at least 50% above the nadir. 
If the PSA never shows a 50% increase over the nadir value, then the patient will be assessed 
at the last PSA measurement. 
 
Time to Disease Progression 
For patients who have achieved a ≥ 50% decrease from the screening (baseline) PSA, 
assessment of time to disease progression is when the PSA has increased 50% above the nadir 
and at a minimum of 5ng/mL.   For patients without a PSA decrease of this magnitude or 
without a decrease, the time for progression is calculated at the time a 25% increase from 
screening (baseline) PSA has been achieved.  
 
 
 

 
 
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Appendix E 
 
RESPONSE EVALUATION CRITERIA in SOLID TUMORS (RECIST 1.1) 42, 46 
 
Eligibility 
 Only patients with measurable disease at baseline should be included in protocols where 
objective tumor response is the primary endpoint.  
 
Measurable disease - the presence of at least one measurable lesion. If the measurable disease is 
restricted to a solitary lesion, its neoplastic nature should be confirmed by cytology/histology.  
 
Measurable lesions - lesions that can be accurately measured in at least one dimension with 
longest diameter 20 mm using conventional techniques or 10 mm with spiral CT scan. 
 
Lymph nodes: To be considered pathologically enlarged and measurable, a lymph node must be 
at least 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to 
be not greater than 5 mm). Lymph nodes that are at least 10 mm but less than 15 mm in short axis 
may be pathologic and can be considered non-measurable/non-target lesions (that are not 
measured). At baseline and in follow-up, only the short axis will be measured and followed. 
 
Non-measurable lesions - all other lesions, including small lesions (longest diameter <20 mm 
with conventional techniques or <10 mm with spiral CT scan), i.e., bone lesions, leptomeningeal 
disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis 
cutis/pulmonis, cystic lesions, and also abdominal masses that are not confirmed and followed by 
imaging techniques; and. 
 
 All measurements should be taken and recorded in metric notation, using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.  
 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.  
 Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules and palpable lymph nodes). For the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended. 
 
Methods of Measurement  
 CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 10 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm.  This applies to tumors of the chest, 
abdomen and pelvis. Head and neck tumors and those of extremities usually require 
specific protocols. 
 Lesions on chest X-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung. However, CT is preferable.  

 
 
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 When the primary endpoint of the study is objective response evaluation, ultrasound (US) 
should not be used to measure tumor lesions. It is, however, a possible alternative to 
clinical measurements of superficial palpable lymph nodes, subcutaneous lesions and 
thyroid nodules. US might also be useful to confirm the complete disappearance of 
superficial lesions usually assessed by clinical examination. 
 The utilization of endoscopy and laparoscopy for objective tumor evaluation has not yet 
been fully and widely validated. Their uses in this specific context require sophisticated 
equipment and a high level of expertise that may only be available in some centers. 
Therefore, the utilization of such techniques for objective tumor response should be 
restricted to validation purposes in specialized centers. However, such techniques can be 
useful in confirming complete pathological response when biopsies are obtained. 
 Cytology and histology can be used to differentiate between PR and CR in rare cases 
(e.g., after treatment to differentiate between residual benign lesions and residual 
malignant lesions in tumor types such as germ cell tumors). 
 
Baseline documentation of “Target” and “Non-Target” lesions 
 All measurable lesions up to a maximum of five lesions per organ and 10 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 their suitability for accurate repeated measurements (either by imaging 
techniques or clinically).  
 A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference by which to 
characterize the objective tumor. 
 All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements of these lesions are not required, but the 
presence or absence of each should be noted throughout follow-up.  

 
 
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Response Evaluation:  Evaluation of target lesions 
 
* Complete Response (CR): 
Disappearance of all target lesions 
* Partial Response (PR): 
At least a 30% decrease in the sum of the LD of target 
lesions, taking as reference the baseline sum LD 
* Progressive Disease (PD): 
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or more 
new lesions 
* Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started 
 
Evaluation of non-target lesions 
* Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumor marker level 
* Incomplete Response/ Stable 
Disease (SD):  
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits 
* Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions (1)  
(1) Although a clear progression of “non target” lesions only is exceptional, in such 
circumstances, the opinion of the treating physician should prevail and the progression status 
should be confirmed later on by the review panel (or study chair). 
 
Evaluation of best overall response 
The best overall response is the best response recorded from the start of the treatment until disease 
progression/recurrence (taking as reference for PD the smallest measurements recorded since the 
treatment started). In general, the patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria  
 
Target lesions 
Non-Target lesions 
New Lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Incomplete response/SD 
No 
PR 
PR 
Non-PD 
No 
PR 
SD 
Non-PD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 

 
 
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having “symptomatic deterioration”. Every effort should be made to document the 
objective progression even after discontinuation of treatment.  
 In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the complete response status. 
 
Confirmation 
 The main goal of confirmation of objective response is to avoid overestimating the 
response rate observed.  In cases where confirmation of response is not feasible, it should 
be made clear when reporting the outcome of such studies that the responses are not 
confirmed. 
 To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed no less than 4 weeks after the criteria for 
response are first met. Longer intervals as determined by the study protocol may also be 
appropriate.  
 
In the case of SD, follow-up 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 

 
 
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