Clinical trial NCT01630590
Conditions: Prostate Cancer
Keywords: Prostate Cancer Metastatic Prostate Cancer Prostate adenocarcinoma Androgen-Dependent Prostate Cancer Cabozantinib XL 184 Androgen Ablation
Sponsor: M.D. Anderson Cancer Center
Start date: 2014-01-08; Completion date: 2021-04-06
Enrollment: 62 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The goal of this clinical research study is learn if adding cabozantinib (also known as XL184) to hormonal therapy can help to control prostate cancer. The safety of this drug will also be studied.

Cabozantinib is designed to block certain proteins in your blood that cause cancer cells to grow. This may cause cancer cells to die.

Detailed description:
Study Drug Administration:

If you are found to be eligible to take part in this study, you will take 1 capsule of cabozantinib by mouth 1 time every day while you are on study. You should not eat or drink anything other than water for 2 hours before and 1 hour after taking the study drug. You should take the capsule with at least 1 cup (8 ounces) of water. You will also be given separate directions about how to take the study drug.

You will also receive hormone therapy. The hormone drug you receive will be standard of care hormone therapy. The study doctor will decide what hormone therapy you will receive and will explain when and how you should take the hormone therapy, as well as its risks.

You will be given a drug diary where you will record when you take cabozantinib. You should return this diary to the study staff when you come into the clinic.

Study Visits:

At every visit, you will be asked about any side effects you may have had and any other drugs you may be taking.

If you are receiving Coumadin, every week for the first 3 weeks, you will have blood drawn (about 1 teaspoon) to test your blood clotting function.

Every 3 weeks for the first 12 weeks of the study, and then every 6 weeks after that:

* You will have a physical exam.
* Blood (about 3-4 teaspoons) will be drawn for routine tests.

Every 3 weeks for the first 12 weeks of the study, and then every 12 weeks after that, blood (about 1 teaspoon) will be drawn to check your thyroid and pancreatic function. The frequency of the testing may change if the study doctor thinks it is needed.

Every 6 weeks, you will have the following tests performed:

* Blood (about 2-3 teaspoons) will be drawn to measure your PSA levels and for biomarker testing.
* Urine will be collected for routine tests.
* You may have these test performed near your home if the study doctor thinks you are tolerating the treatment.

Every 12 weeks, you will have a bone scan and CT scans of the chest, abdomen, and pelvis to check the status of the disease.

Length of Study:

You may continue receiving the study drug for as long as the study doctor thinks it is in your best interest. You will be taken off study early if the disease gets worse, if you have intolerable side effects, or if your study doctor thinks it is in your best interest to stop.

Long-Term Follow-Up:

You will be contacted every 6 months after you stop taking the study drug to check on how you are feeling and the status of the disease. This will consist of a phone call, e-mail, or medical record review. If you are called, each call should last about 5 minutes.

This is an investigational study. Cabozantinib is FDA approved to treat patients with certain types of thyroid cancer. Its use in this study is investigational.

Up to 60 participants will take part in this study. All will be enrolled at MD Anderson.

Arms: arm 1: Patients receive Cabozantinib at starting dose of 60 mg by mouth every day. Study cycles 3 weeks in duration. Patients stay on treatment as long as they are benefitting. Patients receive androgen ablation therapy, either by means of luteinizing hormone-releasing hormone super-agonist (of any formulation), LHRH antagonist, or surgical castration. Study doctor will decide what hormone therapy patient will receive.
Interventions: intervention 1: Cabozantinib intervention 2: Androgen Ablation Therapy
Intervention descriptions: intervention 1: Starting dose of 60 mg by mouth every day of a 21 day cycle. intervention 2: Androgen ablation therapy, either by means of luteinizing hormone-releasing hormone super-agonist (of any formulation), LHRH antagonist, or surgical castration given upon decision of study doctor.

Protocol documents:
Prot_SAP_000.pdf: 
Protocol 2012-0252
November 11, 2016
Page 1
THE UNIVERSITY OF TEXAS MD 
ANDERSON CANCER CENTER
 
DIVISION OF CANCER MEDICINE
 
An Observational Study of cabozantinib and Androgen Ablation in Patients with
Androgen-Dependent Metastatic Prostate Cancer
 
Lead Institution:
The University of Texas MD Anderson Cancer Center
 
Principal Investigator:  Paul Corn, M.D., Ph. D.
1155 Pressler Street, Unit 1374
Houston, TX 77030
Telephone: (713) 792-2830
Fax: (713) 745-1625
E-mail: pcorn@mdanderson.org
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Protocol 2012-0252
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Page 2
1.0
Objectives
 
Primary Objective(s) / Endpoint(s)
In this study, we will explore the safety and clinical efficacy of cabozantinib combined 
with androgen ablation in men with newly diagnosed androgen-dependent prostate cancer 
based on progression free survival. The primary end points are:
1.
To assess the tolerance and safety of cabozantinib in combination with androgen 
ablation in this patient group.
2.
To estimate the time to castrate-resistant progression defined by any of the following: 
(a) radiographic progression (using RECIST 1.1 for visceral disease and PCWG2 for 
Bone Scans), (b) receipt of additional anti-cancer therapy, or (c) clinical progression 
warranting discontinuation from the study as judged by the treating physician.
3.
To collect and bank blood and tissue specimens for future hypothesis-generating 
studies.
 
Secondary Objective(s) / Endpoint(s)
Secondary endpoints will include:
1.   Overall Survival
2.   Radiologic responses
3.   Biomarker modulation (for example PSA, CTC, serum cytokine profiles, bone specific 
alkaline phosphatase, urine n-telopeptides)
4.   Tumor pharmacodynamic measures (molecular-pathologic analysis of c-Met/VEGFR
signaling pathways using metastatic tissue samples).
 
 
2.0
Background
Cabozantinib (XL184) is a novel small molecule inhibitor of multiple receptor tyrosine
kinases (RTKs) that promote tumor cell proliferation and/or angiogenesis including RET, 
MET, VEGFR2/KDR, and KIT. In a recently reported phase II randomized discontinuation 
study of cabozantinib in patients with advanced solid tumors, a high proportion of patients 
with mCRPC achieved clinically significant responses while on therapy characterized by 
reductions in PSA, reductions in lymphadenopathy, reductions in pain, and improvement in 
bone scans(1). These results are attributed to the fact that overexpression of MET (and/or its
ligand HGF) correlates with prostate cancer progression and the development of metastasis
(2-4). Based on these encouraging results, a multi-center, non-randomized expansion (NRE)
cohort for patients with mCRPC has been initiated. We now propose to study the potential
safety and benefit of cabozantinib in patients with metastatic androgen-dependent
prostate cancer.
 
The front-line paradigm for the treatment of metastatic androgen-dependent prostate cancer 
remains disruption of androgen receptor signaling (5). Despite reliable initial responses, 
however, all patients eventually develop castrate-resistant progression, a disease state 
responsible for 32,050 deaths last year in the United States (6, 7). Recent advances in
tumor biology have elucidated growth-promoting pathways that contribute to the 
development of castrate-resistant disease. Importantly, these oncogenic pathways provide 
crosstalk between the “epithelial compartment” and the “stromal compartment” (8). For


Protocol 2012-0252
November 11, 2016
Page 3
 
example, stromal elements within bone – the most frequent organ site for prostate cancer 
metastases - promote the evolution of castrate-resistant disease. The rationale to disrupt this 
crosstalk has led to the discovery of drugs that target tumor stromal elements in additional to
the cancer epithelial cell (9).
 
There is increasing evidence from data derived from primary human tumors and pre- clinical
models that Met is a critical oncogenic pathway that contributes to the evolution of castrate-
resistant disease. For example, Met is upregulated by removing androgens and the anti-
proliferative effect of Met inhibitors is greater in castrate-resistant versus androgen-
dependent cell lines (10, 11). Furthermore, the anti-tumor effect of Met inhibitors is greatly 
enhanced when combined with androgen ablation therapy in pre-clinical models (11). These
results suggest the hypothesis that combining Met inhibition with androgen ablation will
prevent (or delay) the development of castrate-resistant disease.
 
In the present study, we will explore this hypothesis by combining cabozantinib with 
androgen deprivation in patients with newly diagnosed, androgen-dependent metastatic 
disease. Data from our own institution suggest that the median time to progression (as 
defined by the development of castrate-resistant disease) in unselected patients treated with 
androgen ablation alone is approximately 24 months. However, in a subset of patients with 
“high-volume” disease (>3 bone lesions and/or visceral metastases), the median time to 
progression is 11.2 months (12).
 
 
3.0 Eligibility Criteria
 
Inclusion Criteria:
 
1.   Histologic proof of prostate adenocarcinoma
 
2.   Newly diagnosed Androgen-Dependent Prostate Cancer. Patients already on ADT are 
eligible as long as the time from initiation of LHRH analog or antagonist is not greater
than 3 months.
 
3.  Metastatic disease on bone scan and/or involvement of soft tissues (lymph nodes and/or 
viscera) by CT scan, PET/CT, or MRI
 
4.   PSA > 1 ng/ml, unless anaplastic features are present (according to eligibility 10)
 
5.   Life expectancy from a co-morbid illness > 3 years
 
6.   ECOG performance status 
7.   Patients must have adequate organ function as defined by:
x
AN&XO (unless due to bone marrow infiltration by tumor in which case ANC 
>500/ml are allowed)
x
+JEJm/dL (unless due to bone marrow infiltration by tumor in which case Hgb>8 
gm/dL)
x
Total bilirubin WLmes the upper limit of normal. For patients with known Gilbert’s


Protocol 2012-0252
November 11, 2016
Page 4
disease, total bilirubin should be mg/dL
x
platelet count Pm3 (unless due to bone marrow infiltration by tumor in 
which case >50,000/ml are allowed)
x
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) u ULN if
no liver involvement, RUu ULN with liver involvement
 
x
Lipase < 2 x the upper limit of normal
 
x
Urine protein/creatinine ratio 83&5
 
x
Serum phosphorus LLN
 
x
estimated creatinine clearance of  40 ml/min.
8.   Prior ADT is allowed if it was an adjunct to definite local therapy, was given for < 1
year, and was completed at least 12 months before initiating therapy for metastatic 
disease.
 
9. Prior therapy with other TKI inhibitors or any other type of investigational agent is 
allowed if it was an adjunct to definitive local therapy, was given for <6 months, and 
was completed at least 12 months before initiating therapy for metastatic disease.
10. Patients with “anaplastic” features are eligible for this trial as defined by at least one of 
the following:
 
a) Any of the following metastatic presentations: exclusive visceral metastases, 
radiographically predominant lytic bone metastases identified by plain X-ray or CT 
scan, bulky (>5 cm in longest dimension) lymphadenopathy or high-grade (gleason
>8) tumor mass in the prostate/pelvis.
 
b) Low PSA ( 10 ng/ml) at initial presentation (prior to androgen ablation or at 
symptomatic progression in the castrate-setting) plus high volume (ERQH
metastases.
 
c) Elevated serum LDH ([8/1RUHOHYDWHG serum CEA ([8/1LQ the 
absence of other etiologies.
 
d) Short interval GD\VWR castrate-resistant progression following initiation of 
hormonal therapy.
11. Sexually active fertile subjects, and their partners, must agree to use medically accepted 
methods of contraception (eg, barrier methods, including male condom, female condom,
or diaphragm with spermicidal gel) during the course of the study and for 4 months after
the last dose of study drug(s).
 
 
Exclusion Criteria:
 
1.   Biological agents (antibodies, immune modulators, cytokines, or vaccines) or 
radionuclide treatment within 6 weeks of the first dose of study treatment.
 
2.   Radiation therapy within 2 weeks prior to initiation of study treatment.
 


Protocol 2012-0252
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Page 5
3.   Symptomatic or uncontrolled brain metastasis or epidural disease requiring current 
treatment including steroids and anti-convulsant.
 
4.   The subject has had another diagnosis of malignancy requiring systemic treatment 
within the last two years, unless non-melanoma skin cancer, or superficial bladder 
cancer.
5.   The subject has uncontrolled or significant intercurrent illness including, but not limited 
to, the following conditions:
 
x
Chronically uncontrolled hypertension, defined conventionally as consistent and 
repeated systolic pressures above 140 mmHg or diastolic pressures above 90 mmHg 
despite anti-hypertensive therapy. This may be better established with home BP 
readings than with clinic visit results. There is no criterion related to a specific BP 
result required for eligibility, nor are acute BP elevations that are related to iatrogenic 
causes, acute pain, or other transient reversible causes considered to be an exclusion 
criteria. The intent is to exclude patients with chronically uncontrolled hypertension 
that might be further exacerbated by Cabozantinib.  
x
Other cardiovascular disorders such as symptomatic congestive heart failure (CHF), 
unstable angina pectoris, clinically-significant cardiac arrhythmias, history of stroke
(including TIA, or other ischemic event) within 6 months of study treatment,
myocardial infarction within 6 months of study treatment, history of thromboembolic
event requiring therapeutic anticoagulation within 6 months of study treatment or 
main portal vein or vena cava thrombosis or occlusion.
 
x
Gastrointestinal disorders particularly those associated with a high risk of 
perforation or fistula formation including:
 
o
Any of the following at the time of screening
 
a) intra-abdominal tumor/metastases invading GI mucosa b) 
active peptic ulcer disease,
c) inflammatory bowel disease (including ulcerative colitis and Crohn’s 
disease), diverticulitis, cholecystitis, symptomatic cholangitis or 
appendicitis
 
o
Any of the following within 6 months before the first dose of study 
treatment:
 
a)  history of abdominal fistula 
b) gastrointestinal perforation
c) bowel obstruction or gastric outlet obstruction
 
d) 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.
 
o
GI surgery (particularly when associated with delayed or incomplete 
healing) within 28 days.  Note: Complete healing following abdominal 


Protocol 2012-0252
November 11, 2016
Page 6
surgery must be confirmed prior to initiating treatment with cabozantinib 
even if surgery occurred more that 28 days ago.
 
x
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.
 
 
6.   The subject is unable to swallow tablets.
 
7.   The subject has a previously-identified allergy or hypersensitivity to components of 
the study treatment formulation.
 
8. Oral corticosteroids > 7.5mg prednisone (or prednisone equivalents).
 
9. Prior treatment with cabozantinib.
 
10. The subject has a corrected QT interval calculated by the Fridericia formula (QTcF)
>500 ms within 28 days before randomization.
 
 
4.0
Drug Information
 
4.1
Cabozantinib
 
Cabozantinib (XL184) is a new chemical entity that inhibits multiple RTKs with 
growth-promoting and angiogenic properties. The primary targets of cabozantinib
are RET, MET, VEGFR2/KDR, and KIT (Table 1).
 
Table 1: Cabozantinib(XL184) IC50 Values in Biochemical, Enzymatic Assays
Kinase
IC50 (biochemical) [nM]
RET
3.8
MET
1.8
VEGFR2/KDR
0.035
KIT
I
4.6
ICSO, concentration required for 50 %target inhibition.
Treatment with cabozantinib shows rapid effects on the tumor endothelium,
resulting in breakdown of the vasculature beginning 24 hours after administration
of cabozantinib, thus suggesting potent anti-angiogenic effects of cabozantinib.
These effects translate into significant tumor growth inhibition after cabozantinib
treatment in multiple tumor models including human medullary thyroid cancer
(MTC), human breast cancer, human lung carcinoma, and rat glioblastoma. Overall,
the data generated in vivo demonstrate that the target profile of cabozantinib
translates to potent anti-angiogenic activity and potent anti-tumor efficacy.


Protocol 2012-0252
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Page 7
4.1.1
Clinical Experience with Cabozantinib
 
As of 04 May 2011, 1003 subjects have been enrolled in open-label clinical 
studies of cabozantinib, and 330 subjects have been enrolled in a placebo-
controlled blinded Phase 3 study. Clinical data are available from nine studies of 
cabozantinib including four Phase 1 studies, one Phase 1b/2 study, three Phase 2 
studies, and one Phase 3 study. A summary of the availability of clinical data for 
cabozantinib, including the data sources and the dates of data cutoffs, is shown 
in the table below.
Study
Data Set
Number of 
Subjects
Cutoff Date
XL184-00I
SAEs
85
04 May 2011
Clinical database (AEs)
86a
01 March 2011
Clinical database(antitumor activity)
85
16 April2010
XL184-002
SAEs
26
04 May 2011
Clinical database (AEs)
19
01 March 2011
Clinical database(antitumor activity)
-
-
XL184-008
SAEs
23
04 May 2011
Clinical database (AEs)
11
01 March 2011
Clinical database(antitumor activity)
-
-
CA205-00I
SAEs
3
04May2011
IXL184-014
Clinical database (AEs)
3
01 March 2011
Clinical database(antitumor activity)
-
-
XL184-201
SAEs
222
04 May 2011
Clinical database (AEs)
214
01 March 2011
Clinical database(antitumor activity)
105
28 Apri12010b
XL184-202
SAEs
93c
04 May 2011
Clinical database (AEs)
77
01 March 2011
Clinical database(antitumor activity)
54
01 March 2011
XL184-203
SAEs
531
04 May 2011
Clinical database (AEs)
174d
01 March 2011d
Clinical database (AEs)
490d
09May2011d
Clinical database(antitumor activity)
490
09May2011
XL184-205
SAEs
19
04 May 2011
Clinical database (AEs)
17
01 March 2011
Clinical database(antitumor activity)
XL184-301
SAEs
330
04 May 2011
AE, adverse event; SAE, serious adverse event.
a. One subject withdrew from and re-enrolled in XL184-001. This subject is counted once in 
enrollment, demographic tables, and SAE analyses (N = 85) and twice in adverse event analyses 
(N= 86).
b. Data available for Groups A and B.
c. Includes subjects treated with the combination of cabozantinib plus erlotinib as well as those
treated with cabozantinib alone. One subject discontinued during the erlotinib Rum-In Stage 
and never received any dose of cabozautinib.
d. The summary of pooled adverse events presented in Section 5.4.1 includes data from 174 subjects 


Protocol 2012-0252
November 11, 2016
Page 8
from Study XL184-203 as of the cutoff date of 01 March 2011 for the open-label l2-week Lead-In 
Stage; for Study XL184-203 only, an updated safety analysis based on data from 490 subjects 
(Lead-In Stage) as of the cutoff date of 09 May 2011 was also conducted for the RDT Cohorts of 
the study (see Section 5.1.7 for description of cohorts), and the safety profile was not significantly 
changed from the 01 March 2011 data cutoff. A separate AE summary table for Study XL184-203
as of 09 May 2011 is presented in Appendix D.
4.1.2
Clinical Safety Profile
The AE and SAE data summarized in the following sections include those 
reported and entered in the clinical database and safety database, respectively, as 
of 01 June 2010. The clinical studies with cabozantinib are ongoing, thus the AE 
data from the clinical database does not yet include all SAEs. Data from double-
blinded studies is not presented. To date more than 561 subjects have been
studied in open-label clinical trials with cabozantinib, including treatment with
cabozantinib as a single agent, as well as cabozantinib in combination with
temozolomide and radiation therapy, and cabozantinib in combination with
erlotinib.
 
4.1.3
Adverse Events
The general adverse event profile of cabozantinib includes GI symptoms (such as 
nausea, vomiting, and diarrhea), fatigue, anorexia, palmar-plantar 
erythrodysesthesia (PPE) syndrome, skin rash, elevated ALT and AST, increased
pancreatic enzymes with rare cases of  pancreatitis, as well as side effects
associated with inhibition of VEGF signaling such as thrombotic events (eg,
pulmonary embolism [PE] and deep vein thrombosis [DVT]), hypertension,
proteinuria, hemorrhagic events, and rare cases of gastrointestinal [GI]
perforation and rectal/perirectal abscess. Arterial thromboembolism (transient
ischemic attack [TIA], myocardial infarction [MI]) have been reported rarely.
 
4.1.4
Serious Adverse Events
Out of all 561 subjects enrolled in open-label clinical trials with cabozantinib 
(XL184), 224 subjects (40%) experienced one or more SAEs, and 96 subjects 
experienced one or more SAE that was assessed to be related to treatment with
cabozantinib. This total includes two late-breaking cases (one case of abdominal
distension and failure to thrive in Study XL184-201 and one fatal respiratory
failure in Study XL184-203) that were reported after the data cut- off. Across 
all open-label studies, the most commonly reported events, regardless of 
relationship to cabozantinib, were PE (in 21 subjects), convulsion (in 17
subjects), DVT (in 13 subjects), pneumonia (in 13 subjects), vomiting (in 12 
subjects), abdominal pain (in 11 subjects), diarrhea (in 11 subjects), nausea (in
11 subjects), dehydration (in 10 subjects), and dyspnea (in eight subjects). The
most commonly reported events across all open-label studies that were assessed
as drug-related were PE (in 14 subjects), diarrhea (in nine subjects), DVT (in
seven subjects), nausea (in seven subjects), hypertension (in five subjects),
thrombocytopenia (in five subjects), dehydration (in four subjects), vomiting (in
four subjects), abdominal pain (in three subjects), and perirectal abscess (in


Protocol 2012-0252
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Page 9
three subjects). In addition, one late- breaking case of reversible posterior
leukoencephalopathy syndrome (RPLS) was reported after the data cut-off in
the double-blinded placebo-controlled Study XL184-301.
 
4.1.5
Deaths
A total of 52 deaths were reported within 30 days of the last dose of study drug;
the majority was due to disease progression, and 5 deaths were assessed to be
related to cabozantinib: GI hemorrhage (in one subject), PE (in two subjects),
respiratory failure (in one subject), and hemoptysis (in one subject).
 
4.1.6
Clinical Pharmacokinetics
In Exelixis study XL184-001, in which doses are expressed in terms of their L-
malate salt weight (see Appendix J for freebase weight equivalents), a
preliminary PK analysis has been performed for 74 subjects. The cut-off date for 
the data used for this PK analysis is 02 September 2008. Pharmacokinetic 
results from Cohorts 1-9 (0.08-11.52 mg/kg, Intermittent 5&9, PIB) show that 
systemic exposure (Cmax and area under the plasma drug concentration time
curve from time 0 to the last quantifiable concentration following dosing 
[AUC0-last]) values increased generally dose-proportionally with increasing 
cabozantinib dose. Terminal phase half-life (t1/2, z) values were long (range:
59.1 to 136 hours). Data from Cohorts 10-13 (175 mg qd PIB; 265 mg qd PIB;
175 mg qd capsule; 250 mg qd capsule) and Cohort 99 (175 mg qd capsule) 
show that drug accumulation (based on Cmax and AUC0-24 values) at steady-
state after daily dosing is approximately 4- to 6-fold.
 
In addition, exposure values from PIB (Cohorts 10) or Capsule (Cohorts 12 
and 99) are compared in Table 2. The data show that cabozantinib exposure 
(AUC) values from capsule cohorts are about 2.0 fold greater than those 
observed in the respective PIB cohort.
 
Table 2: Comparison of Exposure from PIB (Cohorts 10) or Capsule
(Cohorts 12& 99)
Day 19 Cmax
(ng/mL)
Day 19 AUC 
(ng×h/mL)
Cohort 10
175 mga qd PIB, n = 3
1410
21200
Cohort 12 and 99
175 mga qd capsule, n = 19
2310
41600
AUC, area under the plasma drug concentration time 
curve; Cmax, maximum plasma concentration; PIB, 
powder in bottle; qd, once daily.
 
Data from 18 subjects in XL184-201 (GBM) are available as of 26 January 2009.
The data show that pre-dose concentration values at C1D15 are consistent with
those reported in the Phase 1 setting: 1800 ± 868 ng/mL (n =18) versus 1920 ±
751 ng/mL (n = 16). In addition, the peak to trough concentration ratios at steady-


Protocol 2012-0252
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Page 10
state are moderate, with a value approximately equal to unity.
 
Pharmacokinetic analysis of cabozantinib has not been studied in subjects 
receiving a capsule dose of 125 mg (salt weight) qd, but simulated exposure 
values are expected to be about 70% of those from 175 mg (salt weight). 
Based on the simulated data, exposure values from the 125-mg (salt weight) 
cohort or the 175-mg (salt weight) cohort are statistically different: 95% 
confidence interval for AUC values are 26399 ± 1022 vs. 37651 ± 1730
ng×h/mL, respectively. In addition, the simulated steady-state average 
concentration from cabozantinib at 125 mg (salt weight) is 1100 ng/mL.
4.1.7
Comparative Bioavailability Study of Cabozantinib Tablet and Capsule
Formulations in Healthy Adult Subjects (Study XL184-005)
 
Study XL184-005 is a Phase 1, open-label, randomized, single-dose, two-
treatment, two-way crossover comparative bioavailability study of cabozantinib
tablet and capsule formulations in healthy volunteers. Subjects received single
oral doses of the assigned treatment of Test (100 mg cabozantinib, dosed as one
100-mg tablet) or Reference (100 mg cabozantinib, dosed as two 50-mg
capsules), according to a randomization scheme. Each dosing was administered
under fasting conditions, and blood samples were collected up to 504 hours post-
dose for each subject after each treatment to assess plasma cabozantinib PK.
Based on the preliminary PK data from 23 subjects who completed both 
treatments, after a single oral dose of cabozantinib at 100 mg, the terminal- phase
half-life (t1/2, z) of cabozantinib appeared to be similar for both tablet and capsule
formulations, with approximately mean values of 110 hours. The median time to
the maximum plasma concentration (tmax) was 4 hours for the tablet formulation
and 5 hours for the capsule formulation. High inter-subject variability for the
maximum plasma concentration (Cmax) and the area under the plasma drug 
concentration time curve (AUC) values were observed for both formulations
(coefficient of variation [CV]% Cmax: 51% for the tablet formulation, 61% for 
the capsule formulation; CV% for the AUC from time zero to the last
quantifiable timepoint or to infinity [AUC0-last or AUC0-inf]: 40-43% for the tablet
formulation, 43% for the capsule formulation.) The geometric mean Cmaxof the
tablet formulation was approximately 39% higher than the value observed for the
capsule formulation. The geometric mean AUC0-lastand AUC0-inf values for the
tablet formulation were also higher (15% and 19%, respectively) than those
observed for the capsule formulation. However, due to the high within-
formulation variability observed, no statistical difference in exposure between the
two formulations was apparent.
4.1.8
Effect of Food on the Bioavailability of Cabozantinib in Healthy Adult Subjects
(Study XL184-004)
 
Study XL184-004 is a Phase 1, open-label, randomized, single-dose, two-
treatment, two-way crossover study to assess the effect of food on the 
bioavailability of cabozantinib in healthy adult subjects. According to a
randomization scheme, 56 subjects received single oral doses of the assigned 


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treatment of Test (175 mg cabozantinib, dosed as one 100-mg capsule and 
three 25-mg capsules 30 minutes after administration of a high-fat breakfast) or 
Reference (175 mg cabozantinib, dosed as one 100-mg capsule and three 25-
mg capsules under fasting conditions). Blood samples were collected up to 504
hours post-dose for each subject after each treatment to assess plasma
cabozantinib pharmacokinetics.
 
Based on the preliminary PK data from 46 subjects who completed both 
treatments, a high-fat meal did not appear to alter the terminal t1/2, z of 
cabozantinib [mean t1/2, z : 131 hours (fed) vs 128 hours (fasted)]. The high-fat 
meal significantly increased the median tmax to 6 hours from 4 hours (fasted). The
high-fat meal also significantly increased both the cabozantinib 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, cabozantinib
should be taken on an empty stomach (fasting is required 2 hours before and 1
hour after each cabozantinib dose).
 
4.1.9
Composition, Formulation, and Storage
At study sites, all study medication will be stored at room temperature. For 
additional information relating to the study drug formulation and composition, 
please see the current version of the investigator’s brochure.
 
Destruction of Cabozantinib
If cabozantinib is to be destroyed on site, it is the Investigator’s responsibility to
ensure that arrangements have been made for disposal and that procedures for 
proper disposal have been established according to applicable regulations, 
guidelines, and institutional procedures. Appropriate records of the disposal 
must be maintained.
 
 
4.1.10 Investigational Treatment
Chemical Name: Chemical Name: N-{4-[(6,7-dimethoxyquinolin-4-
yl)oxy]phenyl}-N’-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (2S)-
hydroxybutanedioate
 
4.1.11  Cabozantinib Tablets
Cabozantinib tablets are supplied as film coated tablets containing cabozantinib
malate equivalent to 20 mg and 60 mg of cabozantinib and contain
microcrystalline cellulose, lactose anhydrous, hydoxypropyl cellulose, 
croscarmellose sodium, colloidal silicon dioxide, magnesium stearate and 
Opadry® yellow. All tablet strengths are prepared from a common blend and are
distinguished by shape. The 20 mg tablets are round and the 60 mg tablets are
oval. The components of the tablets are listed in Table .
 
 


Protocol 2012-0252
November 11, 2016
Page 12
Table 4-1:Cabozantinib Tablet Components and Composition
 
Ingredient
Function
% w/w
 
Cabozantinib malate (25% drug load as cabozantinib)
Active Ingredient
31.7
Microcrystalline Cellulose (Avicel PH-102)
Filler
38.9
Lactose Anhydrous (60M)
Filler
19.4
Hydroxypropyl Cellulose (EXF)
Binder
3.0
Croscarmellose Sodium (Ac-Di-Sol)
Disenegrant
6.0
Colloidal Silicon Dioxide,
Glidant
0.3
Magnesium Stearate
Lubricant
0.75
Opadry Yellow Film Coating which includes: 
-
HPMC 2910 / Hypromellose 6 cp
-
Titanium dioxide  
 
 
 
Film Coating
4.00
-
Triacetin
-
Iron Oxide Yellow
  
4.1.12  Storage Conditions
The investigator or pharmacist will inventory and acknowledge receipt of all 
shipments of the investigational product. The investigational product must be 
kept in a locked area with restricted access. The investigational product must be
stored and handled in accordance with local regulations, labeling specifications,
policies, and procedure.
 
The investigator or pharmacist will also keep accurate records of the quantities
of the investigational products dispensed and used for each subject. The study 
monitor will periodically check the supplies of investigational product held by 
the investigator or pharmacist to verify accountability of all investigational 
product used.
 
4.2
Androgen Deprivation Therapy
A luteinizing hormone-releasing hormone (LHRH) analog or antagonist, such as 
Leuprolide (Lupron),Goserelin (Zoladex) or Degarelix (Firmagon) will be used as 
androgen deprivation therapy (ADT).  Anti-androgens (such as bicalutamide) may be 
used for up to 4 weeks to prevent a “flare-response”.  
 
 
5.0
Treatment Plan
 
All patients will receive androgen ablation therapy, either by means of luteinizing 
hormone–releasing hormone super-agonist (of any formulation), LHRH antagonist, or 
surgical castration. The use of anti-androgens to prevent a “flare-response” is permitted
for up to 4 weeks at the discretion of the treating physician. Since patients with
metastatic prostate cancer are typically started on hormonal therapy before being seen at
M.D. Anderson, eligible patients may have received up to 3 months of androgen
deprivation therapy prior to initiating cabozantinib. The time-to-progression data will be
calculated from the start of hormonal therapy, not from the date of initiation of study drug 


Protocol 2012-0252
November 11, 2016
Page 13
cabozantinib.
 
All patients will receive cabozantinib at a starting dose of 60mg PO q day. Study cycles 
will be 3 weeks in duration (+/- 3 days). All patients will stay on treatment as long as
they are benefitting.
 
Patients will be removed from study if they meet any of the following criteria:
x
Disease progression
x
Unacceptable toxicity
x
Patient decision to withdraw
x
Palliative radiation involving more than one site
x
In the judgment of the investigator, further treatment would not be in the best interest
of the patient.
x
Receipt of any additional prostate cancer specific therapy as prescribed by the treating 
physician.
 
 
6.0
Patient Evaluations
Pre-Study Treatment (to be completed within 6 weeks of study entry):
x
Medical history will be recorded, along with performance status, AE assessment,
concomitant medications, vital signs (temperature, blood pressure, breathing rate,
and heart rate), weight and disease related symptoms.
 
x
Physical exam, CBC with differential and platelets, serum chemistries (sodium,
potassium, chloride, carbon dioxide, magnesium, glucose, calcium, phosphorus, 
BUN, albumin, total protein, bone specific and total alkaline phosphatase, creatinine,
ALT and/or AST, total bilirubin, direct bilirubin, LDH, Lipase, TSH, free T4),
testosterone, PSA, PT/PTT, urinalysis and urine for UPCR (24 hr urine for total
protein if UPCR is >1) and N- telopeptides, radiographic studies (Bone Scan, CT
scan of the Chest/Abdomen/Pelvis – PET/CT or MRI scans are also acceptable), 
Electrocardiogram (ECG) and specimens for correlative studies (see Section 6.1).
 
On-Study Treatment (evaluations have a standing window of allowance of +/- 3 days):
x
Weeks 1 through 12: Patients will be evaluated every 3 weeks after the start of Week
1 until the end of Week 12 (ie, end of Week 3, end of Week 6, end of Week 9, and end
of Week 12).  Evaluations will include physical exam, vital signs, weight, toxicity
review, concomitant medications, CBC with differential and platelets, serum
chemistries (sodium, potassium, chloride, carbon dioxide, magnesium, glucose,
calcium, phosphorus, BUN, albumin, total protein, total alkaline phosphatase,
creatinine, ALT and/or AST, total bilirubin, direct bilirubin, LDH), and optional
specimens for correlative studies (see Section 6.1). Imaging studies will be repeated at
Week 12. If there was no evidence for soft tissue disease in the thorax at baseline, 
repeat CT scans of the chest may be omitted at the discretion of the treating physician.  
Adverse events will be recorded at each visit.
o
Patients on therapeutic Coumadin will have PT/PTT testing every week for the first 
3 weeks.
o
TSH, free T4, and Lipase will be measured every 3 weeks up to and including Week 


Protocol 2012-0252
November 11, 2016
Page 14
12.  If no abnormalities are detected by Week 12, measurements may be repeated
every 12 weeks. If abnormalities are detected, the frequency of testing will be at the 
discretion of the treating physician.
o
PSA, bone specific alkaline phosphatase (BSAP), urinalysis and urine for n-
telopeptides will be measured every 6 weeks. UPCR will be performed only if 
urinalysis reveals >100 mg/dL.
 
x
After Week 12 until completion of study treatment: Patients treated beyond week 12
will be evaluated every 6 weeks. Evaluations will include physical exam, vital signs, 
weight, toxicity review, concomitant medications, CBC with differential and platelets,
serum chemistries (sodium, potassium, chloride, carbon dioxide, magnesium, glucose, 
calcium, phosphorus, BUN, albumin, total protein, total alkaline phosphatase, creatinine,
ALT and/or AST, total bilirubin, direct bilirubin, LDH), and optional specimens for 
correlative studies (Section 6.1). Imaging studies should be repeated every 12 weeks or 
sooner at the discretion of the treating physician if disease progression is suspected.
 
o
PSA, bone specific alkaline phosphatase (BSAP), urinalysis and urine for n-
telopeptides will be measured every 6 weeks. UPCR will be performed only if 
urinalysis reveals >100 mg/dL.
o
TSH, free T4, and Lipase will be measured every 3 weeks up to and including 
Week 12.  If no abnormalities detected by week 12, these tests do no need to be 
repeated thereafter unless clinically indicated at the discretion of the treating 
physician.   If abnormalities are detected, the frequency of repeat testing will be at 
the discretion of the treating physician as clinically indicated.
o
Patients who are clinically stable for at least 6 months and for whom travel to MDACC 
is prohibitive (e.g. patients that live out of state) may elect to forgo q6 week clinic 
visits and have labs drawn locally. However, these patients must return every 12 weeks 
when scans are performed. 
o
All concomitant medications (including over-the-counter and nutritional supplements) 
must be recorded in the electronic medical record or source, but not the electronic 
database, GURU.
 
Post-Study treatment
x
Patients will be followed for overall survival. Survival updates will take place at 6 month
intervals from the off treatment date. This will consist of a phone call, e-mail or medical
record review.
 
6.1
Correlative Studies (mandatory at baseline, optional for subsequent time points)
x 
For all patients who provide informed consent, venous blood will be collected for 
correlative studies to include multiplex analysis of cytokines, circulating tumor 
cells (CTCs) will collected and distributed to Dr. Amado Zurita’s lab for 
processing and analysis. .. Samples will be collected at the following time points:
baseline, Week 3, Week 6, Week 9, Week 12, every 6 weeks thereafter (for patients


Protocol 2012-0252
November 11, 2016
Page 15
treated beyond Week 12), and at the time the patient completes treatment with
cabozantinib (either for disease progression, unacceptable toxicity, or patient
withdrawal, or receipt of additional prostate cancer specific therapy as prescribed 
by the treating physician). Additional historic tissue collection will be obtained 
from the MD Anderson tissue bank with prior consent to LAB03-320 and PA13-
0247.
 
x
For patients with metastatic disease to the pelvis that is accessible via trans-iliac biopsy,
unilateral or bilateral bone marrow biopsies/aspirates will be collected at baseline (mandatory), at
Week 6 on treatment (optional), and at the time the patient completes treatment (optional) with
cabozantinib (either for disease progression, unacceptable toxicity, or patient withdrawal, or 
receipt of additional prostate cancer specific therapy as prescribed by the treating physician).
Alternatively, when tumor is not accessible via the trans-iliac approach (e.g. ischium), image guided biopsy 
techniques (e.g. CT-guided) of metastatic sites and biopsies of the primary tumor (if in place) may be 
utilized. Aspirates will assayed for multiplex analysis of cytokines, circulating tumor cells (CTCs).  
Cores will be analyzed for modulation of signaling via the androgen receptor, the c-Met receptor,
and VEGFRs. 
x
All left over samples will be stored and banked for future use, including genetic 
testing, in the GU Biorepository (blood and bone marrow) and the Prostate Tissue 
Bank (tissue). 
 


Protocol 2012-0252
November 11, 2016
Page 16
6.2
Study Calendar
 
On-study tests/visits that must occur within a defined time frame will have a
standing window of allowance that is equal to +/- 3 days.
 
 
 
Screening
Weekly 
for the 
first 3 
weeks
Every 3 Weeks
(for first 12
weeks) and
Every 6 weeks 
afterj
Every 
6
weeks
Week 6
only
Every 12 
Weeks
 
End of
Treatment
Follow- Up
Medical History
xa
 
x 
 
 
 
 
 
Physical examination
xa
x
 
 
 
 
 
Height and Weight
xa
x
 
 
 
 
 
ECOG performance status
xa
 
 
 
 
 
 
 
Vital Signsf
xa
x
 
 
 
 
 
Baseline
Symptoms/Adverse Event
Monitoring
xa
 
x
 
 
 
 
 
Concomitant Medications
xa
x
 
 
 
 
 
CBC with differential and
platelets
xa
x
 
 
 
 
 
Serum Chemistryb
xa
x
 
 
 
 
 
Testosterone
xa
 
 
 
 
 
 
 
PT/PTT
xa
xi
 
 
 
 
 
 
PSA, Bone Specific
Alkaline Phosphatase
xa
x
 
 
 
 
Lipase
xa
XC
 
xc 
 
 
TSH, and free T4
xa
XC
 
xc 
 
 
Urinalysis, UPCR, uNTx
xa
xg  
 
 
 
Imaging Chest, Abd Pelvis
xa
 
 
 
 
xd
 
 
Bone scan
xa
 
 
 
 
xd
 
 
ECG
xa
 
 
 
 
 
 
 
Survival Follow-up
 
 
 
 
 
 
 
xe
Blood for Correlative
Studiesh
x
x
 
 
 
x
 
Unilateral or Bilateral 
BMA/BX for Correlative
Studiesh
x
 
 
x
 
x
 
a. Within 6 weeks of registration
b. Serum chemistries consist of sodium, potassium, chloride, carbon dioxide, magnesium,
glucose, calcium, phosphorus, BUN, albumin, total protein, total alkaline phosphatase,
creatinine, ALT and/or AST, total & direct bilirubin, LDH
c. Repeat every 3 weeks up to and including week 12. If no abnormalities detected by week 12, these tests do no 
need to be repeated thereafter unless clinically indicated at the discretion of the treating physician.  If 
abnormalities are detected, the frequency of repeat testing will be at the discretion of the treating physician as 
clinically indicated


Protocol 2012-0252
November 11, 2016
Page 17
d. Imaging studies will be repeated at Week 12 and every 12 weeks thereafter. If there was no evidence for soft 
tissue disease in the thorax at baseline, repeat CT scans of the chest may be omitted at the discretion of the 
treating physician.
e. Patients will be followed by phone call, medical record review, or e-mail correspondence every 6 
months for survival.
f.  To include temperature, blood pressure, breathing rate, and heart rate
g. UPCR will be performed only if urinalysis reveals >100 mg/dL.
h. Mandatory at baseline, optional at subsequent time points.
i. For patients on therapeutic Coumadin. This lab may be checked locally and Coumadin dosing regulated per 
treating physician
j.   Patients who are clinically stable for at least 6 months and for whom travel to MDACC is prohibitive (e.g. 
patients that live out of state) may elect to forgo q6 week clinic visit and have labs drawn locally 
 
 
7.0     Dose Modifications/Toxicity Management
 
Patients will be treated until development of castration-resistant disease progression,
unacceptable toxicity, or patient withdrawal of consent.
 
Subjects will be monitored closely for AEs and instructed to notify their physician and/or 
study nurse immediately for any and all toxicities. Subjects experiencing one or more AEs 
due to the study treatment may require a dosing delay, or reduction(s), in their dose in
order to continue with study treatment. Assessment of causality (chronology, confounding
factors such as disease, concomitant medications, diagnostic tests, and previous
experience with the study treatment) should be conducted by the PI or a sub-investigator,
before a decision is made to modify the dose or to hold dosing temporarily.
 
Permissible dose reductions are outlined in Table 3. Patients who cannot tolerate 20
mg must come off study.
 
Table 3. Dose Reductions
Dose Level
XL 184 Dose
0
60 mg
-1
40 mg
-2
20 mg
Permissible Alterations in Dosing Schedule
As with other TKIs, it is anticipated that for some patients, the best tolerated and most 
effective dose will require brief interruptions (e.g. 1 to 3 days per week) in the daily 
dosing of cabozantinib rather than a dose reduction. These interruptions are permissible at 
the discretion of the treating physician and will be recorded for data monitoring, reporting, 
and publication.
 
 
7.1
Warnings, Precautions, and Management of Anticipated Events
The general adverse event profile of cabozantinib includes GI symptoms (such as nausea,
vomiting, and diarrhea), fatigue, anorexia, palmar-plantar erythrodysesthesia (PPE) 
syndrome, skin rash, elevated ALT and AST, increased pancreatic enzymes with rare
cases of  pancreatitis, as well as side effects associated with inhibition of VEGF signaling
such as thrombotic events (eg, pulmonary embolism [PE] and deep vein thrombosis
[DVT]), hypertension, proteinuria, hemorrhagic events, and rare cases of gastrointestinal


Protocol 2012-0252
November 11, 2016
Page 18
[GI] perforation and rectal/perirectal abscess. Arterial thromboembolism (transient
ischemic attack [TIA], myocardial infarction [MI]) have been reported rarely.
 
 
7.1.1
Management of Adverse Events
 
 
In the absence of an unacceptable cabozantinib-related toxicity and/or clinical signs of 
disease progression, subjects may continue treatment at the discretion of the 
investigator. Subjects must be instructed to notify their physician immediately for any
and all toxicities.
 
Guidelines for the management of AEs (i.e. dose interruptions and dose reductions) are
presented in the next sections. Each dose reduction of cabozantinib should be to one
dose level lower that the current dose. If study treatment of cabozantinib is restarted
after being withheld or interrupted, the subject should be instructed not to make up the
missed doses of cabozantinib.
 
The reason for treatment delay and reduced dose must be recorded in the medical 
record.  Any dose interruption and/or treatment delay of > 4 weeks will result in the
removal from study treatment.
Dosing may need to be interrupted for AEs considered not related to cabozantinib if
this is clinically indicated or if causality is initially uncertain. Study treatment may be
resumed at the same dose (or a lower dose per investigator judgment) if the AE
is determined not to be related to cabozantinib once the investigator determines that 
retreatment is clinically appropriate and the subject meets the protocol re-treatment 
criteria.
 
Table 4 General Approach to the Management of Study Treatment-Related Non-Hematologic Toxicities
CTCAE Version 4 Grade
Guidelines/Intervention
Grade 1:
Add supportive care as indicated. Continue study treatment at the current dose
levels.
Grade 2:
Grade 2 AEs considered related to 
study treatment that are 
subjectively tolerable or easily 
managed
Add supportive care as indicated. Continue study treatment at the current dose
levels.
Grade 2 AEs considered related to 
study treatment that are 
intolerable to the subject or 
deemed unacceptable in the 
investigator’s judgment; or are 
not easily managed or corrected
x Cabozantinib dosing should be interrupted until the AE resolves to Grade <1.  
8SRQUHVROXWLRQWREDVHOLQHRU*UDGHWUHDWPHQWPD\EHUHVXPHGDWHLWKHU
the same dose or with a dose reduction at the discretion of the investigator 
unless this is a recurring event at which time the dose should be reduced.
Grade 3:


Protocol 2012-0252
November 11, 2016
Page 19
Grade 3 AEs considered related to 
study treatment which occurred 
without optimal prophylaxis or 
which is easily managed by 
medical intervention or resolved 
quickly
x Interrupt study treatment and add supportive care as indicated
x For AEs that are easily managed (e.g., correction of electrolytes) with 
UHVROXWLRQWREDVHOLQHRU*UDGHZLWKLQKRXUVWUHDWPHQWPD\EHUHVXPHG
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
x 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 
*UDGHWUHDWPHQWVKRXOGEHUHVWDUWHGZLWKDGRVHUHGXFWLRQ1RWHLIWKH
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
,QWHUUXSWVWXG\WUHDWPHQWXQWLOUHFRYHU\WR*UDGHRUEDVHOLQHDQGUHVXPH
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 
XQHTXLYRFDOO\GHULYLQJFOLQLFDOEHQHILW,QWKLVFDVHXSRQUHFRYHU\WR*UDGH
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.
 
 
Table 5 General Approach to the Management of Hematologic Toxicities
CTCAE Version 4 Grade
Intervention
Neutropenia
Grade 3 neutropenia with documented 
infection
*UDGHQHXWURSHQLDGD\V
Grade 4 neutropenia
,QWHUUXSWFDER]DQWLQLEWUHDWPHQWXQWLOUHVROXWLRQWR*UDGH 1, and resume 
cabozantinib treatment at a reduced dose.
Thrombocytopenia

Grade 3 thrombocytopenia with 
clinically significant bleeding or Grade 4 
thrombocytopenia
,QWHUUXSWFDER]DQWLQLEWUHDWPHQWXQWLOUHVROXWLRQWR*UDGHDQGUHVXPH
cabozantinib treatment at a reduced dose
Febrile Neutropenia
Grade 3 febrile neutropenia
,QWHUUXSWFDER]DQWLQLEWUHDWPHQWXQWLOUHFRYHU\RI$1&WR*UDGHDQG
WHPSHUDWXUHWR&DQGUHVXPHFDER]DQWLQLEWUHDWPHQWDWDUHGXFHG
dose.
Grade 4 febrile neutropenia
Permanently discontinue study treatment unless determined that the 
subject is unequivocally deriving clinical benefit. In this case, upon 
UHFRYHU\WR*UDGHRUEDVHOLQHWKHVXEMHFWPD\EHUH-treated at a 
reduced dose that is to be determined by the investigator.


Protocol 2012-0252
November 11, 2016
Page 20
x
ANC, absolute neutrophil count; LLN, lower limit of normal
x
1HXWURSHQLD*UDGH//1$1&[9/L; Grade 2 (1 x 109/$1&[9/L), Grade 3 (0.5 x 109/$1&[9/L), Grade 
4 (ANC < 0.5 x 109/L).
x
Febrile Neutropenia: Grade 3 (present); Grade 4 (Life-threatening consequences; urgent intervention indicated). 
x
Thrombocytopenia: Grade 1 (<LLN – 75 x 109/L); Grade 2 (<75.0 – 50.0 x 109/*UDGH3ODWHOHWFRXQW- 25 x 109/L); Grade 4 
(Platelet count < 25 x 109/L).
 
7.1.2
General Guidelines for Non-Hematologic and Hematologic Adverse Events
 
General guidelines for the management of non-hematologic and hematologic 
toxicities are provided in Table 4 and Table 5, respectively. These guidelines are meant to 
be advisory and not compulsory, at the discretion of the treating physician.  As a general
approach, it is suggested that all AEs be managed with supportive care when possible
at the earliest signs of toxicity. Guidance for the management of fatigue, anorexia,
weight loss, non-gastrointestinal fistula, osteonecrosis of the jaw, eye disorders, 
musculoskeletal and connective tissue disorders, nervous system disorders, 
respiratory/thoracic/mediastinal disorders and congenital, familial and genetic 
disorders can be found in the Investigators Brochure. 
 
 
7.1.3
Diarrhea, Nausea, Vomiting, Stomatitis, and Mucositis
Diarrhea
Subjects should be instructed to notify their physician and/or study nurse 
immediately at the first signs of poorly formed or loose stool or an increased 
frequency of bowel movements. Administration of antidiarrheal agents is 
recommended at the first sign of diarrhea as initial management. Loperamide is 
recommended as standard first line therapy. Alternatively, diphenoxylate/atropine 
can be used. Additional agents to consider in subjects with diarrhea that is refractory
to the above include deodorized tincture of opium and octreotide. 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. 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. Caution is 
recommended with the use of aprepitant or fosaprepitant and nabilone as cabozantinib
exposure may be affected by concomitant administration because aprepitant and


Protocol 2012-0252
November 11, 2016
Page 21
fosaprepitant are both inhibitors and inducers of CYP3A4, and nabilone is a weak
inhibitor of CYP3A4.
 
Stomatitis and Mucositis
Preventive measures may include a comprehensive dental examination to identify any
potential complications before study treatment is initiated. Appropriate correction of
local factors should be instituted as indicated, such as modification of ill-fitting
dentures and appropriate care of gingivitis. During treatment with cabozantinib, good 
oral hygiene and standard local treatments such as non- traumatic cleansing, and oral
rinses (eg, with a weak solution of salt and baking soda) should be maintained. The
oral cavity should be rinsed and wiped after meals, and dentures should be cleaned
and brushed often to remove plaque. Local treatment should be instituted at the
earliest onset of symptoms. When stomatitis interferes with adequate nutrition and
local therapy is not adequately effective, dose reduction or temporary withholding of 
cabozantinib should be considered.
 
 
7.1.4
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 (Table 6):


Protocol 2012-0252
November 11, 2016
Page 22
 
Table 6 General Approach to the Management of Hepatobiliary Disorders
 
 
Transaminase elevation
CTCAE v4.0
Intervention
 
Subjects with AST and ALT less than or equal to the ULN at baseline
Grade 1
Continue study treatment with weekly monitoring of liver function tests (LFTs) for
at least 4 weeks.. Then resume the standard protocol-defined monitoring of LFTs.
 
Grade 2
Continue study treatment with at least twice weekly monitoring of LFTs for 2 
weeks. Then weekly for 4 weeks. If LFTs continue to rise within Grade 2, interrupt
study treatment.  Then continue with at least weekly LFTs until resolution to
GradH6Wudy 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
GradH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 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 8/1EXW[ ULN (i.e., Grade 1) at  baseline
 
.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 GradH1.  Study treatment may then be
resumed at a one-dose-level reduction of cabozantinib
 
.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
GradH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 ,IWKH 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 .0 x ULN at  baseline
 
.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 lower
dose as determined by the investigator.
Grade 4                                      Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ,IWKH subject 
was unequivocally deriving clinical benefit, the subject may be able to resume
treatment at a lower dose as determined by the investigator.


Protocol 2012-0252
November 11, 2016
Page 23
 
Cabozantinib treatment should also be interrupted when transaminase increases are 
accompanied by progressive elevations of total bilirubin, and/or elevations of 
coagulation tests (eg, International Normalized Ratio [INR]). Monitoring of 
transaminases should be intensified (2–3 times per week) and cabozantinib should be
held until the etiology of the abnormalities is determined and these abnormalities are
corrected or stabilize at clinically acceptable levels (INR < 1.5 u ULN, total bilirubin
< 1.5 u ULN, aminotransferases < 2.5 u ULN or baseline).
 
Subjects must have cabozantinib permanently discontinued if transaminase elevations 
are accompanied by evidence of impaired hepatic function (bilirubin elevation
>2xULN), in the absence of evidence of biliary obstruction (i.e., significant elevation 
of alkaline phosphatase [ALP]) or some other explanation of the injury (e.g., viral
hepatitis, alcohol hepatitis), as the combined finding (i.e., Hy’s Law cases) represents 
a signal of a potential for the drug to cause severe liver injury.
 
All subjects who develop isolated bilirubin elevations of Grade 3 should have study 
treatment held until recovered to Grade RUEDVHOLQH (or lower). If this occurs 
within 6 weeks of the dosing delay, study treatment may continue at a reduced dose. 
In subjects without biliary obstruction and Grade 4 bilirubin elevation, or with 
recurrence of Grade 3 bilirubin elevation after a dose reduction, study treatment must
be discontinued.
 
 
7.1.5
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- see Tables 7 and 8). Subjects with symptomatic pancreatitis should 
be treated with standard supportive measures.


Protocol 2012-0252
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Table 7 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
x
Interrupt treatment
x
Monitor lipase and amylase twice weekly
x
Upon resolution to Grade  or baseline, cabozantinib may be restarted at 
the same dose or at a reduced dose provided that this occurs within 6 
weeks.
x
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 or
baseline and retreatment must be at a reduced dose.
Grade 4
x
Interrupt treatment
x
Monitor lipase and amylase twice weekly
x
Upon resolution to Grade  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.
x
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 RUbaseline and
retreatment must be at a reduced dose.
Table 8 Symptomatic Pancreatitis
 
Pancreatitis
Grade 1
Continue at current dose level. More frequent monitoring of lipase and amylase
and radiographically is recommended
Grade 2
x
Interrupt treatment
x
Monitor lipase and amylase twice weekly
x
Upon resolution to Grade  or baseline , cabozantinib may be restarted 
at the same dose or at a reduced dose provided that this occurs within 6 
weeks.
x
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 GradH or baseline and retreatment must be at a 
reduced dose.
Grade 3
x
Interrupt treatment
x
Monitor lipase and amylase twice weekly
x
Upon resolution to Grade  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.


Protocol 2012-0252
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7.1.6
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 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 (Table 9). Subjects with skin disorders should be carefully 
monitored for signs of infection (eg, abscess, cellulitis, or impetigo). In the case of 
study treatment-related skin changes (eg, rash, hand-foot syndrome), the 
investigator may request that additional assessments be conducted with the 
subject’s consent. These assessments may include digital photographs of the skin 
changes and/or a biopsy of the affected skin and may be repeated until the skin 
changes resolve.
Table 9 Management of Hand-Foot Syndrome
Hand-Foot Skin Reaction and Hand Foot Syndrome (PPE)
No apparent toxicity
Prophylaxis with Ammonium lactate 12% cream (Amlactin®) twice daily OR
heavy moisturizer (e.g. Vaseline) twice daily
Grade 1
Continue treatment at current dose if tolerable or reduce to the next lower dose if 
intolerable. Start urea 20% cream twice daily AND clobetasol 0.05% cream once 
daily. Assess subject at least weekly for changes in severity. Subjects should be 
instructed to notify investigator immediately if severity worsens. If severity 
worsens at any time or if there is no improvement after 2 weeks, proceed to the
management guidelines for Grade 2 PPE
Grade 2
Reduce study treatment to next lower level and/or interrupt dosing. Start/continue 
urea 20% cream twice daily AND clobetasol 0.05% cream once daily. Pain control
with NSAIDs/GABA agonists/narcotics. Assess subject at least weekly for changes 
in severity. Subjects should be instructed to notify investigator immediately if 
severity worsens.  If severity worsens at any time (eg, peeling, blisters, bleeding,
edema, or hyperkeratosis or affects self-care) or if there is no improvement after 2
weeks, proceed to the management guidelines for Grade 3 PPE.  If the dose was 
reduced, then upon resolution to Grade 0 or Grade 1, treatment may continue at the
reduced dose.  If the dose was only interrupted but not reduced, then treatment may
be restarted at one dose level lower.


Protocol 2012-0252
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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, Ȗ-aminobutyric acid; NSAID, nonsteroidal anti-inflammatory drugs; PPE, palmar-plantar erythrodysesthesia
 
 
7.1.7
Embolism and Thrombosis
In clinical studies with cabozantinib, venous thrombotic events (DVT and PE) have 
been observed in less than 10% of subjects, and arterial thromboembolic events (MI 
and TIA) have been reported rarely. In addition, subjects with cancer have a
significantly increased likelihood of developing thromboembolic complications.
 
Subjects who develop a PE and/or DVT should have study treatment interrupted 
until full anticoagulation is established with low molecular weight heparin 
(LMWH) or Coumadin. Anticoagulation with LMWH is preferred over 
Coumadin if possible and feasible. Venous filters (e.g. vena cava filters) are not
recommended due to the high incidence of complications associated with their use.
Once a subject is fully anticoagulated, treatment can be restarted per investigator
judgment at one dose lower. Subjects should permanently discontinue after a
second thrombotic event. Although routine prophylactic anticoagulation is not
necessary for all subjects, prophylactic anticoagulation is allowed for individual
subjects at the discretion of the investigator.
 
Cabozantinib should be discontinued in subjects who develop an acute MI or any 
other clinically significant arterial thromboembolic complication.
 
 
7.1.8
Hypertension
 
Hypertension is a relatively common complication of other VEGF-pathway 
inhibitors and has been observed in cabozantinib clinical studies.
 
Decisions to decrease or hold the dose of study treatment must be based on BP 
readings taken by a medical professional and must be confirmed with a second 
measurement at least 5 minutes following the first measurement. Other than for 
hypertension requiring immediate therapy, the presence of new or worsened 
hypertension should be confirmed at a second visit before taking new therapeutic 
action. Blood pressure should be monitored in a constant position visit to visit, 
either sitting or supine. Cabozantinib dosing should be interrupted in subjects with 
severe hypertension (180 mm Hg systolic or 120 mm Hg diastolic; or sustained
PP Hg systolic RUGLDVWROLF who cannot be controlled with medical 
interventions and discontinued in subjects with hypertensive crises or hypertensive 
encephalopathy (Table 10).


Protocol 2012-0252
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Table 10 Management of Hypertension Related to Cabozantinib
 
Criteria for Dose Modifications
Treatment/cabozantinib Dose Modification
 
Subjects not receiving optimized anti-hypertensive therapy
 
> 140 mm Hg (systolic) and < 160 mm Hg
OR
> 90 mm Hg (diastolic) and < 110 mm Hg
 
 
 
 
 
 
160 mm Hg (systolic) and < 180 mm Hg
OR
10 mm Hg (diastolic) and < 120 mm Hg
 
 
 
 
 
 
 
 
180 mm Hg (systolic) OR
20 mm Hg (diastolic )
x Increase antihypertension therapy (i.e., increase dose of 
existing medications and/or add new antihypertensive
medications)
x Maintain dose of cabozantinib
x 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.
x Reduce cabozantinib by one dose level.
x Increase antihypertension therapy (i.e., increase dose of 
existing medications and/or add new antihypertensive
medications)
x Monitor subject closely for hypotension.
x 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.
 
x Interrupt treatment with cabozantinib Add new or additional 
anti-hypertensive medications and/or increase dose of existing 
medications.
x Monitor subject closely for hypotension.
x When SBP < 140 and DBP < 90, restart cabozantinib treatment 
at one dose level lower
x 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
 
 
7.1.9
Proteinuria
 
Proteinuria has been reported with approved drugs that inhibit VEGF pathways as 
well as with cabozantinib. Development and worsening of proteinuria should be 
monitored by serial urinalysis (qualitative/semiquantitative assessment by dipstick; 
quantitative assessment by urine protein/urine creatinine ratio [UPCR], or 24-hour 
urine protein excretion). When a UPCR exceeds 1 (mg/dL protein / mg/dL 
creatinine), a repeat UPCR or a 24-hour urine protein and creatinine should be 
performed to confirm the result. Cabozantinib should be discontinued in subjects
who develop nephrotic syndrome (proteinuria > 3.5 grams per day in combination


Protocol 2012-0252
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with low blood protein levels, high cholesterol levels, high triglyceride levels, and 
edema) or any other relevant renal disease. Also, given the nephrotoxic potential of 
bisphosphonates, these agents should be used with caution in patients receiving 
treatment with cabozantinib. Details of management are described in Table 11.
 
 
Table 11 Management of Treatment Emergent Proteinuria
 
Urine Protein/Creatinine Ratio
Action To Be Taken

x
No change in treatment or monitoring
> 1 and < 3.5
x
Confirm with a 24 hour urine protein excretion within 7 days
x
If proteinuria of > 1 g/24 hours is confirmed, hold cabozantinib and
continue with UPCR monitoring. When UPCR returns to < 1,
restart cabozantinib at a reduced dose. Continue monitoring UPCR
once every week until two consecutive readings are < 1, then revert 
to UPCR monitoring frequency specified in the protocol.
3.5
x
Hold cabozantinib immediately and confirm with 24 hour urine
protein excretion.
x
Evaluate for nephrotic syndrome. If present, discontinue 
cabozantinib treatment permanently, and monitor subject for 
resolution of nephrotic syndrome.
x
If proteinuria of g/24 hours is confirmed without diagnosis of 
nephrotic syndrome, continue to hold cabozantinib and monitor
UPCR weekly. If UPCR decreases to < 1, restart cabozantinib at a 
reduced dose. Continue monitoring UPCR once every week until 
two consecutive readings are < 1, then revert to UPCR monitoring 
frequency specified in the protocol.
UPCR, urine protein/urine creatinine ratio
 
7.1.10  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:
 
 
x
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.


Protocol 2012-0252
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x
Recent or concurrent radiation to the thoracic cavity
x
Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI
diseases
x
Underlying medical conditions which affect normal hemostasis (eg, deficiencies 
in clotting factors and/or platelet function, or thrombocytopenia)
x
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 WHDVSRRQ (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.
 
Furthermore, subjects who develop tumors abutting, encasing, or invading a major 
blood vessel or who develop cavitation of their pulmonary tumors while on study 
treatment must be discontinued from cabozantinib treatment.
 
 
7.1.11  Rectal and Perirectal Abscess
 
Rectal and perirectal abscesses have been reported, sometimes in subjects with 
concurrent diarrhea. These should be treated with appropriate local care and 
antibiotic therapy. Cabozantinib should be held until adequate healing has taken 
place.
 
 
7.1.12  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:


Protocol 2012-0252
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GI-perforation/fistula:
x
Intra-abdominal tumor/metastases invading GI mucosa
x
Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis,
diverticulitis, cholecystitis or symptomatic cholangitis, or appendicitis
x
History of abdominal fistula, GI perforation, bowel obstruction, or 
intra- abdominal abscess
x
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:
x
Radiation therapy has been identified as a possible predisposing risk factor
for non-GI fistula formation in subjects undergoing treatment with such 
agents (eg, 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.
 
 
7.1.13  Wound healing and Surgery
VEGF inhibitors can cause wound healing complications and wound dehiscence 
which may occur even long after a wound has been considered healed. Therefore, 
surgical and traumatic wounds must have completely healed prior to starting 
cabozantinib treatment and be monitored for wound dehiscence or wound 
infection while the subject is being treated with cabozantinib.  Treatment with
cabozantinib must be interrupted for any wound healing complication which needs
medical intervention. Treatment with cabozantinib can be resumed once wound 
healing has occurred unless otherwise prohibited in specific protocols.
Cabozantinib should be discontinued in subjects with serious or chronic wound 
healing complications.
 
The appropriate dose hold interval prior to elective surgery to reduce the risk for 
wound healing complications has not been determined. In general, cabozantinib 
should be stopped at least 3 weeks (5 half lives) prior to elective surgery.
 


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7.1.14  Endocrine Disorders
 
Prospective studies of markers of thyroid functions are currently ongoing in two 
single-agent studies to characterize the effects of cabozantinib on thyroid function. 
Preliminary data indicate that cabozantinib affects thyroid function tests (TFTs) in a
high number of subjects. In Study XL184-203, 17 of 34 (50%) euthyroid subjects 
with castration-resistant prostate cancer (CRPC) developed abnormal thyroid-
stimulating hormone (TSH) levels 6 weeks after initiation of cabozantinib treatment 
(6% showed TSH levels between 5 and 7 mU/L, 44% had TSH > 7 mU/L). The 
median TSH level at week 6 was 5.2 mU/L (range, 0.02-29.7 mU/L). In a Phase 1 
combination study of rosiglitazone and cabozantinib (XL184-008) to determine the 
potential for a clinically significant drug-drug interaction of cabozantinib on the 
CYP isozyme CYP2C8, subjects with advanced solid tumors (particularly renal cell 
carcinoma [RCC] and differentiated thyroid cancer [DTC]) are enrolled. Among 11 
evaluable subjects, the AE of hypothyroidism was reported in 55% of subjects. 
Currently available data are insufficient to determine the cause of TFT alterations 
and its clinical relevance. Routine monitoring of thyroid function and assessments 
for signs and symptoms associated with thyroid dysfunction is recommended for 
subjects treated with cabozantinib. Management of thyroid dysfunction (eg,
symptomatic hypothyroidism) should follow accepted clinical practice guidelines.
 
Other endocrine disorders such as hypocalcemia and hyperglycemia, and associated 
laboratory changes, have been observed in less than 10% of subjects. Monitoring 
with standard laboratory tests for endocrine disorders and clinical examination prior 
to initiation and during treatment with cabozantinib is recommended. Cabozantinib 
should be discontinued in subjects with severe or life-threatening endocrine 
dysfunction.
 
 
7.1.15  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 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 


Protocol 2012-0252
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study treatment must be discussed with and approved by the Sponsor on a case by 
case basis.
 
 
7.2 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
ȝ0
 
Cabozantinib is a CYP3A4 substrate (but not a CYP2C9 or CYP2D6 substrate),
based on data from in vitro studies using CYP-isozyme specific neutralizing
antibodies. Preliminary results from a clinical pharmacology study, XL184-006,
showed that concurrent administration of cabozantinib with the strong CYP3A4 
inducer, rifampin, resulted in an approximately 80% reduction in cabozantinib
exposure (AUC values) after a single dose of cabozantinib in healthy volunteers. Co-
administration of cabozantinib with strong inducers of the CYP3A4 family (eg,
dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin,
phenobarbital, and St. John’s Wort) may significantly decrease cabozantinib
concentrations. The chronic use of strong CYP3A4 inducers should be avoided.
Other drugs that induce CYP3A4 should be used with caution because these drugs 
have the potential to decrease exposure (AUC) to cabozantinib. Selection of 
alternate concomitant medications with no or minimal CYP3A4 enzyme induction
potential is recommended. In addition, caution must be used when discontinuing
treatment with a strong CYP3A4 inducer in a subject who has been concurrently
receiving a stable dose of cabozantinib, as this could significantly increase the
exposure to cabozantinib.
 
Preliminary results from a clinical pharmacology study, XL184-007, showed that 
concurrent administration of cabozantinib with the strong CYP3A4 inhibitor, 
ketoconazole, resulted in a 33-39% increase in the cabozantinib exposure (AUC 
values) after a single dose of cabozantinib in healthy volunteers. Co-administration
of cabozantinib with strong inhibitors of the CYP3A4 family (eg, ketoconazole, 
itraconazole, clarithromycin, indinavir, nefazodone, nelfinavir, and ritonavir) may 
increase cabozantinib concentrations. Grapefruit / grapefruit juice and Seville
oranges may also increase plasma concentrations of cabozantinib. Strong CYP3A4 
inhibitors and other drugs that inhibit CYP3A4 should be used with caution because
these drugs have the potential to increase exposure (AUC) to cabozantinib. Selection
of alternate concomitant medications with no or minimal CYP3A4 enzyme
inhibition potential is recommended.
 


Protocol 2012-0252
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Because in vitro studies only assessed the metabolizing capacity of the
CYP3A4, CYP2C9, and CYP2D6 pathways, the potential for drugs that
inhibit/induce other CYP450 pathways (eg, CYP2C8, CYP2C19, CYP2B6, 
CYP1A2) to alter cabozantinib exposure is not known. Therefore, these drugs 
should be used with caution when given with cabozantinib.
As warfarin is metabolized through the CYP450 system, therapeutic anticoagulation 
with warfarin (eg, Coumadin) is not recommended. As an alternative, therapeutic 
anticoagulation may be accomplished using low-molecular weight heparin (eg, 
Lovenox) or heparin.  However, Cabozantinib undergoes only minor CYP2C9 
metabolism and does not inhibit CYP2C9. Thus, there is no specific drug-drug 
contraindication and Coumadin can be utilized in select patients if LMWH is not 
feasible. 
Please refer to the Flockhart drug interaction tables for lists of substrates,
inducers, and inhibitors of selected CYP450 isozyme pathways (Flockhart 2007; 
http://medicine.iupui.edu/clinpharm/ddis/table.aspx).
 
Protein Binding: Cabozantinib is highly protein bound (approximately 99.9%) to 
human plasma proteins. Therefore, highly protein bound drugs should be used with 
caution with cabozantinib because there is a potential displacement interaction that 
could increase free concentrations of cabozantinib and/or a co-administered highly 
protein-bound drug (and a corresponding increase in pharmacologic effect). Factors 
that influence plasma protein binding may affect individual tolerance to
cabozantinib. Therefore, concomitant medications that are highly protein bound (eg,
diazepam, furosemide, dicloxacillin, and propranolol) should be used with caution.
Because warfarin is a highly protein bound drug with a low therapeutic index,
administration of warfarin at therapeutic doses should be avoided in subjects
receiving cabozantinib due to the potential for a protein binding displacement
interaction.
 
Other Interactions: In a relative bioavailability study in dogs cabozantinib exposure
was not significantly affected by drugs that alter gastric pH. Nevertheless, drugs such 
as proton pump inhibitors (PPIs) and H2-antagonists produce profound suppression of 
gastric acid secretion and significant increases in gastric pH. By elevating gastric pH, 
PPIs and H2-antagonists may decrease cabozantinib plasma exposure levels and its 
effectiveness in vivo, resulting in clinically significant drug interactions. The use of 
PPIs (eg, omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole) 
and/or H2-antagonists (eg, 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.
 


Protocol 2012-0252
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Page 34
 
8.0
CRITERIA FOR SAFETY AND EFFICACY EVALUATION
 
8.1
Safety Evaluation
All patients who receive at least one dose of cabozantinib will be evaluated for 
safety parameters. Additionally, any occurrence of a SAE from time of consent
forward up to and including follow-up visits will be reported. Safety will be
evaluated for all treated patients using the NCI CTCAE version 4.0
(http://ctep.cancer.gov). Safety assessments will be based on medical review of AE 
reports and the results of vital sign measurements, physical examinations and
clinical laboratory tests.
 
8.2
Efficacy Evaluation
All patients who receive at least one month of cabozantinib will be considered 
evaluable for efficacy. The PI will complete evaluation of bone scans and RECIST 
tumor measurements (if applicable) and document them on standard MDACC 
forms in the medical record.
 
 
9.0
Statistical Methods
 
Objectives and Sample Size: This is a phase II study of cabozantinib in patients with 
previously untreated androgen-dependent disease. The primary objective is to assess 
progression-free survival (PFS). We will assess response and overall survival as 
secondary endpoints. A maximum of 60 patients will be entered into this trial, at an
expected accrual rate of 2-3 patients per month. The trial will require approximately 24
months for patient accrual and an additional 9 months for patient follow-up. If the trial
continues to maximum accrual and maintains sufficient follow-up to observe 49
progression events with a median PFS of 11.2 months, then a 95% credible interval for 
median PFS would extend from 8.5 to 14.9 months. Based on historical mean survival
time 11.2 months, a mean progression-free survival time on average > 13 months would 
be considered promising evidence of anti- disease activity.
 
Design and Interim Analysis: This is phase II study and a Bayesian model will be used to 
monitor the trial with a recommendation to stop the trial if the PFS is worse than historical 
data. In particular, we assume that time to progression T follows an exponential
distribution with mean μ and μ* = median (T) = μlog(2). The trial will be stopped if Pr (μ* 
< μH* | data) > 0.95, where μH* is the median PFS with an inverse gamma distribution
IG(22.07, 235.99), which corresponds to a 95%CI of  (7.3, 17.0) based on the historical
data (Millikan, et al., 2008). The prior for μ* is assumed to be IG(a, b), where the
parameters a =3.25 and b = 25.25 is determined based on PFS with the same mean (11.2 
months) and a larger standard deviation of 10.  Assuming an accrual rate of 2.5 per month,
the operating characteristics for the futility stopping rule under various true states are
summarized in the following table, with results based on 1000 simulations.
 


Protocol 2012-0252
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Median PFS
Prob(Stop Early)
Mean No. of Patients
(25%, 75%)
13.2 months
0.019
59.2 (60, 60)
11.2 months
0.072
57.4 (60, 60)
9.2 months
0.246
52.2 (60, 60)
7.2 months
0.700
40.5 (24, 60)
6.2 months
0.924
31.2 (17, 44)
A Bayesian sequential monitoring method (Thall, 1995) will be used to monitor for any study 
treatment related Grade 4 toxicity that fails to resolve to <Grade 2 within 14 days after the 
cabozantinib is held.
We stop the trial if the toxicity is likely to be greater than 30%. That is, stop the trial if
 
Prob{toxicity rate > 30% | data} > 0.85.
 
The prior distribution of toxicity rate is assumed to be beta (1, 1).  Following this rule, the 
trial will be terminated due to toxicity if [# toxicity]/[# patients evaluated]  9/20, 
12/30, 15/40, 19/50, or 22/60. The operating characteristics table is given in the following table, 
based on 1000 simulations:
 
true Prob(tox)
Pr(stop)
mean # Pts (median)
0.1
0.001
59.9 (60)
0.2
0.04
58.0 (60)
0.3
0.32
47.7 (60)
0.4
0.79
29.2 (20)
0.5
0.98
16.9 (10)
 
 
The trial will be conducted through the Clinical Trial Conduct website 
(https://biostatistics.mdanderson.org/ClinicalTrialConduct), which is hosted on a secure 
server at MDACC and maintained by the MDACC Department of Biostatistics. Access to 
the website will be gained through usernames and passwords provided by the MDACC 
Department of Biostatistics to personnel responsible for enrolling patients and reviewing
and analyzing patient data. Training on the use of the Clinical Trial Conduct website will be 
provided by the study statistician for study personnel prior to the study initiation.
 
Demographic and baseline laboratory results will be summarized using descriptive statistics, 
including means with standard deviations, or medians with ranges, histograms and box-plot. 
Survival or times to failure and time-to-progression functions will be estimated using the 
Kaplan-Meier method. Failure will be classified as: Death due to prostate cancer or unknown 
cause; disease progression, need for palliative radiation to more than 1 site, or serious adverse
event deemed related to study agent. Toxicity will be reported by type, frequency and severity.
Worst toxicity grades per patient will be tabulated for selected adverse events and laboratory
measurements. 
 


Protocol 2012-0252
November 11, 2016
Page 36
10.0  DATA AND PROTOCOL MANAGEMENT
 
10.1  Registration Procedure and Data Reporting
All data will be entered to the Department of Genitourinary Medical Oncology
Oracle database (GURU).  GURU is a password protected database with an audit
trail. Data can be collated with a unique GURU identification in order to de-link
information. The minimum required fields will be entered to the MDACC required 
data collection systems (CORe/PDMS). Registration data entry will occur prior to 
initiation of therapy. All eligibility criteria must be satisfied. Reporting to the 
supporting agency will follow the contract agreement.
 
10.2  Clinical Trial Posting
Information related to this study will be posted on www.clinicaltrials.gov before
the first patient is enrolled in the study.
 
 
11.0  SAFETY AND ADVERSE EVENT REPORTING
 
11.1  Reporting Requirements
 
11.1.1  Adverse Drug Reaction Reporting
Toxicity will be scored using CTC Version 4.0 for toxicity and adverse event 
reporting. A copy of the CTC Version 4.0 can be downloaded from the CTEP 
homepage (http://ctep.info.nih.gov). All appropriate treatment areas have
access to a copy of the CTC Version 4.0.
 
Adverse events will for this protocol will be documented and entered into the case
report form according the Recommended Adverse event Recording Guidelines for 
Phase II protocol.
 
 
Table 12.
Recommended Adverse Event Recording Guidelines
 
Attribution
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
 
 
 
 
 
 
 
Unrelated
 
Phase I
 
Phase I
 
Phase I
Phase II
 
Phase I
Phase II
Phase III
Phase I
Phase II
Phase III
 
Unlikely
 
Phase I
 
Phase I
 
Phase I
Phase II
 
Phase I
Phase II
Phase III
Phase I
Phase II
Phase III
 
Possible
 
Phase I
Phase II
Phase I
Phase II
Phase III
Phase I
Phase II
Phase III
 
Phase I
Phase II
Phase III
Phase I
Phase II
Phase III
Probable
Phase I
Phase I
Phase I
 
Phase I
Phase I


Protocol 2012-0252
November 11, 2016
Page 37
 
 
Phase II
Phase II
Phase III
Phase II
Phase III
 
Phase II
Phase III
Phase II
Phase III
 
Definitive
 
Phase I
Phase II
Phase I
Phase II
Phase III
Phase I
Phase II
Phase III
 
Phase I
Phase II
Phase III
Phase I
Phase II
Phase III
 
The Investigator or physician designee is responsible for verifying and providing 
source documentation for all adverse events and assigning the attribution for each 
event for all subjects enrolled on the trial.
 
11.1.2 Serious Adverse Event Reporting (SAE)
 
An adverse event or suspected adverse reaction is considered “serious” if, in the 
view of either the investigator or the sponsor, it results in any of the following 
outcomes:
 
x
Death
x
A life-threatening adverse drug experience – any adverse experience that 
places the patient, in the view of the initial reporter, at immediate risk of death 
from the adverse experience as it occurred. It does not include an adverse 
experience that, had it occurred in a more severe form, might have caused 
death.
x
Inpatient hospitalization or prolongation of existing hospitalization
x
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions.
x
A congenital anomaly/birth defect.
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the patient or subject and 
may require medical or surgical intervention to prevent one of the outcomes listed in
this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse (21 CFR 312.32).
 
x
Important medical events as defined above, may also be considered serious 
adverse events. Any important medical event can and should be reported as an 
SAE if deemed appropriate by the Principal Investigator or the IND Sponsor, 
IND Office.
x
All events occurring during the conduct of a protocol and meeting the 
definition of a SAE must be reported to the IRB in accordance with the 
timeframes and procedures outlined in “The University of Texas M. D. 
Anderson Cancer Center Institutional Review Board Policy for Investigators 
on Reporting Serious Unanticipated Adverse Events for Drugs and Devices”. 
Unless stated otherwise in the protocol, all SAEs, expected or unexpected, 
must be reported to the IND Office, regardless of attribution (within 5
working days of knowledge of the event).


Protocol 2012-0252
November 11, 2016
Page 38
x
All life-threatening or fatal events, that are unexpected, and related to the
study drug, must have a written report submitted within 24 hours (next
working day) of knowledge of the event to the Safety Project Manager in the 
IND Office.
x
Unless otherwise noted, the electronic SAE application (eSAE) will be 
utilized for safety reporting to the IND Office and MDACC IRB.
x
Serious adverse events will be captured from the time of the first protocol-
specific intervention, until 30 days after the last dose of drug, unless the
participant withdraws consent. Serious adverse events must be followed
until clinical recovery is complete and laboratory tests have returned to
baseline, progression of the event has stabilized, or there has been
acceptable resolution of the event.
x
Additionally, any serious adverse events that occur after the 30 day time
period that are related to the study treatment must be reported to the IND
Office. This may include the development of a secondary malignancy.
 
Reporting to FDA:
 
x
Serious adverse events will be forwarded to FDA by the IND Sponsor (Safety
Project Manager IND Office) according to 21 CFR 312.32.
 
It is the responsibility of the PI and the research team to ensure serious 
adverse events are reported according to the Code of Federal Regulations, 
Good Clinical Practices, the protocol guidelines, the sponsor’s guidelines, and 
Institutional Review Board policy.
 
Investigator Communication with Supporting Companies:
 
As soon as an investigator becomes aware of an AE that meets the definition of
‘serious,’ this should be documented to the extent that information is available.
 
x
This report must be submitted by the study site to Exelixis or designee within 
one to two business days, even if it is not felt to be drug related. Email: 
drugsafety@exelixis.com; Fax 650-837-7392
x
The investigator agrees to provide supplementary information requested by the
Exelixis Drug Safety personnel or designee.
x
Pregnancy, although not itself an SAE, should also be reported on an SAE form
or pregnancy form and be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or 
absence of any birth defects or congenital abnormalities.
 
Regulatory Reporting:
 
All serious unexpected adverse drug reactions (unexpected related SAEs) must be 
reported to the Food and Drug Administration (FDA) by the investigator as required 
by 21 CFR 312.32.
 
x
These reports are to be filed utilizing the Form FDA 3500A (MedWatch Form) or 
the MDACC SAE form.
The final MedWatch or MDACC Form must be submitted by the study site to 


Protocol 2012-0252
November 11, 2016
Page 39
Exelixis within one to two business days of submission to the FDA to allow 
Exelixis time to cross-report to Exelixis’ IND. Email: drugsafety@exelixis.com;
Fax 650-837-7392
 
 
11.2  Clinical Laboratory Adverse Events
 
The results of all laboratory tests required by the protocol will be recorded in the 
patient’s medical record. All clinically important abnormal laboratory tests occurring 
during the study will be repeated at appropriate intervals until they return either to 
baseline or to a level deemed acceptable by the investigator and the diagnosis that 
explains them is made.
 
The criteria for determining whether an abnormal laboratory test result should be 
reported as an adverse event are as follows:
 
1.   Test result is associated with accompanying symptoms, and/or
2.   Test result requires additional diagnostic testing or medical/surgical intervention, 
and/or
3.   Test result leads to a change in study dosing or discontinuation from the study, 
significant additional concomitant drug treatment or other therapy, and/or
4.   Test result leads to any of the outcomes included in the definition of a SAE, 
and/or
5.   Test result is considered to be an adverse event by the investigator.
 
*Merely repeating an abnormal test, in the absence of any of the above conditions, 
does not meet Condition 2 above for reporting as an adverse event.
 
Any abnormal test result that is determined to be an error does not require reporting 
as an adverse event, even if it did meet one of the above conditions except for 
Condition 4.
 
 
11.3  Management of Persistent and Refractory Toxicity
 
Utilizing the NCI CTCAE (version 4.0), events which are moderate and interfere with 
function that are not consistent with a patient’s medical history, and are refractory to 
medical treatment, should be investigated carefully to ensure that no other etiology is 
present. Study drug will be held for any toxicity events deemed definitely, probably, 
or possibly drug-related (such as diarrhea, hypertension, vomiting, diarrhea, and 
dizziness) and that are greater than grade 2.  Drug will be held until severity is reduced
to Grade 1 or less and then resumed daily dosing with a dose reduction as outlined in
Section 6.0.
 
 
11.4  Management of All Other Toxicities
 
Other toxicities may occur. Supportive care should be prescribed as needed. They 
may also be prescribed prophylactically to prevent toxicity from developing or 


Protocol 2012-0252
November 11, 2016
Page 40
recurring. The examples include anti-emetics for nausea/vomiting, analgesics for 
pain, antipyretics for fever and antidiarrheals for diarrhea
 
Abnormal laboratory values will be only be captured as adverse events if they are
Grade 3 or higher.
 
 
11.5  Other Safety Considerations
 
11.5.1  Laboratory Data
All laboratory data required by this protocol and any other clinical investigations 
should be reviewed. Any abnormal value that leads to a change in subject 
management (eg, dose reduction or delay or requirement for additional medication or 
monitoring) or that is considered to be of clinical significance by the investigator 
should be reported as an AE or SAE as appropriate.
 
11.5.2  Medication Errors/ Overdose
Any study drug administration error or overdose that results in an AE, even if it
does not meet the definition of serious, requires reporting within 24 hours to 
Exelixis or designee.
 
11.5.3  Follow-Up of Adverse Events
Any related SAEs or any AEs assessed as related that led to treatment 
discontinuation, including clinically significant abnormal laboratory values that 
meet these criteria, ongoing 30 days after the last dose of study treatment must be
followed until either resolution of the event or determination by the investigator that 
the event has become stable or irreversible. This follow-up guidance also applies to 
related SAEs that occur > 30 days after the last dose of study treatment. The status 
of all other continuing AEs will be documented as of 30 days after the last dose of 
study treatment.
 
12.0  PUBLICATION OF DATA AND PROTECTION OF TRADE SECRETS
 
The Principal Investigator (Protocol Chair) holds the primary responsibility for 
publication of the study results; provided that the PI will provide any such publication to
Exelixis, Inc. for review at least sixty (60) days prior to submission and also comply
with any provisions regarding publication as are agreed to between the PI’s institution
(eg, institution name.) and Exelixis, Inc. in the Clinical Trial Agreement related to this
study. The results will be made public within 24 months of the end of data collection.
However, if a report is planned to be published in a peer-reviewed journal, then that
initial release may be an abstract that meets the requirements of the International
Committee of Medical Journal Editors. In any event, a full report of the outcomes
should be made public no later than three (3) years after the end of data collection.
Authorship for abstracts and manuscripts resulting from this study will be determined
according to guidelines established by the International Committee of Medical Journal
Editors.


Protocol 2012-0252
November 11, 2016
Page 41
 
13.0
REFERENCES
 
 
(1)  Smith DC, Smith MR, Small EJ, Sweeney C, Kurzrock R, Gordon MS, et al. Phase II 
study of XL184 in a cohort of patients (pts) with castration-resistant prostate cancer 
(CRPC) and measurable soft tissue disease. J Clin Oncol 29: 2011 (suppl 7; abstr 127) .
2-17-2011. Ref Type: Generic
 
(2)  Pisters LL, Troncoso P, Zhau HE, Li W, von Eschenbach AC, Chung LW. c-met proto-
oncogene expression in benign and malignant human prostate tissues. J Urol
1995;154:293-8.
 
(3)  Knudsen BS, Gmyrek GA, Inra J, Scherr DS, Vaughan ED, Nanus DM, et al. High 
expression of the Met receptor in prostate cancer metastasis to bone. Urology
2002;60:1113-7.
 
(4)  Knudsen BS, Edlund M. Prostate cancer and the met hepatocyte growth factor receptor.
Adv Cancer Res 2004;91:31-67.
 
(5)  Loblaw DA, Virgo KS, Nam R, Somerfield MR, Ben-Josef E, Mendelson DS, et al.
Initial hormonal management of androgen-sensitive metastatic, recurrent, or progressive
prostate cancer: 2006 update of an American Society of Clinical Oncology practice
guideline. J Clin Oncol 2007;25:1596-605.
 
(6)  Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin 2010;60:277-
300.
 
(7)  Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer:
directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol
2005;23:8253-61.
 
(8)  Karlou M, Tzelepi V, Efstathiou E. Therapeutic targeting of the prostate cancer 
microenvironment. Nat Rev Urol 2010;7:494-509.
 
(9)  Efstathiou E, Logothetis CJ. A new therapy paradigm for prostate cancer founded on
clinical observations. Clin Cancer Res 2010;16:1100-7.
 
(10)  Verras M, Lee J, Xue H, Li TH, Wang Y, Sun Z. The androgen receptor negatively 
regulates the expression of c-Met: implications for a novel mechanism of prostate cancer 
progression. Cancer Res 2007;67:967-75.
 
(11)  Tu WH, Zhu C, Clark C, Christensen JG, Sun Z. Efficacy of c-Met inhibitor for advanced 
prostate cancer. BMC Cancer 2010;10:556.
 
(12)
Millikan RE, Wen S, Pagliaro LC, Brown MA, Moomey B, Do KA, et al. Phase III trial
of androgen ablation with or without three cycles of systemic chemotherapy for advanced 
prostate cancer. J Clin Oncol 2008;26:5936-42.