Conditions: Breast Cancer Breast Neoplasm
Keywords: Advanced Breast Cancer Hormone Resistance Pazopanib anastrozole arimidex letrozole femara
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 30
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the clinical benefit rate at 12 weeks from the addition of pazopanib to a non-steroidal aromatase inhibitor (NSAI) (letrozole or anastrozole) in patients with hormone receptor positive advanced breast cancer progressing on the same NSAI hormone therapy.

Detailed description:
In this trial, the investigators propose to evaluate the role of VEGFR blockade with the tyrosine kinase inhibitor pazopanib in combination with nonsteroidal aromatase inhibitors (NSAI) in patients who are progressing or have relapsed on the same NSAI hormone therapy given for advanced or early stage breast cancer. If this trial demonstrates clinical benefit, this all oral combination could be tested in both the neoadjuvant and metastatic settings in a randomized phase II design.

In order to investigate potential factors predicting response or resistance to pazopanib and NSAIs, several translational studies have been incorporated into this trial.

The prognostic value of circulating tumor cells (CTC) has been demonstrated in several studies in breast cancer, especially in advanced stage \[35-38\]. At University of California, San Francisco (UCSF) in the laboratory of Dr. John Park, the investigators have demonstrated expertise in the measurement of CTC in patients with advanced stage breast cancer by IC/FC assay. CTC are first enriched with immunomagnetic beads coated with EpCAM, then EpCAM+, CD45-, nucleic acid+ cells are detected by flow cytometry. This technique is highly sensitive and reproducable, and allows sorting of cells for molecular analysis as well as analysis of cell surface markers\[39\]. In this trial, the investigators will collect patient's peripheral blood samples every 4 weeks while on treatment and follow any reduction of CTC.

The mechanisms of hormonal resistance includes intrinsic and acquired pathways: decreased ER expression accounts for intrinsic resistance and the increased receptor tyrosine kinase pathway relates to acquired resistance \[40-42\]. The investigators plan to analyze the mutation of PI3K/Akt and deletion of PTEN by sequencing in CTC (depending on numbers of cells, which in turn determines feasibility), in order to make a preliminary assessment of potential markers of response to pazopanib.

The tumor microenvironment plays an important role in cancer development and progression. Clinical studies have revealed that the increased T regulatory cells (Treg), high ratios of CD4/CD8 T lymphocytes, and extra follicular B cells in primary tumors correlated with worse overall survival \[43-45\]. Recently, studies from preclinical models have shown that tumor associated macrophages (TAM) can promote pulmonary metastases in breast cancer animal models, and in both the preclinical and clinical settings are associated with worse clinical outcome \[46-48\]. TGFβ has been linked to hormonal resistance in breast cancer. The activation of TGFβ leads to increased regulatory CD4+ T cells and decreased cytotoxic CD8+ T cells in the tumor microenvironment \[49\]. A recent study in non-small cell lung cancer suggests that baseline and post-treatment levels of cytokines, particularly IL-4 and IL-12 correlated with response to pazopanib\[50\]. In this study, the investigators will collect patient's serum to monitor the level of cytokines at baseline and during treatment, the investigators will compare the change of cytokine level with pazopanib in each patient, and also compare between responders and non-responders. This information may help us to identify biomarkers that would predict response to antiangiogenic therapy and to identify possible mechanisms of resistance.

Arms:
arm 1: Non-randomized, open label

Interventions: intervention 1: Pazopanib
Intervention descriptions: intervention 1: Oral, 800mg tablet daily per cycle

Protocol document:
ICF_001.pdf: 
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HOPE RUGO, MD
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
Study Title: CC#117513:  Reversing Hormone Resistance in Advanced Breast Cancer with 
Pazopanib
This is a clinical trial, a type of research study.  Your study doctor, Hope Rugo, MD and/or her 
associates from the UCSF Helen Diller Family Comprehensive Cancer Center will explain the 
clinical trial to you. 
Clinical trials include only people who choose to take part. Please take your time to make your 
decision about participating. You may discuss your decision with your family and friends and with 
your health care team. If you have any questions, you may ask your study doctor. 
You are being asked to take part in this study because you have metastatic breast cancer (breast 
cancer that has spread to other parts of the body) that is known to be estrogen and/or progesterone 
receptor positive and your cancer has progressed while on hormone treatment. 
Why is this study being done?
The purpose of this study is to find out what effects, good and/or bad, of adding pazopanib (the 
study drug) to your current hormonal treatment (you may take either anastrozole [Arimidex] or 
letrozole [Femara]).  The study will see whether the combination is safe and easy to tolerate.  If 
your study doctor is able to detect tumor cells in your blood before the treatment and/or during the 
treatment, he/she will also monitor the change of these tumor cells. 
Pazopanib is a drug taken by mouth that belongs to a class of medications called tyrosine kinase 
inhibitors. It works by slowing or stopping new blood vessel growth that can feed cancer growth. 
It has been approved by the United States Food and Drug Administration (FDA) for the treatment 
of advanced kidney cancer and certain types of advanced soft tissue sarcoma, but is not approved 
in the treatment of breast cancer.  Thus, its use in this study is considered investigational. 
This study is being coordinated by UCSF.  The makers of pazopanib, Novartis Pharmaceuticals, 
are providing funding necessary for trial conduct and some study related tests. 
How many people will take part in this study?
This study will be conducted at UCSF. Up to 30 patients will be enrolled in this study.  
What will happen if I take part in this research study?
This study will enroll participants in two-steps.  Initially, 14 patients will be enrolled.  If at least 1 
patient shows that he/she is benefiting clinically from the study drug, then the study will proceed 
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to the second step.  At the second step, 13-16 more patients will be enrolled.  The study doctor will 
let you know which step of the study you will be enrolling in.  
If you decide to participate in this study, you will need to have several tests done to make sure that 
you qualify for this study. If you are eligible to participate in the study, you will enter the treatment 
phase of the study. 
Before you begin the main part of the study...
You will need to have the following exams, tests or procedures to find out if you can be in the 
study.  Some of these exams, tests or procedures are part of regular cancer care and may be done 
even if you don’t join the study.  Some exams, tests, and procedures are being done because they 
are a part of the study.  These are indicated as “study tests”.  If you had some of them recently 
(within 3 weeks before the study begins), they may not need to be repeated. This will be up to 
your study doctor.  The screening visit to complete all of the tests and procedures listed below 
will take approximately 2-3 hours.  

Physical examination (including your height and weight)

Medical history (including a review of your prior and current medications)

Vital signs (heart rate, blood pressure, temperature)

Electrocardiogram (ECG) – An ECG records the natural electrical activity of your heart.  
You will lie down, and wires or “leads” will be attached to your chest with an adhesive.  
You will be asked to lie still while the machine prints out an electrical “picture” of your 
heart activity.  The ECG takes about 15 minutes.

Blood tests: a small sample of blood (about 11 teaspoons) for the following:
o
Routine blood tests to measure your blood counts, and kidney, liver, and thyroid 
function. 
o
For research purposes to check for circulating tumor cells (very small numbers of 
cancer cells in the blood) – study test
o
To check your immune system – study test

A urine sample will be collected to check for protein – study test

Tumor assessments ( CT or MRI of the chest, abdomen and pelvis if you have disease that 
can be measured, or a Bone Scan or PET/CT if you have cancer in the bones)

CT scan:  A CT scan uses special x-ray equipment to make detailed pictures of body 
tissues and organs. For the CT scan, you may be given a "contrast material" (a special 
dye that makes it easier for doctors to see different tissues in your body).  The contrast 
material may be given orally, intravenously, or rectally (less likely).  Oral contrast 
material is given to you to drink and is used to help outline the stomach and intestines.  
Intravenous (IV) contrast material is given to you by injecting the contrast material into 
a line which is attached to a needle in your arm, and is used to get clearer pictures of 
your body cavity.  A rectal contrast fills up the loops of your lower bowel so the doctors 
can see your tumor better.  After you have been given the contrast material (either by 
mouth, by vein, or rectum), you will lie flat on a table that will move you into the CT 
scan machine.  You will be asked to lie still and may be asked to hold your breath for 
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a few seconds.  The CT scan is done in the radiology department and takes about half 
an hour.

MRI scan:  An MRI scan takes an image of your body to observe the location and size 
of your tumor.  When having an MRI (Magnetic Resonance Imaging) scan, you will lie 
still on a table that slides into a tunnel slightly wider than your body. People who feel 
uncomfortable in confined spaces (claustrophobia) may feel uncomfortable in the 
narrow cylinder. MRIs use powerful magnets to make images.  Therefore, persons with 
certain metal implants, such as pacemakers should not have an MRI (If you have an 
implant or any metal in your body, please check with your study care doctor to know 
whether you can have an MRI or not.) For people without metal implants, there are no 
known health risks associated with exposure to the magnet.  As images are taken, a 
loud banging noise will be produced.  Earplugs will be available if needed. The MRI 
can be stopped at any time at your request.  You will lie there quietly for about one 
hour, during which time you will hear a loud machine-like noise.  The MRI scan is 
done in the radiology department and takes approximately an hour and a half to 
complete.  

PET/CT scan:  A PET/CT scan is a special type of test to show how the organs and 
cells work in your body and is done to show activity of the cells in your tumor.  Your 
scan will begin with an injection of a radioactive substance into a vein in your arm.  
You will be asked to rest quietly for a period of time (usually about 20 to 40 minutes) 
as the radioactive substance circulates throughout your body.  After this time, you will 
be positioned within a large ring (similar to a big donut hole) on a scanning bed.  Once 
positioned properly, the bed will move you into the scanner.  As pictures are being 
taken, you will be asked to remain very still so clear images will be taken.  The imaging 
time takes about one hour.

Bone scan: a bone scan is a test to find areas of increased or decreased bone cell 
metabolism. Metabolism is the process of tissue cells dying and being replaced by new 
cells. A bone scan may be performed before you start the treatment if you have cancer 
cells in the bone if you have not had a PET scan.

Leftover tumor tissue collection – study test
The researchers will obtain a sample of leftover tumor tissue from any biopsy or surgery 
you may have as part of your regular cancer care if available.  This tissue will be used to 
look for changes (mutations) in genes (DNA) and tumor markers (substances produced 
by your body in response to cancer).  

Tumor Biopsy – Optional – study test. A doctor will remove a piece of your tumor tissue 
if it can be obtained.  This is called a biopsy.  Usually, this biopsy involves the use of a 
small needle which is directed into your tumor site with the guidance of an imaging 
machine such as a CT scan or a Doppler ultrasound, if necessary.  Your tumor sample will 
be used to help us understand the possible mutations your cancer cells may have. This 
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procedure takes about 30 minutes.  You will sign a separate consent page for this procedure.  
Your treating physician will determine if this procedure is safe for you to have.
During the main part of the study...
If the exams, tests and procedures show that you can be in the main part of the study, and you 
choose to take part, then you will need the following tests and procedures. They are part of regular 
cancer care.
If you agree to take part in this study, it is very important that you tell your study doctor before 
starting on this study about all of the medicines you are taking (over-the-counter medications, 
supplements, prescription medications, or illegal drugs) including any medicines you have taken 
within the past 2 weeks.  This is important because some medicines can change the way your body 
handles other medicines and this can increase the risk of side effects.  In addition, please talk with 
the study doctor before you begin taking any new medications or supplements during this study.
Your study doctor will look at the medicines you are currently taking to make sure you are allowed 
to take them on the study.  You may be asked to change some of the medicines you are taking.  If 
you need to take a medicine that is not allowed and it cannot be replaced with another medicine, 
you will not be asked to stop taking it; however, you will not be able to take part in this study.
While you are participating in this study, you will come to the clinic every 2 weeks for the first 4 
weeks.  After that, if you are tolerating the treatment well without significant side effects, you will 
come to the clinic once every 4 weeks.  During these visits, you will have the following tests and 
procedures: 
Day 1 

Physical examination 

Vital signs 

You will be given a supply of pazopanib each month with instructions on how to take the 
study drug and when to return to the doctor’s clinic or office.  Everyone who participates 
in this study will receive pazopanib in addition to the hormonal medication they are taking 
(either anastrozole or letrozole).   
o
For the rest of the study, you will take the study drug and either anastrozole or 
letrozole every day.  
o
You will take up to 4 tablets of pazopanib at least one hour before or two hours 
after a meal.  
o
You should take both medications at about the same time each day.
o
You will continue to obtain your hormonal treatment (anastrozole or letrozole) from 
your pharmacy as you have been prior to joining the study.  
Day 15, Day 28
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
Physical examination 

Medical history 

Vital signs 

Blood tests (about 5-7 teaspoons) for the following  –
o
For liver function tests – you will have blood tests to monitor your liver function 
every 2 weeks during the first two months you are taking pazopanib
o
To check for circulating tumor cells (if your blood test at screening showed that 
you have measurable circulating tumor cells) –Day 28 only, study test

To measure your immune response –Day 28 only, study test 

ECG – Day 28 only – study test
If you are not experiencing any severe side effects, you will continue to be seen every 4 weeks 
until you stop taking pazopanib.  
If you are experiencing severe side effects, you will continue to be seen every 2 weeks. 
Every 4 weeks and beyond

Physical examination

Vital signs 

Blood draw (about 3-5 teaspoons) – 
o
For routine blood tests including liver function tests 
o
To check for circulating tumor cells (if you have measurable circulating tumor 
cells) - at 12 weeks only - study test

Urine will be collected  - study test
12 weeks after starting pazopanib, and every 16 weeks thereafter

ECG –  study test

Disease assessment: CT or MRI or PET/CT or bone scan - every 16 weeks unless your 
doctor requests that a scan be obtained sooner.
When you are finished receiving pazopanib
You will return to the clinic within four weeks after you stop taking pazopanib.  During this visit, 
you will have the following tests and procedures: 

Physical examination 

Vital signs 

Blood draw (about 3-5 teaspoons) 
o
For routine blood tests
o
To check for circulating tumor cells (if you have measurable circulating tumor 
cells) - study test

ECG – study test

Disease assessment - CT, MRI, PET/CT or bone scan
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Study location: All study procedures will be done at 
UCSF – Mt. Zion 
Helen Diller Family Comprehensive Cancer Center 
 
How long will I be in the study?
You will continue to receive pazopanib and your hormonal treatment as long as your disease does 
not progress or you do not have severe side effects, you experience any bad side effects, you decide 
to withdraw your consent to participate in this study, or the study is closed.  If your cancer grows 
or if you begin another anti-cancer treatment, you will have to stop study treatment.  After you are 
finished taking the treatment, the study doctor will ask you to visit the office for a follow-up exam 
within 4 weeks.  The study team will contact you by phone each month for three months after your 
follow-up exam to see how you are doing.  
Can I stop being in the study?
Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping 
or decide to stop. He or she will tell you how to stop your participation safely. 
It is important to tell the study doctor if you are thinking about stopping so any risks from stopping 
the pazopanib and hormonal treatment can be evaluated by your doctor. Another reason to tell your 
doctor that you are thinking about stopping is to discuss what follow-up care and testing could be 
most helpful for you.
The study doctor may stop you from taking part in this study at any time if he/she believes it is in 
your best interest, if you do not follow the study rules, or if the study is stopped.
What side effects or risks can I expect from being in the study?
You may have side effects while on the study. Everyone taking part in the study will be watched 
carefully for any side effects. However, doctors don't know all the side effects that may happen.  
Side effects may be mild or very serious. Your health care team may give you medicines to help 
lessen side effects. If you develop side effects from the pazopanib, most should go away soon after 
you stop taking pazopanib.  In some cases, side effects can be serious, long lasting, or may never 
go away.  
You should talk to your study doctor about any side effects you experience while taking part in 
the study.
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Risks and side effects related to the study drug pazopanib
As of September 9, 2014, approximately 5875 patients and healthy volunteers had received 
pazopanib (either as monotherapy or in combination) out of more than 8600 patients enrolled in 
clinical studies of pazopanib. Pazopanib can cause side effects, although not everybody gets them.  
Some side effects can be life-threatening or fatal.  The side effects below are those reported by 
patients who have taken pazopanib either in a clinical trial or as prescribed by their doctors. The 
side effects are listed according to the highest number of patients who had them in pazopanib 
studies, as very common, common, or uncommon.  Not all side effects of pazopanib are known 
and further studies are under way. If you experience any side effects, please speak with your study 
doctor.
Very common side effects occurring in more than 10% of patients include:  

diarrhea, feeling or being sick (nausea, vomiting, abdominal pain/discomfort)

loss of strength and energy, weakness 

loss of appetite

changes in hair color

high blood pressure

headache

weight loss

unusual hair loss or thinning

a skin reaction or pain on the palms of the hands or soles of the feet (including 
tingling, numbness, pain, swelling or reddening)

loss of skin pigment

chest pain

problems with taste

mouth sores

cough, shortness of breath

dizziness

skin rash

muscle pain

pain in the bones, muscles, ligaments, joints and tendons

swelling caused by fluid in the hands, ankles, or feet

slow heart rate
Very common side effects that may show up in your blood tests:

increase in some substances (enzymes) produced by the liver. Patients over 60 years 
of age may be at greater risk of an increase of one of the enzymes, called ALT.
Common side effects occurring in 1 - 10% of patients include: 

hoarse voice

blurry vision

indigestion  
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
nosebleeds

blood in the urine

low white blood cell counts neutropenia

a decrease in the number of cells involved in blood clotting (thrombocytopenia)

protein in the urine (a sign that kidneys are not working normally)

under-active thyroid gland 

abnormal liver function

increase in lipase (an enzyme from the pancreas) 

changes in heart’s electrical conduction (QT-prolongation)

temporary reduction in blood supply to the brain (mini-stroke)

reduction of blood supply to the heart (angina)

sudden collapse of the lung 

heart becomes less effective at pumping blood (cardiac dysfunction)

chest pain, shortness of breath, leg pain, and swelling of the legs/feet. These could be 
signs of a blood clot in your body (thromboembolism). If the clot breaks off, it may 
travel to your lungs and this may be life threatening or even fatal

severe bleeding in the lung

heart attack

chills

rash, dry skin, nail disorder

flatulence

Inflammation of lining of the mouth

Muscle spams
Common side effects that may show up in your blood or urine tests:

Increase in bilirubin (a substance produced by the liver)

Increase in gamma-glutamyl transpeptidase (a liver enzyme)

Decrease in albumin (a protein found in the blood)
Uncommon side effects occurring in less than 1% of patients include:

severe bleeding in digestive tract (stomach and intestine) and brain

a dangerous rapid fluttering of the heart (Torsade de Points)

hole in digestive tract which is called “perforation”, which may require surgery to 
repair

abnormal connection hole (perforation) in digestive tract

stroke 

liver failure*

a sudden and severe rise in blood pressure  (hypertensive crisis)

inflammation of the pancreas

Swelling of the brain that may be associated with high blood pressure, headache, loss 
of speech or vision, and/or seizure, which may be life threatening 


infections, with or without changes in white blood cells (cells that fight infection)
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
separation or tear of the lining of the back part of the eye (retinal detachment or tear). 
This can result in blurry or impaired vision.
*Two of the patients that received pazopanib died as a result of liver failure.
Rare side effects (these may affect up to 1 in 1000 people):

Blood clots accompanied by a decrease in red blood cells and cells involved in 
clotting. These clots may harm organs such as the brain and kidneys
Other Risks of pazopanib
Neutropenia, thrombocytopenia, and palmar-plantar erythrodysaethesia syndrome were observed 
more frequently in patients of East Asian descent.
Studies in animals indicate that pazopanib may slow or stop bone growth.  There is a possibility 
that pazopanib may affect bone growth in children, adolescents and young adults who are still 
growing.
During this study, blood tests will be checked to look for liver injury.  People with liver injury may 
feel very tired or sick and not want to eat, have yellow skin or eyes, and they may also develop 
rash or fever.  Let your doctor know if you have any of these symptoms, especially if your doctor 
says you have abnormal liver blood tests.  If your doctor finds that your blood tests suggest liver 
injury that is not severe, your doctor may recommend you continue your study drug and may ask 
you to stop taking other drugs which may cause liver injury.  Blood tests (about 1 teaspoon of 
blood per test) for possible liver injury will be repeated every week until you get better.  If your 
blood tests get worse, your doctor may tell you to stop taking the study drug altogether.  If you 
have a liver injury from the study drug, it will usually heal when the drug is stopped.  It is possible 
that a small number of people may continue to have liver injury after they stop taking the study 
drug.  There is a risk of liver failure, which could result in death.
If you are to have surgery, please speak with your doctor because pazopanib may affect wound 
healing.
Risks and side effects related to study procedures:

Safe Handling of Study Drug:  Handling pazopanib and having contact with any urine, feces 
or vomit from patients receiving pazopanib may pose some risk to you and your caregivers.  
To avoid exposure to pazopanib and any associated risks, you and your family 
members/caregivers will be educated by a member of the study team on how to safely handle, 
properly dispose of, and clean products that may be contaminated with pazopanib.

Blood drawing (venipuncture) risks:  Drawing blood may cause temporary discomfort from 
the needle stick, bruising, and infection.

ECG risks:  The adhesive on the leads may cause skin irritation including redness, itching, 
swelling or rash.  These symptoms are generally mild and clear up on their own.
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
Radiation (x-ray) risks:  The amount of radiation you will be exposed to is relatively small.  
Such doses of radiation may be potentially harmful, but the risks are so small that they are 
difficult to measure.  If you have already had many x-rays, you should discuss this with the 
researchers before agreeing to be in the study.

CT scan risks:  CT scans involve the risks of radiation (see above).  In addition, if contrast 
material (iodine dye) is used, there is a slight risk of developing an allergic reaction, from mild 
(itching, rash) to severe (difficulty breathing, shock, or rarely, death).  The contrast material 
may also cause kidney problems, especially if you are dehydrated or have poor kidney 
function.  The study doctors will ask you about any allergies or related conditions before the 
procedure.  If you have any of these problems, you may not be allowed to have a CT scan. 
Having a CT scan may mean some added discomfort for you.  In particular, you may be 
bothered by feelings of claustrophobia when placed inside the CT scanner, or by lying in one 
position for a long time.  If contrast material is used, you may feel discomfort when it is injected 
into your vein.  You may feel warm and flushed and get a metallic taste in your mouth. Rarely, 
the contrast material may cause nausea, vomiting or a headache

MRI risks:  Because the MRI machine acts like a large magnet, it could move iron-containing 
objects in the MRI room during your examination, which in the process could possibly harm 
you.  Precautions have been taken to prevent such an event from happening; loose metal 
objects, like pocket knives or key chains, are not allowed in the MRI room.  If you have a piece 
of metal in your body, such as a fragment in your eye, aneurysm clips, ear implants, spinal 
nerve stimulators, or a pacemaker, you will not be allowed into the MRI room and cannot have 
an MRI.
Having an MRI may mean some added discomfort for you.  In particular, you may be bothered 
by feelings of claustrophobia and by the loud banging noise during the study.  Temporary 
hearing loss has been reported from this loud noise.  This is why you will be asked to wear ear 
plugs.  At times during the test, you may be asked to not swallow for a while, which can be 
uncomfortable.
Because the risks to a fetus from MRI are unknown, pregnant women must not participate in 
this study. 
Contrast agent (gadolinium) risks: A few side effects of gadolinium injection such as mild 
headache, nausea, and local pain may occur. Rarely (less than 1% of the time) low blood 
pressure and lightheadedness occurs. This can be treated immediately with intravenous fluids. 
Very rarely (less than one in one thousand), patients are allergic to gadolinium. These effects 
are most commonly hives and itchy eyes, but more severe reactions have been seen which 
result in shortness of breath.
Patients with severe kidney disease sometimes have a bad reaction to gadolinium contrast. The 
condition is called nephrogenic systemic fibrosis (NSF). It can cause skin to tighten or scar 
and can damage internal organs. Sometimes it can be life-threatening. There are no reports of 
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IRB APPROVAL DATE: 09/20/2017
IRB EXPIRATION DATE: 08/16/2018


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NSF in patients with normal kidney function. Before you have a MRI scan requiring an 
injection of gadolinium contrast, you will have a blood test in order to check the function of 
your kidneys. Based on your medical history and the results of the test, a doctor will decide 
whether it is safe for you to undergo the MRI scans. 

PET/CT scan risks: The PET scan exposes your body to radiation, see radiation risk above.  
The radiation levels come from a tracer which is a radioactive chemical injected into a vein in 
your arm. The tracer lets the doctor see how your cells are functioning and the radiation levels 
are very low. You may have an allergic reaction to the chemical used in the scan. For some 
patients, having to lie still on the scanning table for the length of the procedure may cause 
some discomfort or pain. After the scan your arm may be a little bit sore or have some redness 
where the IV was placed in your arm.  The radioactive solution does not remain in your system 
for a long period of time.  However, you should wait 2 hours before holding an infant or getting 
close to a pregnant woman to avoid exposing them to radiation.  You should drink fluids after 
the scan to help remove the solution from your system.

Bone scan risks:  A bone scan is a diagnostic imaging test used to determine if your bone is 
damaged, either from cancer or from some other cause.  The bone scan involves an injection, 
in the vein of your arm, of a radiotracer (radioactive compound that localizes in the bone).  
Most people do not experience any side effects from the radiotracer.  The injection of the 
radiotracer may feel like a small sting, but there is no burning or other sensation as the 
radiotracer moves through your body.  You will be exposed to a limited and medically 
acceptable dose of radiation during the procedure.  There is always a slight risk of damage 
from being exposed to any radiation.  If you are especially concerned with radiation exposure, 
please discuss this with your doctor.
Bone scan side effects are not common, and when encountered are usually mild, such as nausea 
and vomiting, or you may become uncomfortable lying still for the duration of the examination.

Tumor biopsy risks:  The general risks associated with this procedure are pain, discomfort, 
infection, bleeding and injury to organs nearby.

Study drug combination risks:  The side effects of the combination of pazopanib and 
anastrozole or letrozole are not yet known.  It is possible that this combination of drugs will 
cause new or more serious side effects than taking these drugs separately. You will be 
monitored closely for side effects and your doctor may change your medications if it appears 
that this combination is causing serious side effects. You should tell your doctor about any side 
effects you experience while on this study.  When additional information about side effects is 
known, you will be notified of any further study drug related effects.  

Study design risks:  Since patients will be enrolled in a 2-step design, patients enrolled during 
the first step may receive a study drug that is not effective.  Your study doctor will let you 
know which step you will be enrolled in. 

Reproductive risks:  You should not become pregnant while on this study because the drugs 
in this study can affect an unborn baby.  Women should not breastfeed a baby while on this 
IRB NUMBER: 11-07246
IRB APPROVAL DATE: 09/20/2017
IRB EXPIRATION DATE: 08/16/2018


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HOPE RUGO, MD
study.  You will not be allowed to continue study treatment if you are or become pregnant.  It 
is important to understand that you need to use birth control while on this study.  Check with 
your study doctor about what kind of birth control methods to use and how long to use them.  
Some methods might not be approved for use in this study.  

Unknown Risks: The experimental treatments may have side effects that no one knows about 
yet.  The researchers will let you know if they learn anything that might make you change your 
mind about participating in the study.

For more information about risks and side effects, ask your study doctor.
Are there benefits to taking part in the study?
Taking part in this study may or may not make your health better.  While doctors hope the addition 
of pazopanib will be more useful against cancer compared to hormonal therapy alone, there is no 
proof of this.  We do know that the information from this study will help doctors learn more about 
pazopanib as a treatment for breast cancer, and the benefit of combined pazopanib with hormonal 
treatment for breast cancer.  This information could help future cancer patients.  However, there is 
no guarantee that this will happen.
What other choices do I have if I do not take part in this study?
Your other choices may include:

Changing to a different hormonal therapy or starting chemotherapy.

Getting treatment or care for your cancer without being in a study. 

Taking part in another study.

Getting no treatment

Getting comfort care, also called palliative care.  This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer.  It does not treat 
the cancer directly, but instead tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible.
If you decide not to participate in this study, your decision will not affect your medical care in 
any way.
Please talk to your doctor about your choices before deciding if you will take part in this study.
Will my medical information be kept private?
We will do our best to make sure that the personal information in your medical record is kept 
private.  However, we cannot guarantee total privacy.  Your personal information may be given 
IRB NUMBER: 11-07246
IRB APPROVAL DATE: 09/20/2017
IRB EXPIRATION DATE: 08/16/2018


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HOPE RUGO, MD
out if required by law.  If information from this study is published or presented at scientific 
meetings, your name and other personal information will not be used.
Organizations that may look at and/or copy your medical records for research, quality assurance, 
and data analysis include:

UCSF’s Committee on Human Research

Novartis Pharmaceuticals (the funder of the study) and their authorized agents   

UCSF Helen Diller Family Comprehensive Cancer Center (HDFCCC)

The National Cancer Institute (NCI) and other government agencies, e.g., the Food and 
Drug Administration (FDA), involved in keeping research safe for people. 

The University of California

Governmental agencies in other countries where the study drug may be considered for 
approval
Participation in research may involve a loss of privacy, but information about you will be handled 
as confidentially as possible.  A medical record will be created because of your participation in 
this study.  Your consent form and some of your research test results will be included in this record.  
Therefore, your other doctors may become aware of your participation.  Hospital regulations 
require that all health care providers treat information in medical records confidentially.
What are the costs of taking part in this study?
You and/or your health plan/insurance company will need to pay all of the costs of treating your 
cancer in this study, with the exception of tests done specifically for the study and not for treating 
your cancer.  You and/or your insurance company will be responsible for paying for the costs of 
any procedures that are part of your standard medical care, such as your hormonal treatment, blood 
laboratory analyses, CT scans, MRI scans, PET scans, etc.  Some health plans will not pay these 
costs for taking part in studies.  Your study doctors or their clinical staff will obtain authorization 
from your insurance company prior to beginning your treatment.   Taking part in this study may 
or may not cost you or your insurance company more than the cost of getting regular cancer 
treatment.
The study medication, pazopanib, will be provided to you at no charge. You will not be billed for 
any clinic visits or any of the tests required specifically by the study.  These are procedures noted 
above as “study test” (such as blood draw for circulating tumor cells and to monitor your immune 
system, and collection of leftover tumor tissue) in this consent form.  
For more information on clinical trials and insurance coverage, you can visit the National Cancer 
Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can 
print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site.
Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them 
to send you a free copy.
IRB NUMBER: 11-07246
IRB APPROVAL DATE: 09/20/2017
IRB EXPIRATION DATE: 08/16/2018


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HOPE RUGO, MD
Will I be paid for taking part in this study?
You will not be paid for taking part in this study.
What happens if I am injured because I took part in this study?
It is important that you tell your study doctor, Hope Rugo, MD or her associates if you feel that 
you have been injured because of taking part in this study.  You can tell the doctor in person or 
call him/her 
.
Treatment and Compensation for Injury:  If you are injured as a result of being in this study, 
the University of California will provide necessary medical treatment. The costs of the treatment 
may be billed to you or your insurer just like any other medical costs, or covered by the University 
of California depending on a number of factors. The University does not normally provide any 
other form of compensation for injury. For further information about this, you may call the office 
of the Committee on Human Research at 415- 476-1814.  
What are my rights if I take part in this study?
Taking part in this study is your choice. You may choose either to take part or not to take part in 
the study. If you decide to take part in this study, you may leave the study at any time. No matter 
what decision you make, there will be no penalty to you and you will not lose any of your regular 
benefits. Leaving the study will not affect your medical care. You can still get your medical care 
from our institution. 
We will tell you about new information or changes in the study that may affect your health or your 
willingness to continue in the study.
In the case of injury resulting from this study, you do not lose any of your legal rights to seek 
payment by signing this form.
Who can answer my questions about the study?
You can talk to your study doctor about any questions, concerns, or complaints you have about 
this study.  Contact your study doctor(s) (Hope Rugo, MD or her associates 
.
If you wish to ask questions about the study or your rights as a research participant to someone 
other than the researchers or if you wish to voice any problems or concerns you may have about 
the study, please call the Office of the Committee on Human Research at 415-476-1814.
IRB NUMBER: 11-07246
IRB APPROVAL DATE: 09/20/2017
IRB EXPIRATION DATE: 08/16/2018


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A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time.
************************************************************
Please note: This section of the informed consent form is about an additional research 
study that is being done with people who are taking part in the main study. Participation in 
this extra research is voluntary, and if you choose not to donate your tissue for other 
analyses, it will in no way affect your care or participation in the main study. 
You can say "yes" or "no" to the following study. Please mark and initial your choice.
About Using Tissue for Research
We would like to ask that you have a tumor biopsy so we can use some of the tissue for additional 
research. If you agree, this tissue will be kept and may be used in research to learn more about 
cancer and other diseases. Please read the information sheet called "How Is Tissue Used for 
Research" to learn more about tissue research.
The research that may be done with your tissue is not designed specifically to help you. It might 
help people who have cancer and other diseases in the future.
Reports about research done with your tissue will not be given to you or your doctor. These reports 
will not be put in your health record. The research will not have an effect on your care.
Things to Think About
The choice to let us keep your biopsy tissue for additional research is up to you. No matter what 
you decide to do, it will not affect your care.
If you decide now that your tissue can be kept for research, you can change your mind at any time. 
Just contact us and let us know that you do not want us to use your tissue. Then any tissue that 
remains will no longer be used for research.
In the future, people who do research may need to know more about your health. While UCSF 
may give them reports about your health, it will not give them your name, address, phone number, 
or any other information that will let the researchers know who you are.
Sometimes tissue is used for genetic research (about diseases that are passed on in families). Even 
if your tissue is used for this kind of research, the results will not be put in your health records. If 
any commercial products are developed from the samples, you will not receive any reimbursement 
from any profits derived.
Your tissue will be used only for research and will not be sold. The research done with your tissue 
may help to develop new products in the future.
IRB NUMBER: 11-07246
IRB APPROVAL DATE: 09/20/2017
IRB EXPIRATION DATE: 08/16/2018


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Benefits
The benefits of research using tissue include learning more about what causes cancer and other 
diseases, how to prevent them, and how to treat them. There may or may not be any direct benefit 
to you if you choose to participate in this optional research.
Risks
Tumor biopsy risks: The general risks associated with this procedure are pain, discomfort, 
infection, bleeding and injury to organs nearby.
The greatest risk to you is the release of information from your health records. We will do our best 
to make sure that your personal information will be kept private. The chance that this information 
will be given to someone else is very small.
Making Your Choice
Please read each sentence below and think about your choice. After reading each sentence, put 
your initials in the "Yes" or "No" box.  If you have any questions, please talk to your doctor or 
nurse, or call our research review board at IRB's phone number.
No matter what you decide to do, it will not affect your care.
1. My tissue may be kept for use in research to learn about, prevent, or treat cancer.
YES 
NO
CONSENT
You have been given copies of this consent form and the Experimental Subject's Bill of Rights to 
keep.
You will be asked to sign a separate form authorizing access, use, creation, or disclosure of health 
information about you.
PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to participate 
or to withdraw at any point in this study without penalty or loss of benefits to which you are 
otherwise entitled.
IRB NUMBER: 11-07246
IRB APPROVAL DATE: 09/20/2017
IRB EXPIRATION DATE: 08/16/2018


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HOPE RUGO, MD
If you wish to participate in this study, you should sign below.
Date
Participant's Signature for Consent
Participant's Printed name
Date
Person Obtaining Consent
Date
Witness (only required if participant is a non-English speaker)
IRB NUMBER: 11-07246
IRB APPROVAL DATE: 09/20/2017
IRB EXPIRATION DATE: 08/16/2018


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Medications and Foods to Avoid
CC# 117513:  Reversing Hormone Resistance in Advanced Breast Cancer with Pazopanib
The following is a list of medications to avoid while you are participating in this study. If you go 
to any medical visit, please take this list with you for the doctor’s reference.
Before you begin treatment, Dr. Rugo or one of her associates will review all medications you 
are taking. Make sure you talk with Dr. Rugo before you start or stop taking any medications. 
This list contains only the most common drugs and food that are known to interact with the drugs 
used in this study. It is very important to discuss all medications that you are taking with your 
study doctor. This information will be reviewed at each study visit. 
In addition to the listed medications, you should also avoid eating Seville (sour) oranges, 
grapefruit, starfruit and their juices.  
Permitted Medications – Use with Caution
Generic Name
Brand Names ®
Generic Name
Brand Names ®
Amiodarone
Cordarone, Pacerone
Nevirapine
Viramune
Atomoxetine
Strattera
Oxcarbazepine
Trileptal
Bepridil
Vascor
Phenobarbital
Luminal
Carbamazepine
Carbatrol, Tegretol
Phenytoin
Dilantin
Clozapine
Clozaril, Fazaclo
Pimozide
Orap
Cortisone (>50mg)
Pioglitazone
Actos
Cyclosporine
Sandimmune, Neoral, 
Restatis, Gengraf
Prednisone (>10 mg)
Deltasone
Dexamethasone 
(>1.5 mg)
Decadron, Dexamethasone
Propafenone
Rythmol
Dihydroergotamine
DHE 45
Quetiapine
Seroquel
Efavirenz
Sustiva
Quinidine
Cardioquin, Quinaglute
Ergonovine
Rifabutin
Mycobutin
Ergotamine
Ergomar, Cafergot, Wigraine
Rifampin
Rifadin
Flecainide
Tambocor
Rifapentine
Priftin
Hydrocortisone 
(>40 mg) 
Analpram HC, Carmol HC, 
Cortef, Cortenema
Risperidone
Risperdal 
Lidocaine
Xylocaine
Sirolimus
Rapamune
Methylergonovine
Methergine
St John’s Wort
Methylprednisolone 
(>8 mg)
Medrol
Tacrolimus
Protopic, Prograf
Mexiletine
Mexitil
Warfarin
Coumadin, Jantoven
Modafinil
Provigil
IRB NUMBER: 11-07246
IRB APPROVAL DATE: 09/20/2017
IRB EXPIRATION DATE: 08/16/2018


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Prohibited Medications
Generic Name
Brand Names ®
Generic Name
Brand Names ®
Amprenavir
Agenerase
Nefazodone
Serzone
Clarithromycin
Biaxin
Nelfinavir
Viracept
Fluconazole
Diflucan
Ritonavir
Norvir
Indinavir
Crixivan
Saquinavir
Invirase
Itraconazole
Sporanox
Telithromycin
Ketek
Ketoconazole
(oral forms only)
Troleandomycin
Tao
Lopinavir
(+ritonavir) Kaletra
Voriconazole
VFend
Subjects should not receive other anti-cancer therapy [cytotoxic, biologic, radiation (other 
than leuprolide or other GnRH agonists)] while on treatment in this study.  
IRB NUMBER: 11-07246
IRB APPROVAL DATE: 09/20/2017
IRB EXPIRATION DATE: 08/16/2018

Prot_SAP_002.pdf: 
Protocol Version #:  12.0 
Page 1 of 59 
July 7, 2017 
Protocol #:  117513 
Reversing Hormone Resistance in Advanced Breast Cancer with Pazopanib 
Protocol Number:  117513 
IND Number:  113,357 
Version Number:  12.0 
Version Date:  July 7, 2017 
Study Drug:  Pazopanib 
Coordinating Center 
University of California San Francisco (UCSF) 
Study Chair 
Hope Rugo, MD 
UCSF Helen Diller Family Comprehensive Cancer Center 
Statistician 
Dan Moore Ph.D. 
Participating Center 
Yale University School of Medicine/Yale Cancer Center 
Yale Cancer Center Principle Investigator 
Gina G. Chung, M.D. 
Yale University School of Medicine/Yale Cancer Center 
Revision History 
Version 12.0 July 7, 2017 
Version 6.0 
June 18, 2012 
Version 11.0 February 21, 2017 
Version 5.0 
October 28, 2011 
Version 10.0 March 16, 2016 
Version 4.0 
October 13, 2011 
Version 9.0 
August 6, 2013 
Version 3.0 
July 19, 2011 
Version 8.0 
April 07, 2013 
Version 2.0 
June 29, 2011 
Version 7.0 
August 20, 2012 
Version 1.0 
May 19, 2011 
NCT# 01466972


Protocol Version #:  12.0 
Page 2 of 59 
July 7, 2017 
Protocol #:  117513 
SCHEMA 
 
 
 
 
 
     
 
Registration 
 
Pazopanib 800mg a day by mouth 
AND 
Letrozole, 2.5 mg a day by mouth OR Anastrozole, 1 mg a day by mouth 
 
Scans at 12 weeks and every 16 weeks thereafter (or sooner if clinically indicated) 
 
Continue until progression, withdrawal of consent or unresolved toxicity  


Protocol Version #:  12.0 
Page 3 of 59 
July 7, 2017 
Protocol #:  117513 
TABLE OF CONTENTS 
 
Section No. 
 
 
 
 
 
 
 
 
Page No. 
 
1.0 
Background and Rationale 
 
 
 
 
 
 
 7 
1.1 
Background/Standard Therapies 
 
 
 
 
 7 
1.2 
Investigational Therapy 
 
 
 
 
 
 8 
1.3 
Rationale 
 
 
 
 
 
 
 
10 
 
2.0 
Objectives 
 
 
 
 
 
 
 
 
13 
 
2.1 
Primary Objective 
 
 
 
 
 
 
13 
 
2.2 
Secondary Objectives  
 
 
 
 
 
13 
2.3 
Exploratory Objectives 
 
 
 
 
 
13 
 
3.0 
Study Design and Eligibility Criteria  
 
 
 
 
13 
3.1 
Study Design  
 
 
 
 
 
 
13 
3.2 
Inclusion Criteria 
 
 
 
 
 
 
14 
3.3 
Exclusion Criteria 
 
 
 
 
 
 
16 
 
4.0 
Patient Registration 
 
 
 
 
 
 
 
18 
 
4.1 
Stratification  
 
 
 
 
 
 
18 
 
4.2 
Randomization and Blinding  
 
 
 
 
18 
 
4.3 
Registration  
 
 
 
 
 
 
18 
 
5.0 
Investigational Treatment Plan 
 
 
 
 
 
19 
 
5.1 
Dose and Schedule 
 
 
 
 
 
 
19 
 
5.2 
Duration of Therapy  
 
 
 
 
 
19 
 
6.0  
General Concomitant Medication and Supportive Care Guidelines  
19 
 
7.0 
Toxicity Management & Dose Modifications  
 
 
 
19 
 
 
8.0 
Schedule of Assessments 
 
 
 
 
 
 
24 
 
8.1 
Screening Assessments 
 
 
 
 
 
27 
 
8.2 
Pre-dose Assessments on Day 1 
 
 
 
 
27 
 
8.3 
Assessments During Treatment Period 
 
 
 
28 
 
8.4 
Follow-Up Assessments 
 
 
 
 
 
29 
 
8.5 
Correlative studies 
 
 
 
 
 
 
29 
 
9.0 
Criteria for Evaluation  
 
 
 
 
 
 
30 
 
9.1 
Response Definitions  
 
 
 
 
 
30 
 
9.2 
Toxicity Definitions  
 
 
 
 
 
31 
 
10.0 Criteria for Termination 
 
 
 
 
 
 
31 
 
10.1 
Conditions for Terminating the Study 
 
 
 
31 
 
10.2 
Conditions for Individual Patient Termination 
 
 
31 


Protocol Version #:  12.0 
Page 4 of 59 
July 7, 2017 
Protocol #:  117513 
11.0 Drug Information 
 
 
 
 
 
 
 
32 
 
11.1 
Drug Name 
 
 
 
 
 
 
 
32 
 
 
11.1.1  
Mode of Action 
 
 
 
 
32 
 
 
11.1.2  
Storage and Stability  
 
 
 
32 
 
 
11.1.3  
Dosage and Administration  
 
 
32 
 
 
11.1.4  
Incompatibilities 
 
 
 
 
33 
 
 
11.1.5  
Side Effects 
 
 
 
 
 
35 
 
 
 
12.0 Statistical Considerations 
 
 
 
 
 
 
36 
 
12.1 
Endpoint Definitions  
 
 
 
 
 
36 
 
12.2 
Accrual Objectives 
 
 
 
 
 
 
37 
 
12.3 
Estimated Duration of Study  
 
 
 
 
37 
 
12.4 
Data Safety Monitoring 
 
 
 
 
 
37 
 
12.5 
Analyses Time points 
 
 
 
 
 
37 
 
12.6 
Sample Size  
 
 
 
 
 
 
37 
 
12.7 
Replacement Policy  
 
 
 
 
 
38 
 
13.0 Data Forms & Submission Schedule  
 
 
 
 
38 
 
14.0 Special Instructions 
 
 
 
 
 
 
 
38 
 
15.0 Ethical Aspects  
 
 
 
 
 
 
 
38 
 
15.1 
Regulatory Considerations 
 
 
 
 
 
38 
 
16.0 Reporting Adverse Drug Reactions 
 
 
 
 
 
40 
 
16.1 
Adverse Event Definitions 
 
 
 
 
 
40 
 
 
16.1.1 Clinical Adverse Events 
 
 
 
 
40 
 
 
16.1.2 Laboratory Adverse Events  
 
 
 
40 
 
 
16.1.3 Serious Adverse Events 
 
 
 
 
40 
16.1.4 Treatment of Investigational Product Overdose 
 
41 
 
16.2 
Adverse Event Reporting Procedures 
 
 
 
41 
 
 
16.2.1 Data Safety Monitoring Plan  
 
 
 
41 
 
 
16.2.2 Serious Adverse Event Reporting 
 
 
 
42 
 
17.0 References 
 
 
 
 
 
 
 
 
45 
 
18.0 Appendices 
 
 
 
 
 
 
 
 
48 
 
Appendix I 
Performance Status Scale  
 
 
 
 
48 
 
Appendix II 
NCI CTCAE Version 4.0 
 
 
 
 
49 
Appendix III 
Management of GI toxicity 
 
 
 
 
50 
 
Appendix IV 
Blood Serum Preparation 
 
 
 
 
54 
 
Appendix V  
SAE Fax Cover Sheet – Suspected 
 
 
 
59 
 
Appendix VI  SAE Fax Cover Sheet – Not Suspected 
 
 
60 
 


Protocol Version #:  12.0 
Page 5 of 59 
July 7, 2017 
Protocol #:  117513 
LIST OF ABBREVIATIONS 
 
 
AE 
 
adverse event 
ALT 
 
alanine transaminase 
ANC  
absolute neutrophil count 
ASCO  
American Society for Clinical Oncology 
AST 
 
aspartate transaminase 
AUC  
area under the curve 
BSA  
body surface area 
CHR  
Committee on Human Research (UCSF IRB) 
CR 
 
complete response 
CRA  
Clinical Research Associate 
CRC  
Clinical Research Coordinator 
CRF 
 
case report form 
CT 
 
computerized tomography 
CTC 
 
Common Terminology Criteria 
CXR  
chest x-ray 
DFS 
 
disease-free survival 
DLT 
 
dose limiting toxicity 
FDA  
Food and Drug Administration 
GCP  
Good Clinical Practice 
HGB  
hemoglobin 
IC/FC  
immunomagnetic capture+flow cytometry 
ICH 
 
International Conference on Harmonization 
IND 
 
investigational new drug application 
IEC 
 
Independent Ethics Committee 
IRB 
 
Institutional Review Board 
KPS 
 
Karnofsky Performance Status 
LDH  
lactate dehydrogenase 
MDR  
multi-drug resistance 
MRI 
 
Magnetic Resonance Imaging 
MTD  
maximum tolerated dose 
NCI 
 
National Cancer Institute 
NYHA  
New York Heart Association 
PA 
 
posterior-anterior (chest x-ray) 
PI 
 
Principal Investigator 
PR 
 
partial response 
PRC 
 
UCSF Protocol Review Committee 
QOL  
Quality of Life 
RBC  
red blood cell 
SAE 
 
serious adverse event 
ULN  
upper limit of normal 
WBC  
white blood cell 
 
 


Protocol Version #:  12.0 
Page 6 of 59 
July 7, 2017 
Protocol #:  117513 
1.0 Background and Rationale 
 
1.1 Background/Standard Therapies 
 
Breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer 
death in women in the United States. Despite a decrease in the overall incidence of breast 
cancer, more than 40,000 women are expected to die of this disease each year[1].  Despite 
improvements in therapy, patients with locally advanced or metastatic disease eventually 
relapse and die from their disease.  Investigating treatments aimed at improving outcome is 
critical, and finding new targeted treatment that could delay disease progression would 
significantly advance the care of women with this common malignancy.   
 
The majority of breast cancers express receptors for either or both estrogen and progesterone; 
this finding indicates responsiveness to hormone therapy [2]. For postmenopausal women 
with hormone-receptor positive advanced stage disease, suppression of estrogen with third 
generation aromatase inhibitors (AI) is more effective than tamoxifen for first-line endocrine 
treatment, and AIs  have been demonstrated to improve disease free survival compared to 
tamoxifen in women with early stage, hormone receptor positive disease[3].  However, the 
major limitation of endocrine therapy remains the near universal development of resistance in 
the advanced setting, and recurrence despite hormone therapy due to resistance in the early 
stage setting.  Although there are no proven clinical strategies to reverse or prevent endocrine 
therapy resistance, several pre-clinical investigations suggest opportunities for therapeutic 
intervention[4]. This trial is designed to evaluate whether anti-VEGF therapy with pazopanib 
can reverse resistance and prolong progression-free survival when added at the time of 
progression to endocrine therapy with AIs for hormone-receptor positive metastatic breast 
cancer. 
 
Angiogenesis and estrogen 
Angiogenesis, the formation of new blood vessels, is essential for the development, 
progression, and metastasis of malignant tumors[5-7]. Vascular endothelial growth factor 
(VEGF) is a primary stimulus of angiogenesis in tumors and functions through binding 
VEGF receptor-2 (VEGFR2; also known as flk/kdr) and VEGF receptor-1 (VEGFR1; also 
known as flt) expressed on endothelial cells[7]. 
 
Endothelial cells exposed to the supernatants of estradiol treated breast cancer cells develop 
increased levels of VEGFR2 compared to controls. This increase in VEGFR2 supports 
previous findings that endothelial cells containing estrogen receptors exhibit a proliferative 
response to estradiol[8-10].  In addition, estrogen has been associated with the inhibition of 
apoptosis of cultured human endothelial cells, and therefore indicates the creation of a pro-
angiogenic environment[10].   
 
Estradiol increases intracellular levels of VEGF mRNA and protein in breast cancer cell lines 
as well as extracellular levels of VEGF protein [11].  Additionally, estradiol treatment of 
breast cancer cell lines decreased extracellular sVEGFR1, a soluble form of VEGFR1 that is 
believed to sequester extracellular VEGF and act as an antiangiogenic factor[11, 12].  This 
decrease was also observed in an in vivo xenograft models of breast cancer in nude mice[12].  


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These data indicate that estrogen acts directly on breast cancer cells to induce angiogenesis 
by creating a proangiogenic environment.  Furthermore, subjects whose tumors have lower 
sVEGFR1/VEGF ratios tend to have a poorer prognosis compared to those with higher 
ratios[13, 14]. VEGF may be an important target for hormone receptor-positive breast 
cancer[15]. In patients with operable breast cancer, neoadjuvant antiestrogen therapy with 
tamoxifen reduced breast cancer angiogenesis in responding tumors as measured by 
microvessel count (MVC)[16].  
 
These data support the hypothesis that estradiol can modulate angiogenesis in breast cancer, 
and that angiogenesis is one mechanism of resistance to hormone directed therapy.  Both 
estrogen and angiogenesis are essential for the development and progression of breast cancer, 
making the targeting both pathways in combination appealing.   
 
1.2 Investigational Therapy 
 
Pazopanib 
Pazopanib is a potent, multi-targeted TKI of VEGFR-1, -2, -3, PDGFR- and - and c-kit, 
with IC50 values of 10, 30, 47, 71, 84 and 74 nM, respectively[17]. It inhibits VEGF-induced 
VEGFR-2 phosphorylation in human umbilical vein endothelial cells (HUVEC) as well as in 
mouse lungs in a dose-dependent manner.  Pazopanib shows significant growth inhibition of 
a variety of human tumor xenografts in mice, and also inhibits bFGF- and VEGF-induced 
angiogenesis in two mouse models of angiogenesis, the Matrigel™ plug assay and the cornea 
micropocket model.  
 
To date, the safety experience includes over 1200 cancer subjects who have been treated in 
pazopanib studies. Over 850 subjects have received pazopanib monotherapy; the 
monotherapy safety profile described is based on 225 subjects with renal cell cancer treated 
with pazopanib.  The most common AEs occurring in ≥ 10% of subjects in decreasing order 
of frequency were diarrhea, fatigue, hair depigmentation, nausea, hypertension, dysgeusia, 
headache, anorexia, rash, vomiting, abdominal pain, cough, arthralgia, and constipation.  
Elevations in ALT of any Grade were reported in 50% of subjects with Grade 3 elevations in 
6% and Grade 4 in < 1%.  AST and ALT elevations occurred in parallel.  Hyperbilirubinemia 
of any Grade occurred in 29% of subjects with Grade 3 elevations in 2%.  No Grade 4 
elevations have been reported.  Concomitant elevations in transaminases and bilirubin have 
been observed in less than 1% subjects. Uncommon (≤ 1%) but significant adverse events 
have been reported including: pulmonary embolism, venous thrombosis, hemorrhage, bowel 
perforation, myocardial infarction/angina, cerebrovascular accidents/TIA, atrial fibrillation, 
renal failure, and seizures. 
 
Anemia, leukopenia, and thrombocytopenia were reported in 14 – 20% of subjects with 
Grade 3/4 abnormalities being uncommon (≤ 2%).   Hyponatremia of any grade was 
observed in 32% of subjects; with Grade 3 or 4 hyponatremia in 7% of subjects.  
Hyperkalemia of any grade was reported in 21% of subjects with Grade 3 or 4 hyperkalemia 
in 3% of subjects.  Hyponatremia and hyperkalemia have not occurred concurrently in the 
same subject to suggest adrenal insufficiency.  Increase in creatinine of any grade was 
reported in 25% with Grade 3 or 4 events in 1%.  Elevations in amylase and lipase of any 


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grade were reported in 16% and 17% respectively, with Grade 3 events in 1% and 5% 
respectively.  Pancreatitis was reported in one subject.  Increase in TSH was reported in 24% 
and a decrease in T4 in 18% of subjects. 
 
Serial ACTH stimulation tests were conducted in two Phase I and two Phase II trials in 
cancer subjects.  Adrenal insufficiency was not observed in 47 subjects for whom data was 
available.  Twenty one of the 47 subjects had data beyond 24 weeks and 5 had data beyond 
52 weeks. Additional pazopanib information is included in the pazopanib investigator 
brochure (IB). 
 
In October, 2009, the U. S. Food and Drug Administration granted approval to pazopanib 
tablets (VOTRIENTTM, Novartis Pharmaceuticals) for the treatment of patients with 
advanced renal cell carcinoma. 
 
The efficacy and safety of pazopanib were evaluated in an international, multicenter, 
randomized, double-blind trial comparing pazopanib to placebo in renal cell carcinoma who 
were treatment naïve or who had received prior cytokine therapy. All patients received best 
supportive care.  The trial was conducted in patients with metastatic renal cell carcinoma 
stratified according to performance status, prior nephrectomy, and prior cytokine therapy. 
 
A total of 435 patients were randomized (2:1) to receive pazopanib (n=290) or placebo 
(n=145).  Demographics were balanced between the two arms.  Progression-free survival 
(PFS) was the trial's primary endpoint.  The median PFS was 9.2 and 4.2 months in the 
pazopanib and placebo arms, respectively (HR = 0.46, p value < 0.001).  The effect was 
observed in both subgroups: treatment naïve (HR = 0.40) and cytokine pre-treated (HR = 
0.54).  After documented radiological progression, patients receiving placebo could receive 
pazopanib. 
 
The overall survival results are not mature; 40% of patients had died by the time of data cut-
off.  The objective response rates were 30% and 3% for pazopanib and placebo, respectively. 
The median duration of responses was 13.5 months.   
 
The most common adverse reactions (greater than or equal to 20%) were diarrhea, 
hypertension, hair color changes, nausea, anorexia, and vomiting. Grade 3/4 adverse 
reactions that differed by greater than or equal to 2% between arms were abnormal hepatic 
function, diarrhea, hypertension, and proteinuria.  QT prolongation has been seen with 
pazopanib.  Laboratory abnormalities occurring in >10% of patients and more commonly 
(>5%) in the pazopanib arm included increased transaminases, hyperglycemia, leukopenia, 
hyperbilirubinemia, neutropenia, hypophosphatemia, thrombocytopenia, lymphocytopenia, 
hyponatremia, hypomagnesemia, and hypoglycemia.  Deaths due to serious adverse events 
include cerebrovascular accident, gastric cancer, gastrointestinal hemorrhage, hemoptysis, 
bowel perforation, cardiac failure, myocardial infarction, hepatic failure and pneumonia 
occurred more commonly in the pazopanib arm.  Hepatic dysfunction is included as a boxed 
warning in the product label and two deaths were associated with hepatic failure. 
 


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Recently, a phase II trial was designed for patients with metastatic breast cancer, who failed 
2-3 prior chemotherapy. Total 20 patients were recruited in this study, 70% were ER+, and 
all were Her-2/neu negative. Pazopanib monotherapy was given at 800 mg daily. One patient 
(5%) had a partial response, 11 (55%) had stable disease (SD) [four (20%) with SD > or = 6 
months], and seven (35%) had progressive disease as their best response. One (5%) was not 
evaluable. The median time to progression was 5.3 months. Pazopanib did not cause 
significant severe toxicity aside from grade 3-4 transaminitis, hypertension, and neutropenia 
in three patients each (14% each) and grade 3 gastrointestinal hemorrhage in one patient 
(5%)[18]. 
 
Standard therapy for hormone receptor positive metastatic disease. 
Randomized phase III trials have demonstrated superiority in terms of response and in some 
settings TTP, for  anastrozole, letrozole and exemestane compared totamoxifen in the first-
line metastatic setting[19].  The Tamoxifen or Arimidex Randomized Group Efficacy and 
Tolerability (TARGET) trial, 668 post-menopausal women (approximately 45% of whom 
were either ER or PgR positive while 55% had a tumor with unknown ER/PR status) were 
randomized (1:1) to receive either anastrozole or tamoxifen for the treatment of MBC.  Time 
to progression (TTP) of the subgroup of subjects with hormone receptor positive tumors was 
8.9 months for subjects administered anastrozole compared to 7.8 months for subjects treated 
with tamoxifen (statistical analyses for the sub-populations were not performed).  Treatment 
was well-tolerated in both arms, although the notable adverse events for tamoxifen 
(thromboembolic events and vaginal bleeding) were significantly lower for subjects in the 
anastrozole arm[20].   
 
A second Phase III trial randomized 916 patients with treatment naïve metastatic breast 
cancer (hormone receptor–positive or unknown tumors) to receive letrozole 2.5 mg or 
tamoxifen 20 mg daily.  Treatment with letrozole resulted in a significantly longer median 
TTP than treatment with tamoxifen (9.4 months vs. 6.0 months,  P < .0001)[21].  The 
incidence and severity of AEs were similar for letrozole and tamoxifen arms.  Adverse events 
considered to be related to the study drug were also similar frequency (38% for letrozole and 
37% for tamoxifen) and were similar in nature for both arms. 
 
Lastly exemestane was compared to tamoxifen in 371 patients with MBC (182 exemestane, 189 
tamoxifen). Overall response rate was greater for exemestane than for tamoxifen treatment (46% v 
31%; odds ratio = 1.85; 95% CI, 1.21 to 2.82; P = .005) as was median progression-free survival 
(PFS) (9.9 months; 95% CI, 8.7 to 11.8 monthsvs. 5.8 months; 95% CI, 5.3 to 8.1 months) [22].  
Subsequent trials have demonstrated that hormone therapy is effective in sequence, that the 
order of therapy is not clearly important, and that the nonsteroidal (letrozole and anastrozole) 
and steroidal AIs (exemestane) are non-cross resistant.  Given the above data, AIs have 
become a standard hormone therapy for the treatment of post-menopausal women with 
hormone receptor positive MBC.   
 
1.3   Rationale for the Combination of Aromatase Inhibitor and an Angiogenesis  
        Inhibitor 
 
Angiogenesis, the formation of new blood vessels, is essential for the development, 
progression, and metastatic growth of malignant tumors [23, 24]. Vascular endothelial 


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growth factor (VEGF) is a primary stimulus of angiogenesis in tumors and functions through 
binding VEGF receptor-2 (VEGFR2; also known as flk/kdr) and VEGF receptor-1 
(VEGFR1; also known as flt) expressed on endothelial cells [25]. 
 
Preclinical research has demonstrated that endothelial cells exposed to the supernatants of 
estradiol treated breast cancer cells develop increased levels of VEGFR2 compared to 
controls [26]. This increase in VEGFR2 supports previous findings that endothelial cells 
containing estrogen receptors exhibit a proliferative response to estradiol [27, 28]. In 
addition, estrogen has been associated with the inhibition of apoptosis of cultured human 
endothelial cells, and therefore indicates creation of a proangiogenic environment [28]. In 
vitro studies have revealed that estradiol increases intracellular levels of VEGF mRNA and 
protein in breast cancer cell lines as well as extracellular levels of VEGF protein [11]. 
Additionally, estradiol treatment of breast cancer cell lines decreased extracellular 
sVEGFR1, a soluble form of VEGFR1 that is believed to sequester extracellular VEGF and 
act as an antiangiogenic factor [11, 12]. 
 
The effect of estrogen on angiogenesis was further demonstrated using in vivo xenograft 
breast cancer models [12, 29]. In one study, ovariectomized nude mice bearing slow-release 
estrogen or placebo pellets were injected subcutaneously with a mixture of MCF-7 cells and 
Matrigel. The Matrigel–MCF-7 cell plugs were excised after 6 days and VEGFR was 
analyzed. Levels of VEGFR-1 protein were lower in Matrigel-embedded MCF-7 cells from 
mice implanted with estrogen pellets than in Matrigel-embedded MCF-7 cells from mice 
with placebo pellets. This decrease in VEGFR-1 expression was associated with a 
pronounced increase in the angiogenic response, reﬂected by a statistically signiﬁcant 
increase in vascular density measured in the Matrigel plugs from estrogen-treated mice 
compared with vascular density measured in the Matrigel plugs from placebo-treated mice 
[12] . In another xenograft breast cancer model, castration in a male mouse model bearing 
androgen-dependent breast cancer led to tumor shrinkage and vascular regression. However, 
endocrine resistance emerged in this tumor model and was heralded by a wave of 
neovascularization and tumor regrowth. On a molecular level, castration initially causes a 
reduction in VEGF mRNA levels that parallels tumor and vascular regression. At the time of 
tumor regrowth, VEGF mRNA levels simultaneously rebound. Interestingly, castration in 
this model led to endothelial cell apoptosis before tumor cell apoptosis, supporting a direct 
effect of endocrine therapy on tumor vasculature. These data indicate that estrogen acts 
directly on breast cancer cells to induce angiogenesis by creating a proangiogenic 
environment [29].  
 
In the clinical setting, patients with metastatic breast cancer, who had high VEGF levels in 
tumor tissue by ELISA , had lower response to first-line endocrine therapy compared with 
patients who had low VEGF levels in a multivariate analysis (p=0.025). In addition, a trend 
towards shorter PFS (p=0.075) was also seen [30]. In a randomized trial of tamoxifen in 
premenopausal women in the adjuvant setting, the benefits of tamoxifen for 2 years were 
significantly decreased in patients with high tumor-specific VEGFR2 expression by 
immunohistochemistry[31].  
 


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The addition of antiangiogenic therapy to hormonal therapy has been investigated in several 
clinical trials. In a phase II single arm study, 27 patients with metastatic breast cancer who 
progressed on endocrine therapy alone were recruited. Patients were continued on the same 
hormone therapy to which they had become refractory with the addition of bevacizumab. 
Stable disease was seen in 18 patients (66%) [32]. In a multi-center feasibility trial 
performed at MSKCC and UCSF, 43 patients with treatment naïve metastatic ER positive 
breast cancer, stable or responding to NSAI treatment were treated with the combination of 
letrozole and bevacizumab. 74% of the patients had clinical benefit  with a favorable PFS of 
17.1 months compared with a  9- month historical PFS in postmenopausal women with MBC 
treated with letrozole alone in the first-line setting [33].  This study led to an ongoing Phase 
III trial with the U.S. cooperative group CALGB testing this combined therapy. 
 
These data suggest that co-targeting the tumor with endocrine therapy as well as its 
associated vasculature using anti-angiogenic agents could lead to additive effects, resulting in 
more effective anticancer therapy, and potentially reversing acquired resistance to hormone 
therapy [34]. 
 
In this trial, we propose to evaluate the role of VEGFR blockade with the tyrosine kinase 
inhibitor pazopanib in combination with nonsteroidal aromatase inhibitors (NSAI) in patients 
who are progressing or have relapsed on the same NSAI hormone therapy given for advanced 
or early stage breast cancer.  If this trial demonstrates clinical benefit, this all oral 
combination could be tested in both the neoadjuvant and metastatic settings in a randomized 
phase II design.  
 
In order to investigate potential factors predicting response or resistance to pazopanib and 
NSAIs, several translational studies have been incorporated into this trial. 
 
The prognostic value of circulating tumor cells (CTC) has been demonstrated in several 
studies in breast cancer, especially in advanced stage [35-38]. At UCSF in the laboratory of 
Dr. John Park, we have demonstrated expertise in the measurement of CTC in patients with 
advanced stage breast cancer by IC/FC assay. CTC are first enriched with immunomagnetic 
beads coated with EpCAM, then EpCAM+, CD45-, nucleic acid+ cells are detected by flow 
cytometry. This technique is highly sensitive and reproducable, and allows sorting of cells 
for molecular analysis as well as analysis of cell surface markers[39]. In this trial, we will 
collect patient’s peripheral blood samples every 4 weeks while on treatment and follow any 
reduction of CTC.   
 
The mechanisms of hormonal resistance includes intrinsic and acquired pathways: decreased 
ER expression accounts for intrinsic resistance and the increased receptor tyrosine kinase 
pathway relates to acquired resistance [40-42]. We plan to analyze the mutation of  PI3K/Akt 
and deletion of PTEN by sequencing in CTC  (depending on numbers of cells, which in turn 
determines feasibility), in order to make a preliminary assessment of potential markers of 
response to pazopanib.  
 
 
The tumor microenvionment plays an important role in cancer development and progression. 
Clinical studies have revealed that the increased T regulatory cells (Treg), high ratios of 


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CD4/CD8 T lymphocytes, and extrafollicular B cells in primary tumors correlated with 
worse overall survival [43-45]. Recently, studies from preclinical models have shown that 
tumor associated macrophages (TAM) can promote pulmonary metastases in breast cancer 
animal models, and in both the preclinial and clinical settings are associated with worse 
clinical outcome [46-48]. TGFβ  has been linked to hormonal resistance in breast cancer. The 
activation of TGFβ leads to increased regulatory CD4+  T cells and decreased cytotoxic CD8+ 
T cells in the tumor microenvironment [49].  A recent study in non-small cell lung cancer 
suggestes that baseline and postreatment levels of cytokines, particularly IL-4 and IL-12 
correlated with response to pazopanib[50]. In this study, we will collect patients’s serum to 
monitor the level of cytokines at baseline and during treatment,  we will compare the change 
of cytokine level with panzopanib in each patient, and also compare between responders and 
non-responders. This information may help us to identify biomarkers that would predict 
response to antiangiogenic therapy and to identify possible mechanisms of resistance.  
 
2.0 
Objectives 
 
2.1 Primary Objectives:  
 
To evaluate the clinical benefit rate (including complete response, partial response, and 
stable disease)  at 12 weeks from the addition of pazopanib to a non-steroidal aromatase 
inhibitor (NSAI) (letrozole or anastrozole) in patients with hormone receptor positive 
advanced breast cancer progressing on the same NSAI hormone therapy.   
 
2.2 Secondary Objectives: 
 
To evaluate progression free survival in patients treated with the combination of 
pazopanib and a NSAI. 
 To evaluate safety of the combination of pazopanib and a NSAI. 
 
2.3 Exploratory objectives:  
 To quantify CTC as a surrogate marker of response. 
 
To evaluate specific markers including estrogen receptor, PI3K/AKT and PTEN on CTC 
at the time of study entry 
 
To evaluate the immune signature in serum samples from patients enrolled in this trial, 
including: IL-6, IL-8, VEGF, sVEGFR2, E-selectin, GRO-1,IL-4, IL-16, IP-10, IL-12, 
CSF-1, TIMP-1, OPN. HGF, SDF-1a and TRAIL.  
 
3.0  Study Design and Eligibility Criteria 
 
3.1 Study Design 
 
This is a nonrandomized, open label, multicenter phase II trial to evaluate the efficacy of 
pazopanib in combination with a NSAI in patients with advanced breast cancer. 
 
Patients with metastatic breast cancer progressing or relapsing on a NSAI will be eligible for 
enrollment in this study.  Progression must be documented by radiographic studies.  This will 
be a two-step protocol; 14 patients will be enrolled initially.  If at least 1 response (response 
defined as clinical benefit) is observed in the first 14 patients at 12 weeks, we will proceed to 


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the second stage, where an additional 13 patients will be enrolled.  We plan to enroll a total 
of 30 patients at 2 sites:  UCSF and Yale Cancer Center (Yale), expecting that up to 3 
patients will be un-evaluable due to unexpected events.   
 
Treatment will consist of pazopanib, 800 mg a day by mouth and continuation of the NSAI 
(letrozole, 2.5 mg a day, or anastrozole, 1 mg a day) the patient was taking at the time of 
progression.  This treatment will be continued until progression or toxicity.  Dose reduction 
of pazopanib for toxicity will be allowed.  Patients will be evaluated by serial radiographic 
studies as well as circulating tumor cells. The primary endpoint is clinical benefit rate at 12 
weeks. 
 
3.2 Inclusion Criteria 
 
A subject will be considered eligible for inclusion in this study only if all of the following 
criteria are met: 
1. Subjects must provide written informed consent prior to performance of study specific 
procedures or assessments, and must be willing to comply with treatment and follow up. 
a. Procedures conducted as a part of routine clinical management of the subject (e.g., 
blood count, imaging study) and obtained prior to signed informed consent may be 
utilized for Screening or Baseline purposes provided these tests are obtained as 
specified in the protocol). 
2. Subjects must have measurable or evaluable disease. Disease sites that are evaluable for 
progression but not measurable per RECIST guidelines version 1.1  include: 
a. Bone lesions 
b. Previously irradiated lesions 
c. Cutaneous manifestations (non-discrete lesions only)  
3. Age  18 years. 
4. Postmenopausal women defined by one of the criteria:  
a. No spontaneous menses for at least 12 months if the subject is ≥ 50 years old; 
b. Amenorrheic for at least 12 months if the subject is < 50 years old, with serum 
estradiol within the institutional postmenopausal range;  
c. Bilateral oophorectomy;  
d. If prior hysterectomy but intact ovaries, must be ≥ 55 years old, or have serum 
estradiol within the postmenopausal range;  
e. If premenopausal, must be on a GnRH agonist (leuprolide or goserelin) with serum 
estradiol levels within the institutional postmenopausal range. 
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS)  2. 
6. Histologically or cytologically confirmed estrogen receptor (ER) and/or progesterone 
receptor (PgR) positive carcinoma of the breast with unresectable, locally advanced 
and/or metastatic (AJCC Stage IV) disease.  


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7. Subjects must have received prior hormonal therapy for the treatment of breast cancer as 
follows:  
a. Progression must be documented while taking a nonsteroidal aromatase inhibitor 
including anastrozole or letrozole. 
b. If hormonal therapy was administered in the adjuvant setting, subjects must have 
received therapy for at least 6 months prior to developing metastatic disease. 
 
 
c. If hormonal therapy was administered in the metastatic setting, subjects must have 
received therapy for at least 3 months prior to progression 
8. Subjects whose tumors overexpress ErbB2 are eligible provided that they have 
progressed following therapy which included trastuzumab and/or lapatinib. 
Note for prior lapatinib: Subjects must have completed therapy with lapatinib at least 7 
days prior to the first dose of study drug.   
Note for prior trastuzumab: Subjects who received Q3 weekly, Q2 weekly or Q1 weekly 
must have completed therapy with trastuzumab at least 3 weeks, 2 weeks or 1 week, 
respectively, prior to the first dose of study drug. 
9. Adequate hematologic and hepatic function as defined in Table 1. 
 
Table 1  Definitions for Adequate Hematologic and Hepatic Function 
System 
Laboratory Values 
Hematologic 
 
Absolute neutrophil count (ANC) 
1.0 X 109/L 
Hemoglobina  
9 g/dL (5.6 mmol/L)  
Platelets 
100 X 109/L 
Prothrombin time (PT) or international normalized ratio (INR)b  
1.2 X ULN 
Activated partial thromboplastin time (aPTT) 
1.2 X ULN 
Hepatic 
 
Total bilirubin 
1.5 X ULN (except in 
patients with Gilbert’s)   
Alanine amino transferase (ALT) and Aspartate aminotransferase 
(AST)  c  
2.5 X ULN 
Renal 
 
Serum creatinine 
1.5 mg/dL (133 µmol/L) 
Or, if >1.5 mg/dL: Calculated creatinine clearance 
30 mL/min   
Quantitative urine protein by dipstick 
Urine Protein to Creatinine Ratio (UPC)d  
<100 
<1 
a. 
Subjects may not have had a transfusion within 7 days of screening assessment. 
b. Subjects receiving anticoagulant therapy are eligible if their INR is stable and within the recommended range 
for the desired level of anticoagulation.   
c. 
Concomitant elevations in AST/ALT above 1.0 x ULN (upper limit of normal) are not permitted.  Bilirubin  
1.5 except if Gilbert’s (elevation due to direct bilirubin) 
d. A UPC is required only if the urine protein is > 100.  If UPC >1, then a 24-hour urine protein must be 
assessed.  Subjects must have a 24-hour urine protein value <1 g to be eligible. 


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10. Subjects must have discontinued hormone replacement therapy (HRT) (e.g., conjugated 
estrogens tablets, USP or premarin), at least 28 days prior to receiving the first dose of 
randomized therapy. 
11. Radiotherapy prior to initiation of therapy is allowed to a limited area (e.g., palliative 
treatment for painful bone metastases), if it is not the sole site of disease. Subjects must 
have completed treatment at least one week prior to starting study drugs, and must have 
recovered from all treatment-related toxicities. 
12. Bisphosphonate or RANK ligand inhibitor therapy for bone metastases is allowed.  
Prophylactic use of bisphosphonates in subjects without bone disease, except for the 
treatment of osteoporosis, is not permitted; 
13. Ability to swallow and retain oral medication. 
 
3.3 Exclusion Criteria 
 
Subjects meeting any of the following criteria must not be enrolled in the study: 
1. Prior use of pazopanib or other agents targeting angiogenesis pathway (such as 
bevacizumab, sunitinib, or sorafenib) in the metastatic setting  
2. Premenopausal levels of estradiol, or ongoing menses (see definitions of menopause 
above). 
3. Known central nervous system (CNS) metastases or leptomeningeal carcinomatosis.  
Screening with CNS imaging studies (computed tomography [CT] or magnetic resonance 
imaging [MRI]) is required only if the subject has clinical findings suggestive of CNS 
metastasis. 
4. History of another active malignancy.  
Note: Subjects who have had another malignancy and have been disease-free for 5 years, 
or subjects with a history of completely resected non-melanomatous skin carcinoma or 
successfully treated in situ carcinoma are eligible. 
5. Clinically significant gastrointestinal abnormalities which might interfere with oral 
dosing, including, but not limited to: 
a. Malabsorption syndrome 
b. Major resection of the stomach or small bowel that could affect the absorption of 
study drug 
c. Inflammatory bowel disease 
d. Ulcerative colitis, or other gastrointestinal conditions with increased risk of 
perforation 
e. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess 
within 28 days prior to beginning study treatment  
6. Presence of uncontrolled infection. 


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7. Prolongation of corrected QT interval (QTc) >480msecs. 
8. History of any one or more of the following cardiovascular conditions within the past 6 
months: 
a. Angioplasty or stenting 
b. Myocardial infarction 
c. Unstable angina 
d. Coronary artery by-pass graft surgery 
e. Symptomatic peripheral vascular disease 
9. Class II, III or IV congestive heart failure, as defined by the New York Heart Association 
(NYHA). 
10. Use of an investigational agent, including an investigational anti-cancer agent, within 14 
days prior to the first dose of study drug. 
11. Prior use of an investigational drug that targets VEGF or VEGF receptors.  
12. Any ongoing toxicity from prior anti-cancer therapy that is > Grade 1 and/or that is 
progressing in severity. 
13. Poorly controlled hypertension (defined as systolic blood pressure (SBP) of ≥140mmHg 
or diastolic blood pressure (DBP) of ≥ 90mmHg). 
Note: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study 
entry.  Blood pressure must be re-assessed prior to start of study therapy.  The mean 
SBP/DBP values must be <140/90mmHg (OR 150/90mmHg, if this criterion is approved 
by Safety Review Team) in order for a subject to be eligible for the study.   
14. History of cerebrovascular accident (CVA), pulmonary embolism or untreated deep 
venous thrombosis (DVT) within the past 6 months.   
 Note: Subjects with recent DVT who have been treated with therapeutic anti-coagulant 
agents for at least 6 weeks are eligible.   
15. Major surgery or trauma within 28 days prior to first dose of study drug and/or presence 
of any non-healing wound, fracture, or ulcer not related to cancer (procedures such as 
catheter placement not considered to be major). 
16. Evidence of active bleeding or bleeding diathesis. 
17. Any serious and/or unstable pre-existing medical, psychiatric, or other condition that 
could interfere with subject’s safety, provision of informed consent, or compliance to 
study procedures 
 
4.0 
Patient Registration 
 
4.1 Stratification 
 
No stratification will be performed in this study  
 


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4.2 Randomization and Blinding 
 
No randomization or blinding will be performed in this study. 
 
4.3 Registration and Enrollment 
 
The Coordinating Center for this study will be UCSF.  All patients who are consented will be 
entered into the UCSF Cancer Center OnCore database, which is password protected and 
meets HIPAA guidelines.  All data will be collected and entered into OnCore® by Clinical 
Research Coordinators (CRCs) from UCSF and Yale.    
 
Patients can be registered only after the pretreatment evaluation is complete and all eligibility 
criteria have been met. The patient must have signed and dated the currently approved 
consent form prior to any study-related screening procedures are performed. 
 
The registration procedure at Yale will be as follows:  when the Principal Investigator 
determines that a patient meets eligibility criteria; the study site will fax or e-mail a 
completed eligibility checklist and supporting source documentation to UCSF CRC.  The 
CRC will check the forms for completeness and contact Yale regarding any discrepancies.   
The Study Chair will approve each patient registration by signing the eligibility checklist and 
will assign a patient number.  Upon obtaining signed informed consent, the patient 
information will be entered into OnCore.  UCSF will provide a study-specific patient ID 
number to Yale.  All future study documentation related to that patient should include the 
assigned patient ID number. 
 
5.0 
Investigational Treatment Plan 
 
5.1 Dose and Schedule 
   
Pazopanib, 800 mg a day by mouth 
  
Letrozole 2.5 mg, OR anastrozole 1 mg a day by mouth;  
 
5.2 Duration of Therapy 
 
Treatment is continued until progression, withdrawal of consent, or unresolved toxicity. 
 
6.0  
General Concomitant Medication and Supportive Care Guidelines 
 
Subjects will be asked to provide a complete list of prescription and over-the-counter 
medications that have been taken within the previous 4 weeks prior to their screening visit. The 
investigator must be informed as soon as possible about any new medication taken from the time 
of screening until the end of the clinical phase of the study (final laboratory sample). 
 


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Subjects should receive full supportive care during the trial, including transfusion of blood and 
blood products, treatment with antibiotics, analgesics, erythropoietin, or bisphosphonates, when 
appropriate. 
 
Anti-emetics (such as prochlorperazine, lorazepam, ondansetron or other 5-HT antagonists) may 
be administered prophylactically in the event of nausea.  Anti-diarrheals, such as loperamide, 
may be administered as needed in the event of diarrhea (please refer Appendix III for detail 
management).  Although acetaminophen at doses of 2 g/day is permitted, it should be used with 
caution in subjects with impaired liver function. 
 
7.0 
Toxicity Management & Dose Modifications 
 
At each visit during the Treatment Period, subjects should first be evaluated for the occurrence of 
AEs and laboratory abnormalities. The potential causes of the adverse events should be 
thoroughly investigated and confounding factors should be identified and eliminated whenever 
possible. 
 
Treatment emergent hypertension or proteinuria is relatively common in subjects receiving 
pazopanib and is handled by dose modification of pazopanib. Some adverse events, although 
rare, can result in significant clinical consequence such as arterial/venial thrombosis, severe 
hemorrhage, bowel perforation and severe fatigue/asthenia, therefore should be promptly 
identified and managed. Some clinical signs and symptoms may be early indicators for severe 
toxicity that should be thoroughly investigated (e.g., abdominal pain may be an early sign for 
bowel perforation). 
 
Specific recommendations for management of these possible AEs along with guidelines for dose 
delay/modification or discontinuation of study treatment are provided in Tables 2 and 3. 
 
If dose reduction of pazopanib is necessary, the dose should be reduced stepwise by 200 mg at 
each step, and the subject should be monitored for 10 to 14 days at each dose level.  If toxicity 
does not abate during this monitoring time, pazopanib may need to be interrupted and/or the dose 
further decreased with continued monitoring for an additional 10-14 days at each dose level, and 
so on.  
 
If the toxicity has abated with reduction of the dose and dose re-escalation is considered safe by 
the investigator, the dose can then be increased step-wise back to the pre-event dose (in 200 mg 
increments, after monitoring for 10-14 days at each dose level to ensure that toxicity did not 
recur or worsen).  
 
If a subject’s treatment has been interrupted for more than 21 days, the Investigator must contact 
the PI to review the subject’s condition in order to resume the treatment. 
 
Dose Interruptions/Modifications for Specific, Non-liver Related, Toxicities 
Recommendations for investigational product dose interruptions/modifications in case of specific 
treatment-emergent AEs are provided in Table 2. 
 


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Table 2 Dose Modification Algorithms for Potential Treatment-Related Adverse Events 
AE Terms & Descriptions 
Dose Modification Algorithms 
Hypertensiona 
(A). Asymptomatic and 
persistent SBP of 150 and 
<170 mmHg, or DBP 90 
and <110 mmHg. 
Step 1. Continue investigational product pazopanib at the 
current dose.  
Step 2. Adjust current or initiate new antihypertensive 
medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2 
weeks as indicated to achieve well-controlledb blood pressure 
(BP). If BP is not well-controlled within 2 weeks, consider 
referral to a specialist and go to scenario (B). 
 
(B). Asymptomatic SBP 
170 mmHg, or DBP 
110 mmHg, or failure to 
achieve well-controlled BP 
within 2 weeks in scenario 
(A).  
 
Step 1.Interrupt  pazopanib.. 
Step 2. Adjust current or initiate new antihypertensive 
medication(s).  
Step 3. Titrate antihypertensive medication(s) during next 2 
weeks as indicated to achieve well-controlled BP.  
Step 4. Once BP is well-controlled, restart pazopanib dose-
reduced by 200 mg.  
(C). Symptomatic 
hypertension or recurring 
SBP 170 mmHg, or DBP 
110 mmHg, despite 
modification of 
antihypertensive 
medication(s) 
Step 1. Interrupt pazopanib  
Step 2. Adjust current or initiate new antihypertensive 
medication(s).  
Step 3. Titrate antihypertensive medication(s) during next 2 
weeks as indicated to achieve well-controlled BP.  Referral to a 
specialist for further evaluation and follow-up is also 
recommended. 
Step 4. Once BP is well-controlled, restart pazopanib dose-
reduced by 200 mg. 
(D). Refractory hypertension 
unresponsive to above 
interventions. 
Discontinue pazopanib and continue follow-up per protocol. 
Proteinuria 
UPC > 3 grams or 24-hr 
urine protein > 3 grams 
Step 1. Interrupt pazopanib. 
Step 2. Test weekly the 24-hour urine protein until the level is 
<3 grams.  Then, restart pazopanib, dose reduced by 200 mg. 
Step 3. If 24-hour urine protein ≥ 3 grams recurs, repeat Steps 
1 and 2. 
Step 4.  If 24-hour urine protein ≥ 3 grams recurs and the 
pazopanib dose can no longer be reduced, discontinue 
pazopanib and continue follow up per protocol. 


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Hemorrhage /Bleeding 
Grade 1 
For hemoptysis, interrupt pazopanib and contact the study PI to 
discuss whether further treatment with pazopanib is 
appropriate. 
Continue pazopanib with current dose; monitor as clinically 
indicated. 
Grade 2 
Step 1. If pulmonary or GI bleed (other than hemorrhoidal 
bleeding), discontinue pazopanib and continue follow-up per 
protocol. Otherwise, interrupt pazopanib until the AE resolved 
to  Grade 1.  
Step 2. Restart pazopanib; consider reducing dose and monitor 
as clinically indicated.  
Grade 3 or 4, or  
Recurrent  Grade 2 event 
after dose 
interruption/reduction. 
Discontinue pazopanib and continue with follow-up per 
protocol.  
 
Venous Thrombosis (DVT, PE) 
Grade 1 and 2 
Continue pazopanib with same dose; initiate and monitor 
anticoagulation as clinically indicated. 
Grade 3 or > 
 
Discontinue pazopanib and continue follow-up per protocol. 
Grade 4 and/or PE 
Discontinue pazopanib and continue follow-up per protocol.  
Arterial Thrombosis/Ischemia 
Any Grade 
Discontinue pazopanib and continue follow-up per protocol.  
Thrombocytopenia: Investigate and document underlying cause 
Grade 1 or 2 
Continue pazopanib with current dose; monitor as clinically 
indicated.  
Grade 3 or 4 
Step 1. Interrupt pazopanib until toxicity resolves to ≤ Grade 2. 
Step 2. Restart pazopanib dose-reduced by 200 mg and monitor 
as clinically indicated.  
If no recovery to ≤ Grade 2 or recurrent Grade 3 or 4 
thrombocytopenia, discontinue pazopanib and follow-up per 
protocol 
Anemia:  No specific dose reduction rules are indicated for anemia unless due to hemorrhage 
or bleeding as noted above. 
 


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Palmar-plantar Erythrodysesthesia Syndrome 
Grade 1 
Minimal skin changes or 
dermatitis without pain 
(erythema, oedema, 
hyperkeratosis) 
1. Continue IP at present dose 
 Grade 2 
Skin changes with pain; 
limiting instrumental 
activities of daily living 
(ADLs) (peeling, blisters, 
oedema, bleed, 
hyperkeratosis) 
1. Hold IP  
2. Treat as clinically appropriate 
3. Upon resolution to Level 1 or better restart  IP with a 
dose reduction to 400 mg 
4. If recurrent consider a further dose reduction to 200mg 
or discontinuation 
Grade 3 
Severe skin changes with 
pain and limiting self care  
1. Discontinue IP 
 
Other Clinically Significant Adverse Events c  
Grade 1 
Continue pazopanib; monitor as clinically indicated. 
Grade 2 or 3, if clinically 
significant  
Step 1. Interrupt pazopanib until toxicity resolves to  Grade 1. 
Step 2. Restart pazopanib dose-reduced by 200 mg and monitor 
as clinically indicated.  
Grade 4 
Discontinue pazopanib and continue follow-up per protocol.    
 
Prolongation of QTc Interval: If the QTc is prolonged, the ECG should be manually read to 
ensure accuracy of the reading.  The values below refer to manually-read ECGs. 
QTc   480 < 500 msec 
Continue pazopanib; monitor as clinically indicated. 
QTc 500 msec 
Discontinue pazopanib and continue follow-up per protocol. 
a. 
Patients are encouraged to self-monitor BP twice a week  
b. Well-controlled BP defined as mean SBP <150 mmHg and mean DBP <90 mmHg. 
c. AEs are graded according to NCI Common Terminology Criteria for Adverse Events v4.0 (NCI CTCAE v4) 
 for the management of treatment related diarrhea, please refer to Appendix III.  Abbreviations: BP, blood 
pressure; PAZOPANIB, investigational product. 
 
Dose Interruptions/Modifications for Hepatotoxicity 
Recommendations for investigational product dose interruptions/modifications in case of liver-
related treatment-emergent AEs are provided in Table 3.  As a general rule, since many subjects 
are taking multiple concurrent medications, it is critical to (a) do a thorough evaluation of the 
subject’s concurrent medications, and (b) identify and discontinue those with known 
hepatotoxicity and replace with a non-hepatotoxic equivalent for the same indication if 
necessary. 
 


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Table 3  Guidelines for Management of Treatment Emergent Hepatotoxicity  
Event 
Dose Modification Algorithms 
(A). ALT of ≤ 3.0 x 
upper limit of normal 
(ULN)  
Continue IP at current dose with full panel liver function tests 
(LFTs)a monitored as per protocol. 
(B). ALT >3.0 x ULN to  
≤8.0 x ULN without 
bilirubin elevation 
(defined as total bilirubin 
<2.0 x ULN or direct 
bilirubin ≤35%) and 
without hypersensitivity 
symptoms (e.g., fever, 
rash)  
1. Continue pazopanib at current dose.  
2. Work up for other etiologies as clinically indicated.  
3. Monitor subject closely for clinical signs and symptoms; 
perform full panel LFTs weekly or more frequently if 
clinically indicated until alanine aminotransferase 
(ALT)/aspartate aminotransferase (AST) reduced to Grade 1.   
(C). ALT >8.0 x ULN 
without bilirubin 
elevation (defined as 
total bilirubin <2.0 x 
ULN or direct bilirubin 
≤35%) and without 
hypersensitivity 
symptoms (e.g., fever, 
rash), not attributed to 
malignancy. 
1st occurrence 
1. Discontinue pazopanib until toxicity resolves to  Grade 1 or 
baseline.  Report the event to Novartis as an SAE within 24 
hours of learning of its occurrence (section 16.2, SAE 
reporting), and complete the eCRF liver event forms.  Make 
every reasonable attempt to have subjects return to the clinic 
within 24 to 72 hours for repeat liver chemistries and liver 
event follow up assessments. 
Pazopanib may only be restarted following recovery is 
toxicity is clearly unrelated to study drug (e.g. alcohol or 
significant acetaminophen ingestion) 
2. Work up for other etiologies as clinically indicated . 
3. Monitor subject closely for clinical signs and symptoms; 
perform full panel LFTs weekly or more frequently if 
clinically indicated until alanine aminotransferase 
(ALT)/aspartate aminotransferase (AST) reduced to Grade 1.  


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Event 
Dose Modification Algorithms 
(D). ALT >3.0 x ULN 
with concomitant 
elevation in bilirubin 
(defined as total bilirubin 
<2.0 x ULN; with direct 
bilirubin >35%) not 
related to disease 
progression, or with 
hypersensitivity 
symptoms (e.g., fever, 
rash).  
1. Discontinue pazopanibpazopanib immediately, report the 
event to Novartis as an SAE within 24 hours of learning of 
its occurrence (section 16.2, SAE reporting), and complete 
the eCRF liver event forms.  Make every reasonable attempt 
to have subjects return to the clinic within 24 hours for 
repeat liver chemistries and liver event follow up 
assessments.  
2. Consult a gastroenterologist / hepatologist and perform the 
following assessments to identify potential co-factors: 
 Eosinophil count 
 Viral serology for hepatitis A, B, C and E, 
cytomegalovirus, Epstein-Barr virus IgM antibody, or 
heterophile antibody, or monospot testing) 
 Anti-nuclear antibody, anti-smooth muscle antibody, 
anti-mitochondrial antibody 
 Serum creatinine phosphokinase for possible muscle 
injury caused LFT elevation  
 Liver imaging (ultrasound or CT scan) 
3. Monitor subject closely for clinical signs and symptoms; 
perform full panel LFTs weekly or more frequently if 
clinically indicated until LFTs reduced to Grade 1.   
For isolated total 
bilirubin elevation 
without concurrent ALT 
increases (defined as 
ALT < 3 X ULN) 
 
1. Isolated hyperbilirubinemia (ie in the absence of elevated 
ALT or other signs/symptoms of liver injury) does not 
require dose modification.  Pazopanib inhibits UGT1A1 and 
OATP1B1, which can cause elevation of indirect 
(unconjugated) bilirubin in the absence of liver injury.   
2. If bilirubin is > 2 x ULN in the absence of ALT elevation, 
fractionation of bilirubin elevation should be performed.  If 
the bilirubin is predominantly indirect (unconjugated), 
continue pazopanib at the same dose.  If bilirubin is >35% 
direct (conjugated), further evaluation for underlying cause 
of cholestasis should be performed. 
 
8.0 
Schedule of Assessments 
 
The study-specific assessments are detailed below and are outlined in the Schedule of 
Assessments Table. Screening assessments must be performed within 21 days prior to the first 
dose of investigational product (unless otherwise specified). Screening assessments performed 
within 7 days of dosing may also be used as Day 1 assessments. Any results falling outside of the 
reference ranges may be repeated at the discretion of the investigator. All on-study visit 
procedures are allowed a window of ± 7 days unless otherwise noted.  Treatment or visit delays 
due to public holidays, weather conditions, or natural disasters, do not constitute protocol 
violations.   
 


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A signed, written, informed consent form must be obtained prior to screening assessments, and 
before any study-specific assessments are initiated. 


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Schedule of Assessments 
 
Period/Procedure 
Screening1 
Treatment 
Follow-Up 
Week or Day  
Study Day 
-21 to -1 
Day 1 
Every 2 weeks 
(until week 4) 
Week 4 
only 
Every 4 
weeks2 
Week 12 
only 
Every 16 
weeks (after 
week 12) 
End of Study 
Follow-up 
Assessments 
Informed Consent  
X 
 
 
 
 
 
 
 
Randomization 
N/A 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
Study drug 
 
Study drug is taken orally once a day 
 
Clinical Procedures 
 
 
 
 
 
 
 
 
Medical History 
X 
 
X 
 
 
 
 
 
Physical Exam with weight 
X 
X 
X 
 
X 
 
 
X 
Vital Signs 
X 
X3 
X 
 
X 
 
 
X 
Disease Assessment4 
X 
 
 
 
 
X5 
X5 
X 
ECOG Performance Status 
X 
X 
X 
 
X 
 
 
X 
EKG with QTc measurement 
X 
 
 
X 
 
X 
X 
X 
Laboratory Assessments6 
X 
 
 
 
X 
 
 
X 
Liver Function Tests (LFT)7  
X 
 
X7 
 
X7 
 
 
 
Urinalysis 
X 
 
 
 
X 
 
 
 
Quantitative dipstick for urine protein8 
X 
 
 
 
X 
 
 
 
Thyroid function (TSH, free T3 and free T4) 
X 
 
 
 
 
 
 
 
Blood for CTC9 
X 
 
 
X 
 
X 
 
X 
Blood for cytokines10 
X 
 
 
X 
 
 
 
 
Archival tumor tissue collection 
X 
 
 
 
 
 
 
 
Tissue biopsy, Optional11 
X 
 
 
 
 
 
 
 
Other 
 
 
 
 
 
 
 
 
Adverse Event Assessment 
 
X 
X 
 
X 
 
 
X 
Con Meds 
X 
X 
X 
 
X 
 
 
X 


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¹ All screening and baseline procedures must be completed within 21 days prior to the first dose of study medication 
² If stable without grade 2 or greater toxicity 
3 Subjects must have a pre-dose BP reading of  150/90mmHg 
4 CT of chest, abdomen and pelvis for subjects with measurable disease; CTMRI or Bone scan for subjects with bone only disease; Bone scan to be performed 
on all patients at screening.  PET/CT can be used in place if CT scan is diagnostic  
5 Unless indicated sooner by clinical findings 
6 Blood urea nitrogen (BUN), Creatinine, Calcium, Potassium, Sodium, Glucose, Hematology: Hematocrit (HCT), Hemoglobin (HGB), Platelet count, White 
blood cell count (WBC), and differential are collected every 2 weeks until week 4, then every 4 weeks  
7Liver Function Tests (LFT) including Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline Phosphatase, Total Bilirubin and Albumin.  
Hematology: Hematocrit (HCT), Hemoglobin (HGB), Platelet count, White blood cell count (WBC), and differential.  LFTs are collected every 2 weeks at 
weeks 3, 5, 7, and 9, then every 4 weeks and as clinically indicated. 
8 UPC is required only if urine protein is > 100. 
9 CTCs will be collected at baseline, and then at 4 weeks, at 12 weeks and at the first visit documenting progression. One CellSave tube (7.5 ml) and one purple 
top tube (10 ml) should be sent at baseline, subsequent collections should include only one CellSave tube.  Quantification of CTC will be conducted at Dr. 
John Park’s laboratory at UCSF 
10 Serum will be collected at baseline and at 4 weeks. The cytokine levels will be measured by ELISA. 
11 Tissue biopsy is optional in this study, the safety of the biopsy will be determined by treating physicians.  
  


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8.1 Screening Assessments 
Eligible patients will have the following procedures performed within 3 weeks prior to study 
entry:  
 
1. Medical history. 
2. Physical examination including height (recorded only at baseline) and body weight. 
3. Vital signs  
4. Disease assessment (CT of chest, abdomen and pelvis for subjects with measurable 
disease; CT/MRI or Bone Scan for subjects with bone only disease, or PET/CT).  
Bone scan to be performed on all patients at screening.  PET/CT can be used in place 
if CT scan is diagnostic. 
5. ECOG Performance Status 
6. EKG with QTc measurement 
7. Laboratory assessments including: 
a. Clinical chemistry laboratory tests: Blood urea nitrogen (BUN), Creatinine, 
Calcium, Potassium, Sodium, Glucose, and  
b. Hematology: Hematocrit (HCT), Hemoglobin (HGB), Platelet count, White blood 
cell count (WBC), and differential. 
8. Liver Function Tests (LFT) including: 
a. Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), Alkaline 
Phosphatase, Total Bilirubin and Albumin. 
9. Urinalysis with quantitative protein by dipstick.  If > 100 by dipstick a UPC must be 
performed. 
10. Thyroid function (TSH, free T3 and free T4). 
11. Blood for circulating tumor cells. 
a. One 7.5 ml CellSave tube, and one 10 ml purple top tube   
12. Blood for cytokines  
13. Archival tumor tissue collection: Paraffin-embedded tissue either at the time of 
diagnosis or disease relapse 
14. Record all medication(s) received within 30 days prior to the first dose of study 
treatment and note if the medication is ongoing. 
 
8.2 Pre-dose Assessments on Day 1 
 
1. Physical examination (including body weight) 
2. Vital signs (Subjects must have a pre-dose BP reading of 150/90mmHg) 
3. ECOG Performance Status 
4. AE/SAE Assessments 
5. Concomitant Medications 
 


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8.3 Assessments During Treatment Period 
 
8.3.1. Every 2 weeks until week 4 
1. Medical History 
2. Physical Exam including weight 
3. Vital Signs  
4. ECOG Performance Status 
5. Adverse Event Assessment 
6. Con Meds 
 
If stable without grade 2 or greater toxicity, visits can be decreased to monthly after the first 4 
weeks of therapy. 
 
8.3.2. Every 2 weeks (weeks 3, 5, 7, and 9) until week 9 
1. Liver Function Tests (LFT) including Alanine aminotransferase (ALT), Aspartate 
aminotransferase (AST), Alkaline Phosphatase, Total Bilirubin and Albumin. 
 
8.3.3. Week 4 only 
1. 12-Lead EKG  
2. Blood for CTC.  One CellSave tube (7.5 ml) will be drawn. 
3. Blood for cytokines  
 
 
8.3.4 Every 4 weeks 
1. Physical Exam including body weight 
2. Vital Signs  
3. ECOG Performance Status 
4. Laboratory assessments including: 
a. Clinical chemistry laboratory tests: Blood urea nitrogen (BUN), Creatinine, 
Calcium, Potassium, Sodium, Glucose, and  
b. Hematology: Hematocrit (HCT), Hemoglobin (HGB), Platelet count, White blood 
cell count (WBC), and differential. 
5. Liver Function Tests (LFT) including Alanine aminotransferase (ALT), Aspartate 
aminotransferase (AST), Alkaline Phosphatase, Total Bilirubin and Albumin. 
6. Urinalysis with quantitative protein by dipstick.  If > 100 by dipstick a UPC must be 
performed. 
7. Adverse Event Assessment 
8. Con Meds 
 
8.3.5 Week 12 only 
1. Blood for CTC.  One CellSave tube (7.5 ml) will be drawn. 
2. Disease assessment (CT of chest, abdomen and pelvis for subjects with measurable 
disease [unless indicated sooner by clinical findings] or Bone Scan for subjects with 
bone only disease, or PET/CT).  PET/CT can be used in place if CT scan is 
diagnostic. 
3. 12-Lead EKG 
 
8.3.6 Every 16 weeks (after week 12) 


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1. Disease assessment (CT of chest, abdomen and pelvis for subjects with measurable 
disease [unless indicated sooner by clinical findings] or Bone Scan for subjects with 
bone only disease, or PET/CT).  PET/CT can be used in place if CT scan is 
diagnostic. 
2. 12-Lead EKG 
 
8.4 Follow-Up Assessments 
The following assessments will be performed following completion of study treatment.  
 
1. Physical examination including body weight. 
2. Vital signs  
3. Disease assessment (CT of chest, abdomen and pelvis for subjects with measurable 
disease; CT/MRI or Bone Scan for subjects with bone only disease, or PET/CT) PET/CT 
can be used in place if CT scan is diagnostic. 
4. ECOG Performance Status. 
5. 12-Lead EKG 
6. Laboratory assessments including: 
a. Clinical chemistry laboratory tests: Blood urea nitrogen (BUN), Creatinine, Calcium, 
Potassium, Sodium, Glucose, and Hematology: Hematocrit (HCT) 
b. Hematology: Hematocrit (HCT), Hemoglobin (HGB), Platelet count, White blood 
cell count (WBC), and differential. 
7. Blood for CTC at the first visit documenting disease progression if measurable ONLY.  
One CellSave tube (7.5 ml) will be drawn. 
8. Record any AE(s) and SAEs and assign appropriate grade (NCI CTCAE v4). 
9. Record all concomitant medications(s) added and/or changed. 
 
Patients will be followed for four weeks after removal from study or until death, whichever 
occurs first.  Patients removed from study for unacceptable adverse events will be followed 
until resolution or stabilization of the adverse event. 
 
8.5 Correlative studies: 
1. CTC quantification:  peripheral blood will be collected for CTC at baseline, at 4 weeks 
and 12 weeks, then at the first visit documenting disease progression. 
2. Evaluate PI3K/AKT and PTEN mutation on archival tissue sample and fresh tissue if 
available: PI3K/AKT and PTEN mutation will be tested on paraffin-embedded tumor 
tissue by DNA sequencing, this data will be compared to the mutation study obtain from 
CTC at the time of study entry and during the treatment.  
3. Exploratory analysis of CTC will be undertaken depending on the number of CTCs for: 
a. Estrogen receptor 
b. PI3K/AKT and PTEN 
c. Other genes based on availability of DNA and RNA and depending on the gene 
panel utilized for this trial 
4. Changes in immune signature: serum will be collected within two weeks of study start 
and at 4 weeks. Immune signature (cytokines and chemokines) including: IL-4, IL-16, IP-
10, IL-12, CSF-1, TIMP-1, OPN. HGF, SDF-1a and TRAIL will be measured by ELISA 
(Appendix IV) 


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9.0 
Criteria for Evaluation 
 
9.1 Response Definitions 
 
Measurable Lesion: Bidimensionally measurable, with clearly defined margins on 
physical exams, x-ray, or scan.  At least one diameter must be greater than 0.5 cm.  Bone 
lesions are not included.  
 
Evaluable Disease: Unidimensionally measurable lesions, masses with margins not 
clearly defined, palpable nodal disease, lesions with both diameters less than .5 cm, bone 
disease.  Markers which have been shown to be highly correlated with extent of disease 
are also considered evaluable.  
 
Non-Evaluable Disease:  Pleural effusions, ascites, disease documented by indirect 
evidence only (e.g., by lab values which don't qualify as evaluable). 
 
Objective Status: To be recorded at each evaluation:  If an organ has too many 
measurable lesions to measure at each evaluation, choose three to be followed before the 
patient is entered on study.  The remaining measurable lesions in that organ will be 
considered evaluable for the purpose of objective status determination.  Unless 
progression is observed, objective status can only be determined when ALL measurable 
and evaluable sites and lesions are assessed. 
 
Complete Response (CR):  Complete disappearance of all measurable and evaluable 
disease.  No new lesions.  If patient has effusions, ascites or disease assessable by 
surgical restaging (e.g., testicular and extragonadal germ cell cancer), disease must be 
cytology negative.  Patients with markers or indirect evidence of involvement must have 
normalization of abnormal values.  All measurable, evaluable and non-evaluable lesions 
and sites must be assessed.  
 
Partial Response (PR):  Applies only to patients with at least one measurable lesion 
greater than or equal to 50% decrease under baseline in the sum of the products of 
perpendicular diameters of all measurable lesions.  No progression of evaluable disease.  
No new lesions.  All measurable and evaluable lesions and sites must be assessed 
 
Stable:  Does not qualify for complete response, partial response or progression.  All 
measurable and evaluable sites and lesions must be assessed.  
 
Progression:  25% increase or an increase of 10 sq. cm (whichever is smaller) in the sum 
of products of measurable lesions over smallest sum observed (over baseline if no 
decrease), OR appearance of any lesion which had disappeared, OR clear worsening of 
any evaluable disease, OR appearance of any new lesion/site, OR failure to return for 
evaluation due to deteriorating condition (unless deterioration is clearly unrelated to this 
cancer).  For scan only bone disease, increased uptake does not constitute clear 
worsening and new lesions are required for progression.  Worsening of existing non-
evaluable disease does not constitute progression.  


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Best Response:  This will be calculated from the serial evaluation of objective status.  
For patients with all disease sites assessed every three to six weeks, two objective 
determinations of CR, will be required for a best response of CR; two of PR or better, but 
not qualifying for CR, will be required for PR; two of stable or better, but not qualifying 
as PR or CR, will be required for stable; and patients with objective status of progression 
on or before the second evaluation (second AFTER the prestudy evaluation) will have a 
best response of increasing disease. 
 
9.2 Toxicity Definitions 
 
All study toxicities will be graded by the NCI Common Terminology Criteria Version 
4.0. 
 
10.0 Criteria for Termination 
 
10.1 
Conditions for Terminating the Study 
 
The Study Chair may terminate the study for any of the following reasons: 
 
 Significant toxicities 
 
 If it becomes clear that the study treatment is less effective than standard 
treatment 
 
 Once all data have been completed. 
 
10.2 
Conditions for Individual Patient Termination 
 
The Principal Investigator at each site may terminate the participation of an individual 
patient for any of the following reasons: 
 
 Disease progression 
 
 Need for exclusionary concurrent treatment 
 
 Withdrawal of informed consent 
 
 Protocol non-compliance 
 
 Lost to follow-up. 
 


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11.0 Drug Information 
 
11.1 
Drug Name 
 
Pazopanib. 
 
 
11.1.1 Mode of Action 
Pazopanib is a novel compound being developed for the treatment of various cancers.  
Pazopanib is a potent, multi-targeted TKI of VEGFR-1, -2, -3, PDGFR-α and -β and c-
kit, with IC50 values of 10, 30, 47, 71, 84 and 74 nM, respectively inhibits VEGF 
induced VEGFR-2 phosphorylation in human umbilical vein endothelial cells (HUVEC) 
as well as in mouse lungs in a dose-dependent manner. Pazopanib shows significant 
growth inhibition of a variety of human tumor xenografts in mice, and also inhibits 
bFGF- and VEGF-induced angiogenesis in two mouse models of angiogenesis, the 
Matrigel plug assay and the cornea micropocket model. 
 
11.1.2 Shipment, Storage and Stability 
Investigational product must be dispensed or administered according to procedures 
described herein, and in accordance with procedures at each participating site.  Study 
drugs will be shipped from the drug manufacturer directly to the participating sites for 
direct distribution of the drugs to the study patients.  The participating site will be 
responsible for drug accountability at their site.  Only subjects enrolled in the study may 
receive investigational product, in accordance with all applicable regulatory 
requirements.  Only the site pharmacist or authorized site personnel may supply or 
administer investigational product. Investigational product will be dispatched to the site 
only after receipt of required documents in accordance with applicable regulatory 
requirements and Novartis Pharmaceuticals procedures. 
 
Investigational product(s) will be dispensed to the subject on Day 1 after it has been 
confirmed that the subject meets all eligibility criteria and all screening assessments have 
been completed and the results reviewed. Subjects are to return to the site approximately 
every 4 weeks for re-supply of investigational product(s). 
 
11.1.3 Dosage and Administration 
Pazopanib tablets are supplied as different strengths as summarized in the table below: 
 
Strengths 
(mg as free base) 
Description 
Color 
Shape 
50 
white to off-white 
round 
200 
white 
oval 
gray or pink 
capsule-shaped, may be 
debossed 
400 
white 
oval 
white or yellow 
capsule-shaped, may be de-
bossed 
 


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Placebo tablets to match the round 50 mg tablets and the oval-shaped 200 mg and 400 mg 
tablets are available. 
 
The tablets are packaged in white high density polyethylene (HDPE) bottles with white 
plastic, induction seal, child-resistant caps. 
 
Powder for Oral Suspension 
 
Panzopanib Powder for Oral Suspension (PfOS) is a white to slightly colored powder 
supplied as multiple-dose formulation in amber glass (USP Type III) bottles with 
childresistant, polypropylene closures. Each bottle contains panzopanib 
(monohydrochloride salt) equivalent to 5 g of free base. A Placebo to Match panzopanib 
PfOS is available. The Placebo visually matches the active GW786034B PfOS. The 
Placebo contains the same excipients as the multiple-dose PfOS, and also contains 
microcrystalline cellulose, titanium dioxide, magrogol/polyethylene glycol 400, and 
polysorbate 80 to aid the visual blinding. 
 
The PfOS formulations have been manufactured for use in clinical studies for adults and 
pediatric oncology patients. 
 
Store at room temperature between 20C and 25C (68F to 77F); excursions permitted 
to 15C to 30C (59F to 86F) [see USP Controlled Room Temperature]. 
 
Pazopanib should be taken orally without food at least one hour before or two hours after 
a meal. The tablets should be swallowed whole and must not be crushed or broken. The 
time of day the tablets are taken should be relatively constant.  If a dose is missed, the 
subject should take the dose as soon as possible, but not if there are less than 12 hours 
before the next dose is due.  If the next dose is due in less than 12 hours, the subject 
should skip the missed dose and take the next dose as scheduled.  If vomiting occurs after 
taking pazopanib another dose is not permitted on that day.  The subject should resume 
taking pazopanib at the next scheduled dose.  If vomiting persists, the subject should be 
instructed to notify the investigator. 
 
11.1.4   Incompatibilities 
Concomitant Medications and Non-Drug Therapies 
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by Novartis Pharmaceuticals and stored in the study file.  
Any such changes will be communicated to the investigative sites in the form of a letter. 
Permitted Medications 
All subjects will be asked to provide a complete list of prescription and over-the-counter 
medications that have been taken within the 4 weeks prior to Screening.  The investigator 
must be informed as soon as possible about any new medication(s) taken from the time 
of Screening until the completion of the post-treatment follow-up visit.   
All concomitant medications taken during the study will be recorded in the electronic 
case report form (eCRF) with indication, dose information, and dates of administration. 


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Subjects should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, analgesics, erythropoietin, or 
bisphosphonates, when appropriate.   
 
Anti-emetics (such as prochlorperazine, lorazepam, ondansetron or other 5-HT 
antagonists) may be administered prophylactically in the event of nausea.  Anti-
diarrheals, such as loperamide, may be administered as needed in the event of diarrhea.  
Although acetaminophen at doses of 2 g/day is permitted, it should be used with caution 
in subjects with impaired liver function.   
Permitted Medications – Use with Caution 
Specific recommendations regarding anticoagulants: 
Results from drug-drug interaction studies conducted in subjects with cancer suggest that 
pazopanib has no effect on the metabolism of S-warfarin.  Hemorrhagic events, however, 
have been reported in clinical studies with pazopanib; therefore, pazopanib should be 
used with caution in subjects with increased risk of severe bleeding or who are receiving 
concomitant anticoagulant therapy (e.g., warfarin or its derivatives, low molecular weight 
heparin, unfractionated heparin).  Subjects taking concomitant anticoagulant therapy 
should be monitored regularly for changes in relevant coagulation parameters as 
clinically indicated, as well as for any clinical bleeding episodes. 
 
Specific recommendations regarding hypoglycemic therapy including insulin: 
Results from drug-drug interaction studies conducted in subjects with cancer suggest that 
there will be no clinically relevant pharmacokinetic interaction between pazopanib and 
hypoglycemic agents.  Transient decreases in serum glucose (mainly Grade 1 and 2, 
rarely Grade 3) have been observed in clinical studies with pazopanib.  In addition, 
decreases in blood sugar have been recently reported in subjects treated with another 
small molecule tyrosine kinase inhibitor, sunitinib [51].  Such changes may require an 
adjustment in the dose of hypoglycemic and/or insulin therapy.  Subjects should be 
advised to report symptoms of hypoglycemia (e.g., confusion, visual disturbances, 
palpitations, sweating).  Serum glucose should be tested during treatment with pazopanib 
as outlined in the protocol and as clinically indicated. 
 
Effects of Concomitant Pazopanib and Simvastatin 
A potential interaction with concomitant administration of 800 mg of pazopanib and 
simvastatin has been indentified in oncology studies. Pooled data from 11 clinical studies 
in which cancer patients received pazopanib monotherapy revealed that the incidence of 
ALT elevation >3 X ULN increased with concomitant pazopanib and simvastatin therapy 
(11/41 patients; 27%) compared with the incidence with pazopanib and no concomitant 
statin therapy (126/895 patients; 14%). Due to the lower systemic exposures achieved 
with both eye drops and low-dose oral pazopanib tablets, and the frequency of liver 
function monitoring, the use of simvastatin or other statins has been permitted during 
clinical trials. 
 
The Effects of Pazopanib on Other Drugs 
In vitro data indicate that pazopanib is a potential inhibitor for CYP3A4, CYP2C8, 
CYP2D6, CYP1A2, CYP2C9, CYP2C19, CYP2A6, CYP2B6, and CYP2E1.  Pregnane 


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X receptor transient transfection assay suggested some potential for human CYP3A4 
induction at high concentrations.  Results from drug-drug interaction studies conducted 
in subjects with cancer suggest that pazopanib is a weak inhibitor of CYP3A4, CYP2C8, 
and CYP2D6 in vivo, but had no clinically relevant effect on CYP1A2, CYP2C9 or 
CYP2C19 metabolism.  Therefore, concomitant use of pazopanib with certain 
medications (substrates of CYP3A4, CYP2C8, and CYP2D6) with a narrow therapeutic 
window should be undertaken with CAUTION due to the potential for alterations in the 
pharmacologic effects of these medications or an increased risk for serious or life 
threatening adverse events associated with such medications (see below) secondary to 
the inhibition of specific CYP enzymes by pazopanib.  In addition, the potential for drug 
interaction with such medications, although diminished, may persist after the last dose of 
pazopanib due to its long half-life (i.e., mean 30.9 hours); therefore, continue to exercise 
CAUTION for at least 7 days and up to 15 days after the last dose of pazopanib when 
administering these medications.  These medications include (but are not limited to): 
 
 Ergot derivatives:  dihydroergotamine, ergonovine, ergotamine, 
methylergonovine (potential increased risk for developing ergot toxicity that 
includes severe vasospasm leading to peripheral as well as cerebral ischemia) 
 Neuroleptics: pimozide (potential increased risk for QT interval prolongation, 
ventricular arrhythmia, and sudden death) 
 Antiarrhythmics: bepridil, flecainide, lidocaine, mexiletine, amiodarone, 
quinidine, propafenone (potential increased risk for QT interval prolongation and 
Torsade de Pointes) 
 Immune modulators: cyclosporine, tacrolimus, sirolimus (potential increased risk 
for nephrotoxicity and neurotoxicity) 
 Miscellaneous: quetiapine, risperidone, clozapine, atomoxetine. 
 
In this trial, treatment with these medications while on study treatment is prohibited. 
 
The Effects of Other Drugs on Pazopanib 
Results from in vitro studies suggest that the oxidative metabolism of pazopanib in 
human liver microsomes is mediated primarily by CYP3A4, with minor contributions 
from CYP1A2 and CYP2C8.  Furthermore, in vitro data suggest that pazopanib is a 
substrate for p-glycoprotein.  Substances that induce or inhibit CYP3A4 may alter the 
pharmacologic effects of pazopanib and should be used with CAUTION.   
Medications that inhibit CYP3A4 may result in increased plasma pazopanib 
concentrations.  Selection of an alternate concomitant medication with no or minimal 
potential to inhibit CYP3A4 is recommended.  A dose reduction to 400 mg pazopanib 
should be considered when it must be co-administered with strong CYP3A4 inhibitors.   
 
Strong CYP3A4 inhibitors include (but are not limited to): 
 Antibiotics: clarithromycin, telithromycin, troleandomycin 
 HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, 
lopinavir) 


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 Antifungals:  itraconzaole, ketoconazole, voriconazole, fluconazole   
 Antidepressants:  nefazodone 
 Diet: grapefruit, seville oranges, starfruit, and their juices 
CYP3A4 inducers may decrease plasma pazopanib concentrations.  Selection of an 
alternate concomitant medication with no or minimal enzyme induction potential is 
recommended.   
 
Drugs that induce CYP3A4 and may decrease pazopanib plasma concentrations 
include (but are not limited to): 
 Glucocorticoids:  cortisone (>50 mg), hydrocortisone (>40 mg), prednisone (>10 
mg), methylprednisolone (>8 mg), dexamethasone (>1.5 mg) 
 Anticonvulsants:  phenytoin, carbamezepine, phenobarbital, oxcarbazepine 
 HIV antivirals:  efavirenz, nevirapine 
 Antibiotics:  rifampin (rifampicin), rifabutin, rifapentene 
 Miscellaneous:  St. John’s Wort, modafinil, pioglitazone, troglitazone 
Prohibited Medications 
Subjects should not receive other anti-cancer therapy [cytotoxic, biologic, radiation (other 
than leuprolide or other GnRH agonists)] while on treatment in this study.   
Medications that inhibit CYP3A4 may result in increased plasma pazopanib concentrations; 
therefore, co-administration of strong CYP3A4 inhibitors is PROHIBITED beginning 7 
days prior to the first dose of study drug until discontinuation from the study.  Strong 
CYP3A4 inhibitors include (but are not limited to): 
 Antibiotics: clarithromycin, telithromycin, troleandomycin 
 HIV: protease inhibitors (ritonavir, indinavir, saquinavir, nelfinavir, amprenavir, 
lopinavir) 
 Antifungals:  itraconzaole, ketoconazole, voriconazole, fluconazole 
 Antidepressants:  nefazodone 
 Diet: grapefruit, seville oranges, starfruit, and their juices at or near time of drug 
ingestion 
11.1.5. Side Effects 
 
 
See Section 7.0 
 
12.0 
Statistical Considerations 
The response rate with no additional treatment in women with disease progression while 
receiving aromatase inhibitors is expected to be <5%.  We will consider an overall response 
rate of 20% to be clinically meaningful.  For the purpose of this study, response will be 
defined as clinical benefit rate, including complete response, partial response, and stable 
disease for at least 12 weeks.   
 


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Therefore, we used the American Cancer Society's website 
(http://cryptnet.net/kepner/one_sample.html) for a 2 stage design with p0=0.05, p1=0.20 and 
power 80% at alpha=5%. This design specifies that if 0 of the first 14 eligible and evaluable 
subjects do not respond to the treatment at 12 weeks, then we are unlikely to reach a true 
overall response rate of 20%.  The 15th patient will not be enrolled until we have confirmed 
that we have met criteria of at least 1 responses (response defined as clinical benefit) 
observed in the first 14 patients, to proceed to the second stage.  An additional 13 patients 
will be enrolled in stage 2 for a total of 27 patients. If at least 4 of the total patients respond, 
we will conclude that the addition of pazopanib in this setting has the possibility of reversing 
resistance to hormone therapy with aromatase inhibitors. Using this design, we will have a 
less than 5% chance of incorrectly accepting the null hypothesis (alpha 0.05), and an 80% 
chance of correctly rejecting the null hypothesis (beta 0.2). 
 
To determine whether the level of cytokines at baseline and during treatment could predict 
response to antiangiogenic therapy, we will divide patients into two groups; responder and 
non-responder group. The student t test will be used to analyze the differences of cytokine 
levels at baseline and at 4 weeks between these 2 groups.  
 
CTC quantification data will be correlated with response and time to progression.   
 
We will make preliminary observations regarding mutations or deletions in PIK3CA and 
PTEN in patients with measurable CTC, correlating changes with response and disease 
history, as well as presence or absence of these alterations in archival tumor tissue. 
 
12.1 
Endpoint Definitions 
 
Primary endpoint: 
 
The primary endpoint of this study is clinical benefit (including complete 
response, partial response, and stable disease ) of at least 12 weeks.   
 
Secondary endpoint: 
 
PFS:  evaluate progression free survival in patients treated with the 
combination of pazopanib and a NSAI in this trial  
 
Safety : adverse events, SAEs 
 
Exploratory endpoints: 
 
Evaluate the impact of the combination of pazopanib and a NSAI on 
circulating tumor cells 
 
Evaluate the change of immune profile with the combination of pazopanib 
and a NSAI 
 
12.2 
Accrual Objectives 
 
This will be a two stage design with 14 patients enrolled in the first stage.  If at least one  
patient responds (response defined as clinical benefit), an additional 13 patients will be 


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enrolled for a total of 27 patients.  Expecting that approximately 3 patients will be un-
evaluable due unexpected events, a total of 30 patients will be enrolled in the protocol. 
 
All patients who take at least two weeks of study drug and the non-steroidal aromatase 
inhibitor will be evaluable for toxicity and efficacy. Depending on accrual, patients who 
stop study therapy within the first two weeks may be replaced. 
 
12.3 
Estimated Duration of Study 
 
Enrollment will occur over 18 months. 
Follow-up 6-8 months after last subject enrolled 
 
12.4   
Data and Safety Monitoring 
 
Review of adverse events and serious adverse events (defined below) will be done at Site 
Committee meetings at UCSF and during monthly teleconferences with Yale.  In addition, 
toxicity reviews will occur once a month in the Breast Oncology Program Site Committee 
meetings at UCSF.  We will hold enrollment to review the safety data after the 5th patient 
has been on pazopanib for 2 weeks and resume once the study is deemed to be safe.  The 
Study Chair will notify Yale of the enrollment hold.   
 
The UCSF DSMC will monitor the study at UCSF and the Yale DSMC will monitor the 
study at Yale.  The Data and Safety Monitoring reports from Yale will be audited by the 
Quality Assurance, Compliance, and Safety Committee (QUACS) as they are generated 
from the monitoring reports for the Yale Site.   
 
12.5 
Analyses Timepoints 
 
After the first 14 patients have completed 12 weeks of treatment.  
12 weeks after the last patient has been enrolled. 
 
12.6 
Sample Size 
 
With 30 patients enrolled, we expect 27 for evaluation at 12 weeks.  The two-stage design 
has 80% power to detect clinical benefit (defined as complete or partial response of stable 
disease) in 20% of patients compared to <5% of patients without this treatment. 
 
12.7 
Replacement Policy 
 
30 patients will be enrolled for a final estimated study sample size of 27.  Patients stopping 
therapy before 2 weeks will be replaced after discussion with the Study Chair. 
 
13.0 Data Forms & Submission Schedule 
 
Patients will be evaluated in clinic at least once per cycle of treatment.  All collected data will be 
entered into template forms in OnCore within one week of each patient visit. 


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14.0 Special Instructions 
 
None 
 
15.0 Ethical Aspects 
 
15.1 
Regulatory Considerations 
 
This study will be reviewed by the UCSF and the Yale IRBs as described below.  At 
UCSF, the protocol will also be reviewed by the Helen Diller Family Comprehensive 
Cancer Center Protocol Review Committee prior to IRB submission.  In addition, UCSF 
will file an Investigational New Drug application with the FDA as described below.   
 
Independent Ethics Committees/Institutional Review Board 
 
This protocol and the informed consent will be approved by the Committee on Human 
Research (CHR) (UCSF’s IRB).  Once approved, the protocol will be reviewed by the Yale 
School of Medicine Human Investigation Committee.  The Principal Investigator at each 
site is responsible for keeping the IRB apprised of the progress of the study and of any 
changes made in the protocol prior to implementation.  The Principal Investigator at each 
site will also keep his/her own IRB informed of any significant adverse reactions and any 
protocol exceptions or deviations.  Records of all study review and approval documents 
must be kept on file by the Principal Investigator at each site, and copies of IRB 
documentation from Yale will be forwarded to UCSF.  All records are subject to FDA 
inspection during or after completion of the study.  The IRBs will receive notification of 
the termination of the study.  
 
Protocol and Protocol Amendments 
 
Protocol and protocol amendments will be submitted to and approved by the UCSF 
Protocol Review committee (PRC), in addition to CHR, prior to implementation at UCSF.   
 
It is the responsibility of the UCSF Study Chair (or designee) to distribute the protocol and 
the protocol amendments to Yale upon IRB approval at UCSF.  The protocol may be 
distributed via e-mail or private courier with confirmation of receipt.   
 
Upon approval of the protocol or protocol amendment by Yale’s IRB, a copy of the 
approval documentation must be submitted to Study Chair.  All protocol amendments are 
expected to be approved by Yale’s IRB within 90 days of receipt. 
 
Documentation of Yale’s protocol approvals will be maintained in the correspondence 
files by the Study Chair or designee, and provided to the UCSF centralized regulatory 
staff.  It is the responsibility of the Study Chair to review these documents to ensure that 
the participating sites are using the current protocol version. 
 


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Prestudy Documentation at Participating Sites 
 
Before the study may be initiated at Yale, the following documentation must be 
submitted to UCSF: 
 
 Copy of the official IRB approval letter for the protocol and informed consent form 
 IRB membership list 
 Form FDA 1572, signed and dated by the Principal Investigator. 
 Current curricula vitae and medical licenses of the site’s Principal Investigator and all 
sub investigator(s) listed on Form FDA 1572. 
 Contact information (email, phone number, address) for the research pharmacist and 
designated contact person(s) (CRC and/or nurse) assigned to this study. 
 CAP and CLIA Laboratory certification and institution lab normal values 
 Executed clinical research contract 
 
Investigational New Drug Application (IND) 
 
The Coordinating Center (UCSF) is responsible for the preparation and submission of the 
Investigational New Drug Application (IND) to the FDA.  An electronic file (PDF) of all 
FDA correspondence concerning the IND will be maintained in OnCore, the UCSF Helen 
Diller Family Comprehensive Cancer Center Clinical Trial Management System.  It is the 
responsibility of the Study Chair to keep the regulatory staff informed of any 
communications with FDA that affect the status of the IND.   
 
Coordinating Center Documentation  
 
It is the responsibility of the Study Chair to maintain adequate files documenting the 
distribution of study documents as well as their receipt (as applicable). The UCSF Helen 
Diller Family Comprehensive Cancer Center recommends that the Study Chair maintain 
a correspondence file and log for each segment of distribution (e.g., FDA, drug 
manufacturer, sub sites, etc.). 
 Correspondence file: should contain copies (paper or electronic) of all protocols and 
protocol amendments, cover letters, amendment outlines (summary of changes), etc., 
along with distribution documentation and (when available) documentation of receipt. 
 Correspondence log: should be a brief list of all documents distributed including the 
date sent, recipient(s), and (if available) a tracking number and date received. 
 
At a minimum, the Study Chair must keep documentation of when and to whom the 
protocol and its updates and safety information are distributed. 
 
 
 
 


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16.0 Reporting Adverse Drug Reactions 
 
16.1 
Adverse Event Definitions 
 
16.1.1 Clinical Adverse Events 
 
A clinical adverse event is any unfavorable or unintended sign, symptom or 
disease temporally associated with the use of the study drug occurring in a 
research patient treated with the study drug during treatment or post-treatment 
follow-up period, regardless of causality assessment.  This includes adverse 
clinical or laboratory findings, intercurrent illness, or an exacerbation or 
progression of a disease/condition present at baseline. 
 
An adverse event is unexpected if it is not listed in the current labeling for the 
study drug.  An adverse event is considered non-serious if it does not meet any of 
the serious criteria below. 
 
16.1.2 Laboratory Adverse Events 
 
Laboratory test value abnormalities will not be recorded as adverse events unless 
they are designated as serious, require treatment, or cause premature withdrawal. 
 
16.1.3 Serious Adverse Events 
 
A serious adverse event (SAE) is any adverse event occurring at any dose that 
results in any of the following outcomes: 
 death, 
 life-threatening (places the subject, in the view of the investigator, at 
immediate risk of death from the reaction as it occurred), 
 inpatient hospitalization or prolongs existing hospitalization, 
 persistent or significant disability/incapacity (a substantial disruption of a 
person’s ability to conduct normal life functions), 
 birth defect/congenital anomaly, 
 or any important medical event that may not result in prior listed outcomes 
but, based upon appropriate medical judgment, may jeopardize the subject, 
and may require medical or surgical intervention to prevent one of the prior 
listed outcomes. 
 
16.1.4 Treatment of Investigational Product Overdose 
 
No maximum tolerated dose (MTD) was reached in the dose escalation study of 
pazopanib administered as a single agent at repeated doses of up to 2000mg/day 
(Study VEG10003).  Systemic exposure to pazopanib at steady-state appeared to 
plateau at doses greater than 800 mg once daily.  Increases in the daily pazopanib 
dose above 800 mg in the fasted state resulted in a small or no increase in mean 
systemic exposure to pazopanib.     


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In the event of pazopanib overdose (defined as administration of more than the 
protocol-specified dose), the Study Chair should contact the Novartis 
Pharmaceuticals Study Physician.  If the event takes place at Yale, the Principal 
Investigator will immediately notify the Study Chair.   
 
Decisions regarding pazopanib dose modifications or interruptions will be made 
by the Study Chair in consultation with the Novartis Pharmaceuticals Study 
Physician, and with the Yale Investigator, if applicable, based on the clinical 
evaluation of the subject.    
 
Following an overdose, additional monitoring of the subject for AEs/SAEs and 
laboratory abnormalities should be considered.  A plasma sample for 
pharmacokinetic analysis for pazopanib and NSAI may be requested by the 
Novartis Pharmaceuticals Study Physician on a case-by-case basis.  This plasma 
sample should be collected as soon as possible, but within 7 days from the date 
of the last dose of study drug.   
 
Information regarding the quantity of the excess dose, as well as the duration of 
overdosing, should be documented in the eCRF. 
 
NSAI overdose is very rare; currently there is no standard guideline on the 
management of NSAI overdose.  
 
16.2 
Adverse Event Reporting Procedures 
 
16.2.1 Data and Safety Monitoring Plan  
 
 
 
Oversight and Monitoring Plan 
 
The UCSF- Helen Diller Family Comprehensive Cancer Center (HDFCCC) Data 
Safety Monitoring Committee (DSMC) is responsible for monitoring data quality 
and patient safety for all HDFCCC institutional clinical studies.  A summary of 
DSMC activities for this study at UCSF includes:  
 
 Review of subject data 
 Review of suspected adverse reactions considered “serious”  
 Monitoring every six months (depending on study accrual) 
 Minimum of a yearly audit  
 
At Yale, monitoring takes place after the first two patients and then 10% annually 
thereafter.  The monitoring plan is set at the scientific review committee meeting 
as determined by the local PRC (Protocol Review Committee). 
 
 
 


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Monitoring and reporting Guidelines 
 
All institutional Phase 2 therapeutic studies are designated with a moderate risk 
assessment. The data is monitored every six months, with twenty percent of the 
subjects monitored (or at least three subjects if the calculated value is less than three). 
 
The UCSF Coordinating Center provides administration, data management, and 
organizational support for the participating sites in the conduct of a multicenter 
clinical trial. The UCSF Coordinating Center will also coordinate monthly conference 
calls with the participating sites to communicate the review of adverse events, safety 
data, and other study matters. 
 
The Principal Investigator at the UCSF Coordinating Center will hold the role of 
Study Chair. The Study Chair is responsible for the overall conduct of the study and 
for monitoring its safety and progress at all participating sites. The Study Chair will 
conduct continuous review of data and patient safety and discuss at monthly study 
group or site committee meetings at UCSF, and during monthly teleconferences 
with Yale.  At UCSF Site Committee, the results of each patient’s treatment are 
discussed and the discussion is documented in the minutes. The discussion will 
include the number of patients, significant toxicities as described in the protocol, 
doses adjustments, and observed responses.  All grade 3 or above AEs and SAEs 
will be entered in the UCSF Helen Diller Family Comprehensive Cancer Center 
CTMS database.   
 
Multicenter communication  
 
The UCSF Coordinating Center provides administration, data management, and 
organizational support for the participating sites in the conduct of a multicenter 
clinical trial. The UCSF Coordinating Center will also coordinate, at minimum, 
quarterly conference calls with the participating sites or more frequently as needed to 
discuss risk assessment. The following issues will be discussed as appropriate: 
 Enrollment information  
 Adverse Events (i.e. new adverse events and updates on unresolved adverse 
events and new safety information) 
 Protocol Violations  
 Other issues affecting the conduct of the study  
 
Adverse events reporting to the DSMC will include reports from both the UCSF 
Coordinating Center, as well as the participating sites. The DSMC will be responsible 
for monitoring all data entered in OnCore® at the UCSF Coordinating Center and the 
participating sites. The data (i.e. copies of source documents) from the participating 
sites will be faxed over to the UCSF Coordinating Center prior to the monitoring 
visits in order for the DSMC to monitor the participating site’s compliance with the 
protocol, patient safety, and to verify data entry. 
 
 
 
 
 


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Review and Oversight Requirements 
 
Adverse Event Monitoring  
 
Adverse Events (AEs) will be recorded on the UCSF Helen Diller Family 
Comprehensive Cancer Center CTMS database, all grade 3 and above expected 
and unexpected AEs will be recorded and updated at each visit.    
 
All Grade 3-5 adverse events entered into OnCore® will be reviewed on a monthly 
basis at the UCSF Site Committee meetings. All clinically significant adverse events 
must be reported to the UCSF Coordinating Center by the participating sites within 
10 business days of becoming aware of the event or during the next scheduled 
quarterly conference call, whichever is sooner. The UCSF Site Committee will 
review and discuss the selected toxicity, the toxicity grade, and the attribution of 
relationship of the adverse event to the administration of the study drug(s) from the 
UCSF Coordinating Center and the participating sites.  
 
In addition, all suspected adverse reactions considered “serious” must be entered in 
OnCore® and reported to the UCSF Coordinating Center within 1 business day. The 
suspected adverse reactions considered “serious” will be reviewed and monitored by 
the Data and Safety Monitoring Committee on an ongoing basis and discussed at the 
DSMC meeting, which take place every six (6) weeks.  
 
If a death occurs during the treatment phase of the study or within 30 days after the 
last administration of the study drug(s) and is determined to be related either to the 
investigational drug or any research related procedure, the Study Chair at the UCSF 
Coordinating Center or the assigned designee must be notified within 1 business day 
from the participating site(s) and the Study Chair must then notify the DSMC Chair 
or qualified alternate within 1 business day of this notification. The contact may be 
by phone or e-mail. 
 
 
16.2.2 Serious Adverse Event Reporting  
 
Serious Adverse Event reporting will be in accordance with the UCSF- 
Committee on Human Research and the Yale School of Medicine Human 
Investigation Committee guidelines and Code of Federal Regulation Title 21 
Volume 5 Part 312.32.  
 
UCSF CHR website for guidance in reporting serious adverse events 
http://www.research.ucsf.edu/chr/Guide/Adverse_Events_Guidelines.pdf 
 
FDA website for guidance in reporting serious adverse events  
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=312.3
2 
 
MedWatch forms and information:  
http://www.fda.gov/medwatch/getforms.htm 


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Serious Adverse events will be reported on the MedWatch form. The date the 
SAE was sent to all required reporting agencies will be documented on the UCSF 
Helen Diller Family Comprehensive Cancer Center CTMS database. 
 
Participating Sites Reporting to Study Chair (UCSF) 
 
In addition to complying with all applicable regulatory reporting laws and 
regulations, each site will report the following information in writing to the 
Sponsor-Investigator within one business day of the Investigator’s awareness of 
occurrence: 
 All SAEs 
 Reports of pregnancy exposure (pregnancy encompasses the entire course 
of pregnancy and delivery, perinatal and neonatal outcomes, even if there 
were no abnormal findings; both maternal and paternal exposure is 
collected); 
 Reports of lactation exposure; 
 Overdose (with or without an SAE); 
 Abuse (use for non-clinical reasons with or without an SAE); 
 Inadvertent or accidental exposure; and 
 Follow-up information regarding any of the above.  
 The participating investigator should include his or her assessment of the 
causal relationship between each SAE and the Grantor product. 
 
Reports will include the cover page provided, and reference the Protocol 
Number.   
 
A copy of the report should be sent to the coordinating center CRC at UCSF.  
Information will be provided. 
 
Study Chair (UCSF) AE reporting to Novartis Pharmaceuticals   
 
Any serious adverse events which occur during the clinical study or within 5 days 
of receiving the last dose of study medication, whether or not related to the study 
drug, must be reported by the Study Chair. In addition, any SAEs which occur as 
a result of protocol specific diagnostic procedures or interventions must also be 
reported. 
 
 
Initial Reports 
Follow-up Information on a 
Previous Report 
Type of Event 
Time 
Frame 
Documents 
Time 
Frame 
Documents 
All SAEs 
24 hours 
SAE data collection tool 
24 hours 
Updated SAE data 
collection tool  
Pregnancy 
2 weeks 
Pregnancy Notification 
Form 
2 weeks 
Pregnancy Follow 
up Form 
Liver chemistry abnormalities: 
 
 
 
 


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ALT: >3.0 x ULN  
with concomitant elevation in 
bilirubina (defined as  
total bilirubin ≥2.0 x ULN 
with direct bilirubin >35%)  
or with hypersensitivity 
symptoms (e.g., fever, rash). 
24 hours 
SAE data collection tool. 
 
bLiver Event Case 
Report Form (CRF) and 
liver imaging and/or 
biopsy CRFs if 
applicable 
24 hours 
Updated SAE data 
collection tool.  
 
bUpdated Liver 
Event CRF 
ALT >8.0 x ULN  
without bilirubin elevation 
(defined as total bilirubina <2.0 x 
ULN or direct bilirubin ≤35%) 
and without hypersensitivity 
symptoms (e.g., fever, rash) 
24 hours 
SAE data collection tool. 
 
Liver Event CRFb  
24 hours 
Updated SAE data 
collection tool.  
 
Updated Liver 
Event CRFb 
a. 
Bilirubin fractionation should be performed if testing is available.  If testing is unavailable and a subject 
meets the criterion of total bilirubin 2.0 x ULN, then the event should be promptly reported as defined. 
b. 
Liver event documents should be completed as soon as possible. 
 
All Events must be reported to Novartis within 24 hours of learning of its 
occurrence.  Information about all SAEs is collected and recorded on a Serious 
Adverse Event Report Form; all applicable sections of the form must be 
completed in order to provide a clinically thorough report. The investigator must 
assess and record the relationship of each SAE to each specific study treatment (if 
there is more than one study treatment), complete the SAE Report Form in 
English, and send the completed, signed form by fax within 24 hours to the 
oncology Novartis DS&E department with the provided FAX cover sheets. 
 
 Novartis DS&E Oncology Department - 
  
 
SAEs brought to the attention of the Study Chair at any time after cessation of 
pazopanib and considered by the Study Chair to be related or possibly related to 
pazopanib must be reported to Novartis Pharmaceuticals if and when they occur. 
Additionally, in order to fulfill international reporting obligations, SAEs that are 
related to study participation (e.g., procedures, invasive tests, change from 
existing therapy) or are related to a concurrent medication will be collected and 
recorded from the time the subject consents to participate in the study until he/she 
is discharged. 
 
Review of Adverse Event Rates 
 
If the study has an increase of unexpected or expected Adverse Event grade 3 or 4 
above the rate reported in the Investigational Brochure or package insert, the 
increase rate of AEs will be reported by the Study Chair to the UCSF DSMC at 
the time of Identification.  The UCSF DSMC Chair and Study Chair will discuss 
the finding and proceed with a written course of action.  If at any time the Study 
Chair stops enrollment or stops the study due to safety issues the UCSF DSMC 
Chair must be notified within 24 business hours via e-mail.  The UCSF DSMC 
must receive a formal letter within 10 business days and the CHR must be 
notified.  


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If any of the above action occurs in a multiple-institutional clinical trial 
coordinated by the UCSF-CCC, the Study Chair will insure that all participating 
sites are notified. 
 
Data and Safety Monitoring Committee Contacts: 
DSMC Chair:  
 
  
 
Email  
 
Box 
 
 
 
DSMC Monitors 
Box 
 
0128 


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17.0 References 
 
1. 
Jemal, A., et al., Cancer statistics, 2008. CA Cancer J Clin, 2008. 58(2): p. 71-96. 
2. 
Block, G.E., E.V. Jensen, and T.Z. Polley, The prediction of hormonal dependency of 
mammary cancer. Ann Surg, 1975. 182(3): p. 342-52. 
3. 
Buzdar, A.U., Advances in endocrine treatments for postmenopausal women with 
metastatic and early breast cancer. Oncologist, 2003. 8(4): p. 335-41. 
4. 
Schafer, J.M. and V.C. Jordan, Models of hormone resistance in vitro and in vivo. 
Methods Mol Med, 2006. 120: p. 453-64. 
5. 
Sledge, G.W., H.S. Rugo, and H.J. Burstein, The role of angiogenesis inhibition in the 
treatment of breast cancer. Clin Adv Hematol Oncol, 2006. 4 Suppl 21(10): p. 1-12. 
6. 
Folkman, J., Angiogenesis in cancer, vascular, rheumatoid and other disease. Nat Med, 
1995. 1(1): p. 27-31. 
7. 
Ferrara, N., Vascular endothelial growth factor: basic science and clinical progress. 
Endocr Rev, 2004. 25(4): p. 581-611. 
8. 
Pietras, R.J., Interactions between estrogen and growth factor receptors in human breast 
cancers and the tumor-associated vasculature. Breast J, 2003. 9(5): p. 361-73. 
9. 
Mendelsohn, M.E., Genomic and nongenomic effects of estrogen in the vasculature. Am 
J Cardiol, 2002. 90(1A): p. 3F-6F. 
10. 
Ihionkhan, C.E., et al., Estrogen causes dynamic alterations in endothelial estrogen 
receptor expression. Circ Res, 2002. 91(9): p. 814-20. 
11. 
Garvin, S., U.W. Nilsson, and C. Dabrosin, Effects of oestradiol and tamoxifen on VEGF, 
soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells. Br J Cancer, 
2005. 93(9): p. 1005-10. 
12. 
Elkin, M., A. Orgel, and H.K. Kleinman, An angiogenic switch in breast cancer involves 
estrogen and soluble vascular endothelial growth factor receptor 1. J Natl Cancer Inst, 
2004. 96(11): p. 875-8. 
13. 
Bando, H., et al., Association between intratumoral free and total VEGF, soluble 
VEGFR-1, VEGFR-2 and prognosis in breast cancer. Br J Cancer, 2005. 92(3): p. 553-
61. 
14. 
Toi, M., et al., Significance of vascular endothelial growth factor (VEGF)/soluble VEGF 
receptor-1 relationship in breast cancer. Int J Cancer, 2002. 98(1): p. 14-8. 
15. 
Garvin, S. and C. Dabrosin, In vivo measurement of tumor estradiol and vascular 
endothelial growth factor in breast cancer patients. BMC Cancer, 2008. 8: p. 73. 
16. 
Makris, A., et al., Reduction in angiogenesis after neoadjuvant chemoendocrine therapy 
in patients with operable breast carcinoma. Cancer, 1999. 85(9): p. 1996-2000. 
17. 
Sonpavde, G., T.E. Hutson, and C.N. Sternberg, Pazopanib, a potent orally administered 
small-molecule multitargeted tyrosine kinase inhibitor for renal cell carcinoma. Expert 
Opin Investig Drugs, 2008. 17(2): p. 253-61. 
18. 
Taylor, S.K., et al., A phase II study of pazopanib in patients with recurrent or metastatic 
invasive breast carcinoma: a trial of the Princess Margaret Hospital phase II 
consortium. Oncologist. 15(8): p. 810-8. 
19. 
Bonneterre, J., et al., Anastrozole is superior to tamoxifen as first-line therapy in 
hormone receptor positive advanced breast carcinoma. Cancer, 2001. 92(9): p. 2247-58. 
20. 
Mouridsen, H., et al., Phase III study of letrozole versus tamoxifen as first-line therapy of 
advanced breast cancer in postmenopausal women: analysis of survival and update of 


Protocol Version #:  12.0 
Page 49 of 59 
July 7, 2017 
Protocol #:  117513 
efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol, 2003. 
21(11): p. 2101-9. 
21. 
Paridaens, R., et al., First results of a randomized phase III trial comparing exemestane 
versus tamoxifen as first-line hormone therapy (HT) for postmenopausal women with 
metastatic breast cancer (MBC) - EORTC 10951 in collaboration with the exemestane 
working group and NCIC. Eur J Cancer (Suppl), 2004. 2(3): p. 126 (abstract #241). 
22. 
Paridaens, R.J., et al., Phase III study comparing exemestane with tamoxifen as first-line 
hormonal treatment of metastatic breast cancer in postmenopausal women: the European 
Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group. 
J Clin Oncol, 2008. 26(30): p. 4883-90. 
23. 
Folkman, J., Angiogenesis in cancer, vascular, rheumatoid and other disease. Nature 
medicine, 1995. 1(1): p. 27-31. 
24. 
Ferrara, N., VEGF and the quest for tumour angiogenesis factors. Nature reviews. 
Cancer, 2002. 2(10): p. 795-803. 
25. 
Ferrara, N., H.P. Gerber, and J. LeCouter, The biology of VEGF and its receptors. Nature 
medicine, 2003. 9(6): p. 669-76. 
26. 
Garvin, S., U.W. Nilsson, and C. Dabrosin, Effects of oestradiol and tamoxifen on VEGF, 
soluble VEGFR-1, and VEGFR-2 in breast cancer and endothelial cells. British journal 
of cancer, 2005. 93(9): p. 1005-10. 
27. 
Pietras, R.J., Interactions between estrogen and growth factor receptors in human breast 
cancers and the tumor-associated vasculature. The breast journal, 2003. 9(5): p. 361-73. 
28. 
Mendelsohn, M.E. and R.H. Karas, The protective effects of estrogen on the 
cardiovascular system. The New England journal of medicine, 1999. 340(23): p. 1801-
11. 
29. 
Jain, R.K., et al., Endothelial cell death, angiogenesis, and microvascular function after 
castration in an androgen-dependent tumor: role of vascular endothelial growth factor. 
Proc Natl Acad Sci U S A, 1998. 95(18): p. 10820-5. 
30. 
Manders, P., et al., Vascular endothelial growth factor is associated with the efficacy of 
endocrine therapy in patients with advanced breast carcinoma. Cancer, 2003. 98(10): p. 
2125-32. 
31. 
Ryden, L., et al., Tumor-specific expression of vascular endothelial growth factor 
receptor 2 but not vascular endothelial growth factor or human epidermal growth factor 
receptor 2 is associated with impaired response to adjuvant tamoxifen in premenopausal 
breast cancer. J Clin Oncol, 2005. 23(21): p. 4695-704. 
32. 
Falkson C, R.J., Nabell L, Carpenter J, Forero A, Kim Y, Saleh M, A phase II trial 
investigating if bevacizumab in combination with hormone therapy reverse acquired 
estrogen indepence in metastatic breast cancer patients. Journal of Clinical Oncology, 
2009. 27(15s). 
33. 
Traina, T.A., et al., Feasibility trial of letrozole in combination with bevacizumab in 
patients with metastatic breast cancer. J Clin Oncol, 2010. 28(4): p. 628-33. 
34. 
Leary, A.F., B. Sirohi, and S.R. Johnston, Clinical trials update: endocrine and 
biological therapy combinations in the treatment of breast cancer. Breast cancer research 
: BCR, 2007. 9(5): p. 112. 
35. 
Graves, H. and B.J. Czerniecki, Circulating tumor cells in breast cancer patients: an 
evolving role in patient prognosis and disease progression. Patholog Res Int. 2011: p. 
621090. 


Protocol Version #:  12.0 
Page 50 of 59 
July 7, 2017 
Protocol #:  117513 
36. 
Criscitiello, C., C. Sotiriou, and M. Ignatiadis, Circulating tumor cells and emerging 
blood biomarkers in breast cancer. Curr Opin Oncol. 22(6): p. 552-8. 
37. 
Andreopoulou, E. and M. Cristofanilli, Circulating tumor cells as prognostic marker in 
metastatic breast cancer. Expert Rev Anticancer Ther. 10(2): p. 171-7. 
38. 
Cristofanilli, M., Circulating tumor cells, disease progression, and survival in metastatic 
breast cancer. Seminars in oncology, 2006. 33(3 Suppl 9): p. S9-14. 
39. 
Magbanua M, L.J., Eisendbud LE , Scott JH,Pinkel D, Gray JW, Park JW, Isolation, gene 
expression and genomic profiling of breast circulating tumor cells (CTCs). 2007 Breast 
Cancer Symposium, 2007. 
40. 
Musgrove, E.A. and R.L. Sutherland, Biological determinants of endocrine resistance in 
breast cancer. Nature reviews. Cancer, 2009. 9(9): p. 631-43. 
41. 
Knowlden, J.M., et al., Elevated levels of epidermal growth factor receptor/c-erbB2 
heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant 
MCF-7 cells. Endocrinology, 2003. 144(3): p. 1032-44. 
42. 
Zuo, T., et al., FOXP3 is an X-linked breast cancer suppressor gene and an important 
repressor of the HER-2/ErbB2 oncogene. Cell, 2007. 129(7): p. 1275-86. 
43. 
Fernández Madrid, F., Autoantibodies in breast cancer sera: candidate biomarkers and 
reporters of tumorigenesis. Cancer letters, 2005. 230(2): p. 187-198. 
44. 
Bates, G.J., et al., Quantification of regulatory T cells enables the identification of high-
risk breast cancer patients and those at risk of late relapse. Journal of clinical oncology : 
official journal of the American Society of Clinical Oncology, 2006. 24(34): p. 5373-80. 
45. 
Shimokawara, I., et al., Identification of lymphocyte subpopulations in human breast 
cancer tissue and its significance: an immunoperoxidase study with anti-human T- and B-
cell sera. Cancer, 1982. 49(7): p. 1456-64. 
46. 
Shiao, S.L. and L.M. Coussens, The tumor-immune microenvironment and response to 
radiation therapy. Journal of mammary gland biology and neoplasia, 2010. 15(4): p. 411-
21. 
47. 
Demaria, S., et al., Cancer and inflammation: promise for biologic therapy. Journal of 
immunotherapy, 2010. 33(4): p. 335-51. 
48. 
DeNardo, D.G., M. Johansson, and L.M. Coussens, Immune cells as mediators of solid 
tumor metastasis. Cancer metastasis reviews, 2008. 27(1): p. 11-8. 
49. 
Buck, M.B. and C. Knabbe, TGF-beta signaling in breast cancer. Annals of the New 
York Academy of Sciences, 2006. 1089: p. 119-26. 
50. 
Nikolinakos, P.G., et al., Plasma cytokine and angiogenic factor profiling identifies 
markers associated with tumor shrinkage in early-stage non-small cell lung cancer 
patients treated with pazopanib. Cancer Res, 2010. 70(6): p. 2171-9. 
51. 
Billemont, B., et al., Blood glucose levels in patients with metastatic renal cell carcinoma 
treated with sunitinib. Br J Cancer, 2008. 99(9): p. 1380-2. 
 


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18.0 Appendices 
 
Appendix I:  ECOG Performance Status 
 
ECOG PERFORMANCE STATUS* 
Grade ECOG 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair 
5 
Dead 
* As published in Am. J. Clin. Oncol.: 
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., Carbone, 
P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology Group. Am J Clin 
Oncol 5:649-655, 1982.  
The ECOG Performance Status is in the public domain therefore available for public use. To 
duplicate the scale, please cite the reference above and credit the Eastern Cooperative Oncology 
Group, Robert Comis M.D., Group Chair.  
 
 
 
 


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Appendix II:   
 
NCI CTCAE v4 
 


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Appendix III: management of GI toxicity: 
 
Diarrhea 
In cancer patients, diarrhea can be debilitating and potentially life threatening, with dehydration, 
renal insufficiency, and electrolyte imbalances. Pazopanib as a monotherapy has been associated 
with an increased incidence of diarrhea, which is grade 1 or 2 in the majority with grade 3/4 
diarrhea occurring in approximately 4% of subjects.  The incidence and severity may increase 
when administered with other agents known to cause diarrhea. 
Early identification and intervention is critical for the optimal management of diarrhea. A 
subject’s baseline bowel pattern should be established so that changes in that pattern can be 
identified.  In addition, subjects should be educated on signs and symptoms of diarrhea with 
instructions to report any changes in bowel pattern to the physician.   
Diarrhea 
The NCI CTCAE Version 4.0 criteria for defining diarrhea are provided below. 
Toxicity 
Grade 
Diarrhea  
(includes diarrhea of small bowel or colonic origin and/or ostomy diarrhea) 
1 
Increase of <4 stools/day over baseline; mild increase in ostomy output 
compared to baseline 
2 
Increase of 4-6 stools/day over baseline; IV fluids indicated < 24 h; moderate 
increase in ostomy output compared to baseline; not interfering with daily living 
3 
Increase of 7 stools/day over baseline; incontinence; IV fluids  24 h; 
hospitalization; severe increase in ostomy output compared to baseline; 
interfering with activities of daily living 
4 
Life threatening consequences (e.g., hemodynamic collapse) 
5 
Death 
 
Uncomplicated diarrhea is considered mild to moderate and defined as CTCAE Grade 1 to 2 
with no complicating signs or symptoms. 
 
Complicated diarrhea is severe and defined as CTCAE Grade 3 or 4 or Grade 1 or 2 with 1 or 
more of the following signs or symptoms; cramping, nausea/vomiting, ≥ Grade2, decreased 
performance status, fever, sepsis, neutropenia, frank bleeding, and/or dehydration.  If 
complicated diarrhea goes unrecognized or untreated, it may lead to death. 
 
Experience thus far suggests that, when pazopanib is used as monotherapy, uncomplicated 
CTCAE Grade 1 or 2 diarrhea may ensue.  In rare cases, subjects treated with monotherapy 
pazopanib may develop debilitating and potentially life-threatening diarrhea with dehydration, 
renal insufficiency, and electrolyte imbalances.  The pathophysiologic mechanism of diarrhea 
with pazopanib is not known. 
 
The following broad general management principles are recommended as means by which a 
subject with diarrhea may avoid more serious complications. Guidelines such as these should 
never replace sound clinical judgment.  Standardized and universal guidelines have been 


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developed by an American Society of Clinical Oncology (ASCO) panel for treating 
chemotherapy-induced diarrhea [Benson, 2004].  The guidance provided here is a modification 
of the ASCO guidelines. 
 
Early identification and intervention is critical for the optimal management of diarrhea:  
 A subject’s baseline bowel pattern should be established so that changes in that pattern 
can be identified.   
 Subjects should be educated on the signs and symptoms of diarrhea with instructions to 
report any changes in bowel pattern to the physician. 
 At the initiation of diarrhea, an assessment of frequency, consistency, duration and other 
symptoms such as fever, cramping pain, nausea, vomiting, dizziness and thirst should be 
taken to identify subjects at high risk of complications. 
Several treatments have demonstrated efficacy in diarrhea management: 
 
Loperamide, administered as an initial 4-mg dose, followed by 2-mg doses after every 
unformed stool with a maximum of 16mg per day.  This dose and regimen are 
moderately effective.  Continuation of loperamide is suggested until the subject is 
diarrhea-free for 12 hours.  Dose should not exceed a maximum of 8 tablets (16 mg) per 
day. 
 
The synthetic octapeptide, octreotide, has been shown to be effective in the control of 
diarrhea induced by fluoropyrimidine-based chemotherapy regimens when administered 
as an escalating dose by continuous infusion or subcutaneous injection.  In the treatment 
of chemotherapy-induced diarrhea, octreotide can be administered at doses ranging from 
100g twice daily to 500g 3 times daily, with a maximum-tolerated dose of 2000g 3 
times daily in a 5-day regimen.  However, the effect of octreotide on diarrhea associated 
with use of pazopanib is unknown.  


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Figure 1.  Generic flow chart for suggested management of Diarrhea 
 EVALUATE 
•
Obtain history of onset and duration of diarrhea 
•
Describe number of stools and stool composition 
•
Assess patient for fever, dizziness, abdominal pain/cramping or weakness 
•
Medications and dietary profile 
UNCOMPLICATED 
grade 1-2 
no complicating signs or symptoms 
ADDED RISK 
FACTORS 
COMPLICATED 
grade 3 or 4 diarrhea or grade 1 or 2 with 
≥ 1 of these signs or symptoms: 
•
Cramping 
•
Nausea/vomiting (≥ grade 2) 
•
Decreased performance status 
•
Fever 
•
Sepsis 
•
Neutropenia 
•
Frank bleeding 
•
Dehydration 
 MANAGEMENT 
•
Discontinue lactose products and alcohol 
•
Drink 8-10 large glasses of clear liquids per day 
•
Eat frequent small meals (e.g., bananas, rice, applesauce, and toast) 
•
Grade 2 diarrhea: Consider holding cytotoxic chemotherapy (if applicable) and consider 
pazopanib dose reduction until symptoms resolve 
 
SUGGESTED TREATMENT 
•
Administer standard anti-diarrheal (e.g. loperamide) 
Reassess 12-24 hours later 
Diarrhea resolving 
•
Continue instructions for dietary 
modification 
•
Gradually add solid food to diet 
•
Discontinue standard anti-
diarrheal after 12-hour diarrhea-
free interval 
Diarrhea unresolved 

Continue standard anti-
diarrhea treatment (e.g. 
loperamide) 

Evaluate for  possible 
infection 

Administer oral 
antibiotics, if warranted 
Reassess 24 hours later 
Diarrhea unresolved 

Start Second line anti-
diarrheal (e.g. octreotide, 
or opiates) 
SYMPTOMS 
PERSIST 
 MANAGEMENT 
•
Patient must call physician immediately 
•
Interrupt  pazopanib and cytotoxic 
chemotherapy (if applicable) 
•
Evaluate for possible infection  
•
Consider hospitalization   
 
SUGGESTED TREATMENT 
•
Administer standard anti-diarrheal 
immediately, (e.g. loperamide)  
•
Hydration (i.v. fluids as needed) 
•
Consider need for antibiotics and consider 
second line anti-diarrheals  
Diarrhea Free for 24 hours 

Discontinue diarrhea intervention 

Consider reintroducing pazopanib 
at either full dose or reduced dose  
depending on clinical interpretation 
of risk-benefit ratio and cytotoxic 
chemotherapy (if applicable) 


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Nausea and Vomiting 
Every attempt should be made to control nausea and vomiting in subjects who have emesis and 
are unable to retain pazopanib. 
Routine pre-medication for nausea is not necessary, but symptomatic subjects should be treated 
with standard anti-nausea/anti-emetic therapy as necessary. 
If a subject vomits after taking study medication, the subject should be instructed not to take a 
replacement dose on that same day.  The subject should resume taking pazopanib at the next 
scheduled dose on the following day.  If vomiting persists then the subject should contact their 
physician. 
To prevent or treat nausea and vomiting standard medications are recommended.  Depending 
upon approved medications in your region, these may include: 5-HT3 receptor antagonist 
(granisetron, ondansetron, dolasetron mesylate); NK-1 receptor antagonists such as aprepitant,  
metoclopramide,  phenothiazines (prochlorperazine); corticosteroids, (dexamethasones, 
prednisone); and cannibinoids (dronabinol).  
References: 
Benson AB, Ajani JA, Catalano RB, Engelking C, Kornblau SM, Martenson JA, et al.  
Recommended Guidelines for the Treatment of Cancer Treatment-Inducted Diarrhea.  J Clin 
Oncol. 2004, 22; 2918-26. 


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Appendix IV:  Blood Serum Preparation 
 
1. Draw 10 ml whole blood into vacutainer tube(s) containing no anticoagulant.  
2. Incubate in an upright position at room temperature for 30-45 min (no longer than 60 min) to 
allow clotting. If using a clot-activator tube, invert carefully 5-6 times to mix clot activator and 
blood before incubation. 
3. Centrifuge for 15 min at 1000-2000 RCF.  Do not use brake to stop centrifuge. 
4. Carefully aspirate the supernatant (serum) at room temperature and pool into a centrifuge tube, 
taking care not to disturb the cell layer or transfer any cells. Use a clean pipette for each tube. 
5. Inspect serum for turbidity. Turbid samples should be centrifuged and aspirated again to 
remove remaining insoluble matter. 
6. Aliquot 1 ml of serum into each cryovial and store at –80 °C. Ensure that the cryovials are 
adequately labeled with the relevant information, including details of additives present in the 
blood. 


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Appendix V: Interventional Clinical Trial SAE Fax Cover Sheet – Suspected 
 
 
 
Interventional Clinical Trial SAE Fax Cover Sheet 
 
To: Local Novartis Drug Safety and Epidemiology Safety Desk 
 
 
Investigator contact details: 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
 
 
 
Relationship between study treatment and event(s) is: 
 
Suspected/Unknown 
 
  
Investigator Signature 
 
 
 
This document contains important safety information. 
If fax is received in error, please forward to 
 
 
 
 
Version 1.0, 01_Jul_2010 
 


Protocol Version #:  12.0 
Page 59 of 59 
July 7, 2017 
Protocol #:  117513 
Appendix VI: Interventional Clinical Trial SAE Fax Cover Sheet – Not Suspected 
 
 
 
Interventional Clinical Trial SAE Fax Cover Sheet 
 
To: Local Novartis Drug Safety and Epidemiology Safety Desk 
 
 
Investigator contact details: 
Fax number : ______________________________ 
Phone number : ____________________________ 
 
Study Name 
 
Centre Number 
 
Patient Number 
 
 
 
 
 
Relationship between study treatment and event(s) is: 
 
Not Suspected 
 
  
Investigator Signature 
 
 
 
This document contains important safety information. 
If fax is received in error, please forward to 
 
 
 
 
Version 1.0, 01_Jul_2010