Clinical trial NCT01755195
Conditions: Refractory Soft Tissue Sarcomas
Keywords: Dual Inhibitor of MET and VEGFR XL184 Metastatic Refractory Soft Tissue Sarcoma Rare Heterogeneous Tumor
Sponsor: National Cancer Institute (NCI)
Start date: 2013-01-15; Completion date: 2023-09-11
Enrollment: 55 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

\- Cabozantinib is a cancer treatment drug that blocks the growth of new blood vessels in tumors. It can also block a chemical on tumor cells that allows the cells to grow. A similar drug, pazopanib, is used to treat types of cancer known as sarcomas. Researchers want to see if cabozantinib can be an effective treatment for types of soft tissue sarcoma that have not responded to earlier treatments.

Objectives:

\- To test the effectiveness of cabozantinib for soft tissue sarcomas that have not responded to standard treatments.

Eligibility:

\- Individuals at least 18 years of age who have soft tissue sarcomas that have not responded to standard treatments.

Design:

* Participants will be screened with a physical exam and medical history. Blood samples will be collected. Imaging studies and other tests will be used to study the tumor before the start of treatment.
* Participants will take cabozantinib tablets daily for 28-day cycles of treatment. The tablets should be taken whole on an empty stomach.
* Treatment will be monitored with frequent blood tests and imaging studies.
* Participants will continue to take cabozantinib for as long as the tumor does not become worse and the side effects are not too severe.

Detailed description:
Background:

* Soft tissue sarcomas (STS) are a relatively rare heterogeneous group of tumors that constitute about 1% of adult cancers.
* The mainstay of treatment for advanced disease has been palliative chemotherapy with a median overall survival of approximately 12 months. This has not changed considerably in the past years and there is an unmet need for newer targeted therapies.
* Vascular endothelial growth factor (VEGF) levels are elevated in patients with STS and various sarcoma cell lines express high levels of activated c-Met receptor.
* We hypothesize that dual targeting of the VEGF and mesenchymal-epithelial transition factor (c-MET) pathways with cabozantinib would result in clinical benefit in patients with soft tissue sarcoma.

Objectives:

Primary:

* Assess the response rate (Complete Response (CR)+Partial Response (PR) of cabozantinib in patients with soft tissue sarcomas.
* Assess the 6 month progression free survival (PFS) of cabozantinib in soft tissue sarcomas.

Secondary:

-Determine and compare circulating levels of hepatocyte growth factor (HGF), soluble MET (sMET), VEGF-A, and soluble vascular endothelial growth factor receptor 2 (VEGFR2) (sVEGFR2) prior to and following administration of cabozantinib.

Eligibility:

* Patients must have had disease progression following one line of standard therapy
* Age greater than or equal to 18 years.
* Adequate organ function.

Design:

* All patients will receive cabozantinib at 60 mg by mouth (PO) daily in 4 week cycles.
* Tumor response evaluations by imaging will be done every 2 cycles (less frequently for patients on study more than one year).
* The study will be conducted as a dual-endpoint two-stage Phase II trial to target objective tumor response rate (CR+PR) of 30% against an unacceptably low rate of 10%, and 6-month PFS rate of 65% against an unacceptably low rate of 45% (corresponding to median PFS of 9.6 vs. 5.2 months).
* The trial will accrue up to 55 patients.

Arms: arm 1: 60 mg tablets orally once a day in a 28-day cycle.
Interventions: intervention 1: Cabozantinib
Intervention descriptions: intervention 1: Cabozantinib inhibits multiple receptor tyrosine kinases (RTKs) implicated in tumor growth, metastasis, and angiogenesis, and targets primarily mesenchymal-epithelial transition factor (MET) and vascular endothelial growth factor receptor 2 (VEGFR2).

Protocol documents:
ICF_001.pdf: 
PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/18/2021
Page 1 of 16
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CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
PRINCIPAL INVESTIGATOR:  A.P. Chen, MD, DCTD/NCI
STUDY TITLE: A Phase 2 Study of Cabozantinib (XL184), a Dual Inhibitor of MET and 
VEGFR, in Patients with Metastatic Refractory Soft Tissue Sarcoma
STUDY SITE: NIH Clinical Center
Cohort: Standard
Consent Version:  03/18/2021
WHO DO YOU CONTACT ABOUT THIS STUDY? 
Alice P. Chen, Principal Investigator: 240-781-3320
This consent form describes a research study and is designed to help you decide if you would like 
to be a part of the research study.  
You are being asked to take part in a research study at the National Institutes of Health (NIH). 
Members of the study team will talk with you about the information described in this document. 
Some people have personal, religious, or ethical beliefs that may limit the kinds of medical or 
research treatments they would want to receive (such as blood transfusions).  Take the time needed 
to ask any questions and discuss this study with NIH staff, and with your family, friends, and 
personal health care providers.  Taking part in research at the NIH is your choice.
IT IS YOUR CHOICE TO TAKE PART IN THE STUDY
You may choose not to take part in this study for any reason.  If you join this study, you may 
change your mind and stop participating in the study at any time and for any reason.  In either case, 
you will not lose any benefits to which you are otherwise entitled.  However, to be seen at the NIH, 
you must be taking part in a study or are being considered for a study.  If you do choose to leave 
the study, please inform your study team to ensure a safe withdrawal from the research.  
WHY IS THIS STUDY BEING DONE?
We are doing this study to try to develop better treatments for cancer.  In this study, the 
experimental drug cabozantinib will be given to you.  The purpose of this study is to find out if the 
drug is effective in a particular type of tumor called soft tissue sarcoma, which is what your doctor 
has diagnosed you with.  We are trying to understand how these drugs work in soft tissue sarcomas.  
For that, this study will look at how cabozantinib may affect the levels of certain proteins in your 
tumor.   
The use of cabozantinib in soft tissue sarcoma is experimental.  Cabozantinib works by two 
mechanisms.  Firstly, it acts by blocking the formation of new blood vessels in tumors, a process 
called angiogenesis.  New blood vessels provide oxygen and nutrients to growing cancers, and 
blocking this process can cause cancer cells or the supporting blood vessels to stop growing.  A 
IRB NUMBER: 13C0044
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drug that works by the same mechanism, pazopanib, has already been approved by the FDA for 
the treatment of patients with sarcoma.  In laboratory studies, some drugs that block angiogenesis 
increase the production of c-MET in tumors, which helps cancer cells adapt to not having enough 
oxygen, so the tumor can keep growing.  Cabozantinib also blocks c-MET in tumors.  By both 
these mechanisms the ability of the sarcoma tumor cells to survive may be markedly reduced by 
the drug.  
Although we hope this drug will decrease the size of your tumor, we cannot promise or predict 
the benefits of the treatment at this time.  The drug used in this study has known side effects that 
will be reviewed with you by your medical team before you sign the consent form. 
WHY ARE YOU BEING ASKED TO TAKE PART IN THIS STUDY?
You are being asked to take part in this research study because you have advanced cancer that has 
progressed after receiving standard treatment, or for which no effective therapy exists.  
HAVE THESE DRUGS BEEN GIVEN TO OTHER PEOPLE? 
Cabozantinib has been studied in many different cancer types like prostate cancer.  So far, more 
than 1300 patients have received cabozantinib in clinical trials for different types of cancers. 
HOW MANY PEOPLE WILL TAKE PART IN THIS STUDY? 
Up to 55 patients will take part in this study at 4 centers across the United States.
DESCRIPTION OF RESEARCH STUDY
WHAT WILL HAPPEN IF YOU TAKE PART IN THIS RESEARCH STUDY?  
Before you begin the study
You will need to have the following examinations, tests, or procedures to find out if you can be 
in the study.  These tests are part of your regular cancer care and should be done by your health 
care team even if you do not join the study.  If you have had them recently, they may not need to 
be repeated.  This will be up to your study doctor.
If you decide that you would like to participate in this study, you will be asked to sign this consent 
form.  You will then have the examinations, tests, and procedures listed below done to see if you 
can take part in the study (this is called the screening/baseline evaluation).

Complete medical history.

Physical examination, including height, weight, blood pressure, pulse, and temperature.

Standard blood tests (requiring about 1 tablespoon of blood in total), which include 
measurement of your white blood cells, red blood cells, platelets, blood sugar and 
electrolytes, how your liver and kidneys work, and how well your blood clots.

Pregnancy test in women who are able to become pregnant.
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PATIENT IDENTIFICATION
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
Urine tests: A urine test will be done to check the level of protein excreted by your 
kidneys.  Depending on the results of blood tests, you may be asked to collect your urine 
for 24 hours for further testing.

EKG to check your heart.

CT scans (a computerized x-ray examination) of your chest, abdomen, and pelvis to 
measure your tumor(s).  Other imaging tests may be done as needed.

Pathology slides:  Before starting on the study, we will request tumor slides or blocks to 
confirm your diagnosis.  
During the study
If you are accepted and choose to take part, you will begin taking the study drug cabozantinib.  
Cabozantinib is taken by mouth.  The study drug will be given in cycles.  All cycles are 4 weeks 
(28 days) long.  
Cabozantinib is taken 1 hour before or 2 hours after food.  Each day that you take study drug, 
you will be asked to fill in a diary to show when you took the study drugs, how many pills you 
took, and report any side effects you may have had.  
For some study procedures we will need you to come to the Clinical Center.  You will also have 
tests performed because you are in the study to see how the study drug is affecting your body and 
to find out how your body handles the study drug.  This will include imaging studies (for 
example, CT scans) to find out if your cancer has responded.  
Clinical Center Visits: We will ask that you come to the Clinical Center for at least 2 days 
during the first cycle, and then at the beginning of each cycle after that (less often if you have 
been on study for more than one year).  During the first cycle, you may be admitted to the 
Clinical Center for the first 2 days of drug administration to make it easier to perform study test 
and procedures to see how the drugs are affecting your body.  If you develop any side effects, 
you may be asked to visit more often.  Please see the study chart for more details. 
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IRB APPROVAL DATE: 04/06/2021


PATIENT IDENTIFICATION
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Standard procedures being done because you are in this study; these may be done more often 
because you are in the study:
Clinic visit to ask how you are feeling and to evaluate you with a physical at the beginning 
of each cycle (up to 8 days before the start of each cycle; less often if you have been on 
study for more than one year).
Vital signs and physical examination: will be performed during the clinic visits.
We will ask that you buy a blood pressure monitor (the cost of may be reimbursed to you; 
discuss with your study team) and measure your own blood pressure at home at least once a 
day (preferably twice a day) throughout the study.  You will record the readings in a diary.  
If your systolic blood pressure (top number) is ever more than 150 or your diastolic blood 
pressure (bottom number) more than 90, you should re-measure your blood pressure 1 to 4 
hours later.  If your systolic pressure is still greater than 150 or your diastolic blood 
pressure is still greater than 90, please contact your study team for instructions.  You 
should also call the research team if you experience any symptoms of high blood pressure, 
such as chest pain, shortness of breath, headache, blood in the urine, or double vision.
Blood tests: Measurement of your white blood cells, red blood cells and platelets, and 
measurements of your blood sugar, electrolytes, and how your liver and kidneys work will 
be done each time you are seen in the outpatient clinic.  All of these blood tests combined 
will require 1-2 tablespoons (20-30 mL) of blood each time.
Urine test to check urine protein will be done during the first cycle and then before you 
start each new cycle (less often if you have been on study for more than one year).  You 
may need it more frequently if the study doctor thinks it is needed to check for signs of 
possible damage to your kidneys.  Depending on the results of urine tests, you may be 
asked to collect your urine for 24 hours for further testing.  
CT scans or other imaging tests such as ultrasound (an examination using sound waves) or 
MRI (an examination using magnetic field and radio waves) that detect your tumor will be 
done every 2 cycles (about every 8 weeks; every 12 weeks if you have been on study for 
more than 1 year or every 16 weeks if on study for more than 3 years) while you are 
receiving treatment.  This is done so that any benefit of the treatment can be determined, 
and so that if your cancer is not responding to the treatment, the study team can tell you 
and help you move to a different treatment program (discussed further below).
Tests and procedures being done to see how the drug is affecting your body:
Research blood samples: We will collect blood samples to help us find out if cabozantinib 
affects the levels of certain proteins.  Blood will be collected before you first take the drug 
and on the first day of cycles 1 and 2 only.  Please see the study chart for more details.  The 
total blood for all these tests will be about 2 teaspoons.  
We will also be collecting optional blood samples to find out the effects of the drug on any 
tumor cells in your blood.  Blood samples will be collected before you first take the drug, on 
the first day of cycle 1, and on the first day of every cycle for as long as you are on study 
(every 3 cycles if you have been on study for more than one year or every 4 cycles if more 
than 3 years).  Each blood collection is about 2 teaspoons.  
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IRB APPROVAL DATE: 04/06/2021


PATIENT IDENTIFICATION
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STUDY CHART
The treatment is given over periods called cycles.  All cycles are 4 weeks long.  Treatment cycles 
will be repeated as long as you are tolerating the drugs and your cancer is either stable or getting 
better.  Each cycle is numbered in consecutive order.  The chart below shows what will happen 
during Cycle 1 and future cycles.  The left-hand column shows the day in the cycle, and the 
right-hand column tells you what will happen on that day.  This schedule shows what will 
happen to you after you sign the consent and start the study.  
Cabozantinib should be taken with water at least 1 hour before or 2 hours after a meal.  
The drug tablets should be swallowed whole with water and may not be crushed or broken.
Day
What to do and what will happen to you
Before starting 
study drugs
Check in at Outpatient Clinic
Get routine blood and urine tests
Pregnancy test for women who are able to become pregnant
Have a history taken of how you feel and undergo a physical 
examination including vital signs by a Health Care Provider (can be 
completed up to 8 days before the start of the study)
CT or MRI scan will be done
EKG will be done
Research blood samples will be taken
Cycle 1, 
Day 1
Admitted to Clinical Center
Begin taking cabozantinib 60 mg PO by mouth each day
Research blood samples will be taken 
You will be asked to keep a record of pill consumption and any new 
symptoms
Receive study diary
Cycle 1, 
Days 2 -28
Continue taking cabozantinib by mouth each day
Cycles 2 and 3, 
Day 1
Check in at Outpatient Clinic
Return study diary
Have a history taken of how you feel and undergo a physical 
examination including vital signs by a Health Care Provider (can be 
completed up to 8 days before the start of each new cycle)
Pregnancy test for women who are able to become pregnant
Get routine blood and urine tests (up to 8 days before)
Get a routine EKG (up to 8 days before)
Research blood samples will be taken
Continue taking cabozantinib by mouth each day
Cycles 2 and 3, 
Continue taking cabozantinib by mouth each day
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IRB APPROVAL DATE: 04/06/2021


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Day
What to do and what will happen to you
Days 2 -28
Cycle 4 onwards, 
D1
Clinic visits on D1 
will be every 3 
cycles (every 12 
weeks) if you have 
been on study for 
more than one 
year or every 4 
cycles (every 16 
weeks) if you have 
been on study for 
more than 3 years
Continue taking cabozantinib by mouth each day
Check in at Outpatient Clinic 
Return study diary 
Research blood samples will be taken on the first day of each cycle
Have a history taken of how you feel and undergo a physical 
examination including vital signs by a Health Care Provider (can be 
completed up to 8 days before the start of each new cycle)
Pregnancy test for women who are able to become pregnant
Get routine blood and urine tests (up to 8 days before)
EKG tests (up to 8 days before)
CT scans to determine how your tumor is responding to the treatment 
will be done every 2 cycles (every 8 weeks; every 12 weeks if you 
have been on study for more than one year or every 16 weeks if more 
than 3 years)
RISKS OR DISCOMFORTS OF PARTICIPATION
What side effects or risks can I expect from being in this study? 
If you choose to take part in this study, there is a risk that the XL184 (cabozantinib) may not be as 
good as the usual approach for your cancer or condition at shrinking or stabilizing your cancer.
You also may have the following discomforts:

Spend more time in the hospital or doctor’s office. 

Be asked sensitive or private questions about things you normally do not discuss.

May not be able to take part in future studies.
The XL184 (cabozantinib) used in this study may affect how different parts of your body work 
such as your liver, kidneys, heart, and blood.  The study doctor will test your blood and will let 
you know if changes occur that may affect your health.
There is also a risk that you could have side effects from the study drug(s)/study approach.
Here are important things to know about side effects:

The study doctors do not know who will or will not have side effects.

Some side effects may go away soon, some may last a long time, and some may never go 
away.

Some side effects may make it hard for you to have children.

Some side effects may be mild.  Other side effects may be very serious and even result in 
death.
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You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem:

If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect.

Your study doctor will work with you to treat your side effects.

Your study doctor may adjust the study drugs to try to reduce side effects.
Drug risks
The tables below show the most common and the most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you.”
High blood pressure is one common side effect of cabozantinib.  Your blood pressure will be 
closely watched while you are taking this drug.  You will also be checking your blood pressure at 
home at least once a day (preferable twice a day) for the entire study.  If you have high blood 
pressure while taking cabozantinib, your study doctor may recommend follow-up with your 
primary care physician and/or starting or increasing medication to lower your blood pressure.
Some patients on this study have experienced blood clots in the lungs, possibly related to the study 
drug.  Let your doctor know immediately if you experience any shortness of breath or chest pain.
In addition, some patients on this study have experienced sepsis, or an infection in the bloodstream, 
possibly related to the study drug.  This condition can cause fever, increased heart rate, increased 
breathing rate, and confusion.  Sepsis can be life-threatening.
Grapefruit juice has been shown to affect how the body handles some drugs by blocking the 
activity of the body’s cytochrome P450 (CYP450) system.  CYP450 is important in breaking down 
substances in the body, including cabozantinib.  Do not take grapefruit/ grapefruit juice or Seville 
oranges while participating in this trial.  Inform physician and study healthcare team about current 
medications including over the counter drugs, herbals, or natural medicines.  We do not know if 
taking cabozantinib will cause other drugs you may be taking to work differently.  It is very 
important that you talk to a member of the research team before beginning any new drugs, 
over-the-counter medications, vitamins, or alternative therapies.
Risks and side effects related to cabozantinib may include:
COMMON, SOME MAY BE SERIOUS  
In 100 people receiving XL184 (cabozantinib), more than 20 and up to 100 may have:

Diarrhea, nausea, vomiting

Tiredness

Weight loss, loss of appetite

Changes in taste 

Redness, pain or peeling of palms and soles

High blood pressure which may cause headaches, dizziness, blurred vision
IRB NUMBER: 13C0044
IRB APPROVAL DATE: 04/06/2021


PATIENT IDENTIFICATION
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NIH-2977 (4-17)
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OCCASIONAL, SOME MAY BE SERIOUS  
In 100 people receiving XL184 (cabozantinib), from 4 to 20 may have:

Anemia which may require blood transfusion

Pain

Constipation, heartburn

Dry mouth, skin

Sores in the mouth which may cause difficulty swallowing

Swelling of arms, legs

Infection

Bruising, bleeding

Dehydration

Muscle weakness

Dizziness, headache

Cough, shortness of breath

Internal bleeding which may cause black tarry stool, blood in vomit, coughing up blood, or 
blood in urine

Bleeding from multiple sites including the nose

Changes in voice

Hair loss, rash

Change in hair color

Blood clot which may cause swelling, pain, shortness of breath
RARE, AND SERIOUS
In 100 people receiving XL184 (cabozantinib), 3 or fewer may have:

A tear or hole in internal organs that may require surgery

Non-healing surgical site

Damage to the jawbone which may cause loss of teeth

Bleeding in the brain which may cause confusion

Stroke which may cause paralysis, weakness

Brain damage which may cause headache, seizure, blindness (also known as Reversible 
Posterior Leukoencephalopathy Syndrome)

Lung collapse
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Reproductive Risks
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how cabozantinib would affect your baby or your unborn child.  If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice two effective forms of birth control before starting study treatment, during 
study treatment, and for 4 months after you finish study treatment.  Your study team will talk 
with you about the kinds of birth control that can be used in this study.  
If you think that you or your partner is pregnant, you should tell your study doctor or nurse at 
once.  
Effective forms of birth control include:
•
abstinence 

intrauterine device (IUD)
•
hormonal [injections, or implants]: estrogen containing pills are not allowed due to 
the risk of blood clotting
•
tubal ligation
•
vasectomy
Side Effects of Blood Draw
Infrequent (occurs in 1 to 10 out of 100 people): persistent pain and discomfort at the injection or 
needle insertion site as well as possible infection, bleeding, bruising, and soreness. 
What are the risks of radiation from being in the study?
Potential Risks Related to Research-Related Imaging Studies:
During your participation in this research study, you may be exposed to radiation from up to 7 CT 
scans or FDG-PET/CT scans each year.  The amount of radiation exposure from these procedures 
is equal to approximately 8 rem. A rem is a unit of absorbed radiation. 
Every day, people are exposed to low levels of radiation that come from the sun and the 
environment around them.  The average person in the United States receives a radiation exposure 
of 0.3 rem per year from these sources.  This type of radiation is called “background radiation.”  
This study will expose you to more radiation than you get from everyday background radiation. 
No one knows for sure whether exposure to these low amounts of radiation is harmful to your 
body. 
The CT scans or FDG-PET/CT scans that you get in this study will expose you to roughly the same 
amount of radiation as 28 years’ worth of background radiation.  Being exposed to too much 
radiation can cause harmful side effects such as an increase in the risk of cancer.   The risk depends 
on how much radiation you are exposed to.  Please be aware that about 40 out of 100 people (40%) 
will get cancer during their lifetime, and 20 out of 100 (20%) will die from cancer.  The risk of 
getting cancer from the radiation exposure in this study is 0.8 out of 100 (0.8%) and of getting a 
fatal cancer is 0.8 out of 100 (0.8%).
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Potential Risks for FDG-PET/CT
In addition to the radiation risks described above, there is a chance of developing an allergic 
reaction from the FDG-PET contrast material, which may cause symptoms ranging from mild 
itching or a rash to severe difficulty breathing, shock or rarely, death.  The contrast material may 
also cause kidney problems.  The study doctors will do a blood test prior to the test to confirm that 
it is safe you to receive the contrast.
You may feel discomfort when the contrast material is injected.  You may feel warm, flushed, get 
a metallic taste in your mouth or, rarely, may make you vomit or feel sick to your stomach.  
The risks of IV insertion include temporary pain and bleeding or bruising at the site where the IV 
enters the skin.  In placing the IV, there is a small chance of fluid leaking into the tissue surrounding 
the IV and infection, which may cause some swelling and discomfort.  Rarely, the IV site may 
become infected, which might require treatment with antibiotics.
Potential Risks for MRI
People are at risk for injury from the MRI magnet if they have some kinds of metal in their body.  It 
may be unsafe for you to have an MRI scan if you have pacemakers or other implanted electrical 
devices, brain stimulators, some types of dental implants, aneurysm clips (metal clips on the wall 
of a large artery), metal prostheses (including metal pins and rods, heart valves, and cochlear 
implants), permanent eyeliner, tattoos, an implanted delivery pump, or shrapnel fragments.  
Welders and metal workers may have small metal fragments in the eye.  You will be screened for 
these conditions before having any MRI scan.  If you have a question about metal in your body, 
you should inform the staff.  You will be asked to complete an MRI screening form before each 
MRI scan you have. 
In addition, all magnetic objects (like watches, coins, jewelry, and credit cards) must be removed 
before entering the MRI scan room.
People with fear of confined spaces may become anxious during an MRI. Those with back 
problems may have back pain or discomfort from lying in the scanner.  The noise from the scanner 
is loud enough to damage hearing, especially in people who already have hearing loss.  Everyone 
having a research MRI scan will be fitted with hearing protection.  If the hearing protection comes 
loose during the scan, you should let us know right away.
There are no known long-term risks of MRI scans.
POTENTIAL BENEFITS OF PARTICIPATION
Are there benefits to taking part in this study? 
Taking part in this study may or may not make your health better.  We do not know if you will 
receive personal, medical benefit from taking part in this study.  These potential benefits could 
include shrinking of your tumor or lessening of your symptoms, such as pain, that are caused by 
the cancer.  You should discuss other treatment options with the study team and your home 
doctor before deciding to take part in this study.  We do know that information from this study 
will help doctors learn more about these study drugs.  This information will also help future 
cancer patients.
IRB NUMBER: 13C0044
IRB APPROVAL DATE: 04/06/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
ALTERNATIVE APPROACHES OR TREATMENTS
What other choices do I have if I do not take part in this study? 
Instead of being in this study, you have these options 

Getting treatment or care for your cancer without being in a study

Taking part in another study

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.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible.
Please talk to your doctor about these and other options.
RESEARCH SUBJECT’S RIGHTS
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 
this study.  If you decide to take part, 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 if you are eligible and choose to participate in another trial.  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.
USE OF SPECIMENS AND DATA FOR FUTURE RESEARCH
To advance science, it is helpful for researchers to share information they get from studying human 
samples.  They do this by putting it into one or more scientific databases, where it is stored along 
with information from other studies.  A researcher who wants to study the information must apply 
to the database and be approved.  Researchers use specimens and data stored in scientific databases 
to advance science and learn about health and disease.  
We plan to keep some of your specimens and data that we collect and use them for future research 
and share them with other researchers.  We will not contact you to ask about each of these future 
uses.  These specimens and data will be stripped of identifiers such as name, address or account 
number, so that they may be used for future research on any topic and shared broadly for research 
purposes.  Your specimens and data will be used for research purposes only and will not benefit 
you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.  
My specimens and data may be kept for use in research to learn about, prevent, or treat cancer or 
other health problems.  
IRB NUMBER: 13C0044
IRB APPROVAL DATE: 04/06/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Yes              No               Initials_________
COMPENSATION, REIMBURSEMENT, AND PAYMENT
Will you receive compensation for participation in the study?
Some NIH Clinical Center studies offer compensation for participation in research. The amount 
of compensation, if any, is guided by NIH policies and guidelines. 
You will not receive compensation for participation in this study. 
Will you receive reimbursement or direct payment by NIH as part of your participation?
Some NIH Clinical Center studies offer reimbursement or payment for travel, lodging or meals 
while participating in the research. The amount, if any, is guided by NIH policies and guidelines.
This study does not offer reimbursement for, or payment of, travel, lodging or meals. 
Will taking part in this research study cost you anything? 
NIH does not bill health insurance companies or participants for any research or related clinical 
care that you receive at the NIH Clinical Center. 
If you choose to take part in the study, the following will apply, in keeping with the NIH policy:

You will receive study treatment at no charge to you.  This may include surgery, 
medicines, laboratory testing, x-rays, or scans done at the Clinical Center, National 
Institutes of Health (NIH), or arranged for you by the research team to be done outside 
the Clinical Center, NIH if the study related treatment is not available at the NIH. 

There are limited funds available to cover the cost of some tests and procedures 
performed outside the Clinical Center, NIH.  You may have to pay for these costs even 
if they are not covered by your insurance company.

Medicines that are not part of the study treatment will not be provided or paid for by the 
Clinical Center, NIH.

Once you have completed taking part in the study, medical care will no longer be 
provided by the Clinical Center, NIH.

The study agent, cabozantinib, will be provided free of charge while you are 
participating in this study.  Even though it is unlikely, there is a possibility that at some 
point the supply of study agents may run out, necessitating taking you off-study.  

Even though it is unlikely, the manufacturer may not continue to provide the cabozantinib 
to the NCI for some reason.  If this would occur, other possible options are:
1. You might be able to get cabozantinib from the manufacturer or your pharmacy 
but you or your insurance company may have to pay for it.
2. If there is no cabozantinib available at all, no one will be able to get more and 
the study would close.
IRB NUMBER: 13C0044
IRB APPROVAL DATE: 04/06/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/18/2021
Page 13 of 16
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY

If a problem with getting cabozantinib occurs, your study doctor will talk to you about 
these options.  Medicines that are not part of the study treatment will not be provided or 
paid for by the Clinical Center, NIH.
EARLY WITHDRAWAL FROM THE STUDY 
Your doctor may decide to stop your therapy for the following reasons:

if he/she believes that it is in your best interest

if your disease comes back during treatment

if you have side effects from the treatment that your doctor thinks are too severe

if new information shows that another treatment would be better for you

if too many patients in the study experience severe side effects

if you become pregnant
In this case, you will be informed of the reason therapy is being stopped.
You can stop taking part in the study at any time.  However, if you decide to stop taking part in 
the study, we would like you to talk to the study doctor and your regular doctor first.  
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you.  However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the Cancer Therapy 
Evaluation Program (CTEP) at the National Cancer Institute (NCI) or designated representatives.  
If you withdraw your consent and leave the trial, any samples of yours that have been obtained 
for the study and stored at the NCI can be destroyed upon request.  However, any samples and 
data generated from the samples that have already been distributed to other researchers or placed 
in the research databases cannot be recalled and destroyed.
FOLLOW-UP 
You will be followed for 30 days after taking the last dose of study drug.  We will call you after 
about 30 days to ask about any side effects that were ongoing when you stopped therapy, or any 
new side effects that might be related to the study therapy.  If you have side effects that might be 
related to the study drugs that have not gotten better after 30 days, we will call you every 2 
weeks until the side effects have become stable or gotten better.  The follow-up period will end if 
you enroll on another protocol or start receiving standard therapy.  
CONFLICT OF INTEREST (COI) 
The NIH reviews NIH staff researchers at least yearly for conflicts of interest.  This process is 
detailed in a COI Guide.  You may ask your research team for a copy of the COI Guide or for more 
information.  Members of the research team who do not work for NIH are expected to follow these 
guidelines or the guidelines of their home institution, but they do not need to report their personal 
finances to the NIH.
No NIH investigator involved in this study receives payments or other benefits from any company 
whose drug, product or device is being tested.
IRB NUMBER: 13C0044
IRB APPROVAL DATE: 04/06/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/18/2021
Page 14 of 16
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
CLINICAL TRIAL REGISTRATION AND RESULTS REPORTING
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.
CONFIDENTIALITY PROTECTIONS PROVIDED IN THIS STUDY  
Will your medical information be kept private?
We will do our best to make sure that the personal information in your medical record will be kept 
private.  However, we cannot guarantee total privacy.  Organizations that may look at and/or copy 
your medical records for research, quality assurance, and data analysis include:

The NIH and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people.

National Institutes of Health Intramural Institutional Review Board

The study Sponsor, NCI Cancer Therapy Evaluation Program (CTEP), or their agent(s) 

Designated investigators from other cancer centers participating in this study, including the 
University of Southern California/Norris Comprehensive Cancer Center; the University of 
California, Davis, Cancer Center; and Stanford University Medical Center. 
The researchers conducting this study and the NIH follow applicable laws and policies to keep 
your identifying information private to the extent possible.  However, there is always a chance 
that, despite our best efforts, your identity and/or information about your participation in this 
research may be inadvertently released or improperly accessed by unauthorized persons.
In most cases, the NIH will not release any identifiable information collected about you without 
your written permission.  However, your information may be shared as described in the section of 
this document on sharing of specimens and data, and as further outlined in the following sections.  
Further, the information collected for this study is protected by NIH under a Certificate of 
Confidentiality and the Privacy Act. 
Certificate of Confidentiality
To help us protect your privacy, the NIH Intramural Program has received a Certificate of 
Confidentiality (Certificate). With this certificate, researchers may not release or use data or 
information about you except in certain circumstances.  
NIH researchers must not share information that may identify you in any federal, state, or local 
civil, criminal, administrative, legislative, or other proceedings, for example, if requested by a 
court.  
The Certificate does not protect your information when it:  
1. is disclosed to people connected with the research, for example, information may be used 
for auditing or program evaluation internally by the NIH; or 
2. is required to be disclosed by Federal, State, or local laws, for example, when information 
must be disclosed to meet the legal requirements of the federal Food and Drug 
Administration (FDA); 
3. is for other research;
IRB NUMBER: 13C0044
IRB APPROVAL DATE: 04/06/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
Version Date: 03/18/2021
Page 15 of 16
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
4. is disclosed with your consent. 
The Certificate does not prevent you from voluntarily releasing information about yourself or your 
involvement in this research. 
The Certificate will not be used to prevent disclosure to state or local authorities of harm to self or 
others including, for example, child abuse and neglect, and by signing below you consent to those 
disclosures. Other permissions for release may be made by signing NIH forms, such as the Notice 
and Acknowledgement of Information Practices consent.
Privacy Act
The Federal Privacy Act generally protects the confidentiality of your NIH medical records we 
collect under the authority of the Public Health Service Act.  In some cases, the Privacy Act 
protections differ from the Certificate of Confidentiality.  For example, sometimes the Privacy Act 
allows release of information from your medical record without your permission, for example, if 
it is requested by Congress. Information may also be released for certain research purposes with 
due consideration and protection, to those engaged by the agency for research purposes, to certain 
federal and state agencies, for HIV partner notification, for infectious disease or abuse or neglect 
reporting, to tumor registries, for quality assessment and medical audits, or when the NIH is 
involved in a lawsuit.  However, NIH will only release information from your medical record if it 
is permitted by both the Certificate of Confidentiality and the Privacy Act.
POLICY REGARDING RESEARCH-RELATED INJURIES  
The NIH Clinical Center will provide short-term medical care for any injury resulting from your 
participation in research here. In general, no long-term medical care or financial compensation for 
research-related injuries will be provided by the NIH, the NIH Clinical Center, or the Federal 
Government. However, you have the right to pursue legal remedy if you believe that your injury 
justifies such action.
PROBLEMS OR QUESTIONS
If you have any problems or questions about this study, or about your rights as a research 
participant, or about any research-related injury, contact the Principal Investigator, Alice P. Chen, 
chenali@mail.nih.gov, 240-781-3320.  You may also call the NIH Clinical Center Patient 
Representative at 301-496-2626, or the NIH Office of IRB Operations at 301-402-3713, if you 
have a research-related complaint or concern.
CONSENT DOCUMENT 
Please keep a copy of this document in case you want to read it again.
IRB NUMBER: 13C0044
IRB APPROVAL DATE: 04/06/2021


PATIENT IDENTIFICATION
Consent to Participate in a Clinical Research Study
NIH-2977 (4-17)
File in Section 4: Protocol Consent (1)
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MEDICAL RECORD
CONSENT TO PARTICIPATE IN AN NIH CLINICAL RESEARCH STUDY
Adult Research Participant: I have read the explanation about this study and have been given the opportunity 
to discuss it and to ask questions. I consent to participate in this study.
Signature of Research Participant
Print Name of Research Participant
Date
Legally Authorized Representative (LAR) for an Adult Unable to Consent: I have read the explanation 
about this study and have been given the opportunity to discuss it and to ask questions. I am legally authorized 
to make research decisions on behalf of the adult participant unable to consent and have the authority to provide 
consent to this study. As applicable, the information in the above consent was described to the adult participant 
unable to consent who agrees to participate in the study.
Signature of LAR
Print Name of LAR
Date
Investigator:
Signature of Investigator
Print Name of Investigator
Date
Witness to the oral short-form consent process only: 
Witness:
Signature of Witness*
Print Name of Witness
Date
*NIH ADMINISTRATIVE SECTION TO BE COMPLETED REGARDING THE USE OF AN 
INTERPRETER:
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent and served as a witness. The investigator obtaining consent may not 
also serve as the witness.
An interpreter, or other individual, who speaks English and the participant’s preferred language facilitated
the administration of informed consent but did not serve as a witness. The name or ID code of the person 
providing interpretive support is:
.
IRB NUMBER: 13C0044
IRB APPROVAL DATE: 04/06/2021

Prot_SAP_002.pdf: 
CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
1 
 
TITLE: A Phase 2 Study of Cabozantinib (XL184), a Dual Inhibitor of MET and 
VEGFR, in Patients with Metastatic Refractory Soft Tissue Sarcoma 
 
Abbreviated Title:  
 
Ph2 Cabozantinib Soft Tissue Sarcoma 
 
Coordinating Center: 
 
Developmental Therapeutics Clinic (NCIDTC) 
National Cancer Institute 
10 Center Drive 
Bethesda, MD 20892 
 
Participating Sites:  
 
City of Hope 
 Stanford University School of Medicine 
 University of Southern California  
  
Principal Investigator:   
A. P. Chen, MDA-E 
Center Drive Bldg 31 Rm 3A44 
Bethesda, MD 20892 
Phone: (240) 781-3320; Fax: (301) 402-0172 
chenali@mail.nih.gov 
 
 
 
 
 
 
 
 
 
Statistician: 
 
 
Larry Rubinstein, PhD, BRB/DCTDE 
 
 
 
 
 
9609 Medical Center Dr, Room 5W106 
 
 
 
 
 
Phone: (240) 276-6026 
 
 
 
 
 
rubinsteinl@mail.nih.gov 
 
 
Research Nurse: 
 
Ashley Bruns, RN, DCTD/NIHA,B,E 
 
 
 
10 Center Drive, Bldg 10/Rm 8D53  
 
 
 
Bethesda, MD 20892 
 
 
 
Telephone: (240) 858-3162  
 
 
 
Fax: (301) 451-5625  
 
 
 
ashley.bruns@nih.gov 
 
 
California Cancer Consortium (CCC) Participating Sites: 
 
City of Hope (CoH): 
FWA # FWA00000692 
 
IRB: David Holt 
Director, Clinical Research Protections 
City of Hope 
IRB of Record: City of Hope Natl Med Ctr & 
the 
Beckman Rsch Inst IRB#1 
IRB IORG#: IORG0000042 
Principal Investigator: Mark Agulnik, MD, FACP 
City of Hope Medical Center 
1500 E. Duarte Rd. 
Duarte, CA 91010 
Phone:  626-218-9200 
Fax:  626-218-8233 
magulnik@coh.org  
 
Pharmacy: Oscar Martin, PharmD 
Investigational Drug Service, City of Hope 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
2 
 
1500 E. Duarte Rd, Duarte, CA 91010 
Phone: (626) 218-3099; 
E-mail: daholt@coh.org  
 
1500 E. Duarte Rd., Duarte, CA 91010 
Phone (626) 256-4673 x62398; 
Fax: (626) 930-5378 
E-mail: omartin@coh.org 
 
University of Southern California (USC): 
FWA #00005906 
 
IRB Director: Sandy Jean 
University of Southern California Health 
Sciences Institutional Review Board   
IRB IORG# IRB00000484 
LAC+USC Medical Center 
General Hospital Suite 4700  
1200 North State St.  
Los Angeles, CA 90033 
Phone: (323) 276-2231 
Sandy.Jean@med.usc.edu 
 
Principal Investigator: James Hu, MD 
University of Southern California 
1441 Eastlake Ave. 
Los Angeles CA. 90033 
Phone:  323-865-0813 
Fax: 323-865-0061 
jameshu@med.usc.edu  
 
USC Pharmacy Contact:  Charlene Chiu, PharmD 
USC/Norris Comprehensive Cancer Center / 
Investigational Drug Services 
1441 Eastlake Avenue, Rm. 2407 
Los Angeles, CA. 90033 
Phone: (323) 865-3538; Fax: (323) 865-0857 
IDSPharmacy@med.usc.edu 
Stanford University School of Medicine  
FWA00000935 
 
Stanford University Administrative Panel on 
Human Subject in Medical Research 
IORG #0000208 
3000 El Camino Real, Five Palo Alto Square, 
4th Floor,  
Palo Alto, CA 94306 
 
Pharmacy contact: Martha "Marty" Hamilton 
Stanford Hospital and Clinics 
Investigational Pharmacy 
300 Pasteur Drive, Room H0302 
Stanford, CA 94305 
Phone (650-725-5295) Fax #: 650-725-6262 
MaHamilton@stanfordhealthcare.org 
Principle Investigator: Shivaani Kummar, MD  
Stanford University School of Medicine 
780 Welch Road, Rm CJ250L 
Palo Alto, CA 94304 
(650) 724-9084 
skummar@stanford.edu 
 
 
 
Kristine M. McGlennen, MN, RN 
Cancer Clinical Trials Office 
800 Welch Rd., FC2C19 
Stanford, California 94305 
Tel: (650) 723-3589 / Pager: (650) 723-8222 ext. 
26827 /Fax: (650) 736-8092 
 
CTEP Monitor:  
 
John J. Wright, MD, PhD 
 
NCI Supplied Agent:  
 
Cabozantinib (NSC 761968) 
 
IND number: 
 
 
116059 
 
NCT number: 
 
 
NCT01755195 
 
Protocol Version Date:  
July 12, 2023 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
3 
 
Roles: Aobtains information by intervening or interacting with living individuals for research 
purposes; Bobtains identifiable private information about living individuals; Cobtains the voluntary 
informed consent of individuals to be subjects; Dmakes decisions about subject eligibility; Estudies, 
interprets, or analyzes identifiable private information or data/specimens for research purposes 
 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
4 
 
 
PRÉCIS 
 
Background: 
• Soft tissue sarcomas (STS) are a relatively rare heterogeneous group of tumors that 
constitute about 1% of adult cancers. 
• The mainstay of treatment for advanced disease has been palliative chemotherapy with a 
median overall survival of approximately 12 months.  This has not changed considerably 
in the past years and there is an unmet need for newer targeted therapies. 
• VEGF levels are elevated in patients with STS and various sarcoma cell lines express 
high levels of activated c-Met receptor. 
• We hypothesize that dual targeting of the VEGF and c-MET pathways with cabozantinib 
would result in clinical benefit in patients with soft tissue sarcoma.  
Objectives:  
Primary: 
• Assess the response rate (CR+PR) of cabozantinib in patients with soft tissue sarcomas. 
• Assess the 6 month progression free survival (PFS) of cabozantinib in soft tissue 
sarcomas. 
Secondary: 
• Determine and compare circulating levels of HGF, soluble MET (sMET), VEGF-A, and 
soluble VEGFR2 (sVEGFR2) prior to and following administration of cabozantinib. 
Eligibility: 
• Patients must have had disease progression following one line of standard therapy 
• Age ≥ 18 years. 
• Adequate organ function. 
• Patients will be stratified based on prior VEGFR TKI therapy. 
Design: 
• All patients will receive cabozantinib at 60 mg PO daily in 4 week cycles. 
• Tumor response evaluations by imaging will be done every 2 cycles (less frequently for 
patients on study more than one year). 
• The study will be conducted as a dual-endpoint two-stage Phase II trial to target objective 
tumor response rate (CR+PR) of 30% against an unacceptably low rate of 10%, and  
6-month PFS rate of 65% against an unacceptably low rate of 45% (corresponding to 
median PFS of 9.6 vs. 5.2 months). 
• The trial will accrue up to 50 evaluable patients. 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
5 
 
SCHEMA 
 
 
 
 
 
 
 
 
Cabozantiniba 
D1 
D15 
D22 
D8 
D28 
Cabozantinib 
D1 
D15 
D22 
D8 
D28 
PD Samplingb 
Cycle 1 
Cycle 2 onwards  
aCabozantinib 60 mg po q day continuously throughout.  Cabozantinib will be taken on an 
empty stomach 1 hour before, or 2 hours after, a meal. 
bBlood samples for PD analyses (mandatory at the NCI but optional at participating sites) 
collected at baseline (pre-treatment), on C1D1 (3-6 hours post dose), and on C2D1 (3-6 
hours post dose). 
cBlood samples for CTC analyses (optional) collected at baseline (pre-treatment), on C1D1 
4 hours (+/- 1 hour) post dose, on day 1 of all subsequent cycles before drug 
administration, and at disease progression.   
CTCsc 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
6 
 
TABLE OF CONTENTS 
PRÉCIS ................................................................................................................................4 
SCHEMA .............................................................................................................................5 
1 
OBJECTIVES ..........................................................................................................8 
1.1 Primary Objectives ...................................................................................................8 
1.2 Secondary Objectives ...............................................................................................8 
2 
BACKGROUND .....................................................................................................8 
2.1 Soft Tissue Sarcoma (STS) ......................................................................................8 
2.2 Cabozantinib (XL184) .............................................................................................9 
2.3 Correlative Studies .................................................................................................15 
2.4 Rationale ................................................................................................................16 
3 
PATIENT SELECTION ........................................................................................18 
3.1 Eligibility Criteria ..................................................................................................18 
3.2 Exclusion Criteria ..................................................................................................19 
3.3 Inclusion of Women and Minorities ......................................................................23 
3.4 Eligibility Screening Evaluation ............................................................................23 
4 
REGISTRATION PROCEDURES .......................................................................24 
4.1 Registration Process ...............................................................................................24 
4.2 Participating Site Registration ...............................................................................24 
4.3 Off Protocol Therapy and Off-Study Procedure ....................................................24 
5 
TREATMENT PLAN ............................................................................................25 
5.1 Agent Administration .............................................................................................25 
5.2 General Concomitant Medication and Supportive Care Guidelines ......................27 
5.3 Duration of Therapy ...............................................................................................28 
5.4 Duration of Follow Up ...........................................................................................29 
5.5 Criteria for Removal from Study ...........................................................................29 
6 
DOSING DELAYS/DOSE MODIFICATIONS....................................................29 
6.1 Management of Cabozantinib-related AE .............................................................30 
7 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .................41 
7.1 Comprehensive Adverse Events and Potential Risks List (CAEPR) .....................41 
7.2 CTEP Reporting Requirements ..............................................................................46 
7.3 NIH Reporting Requirements ................................................................................49 
8 
PHARMACEUTICAL INFORMATION ..............................................................50 
8.1 Cabozantinib (NSC 761968) ..................................................................................50 
8.2 Agent Ordering ......................................................................................................51 
8.3 Agent Accountability .............................................................................................52 
8.4 Investigator Brochure Availability ........................................................................52 
8.5 Useful Links and Contacts .....................................................................................52 
9 
CORRELATIVE STUDIES ..................................................................................53 
9.1 Pharmacodynamics ................................................................................................53 
10 
STUDY CALENDAR ...........................................................................................57 
11 
MEASUREMENT OF EFFECT............................................................................59 
11.1 Antitumor Effect – Solid Tumors ..........................................................................59 
11.2 Methods for Evaluation of Measurable Disease ....................................................61 
11.3 Response Criteria ...................................................................................................63 
11.4 Duration of Response .............................................................................................65 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
7 
 
11.5 Progression-Free Survival ......................................................................................65 
12 
DATA REPORTING / REGULATORY REQUIREMENTS ...............................65 
12.1 Data Reporting .......................................................................................................65 
12.2 Data Safety and Monitoring Plan ...........................................................................66 
12.3 Multicenter Guidelines ...........................................................................................67 
12.4 Collaborative Agreements Language .....................................................................68 
13 
STATISTICAL CONSIDERATIONS...................................................................70 
13.1 Study Design/Endpoints.........................................................................................70 
13.2 Sample Size/Accrual Rate ......................................................................................70 
13.3 Stratification Factors ..............................................................................................70 
13.4 Analysis of Secondary Endpoints ..........................................................................70 
13.5 Reporting and Exclusions ......................................................................................71 
14 
HUMAN SUBJECTS PROTECTIONS ................................................................71 
14.1 Justification for Subject Selection .........................................................................71 
14.2 Evaluation of Benefits and Risks/Discomforts ......................................................72 
14.3 Consent and Assent Process and Documentation ..................................................72 
14.4 Procedure for Protecting Against or Minimizing Any Potential Risks ..................73 
14.5 Patient Advocate ....................................................................................................73 
REFERENCES ..................................................................................................................74 
APPENDIX A:PERFORMANCE STATUS CRITERIA ..................................................77 
APPENDIX B: POTENTIAL DRUG INTERACTIONS..................................................78 
APPENDIX C: STUDY DIARY .......................................................................................80 
APPENDIX D: DRUG INTERACTIONS ........................................................................83 
APPENDIX E: CTEP MULTICENTER GUIDELINES ..................................................84 
APPENDIX F: ELIGIBILITY/PRE-REGISTRATION WORKSHEET ..........................86 
APPENDIX G: INFORMED CONSENT TEMPLATE FOR MULTICENTER..............92 
APPENDIX H: PD COLLECTION WORKSHEETS .....................................................103 


CTEP Protocol #9284 
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1 OBJECTIVES 
1.1 
Primary Objectives 
• Assess the response rate (CR+PR) of cabozantinib in patients with soft tissue sarcomas. 
• Assess the 6 month progression free survival (PFS) of cabozantinib in soft tissue 
sarcomas. 
1.2 
Secondary Objectives 
• Determine and compare circulating levels of HGF, soluble MET (sMET), VEGF-A, 
and soluble VEGFR2 (sVEGFR2) prior to and following administration of 
cabozantinib. 
 
 
2 BACKGROUND 
2.1 
Soft Tissue Sarcoma (STS) 
Soft tissue sarcomas (STS) are a relatively rare heterogeneous group of tumors that arise mainly 
from embryonic mesoderm.  They constitute about 1% of adult cancers with 10,000 new cases 
diagnosed every year in the US with an overall mortality rate of 3,920 cases per year including 
adults and children.1  More than 50 different histological types have been identified the most 
common of which are pleiomorphic sarcoma also known as malignant fibrous histiocytoma 
(MFH), GIST, liposarcoma, leiomyosarcoma, synovial sarcoma, malignant peripheral nerve 
sheath tumors.2  Diagnosis at an early stage is crucial since complete surgical resection yields the 
best prognosis.  However, the lack of a screening modality makes it difficult with more than 50% 
of patients developing metastasis during their course of disease decreasing their 5 yr survival to 
below 10%.The mainstay of treatment for the advanced disease patients has been palliative 
chemotherapy.  The chemotherapy backbone of an anthracycline with or without ifosfamide has 
been used for decades and yielded response rates of 20-30% and a median overall survival of 
approximately 12 months.3-10  Anthracycline resistant STS and certain subtypes like 
leiomyosarcoma appear to have better responses to the combination of gemcitabine and 
docetaxel which is the only regimen in STS which has demonstrated an overall survival 
advantage in the phase III randomized setting.11-13  With the median survival of these patients 
having changed very little over the past decade there is an unmet need for newer targeted 
therapies. 
 
One of the targets that have emerged in this setting is the tumor produced angiogenic factor 
vascular endothelial growth factor (VEGF).  It has been shown that VEGF levels are elevated in 
patients with STS and correlates with the grade of the tumor.14-17  Factors other than VEGF, such 
as platelet-derived growth factor (PDGF), are also likely to be involved in STS angiogenesis.18  
Bevacizumab a monoclonal antibody against VEGF has been studied in combination with 
chemotherapy regimens including gemcitabine, docetaxel19 and temozolomide20 with promising 
results.  Pazopanib, an oral angiogenesis inhibitor that targets VEGF receptors (VEGFRs), PDGF 
receptors (PDGFRs), and c-kit has also been studied in STS in phase II21 and III settings22 to 
show improvement in PFS by 13 weeks compared to placebo. 
 


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Hepatocyte growth factor/scatter factor (HGF/SF) activates the c-Met receptor tyrosine kinase 
and promotes cell proliferation, survival, and invasion and also plays a role in angiogenesis.23,24  
Various sarcoma cell lines express high levels of activated c-Met receptor and suggesting that 
HGF/SF signaling pathway may contribute to sarcomagenesis.25  Interruption of autocrine or 
paracrine HGF/SF c-met signaling with the monoclonal antibody AMG102 in leiomyosarcoma 
cell line SK-LMS-1 and in mouse xenograft models has shown significant antitumor effect.26 It 
has also been shown that clear cell sarcoma cells are dependent on HGF/C-Met axis27 for 
invasion, chemotaxis, and survival. 
2.2 
Cabozantinib (XL184) 
Cabozantinib is a new chemical entity that inhibits the receptor tyrosine kinases MET 
(hepatocyte growth factor [HGF] receptor) and VEGFR2 (vascular endothelial growth factor 
receptor 2).  Both MET and VEGFR2 are important mediators of tumor growth and tumor 
angiogenesis, and MET is particularly associated with tumor invasiveness and metastasis.  In 
vivo pharmacodynamic activity of cabozantinib against MET and VEGFR2 has been 
demonstrated in both preclinical and clinical studies and has been associated with tumor growth 
inhibition and tumor regression.  In preclinical studies, cabozantinib treatment has also been 
shown to inhibit tumor angiogenesis, tumor invasiveness and metastasis, and the progression of 
tumors in bone.  Cabozantinib inhibits multiple RTKs implicated in tumor growth, metastasis, 
and angiogenesis (Investigator's Brochure, 2011).  The primary targets of cabozantinib are MET 
and VEGFR2; additional targets include RET, AXL, KIT, and TIE-2. 
 
Cabozantinib is a potent inhibitor of MET and VEGFR2 with half-maximal inhibitory 
concentration (IC50) values of 1.3 nmol/L and 0.035 nmol/L, respectively.28  Cabozantinib 
strongly inhibited several kinases that have also been implicated in tumor pathobiology, 
including KIT, RET, AXL, TIE2, and FLT3 (IC50 = 4.6, 5.2, 7, 14.3, and 11.3 nmol/L, 
respectively).  Cabozantinib did not potently inhibit kinases such as RON, EGFR, IGFR1, and 
EphA4/B4.  In cellular assays, it inhibited phosphorylation of MET and VEGFR2, as well as 
KIT, FLT3, and AXL with IC50s of 7.8, 1.9, 5.0, 7.5, and 42 μmol/L, respectively.28  
 Nonclinical Development of XL184  
In Vivo Activity 
In RIP-Tag2 transgenic mice (model of pancreatic neuroendocrine carcinoma), tumors 
treated with XL184 were smaller (P <0.05) than in mice treated with vehicle or an anti-
VEGF antibody, but were also less invasive (P <0.05) and had no liver metastases.29  All 
mice treated with XL184 (n = 6) survived until 20 weeks, but none treated with vehicle  
(n = 14) or anti-VEGF antibody (n= 8) reached that endpoint.  Tumor vascularity 
decreased after treatment, with reductions ranging from 67% at 3 mg/kg to 83% at 30 
mg/kg for 7 days (You et al., 2011).  Tumors were 35% smaller after XL184 treatment 
than corresponding values for vehicle control mice.  c-Met protein in tumors was slightly 
less, but phosphorylated c-Met was markedly reduced after treatment for 7 days.  
 
Mice bearing MDA-MB-231 cells (expressing MET and VEGF) were administered four 
oral doses of 100 mg/kg.28  XL184 increased tumor hypoxia (13-fold) and apoptosis 
(TUNEL; 2.5-fold) at 8 and 4 hours after the first and second doses, respectively, when 
compared to vehicle-treated tumors.  In addition, XL184 disrupted tumor vasculature by 
inducing endothelial cell death that negatively impacted tumor viability.  XL184 


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treatment resulted in significant tumor growth inhibition of MDA-MB-231 tumors (P 
<0.001) at all doses (1, 3, 10, 30, or 60 mg/kg) when compared to vehicle-treated tumors.  
Dose-dependent inhibition was observed for the 3 and 10 mg/kg doses (P <0.01), and 
complete inhibition was observed at the 30 and 60 mg/kg doses.  A single 100 mg/kg 
dose resulted in sustained MDA-MB-231 tumor growth inhibition for ~8 days after which 
tumors began growing at a rate similar to vehicle-treated control tumors.  In addition, 
XL184 inhibited tumor growth (P <0.001) in the MET-expressing rat C6 glioma cell line 
for all doses (1, 3, 10, 30, or 60 mg/kg) when compared with vehicle-treated tumors.  The 
3 mg/kg and 10 mg/kg doses resulted in significant tumor regression (62% and 85%, P 
<0.0001) when compared with pre-dose tumor weights.  Subchronic administration of 
XL184 was well tolerated in mice and rats with no signs of toxicity, as determined by 
stable and/or increasing body weights during the treatment period.28 
 
Pharmacodynamics 
In vivo pharmacodynamic experiments showed that XL184 inhibits key RTKs that 
promote tumor cell proliferation and/or angiogenesis (MET, VEGFR2, TIE-2, and RET) 
(Investigator's Brochure, 2010).  In mice, the effective dose resulting in 50% inhibition 
(ED50) of targets was achieved at well tolerated doses of XL184 and at plasma exposures 
comparable to exposure observed in clinical trials.  XL184 produced prolonged inhibition 
of receptor phosphorylation, such as sustained inhibition of MET and VEGFR2 for 10 
hours after administration of a single dose of XL184.  This extended inhibition occurred 
in a manner that was generally predicted by plasma exposure, i.e., inhibition was 
diminished when plasma levels fell below approximately 20 μM for MET, 5 μM for 
VEGFR2, and 23 μM for TIE-2. 
 
Once daily administration of XL184 resulted in significant inhibition of MET 
phosphorylation in TT tumors, with maximal inhibition of 70% seen at 60 mg/kg, relative 
to tumors from vehicle control-treated mice (Investigator's Brochure, 2011).  Dose-
dependent inhibition of phosphorylation of MET and RET was observed among the 3, 10, 
and 30 mg/kg dose groups.  
 
MET phosphorylation was inhibited by a single 100 mg/kg oral dose of XL184, 2–8 
hours post dose in H441 tumors (human lung papillary adenocarcinoma) that harbor 
constitutively phosphorylated MET 28. This effect was reversible, as MET 
phosphorylation returned to basal levels by 48 hours after treatment. 
 
 
Toxicology 
In rodents and non-rodents, histopathological changes associated with XL184 
administration were observed in gastrointestinal (GI) tract, bone marrow, lymphoid 
tissues, kidney, and adrenal and reproductive tract tissues (Investigator's Brochure, 2011).  
Histopathological changes present in the bone and pancreas were considered secondary to 
XL184 administration.  Adverse effects following oral exposure to XL184 were generally 
dose-related, clinically monitorable, and self-resolving upon discontinuation of dosing.  
In 6-month chronic toxicity studies, treatment-related changes were present only in 
kidney (rats) and reproductive tissues (dog).  In reproductive/developmental toxicity 
studies, XL184 administration resulted in decreased fertility in male and female rats, in 
embryotoxicity when given to pregnant rats, and in a visceral tissue malformation (small 


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spleen) when given to pregnant rabbits.  The no-observable-adverse-effect-levels 
(NOAELs) for the chronic toxicity and reproductive/developmental toxicity studies 
occurred at plasma exposures (AUC) below steady-state values measured in subjects with 
solid tumors administered 175 mg XL184 capsule form daily (Study XL184-001).  
 
In definitive genotoxicity bioassays, XL184 was negative in an S. typhimurium/E. coli 
bacterial mutagenicity study, an in vitro chromosome aberration study using human 
peripheral blood lymphocytes, and an in vivo mouse bone marrow micronucleus study.  
In safety pharmacology studies, no adverse effects occurred on neurobehavioral or 
respiratory functions in XL184-treated rats or on cardiovascular function in XL184-
treated dogs. 
 Clinical studies with Cabozantinib  
As of 4 May 2011, 1003 subjects have been enrolled in open-label clinical studies of 
cabozantinib, and 330 subjects have been enrolled in a placebo-controlled blinded Phase 
3 study.  Clinical data are available from nine studies of cabozantinib including four 
Phase 1 studies, one Phase 1b/2 study, three Phase 2 studies, and one Phase 3 study.  
Doses in the studies listed in Table 1 are in terms of salt-based dosing with the exception 
of study XL184-203, where the free-base equivalent weight is also noted.  
 
Table 1. 
Study # 
Phase 
Patient 
Population 
Dose and Response 
XL184-001  
 
1 Solid tumors 
Single-agent: Capsules: 25 and/or 100 mg PO daily (QD).  
10 (29%) of 35 patients with MTC had a cPR31.  Overall, of 
85 patients with advanced solid tumors, 18 patients 
experienced tumor shrinkage of 30% or more, including 17 
(49%) of 35 patients with MTC.  In addition, 15 (41%) of 
37 patients with MTC had SD for at least 6 months.  In the 
non-MTC subset, SD of at least 3 months was reported in 
38% of patients with the following tumors: colorectal (three 
patients); melanoma (two patients); carcinoid (two patients) 
tumors; and adenoid cystic, follicular thyroid, papillary 
thyroid, HCC, RCC, CTCL, salivary gland, ASPS, clear-
cell sarcoma, mesothelioma, and neuroendocrine tumor 
originating in the thyroid (one patient each). 
 
XL184-002  
 
1 Newly diagnosed 
glioblastoma 
XL184 qd in combination with TMZ and radiation therapy 
in the concurrent phase and with TMZ in the maintenance 
phase  
Arm 1, XL184: initiated at the start of 6–7 week concurrent 
phase of RT, given as a single agent during the 4-week rest 
phase, and continued subsequently in the maintenance 
phase.  
TMZ: starting dose of 75 mg/m2/day QD with concurrent 
RT for 6 weeks.  Arm 2, XL184: initiated during the 
maintenance phase with TMZ.  TMZ: starting dose of 200 
mg/m2/day given 5 consecutive days and repeated every 28 
days.  MTD Expansion, XL184: initiated at the start of 6–7 
week concurrent phase of RT, given as a single agent during 


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Study # 
Phase 
Patient 
Population 
Dose and Response 
the 4-week rest phase, and continued subsequently in the 
maintenance phase.  XL184 and TMZ will be given at 
MTDs determined in Arms 1 and 2.   
 
XL184-008  
 
1 
Differentiated 
thyroid cancer 
(DTC) or 
metastatic RCC  
 
Drug-drug interaction study with exploratory objective of 
anti-tumor activity.  XL184: 175 mg PO QD.  
Rosiglitazone: one 4 mg dose followed by a second 4 mg 
dose 3 weeks later.   
CA205-001  
 
1 
Advanced or 
metastatic solid 
tumors (Japan)  
 
Starting dose: 75 mg PO QD; reduced to 50 mg.  
Study closed when collaboration with BMS was terminated  
XL184-014  
 
1 
Advanced or 
metastatic solid 
tumors (Japan)  
 
Starting dose 50 mg  
 
XL184-202  
 
1
NSCLC  
 
Multiple dose levels of erlotinib + XL184 were evaluated.  
Response: The dose levels in phase 2 study XL184-202 are: 
arm B (75 mg XL184 + 150 mg erlotinib and 50 mg XL184 
+ 150 mg erlotinib [MTD]) and arm A (75 mg XL184 + 100 
mg erlotinib; 125 mg XL184 + 100 mg erlotinib; and 125 
mg XL184 + 50 mg erlotinib) (Wakelee et al., 2010).  Six 
of 36 evaluable patients, including at least 3 patients with 
prior erlotinib therapy, had 30% reduction in tumor 
measurements on at least 1 post-baseline scan, including 3 
with a cPR (1 with MET amplification).  Prolonged SD of 4 
months was observed in some patients, including one 
patient for 9+ months and one patient with epidermal 
growth factor receptor (EGFR) T790M.  A cPR was 
achieved in 5 of 64 (8%) evaluable patients enrolled in 
phase 1 (Investigator's Brochure, 2011).  In phase 2, a cPR 
was observed in one patient treated with single-agent 
XL184. 
 
XL184-201  
 
2 
Progressive or 
recurrent GB  
 
Group A: initial dose of 175 mg. Groups B and C: initial 
dose of 125 mg.  Response: at the dose of 125 mg QD, 
cPRs were observed in 11 of 37 (30%) patients without 
prior anti-angiogenic therapy, with a median duration of 
response of 5.1 months (range = 0.9–6.7) (Investigator's 
Brochure, 2011).  At 175 mg QD, cPRs were observed in 7 
of 34 (21%) patients without prior anti-angiogenic therapy, 
with a median duration of response of 2.9 months (range = 
1.9–12.8). 
 
XL184-203  
 
2 
Nine tumor-
specific cohorts: 
breast cancer, 
gastric/GEJ 
adenocarcinoma, 
Starting dose: 125 mg QD (100 mg freebase equivalent 
weight) during 12-weeks run-in phase.  Patient with CR or 
PR continued XL184.  Patients with SD were randomized to 
placebo or XL184  
Patients with PD discontinued treatment.  


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Study # 
Phase 
Patient 
Population 
Dose and Response 
HCC, melanoma, 
NSCLC, ovarian 
cancer, pancreatic 
cancer, prostate 
cancer, SCLC  
 
Non-randomized extension cohorts in CRPC and ovarian 
cancer  
Response: One hundred seventy one CRPC subjects were 
enrolled.  Randomization was suspended after 122 subjects 
were enrolled due to demonstrated clinical benefit.  Seven 
patients achieved a cPR at week 12, and three additional 
patients achieved PR after the 12-week lead-in stage.  The 
disease-control rate (rate of response +stable disease) at 
week 12 was 68%.  Seventeen subjects were randomized to 
placebo; 14 to XL184.  Among these subjects, the hazard 
ratio for PFS was 0.013 (p = 0.007).  Of 108 subjects 
evaluable for bone scan response, 19% had complete 
resolution; 56% had partial resolution; 21% had stable 
disease and only 3% had progression as their best response.  
Three hundred nineteen subjects with non-CRPC advanced 
solid tumors were also enrolled in study XL184-203 .The 
overall ORR at week 12 by cohort was: HCC 10% (3/30 
patients), NSCLC 10% (6/60 patients), breast 10% (2/20 
patients), melanoma 5% (4/77 patients), SCLC 5% (1/21 
patients), pancreatic 0% (0/20) and gastric/GEJ 0% (0/21).  
In 51 evaluable epithelial ovarian cancer patients, at 12 
weeks, the overall RR was 24% (12/51 patients), 21% in 
platinum-refractory/resistant patients (7/34)), and 28% in 
platinum-sensitive patients (10/36).  The highest disease 
control rates at week 12 were HCC (73%), ovarian (53%), 
melanoma (47%), breast (45%), and NSCLC (40%).   
 
XL184-205  
 
2 
Grade IV 
astrocytic tumors  
 
25 mg QD continuously (Arm 1); 75 mg QD continuously 
(Arm 2); 125 mg QD for two weeks followed by 50 mg QD 
continuously (Arm 3); and 125 mg QD on an intermittent 3 
weeks on/1 week off schedule (Arm 4).  
 
XL184-301  
 
3 
Unresectable, 
locally advanced 
or metastatic 
MTC  
 
175 mg QD or placebo administered QD. 
Response: Randomized, double blind, placebo-controlled 
study recently reported top line data indicating that the 
primary endpoint of the study, PFS, was met.  PFS on the 
cabozantinib arm was 11.2 months compared to 4 months 
on placebo, hazard ratio [HR] 0.28, p < 0.0001.   
 
The dose of 60 mg proposed in this study is based on a recent trial reported at ASCO 
2012 30.  An adaptive response scheme was used to determine the lowest active daily 
cabozantinib dose among dose levels +1 (60 mg), 0 (40 mg), and -1 (20 mg).  The 
primary endpoint was wk 6 bone scan response (BSR) assessed with an automated FDA 
510(k) approved computer-aided detection system.  A ≥30% decrease in total bone scan 
lesion area (BSLA) was defined as a response.  The first cohort was treated at dose level 
0.  The number of responses (≥8 vs. <8 among 11 evaluable pts) was used to select the 
dose level (-1 vs. +1) for the second cohort.  Based on the observed BSR rate in the 
second cohort of 11 patients, a dose was selected for expansion to treat 13 more pts.  The 
study completed planned enrollment of 36 pts.  Median age was 66; 44% were docetaxel-


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pretreated.  Among 12 pts enrolled at dose level 0, there were 10 BSRs at wk 6 including 
1 complete response (CR), and 1 pt with stable disease (SD).  The median decrease in 
BSLA was 62%.  Ten patients evaluated at wk 12 included 9 BSRs (3 CRs), and 1 
sustained SD.  Among 11 pts then treated at dose level -1, 10 pts were evaluable at wk 6: 
1 BSR, 5 SD, and 4 had progressive disease.  No pts in the 2 cohorts required dose 
reduction or treatment interruption at 12 wks; 1 patient discontinued due to grade 3 AEs 
(anorexia, fatigue).  6/12 pts with ≥ 6 months follow-up remain on study.  5/5 pts enrolled 
at 40 mg with CTCs ≥5 per 7.5 mL converted to <5.  Thirteen pts accrued to the 
expansion cohort at 40 mg daily had confirmed high BSR rate.  The study concluded that 
cabozantinib 40 mg daily achieves a high BSR rate in men with CRPC and bone 
metastases, and is associated with better tolerability than previously reported for 
cabozantinib 100 mg daily.  Hence, the manufacturer is carrying a dose of 60 mg forward 
in phase III trials, which is the dose that we have chosen in our trial. 
 
Pharmacokinetics 
In study XL184-00131, pharmacokinetic (PK) analysis showed dose-proportional 
increases in plasma exposure (Cmax and AUC) both for the PIB formulation (dose range: 
0.08 to 11.52 mg/kg) and the capsule formulation (dose range: 125 mg to 175 mg).  After 
repeat daily dosing, t1/2, z values (mean ± standard deviation) for cabozantinib were 91.3 
± 33.3 hours (n = 23), and apparent steady-state plasma levels were reached by day 15.  
Steady-state clearance for the 175 mg capsule dose derived from repeat dose data was 4.2 
± 1.5 L/h. Patients who received 175 mg capsules had four- to five-fold higher steady-
state exposure (AUC) compared with Day 1 (7.68 ± 2.85 μg·h/mL; n = 23 vs. 41.6 ± 15.5 
μg·h/mL; n = 23), indicating that cabozantinib accumulated with repeat daily dosing.  
There was no significant difference in exposure between patients with MTC and those 
without MTC.  
 
Safety 
As of March 1, 2011, the most frequently (>20%) observed adverse events (AEs) in 806 
patients treated in single agent, open label cabozantinib studies, regardless of the 
relationship to drug, were fatigue, diarrhea, nausea, decreased appetite, constipation, 
palmar-plantar erythrodysesthesia (PPE) syndrome, vomiting, dysphonia and 
hypertension, (Investigator's Brochure, 2011).  Effects that may be related to the 
inhibition of VEGF, including hypertension, thromboembolic events, GI perforation, 
fistula formation, hemorrhage, wound healing complications, and proteinuria, have also 
been observed.  As of 4 May 2011, of the 1003 subjects enrolled in open-label clinical 
trials with cabozantinib (either as a single-agent or in combination with other therapies).  
Across all open-label studies, the most common SAEs, regardless of causality were PE, 
dehydration, vomiting, DVT, pneumonia, diarrhea, nausea, convulsion, mental status 
changes, and abdominal pain.  Fatigue (16%), diarrhea (10%), and nausea (6%) were the 
most common reasons for discontinuation.  There have been 15 deaths considered related 
to cabozantinib treatment within 30 days of the last dose of study treatment: pulmonary 
embolism (2 patients), respiratory failure (pulmonary embolism) (1 patient), respiratory 
failure (1 patient), GI hemorrhage (2 patients), unexplained death (2 patients), hemoptysis 
(1 patient), hemorrhage intracranial (1 patient), enterocutaneous fistula (1 patient), 
respiratory disorder (1 patient), intestinal perforation (1 patient), hemorrhage (1 patient), 
and diverticular perforation–peritonitis (1 patient). 


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2.3 
Correlative Studies  
Substantial inhibition of phosphorylation of MET, RET, and KIT, as well as of downstream 
signaling molecules AKT and extracellular signal-regulated kinase (ERK), was seen following 
administration of cabozantinib (Investigator's Brochure, 2011).  
 
From the first 12 cases in study XL184-201, 80% of samples of tumor cells were positive for 
MET with a lower fraction positive for RET and VEGFR2 (42% and 58%, respectively) 
(DePrimo et al., 2009).  MET signal in blood vessels was limited (33%); whereas, RET and 
VEGFR2 expression was often seen in tumor-associated blood vessels.  Modulation of plasma 
levels of VEGFA, soluble MET, soluble VEGFR2, soluble KIT, and PlGF, was consistent with 
multiple on-target effects.  Objective response was observed in the presence or absence of tumor 
EGFR amplification, phosphatase and tensin (PTEN) mutation, and O6-methylguanine-DNA-
methyltransferase (MGMT) promoter methylation. 
 
Phase 1: Study XL184-001 Changes in pharmacodynamic markers consistent with anti-
angiogenesis activity were observed in Cohorts 6 through 12 and the eMTD Cohort with plasma 
samples taken on Day 1 pre-dose and Day 29.  While small cohort sizes presented a challenge for 
statistical analysis of pharmacodynamic marker changes the combined data of Cohorts 12 and 
the eMTD Cohort (i.e., subjects enrolled at the MTD) demonstrated that changes in PlGF (↑), 
VEGF-A (↑), EPO (↑), and sVEGFR2 (↓) reached statistical significance.  Soluble MET as a 
potential biomarker of MET inhibition was increased upon cabozantinib treatment and changes 
reached statistical significance. 
 
One set of serial skin biopsies was received from a subject enrolled in the eMTD Cohort and was 
analyzed using fluorescence-based IHC.  Changes in total MET, RET and KIT were minimal 
during the course of cabozantinib treatment but the activity (as assessed by the phosphorylation 
status) of these cabozantinib targets (decrease compared to baseline: MET: 40%, RET: 40%, 
KIT: 61%) as well as of the downstream signaling molecules AKT (39%) and ERK (55%) was 
statistically significantly reduced in this surrogate tissue.  These observations support the on-
target inhibitory effect of cabozantinib.  Total levels and phosphorylation of VEGFR2 were not 
affected by cabozantinib treatment in this surrogate tissue. 
 
 Circulating levels of HGF, soluble MET (sMET), VEGF-A, and soluble VEGFR2 
(sVEGFR2) in patients treated with MET and VEGFR inhibitors  
Many proteins are proteolytically released from the cell surface by a process known as 
ectodomain shedding.  Shedding occurs under normal physiologic conditions and can be 
increased in certain pathologies.  MET is among the many receptors for which 
ectodomain shedding has been demonstrated.  HGF stimulates mitogenesis, motogenesis, 
and morphogenesis in a variety of cellular targets during development, homeostasis, and 
tissue regeneration.  Inappropriate HGF signaling resulting in unregulated cell 
proliferation, motility, and invasion occurs in several human malignancies.  This can 
occur through paracrine signaling, autocrine loop formation, receptor mutation, gene 
amplification or gene rearrangement accompanied frequently with overexpression of 
ligand and/or receptor proteins.  Working under the hypothesis that aberrant MET 
pathway activation in cancer might result in increased ectodomain shedding, MET could 
be a useful biomarker of tumor progression; Athauda et al. developed a sensitive 


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electrochemiluminescent immunoassay to quantitate MET protein in biological 
samples.32  Their study showed significant direct correlations between malignant 
potential and sMET production in tumor-derived and genetically engineered cell lines, 
and between tumor burden and plasma sMET levels in mice harboring human tumor 
xenografts.32  These preclinical studies supported the hypothesis that sMET might 
indicate malignant potential and/or tumor burden for cancers where the pathway is active. 
 
Several studies of human clinical samples are now underway to investigate the potential 
utility of sMET to aid diagnosis and patient selection, and as a pharmacodynamic marker 
for drugs that directly target MET kinase activity.  Among these is an ongoing 
collaboration between GlaxoSmithKline (GSK) and the NCI Urologic Oncology Branch 
to measure plasma sMET, HGF, VEGF-A and sVEGFR2 in patients in Phase I and II 
clinical trials of GSK1363089 (GSK089), an inhibitor of MET and VEGFR2 tyrosine 
kinases.  In a Phase II gastric cancer study, patients treated with GSK089 on an 
intermittent dosing schedule showed significantly increased plasma sMET and VEGF-A 
during the treatment periods and decreases during drug holidays.  Follow-up cell-based 
studies show that inhibition of MET kinase activity blocks receptor internalization, 
resulting in increased exposure to cell surface MET shedders(s), suggesting a direct 
short-term relationship between sMET levels and drug target inhibition.  Increased 
VEGF-A levels have been reported as a response to VEGFR inhibitors in previous 
clinical studies.  Median tumor burden did not change significantly over the course of the 
gastric study, so it was not possible to determine whether sMET levels could also reflect 
tumor burden.  This question will be better assessed in an ongoing Phase II clinical trial 
of GSK089 in patients with papillary renal cell carcinoma, where changes in tumor 
burden meeting RECIST criteria were reported in an interim trial report.33 
 
 Circulating Tumor Cells (CTCs)  
CTCs will be isolated from whole blood samples collected at baseline and then 
throughout the study for assessment of DNA damage response markers such as γH2AX.  
We will also evaluate whether we can measure changes in the number and phenotype 
(epithelial-mesenchymal transition) of CTCs in patients over time to explore any 
correlation with response to treatment or disease progression.  This analysis will be 
performed in Dr. Kinders’ lab with the ApoStream instrument, which uses antibody-
independent CTC isolation technology that can isolate viable CTCs from epithelial and 
non-epithelial cancers.   
2.4 
Rationale 
We propose a clinical trial of cabozantinib, a dual VEGFR and MET inhibitor, in refractory soft 
tissue sarcoma for the following reasons:   
 
1. 
It has been shown that VEGF levels are elevated in patients with STS and correlates with 
the grade of the tumor.14-17 Anti-VEGF agents like bevacizumab have been studied in this 
disease with promising results.19,20 Pazopanib has also been studied in STS in phase II21 
and III settings22; patients showed improvement in PFS by 13 weeks compared to placebo. 
 


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2. 
Various sarcoma cell lines express high levels of activated c-Met receptor suggesting that 
HGF/SF signaling pathway may contribute to sarcomagenesis.25 Interruption of autocrine 
or paracrine HGF/SF c-met signaling with the monoclonal antibody AMG102 in 
leiomyosarcoma cell line SK-LMS-1 and in mouse xenograft models has shown significant 
antitumor effect.26 It has also been shown that MiT tumors like clear cell sarcoma cells are 
dependent on HGF/C-Met axis27 for invasion, chemotaxis, and survival. 
 
3. 
The MET pathway may play an important role in resistance to VEGF inhibitors like 
sunitinib.34 Treatment with multiple VEGF inhibitors has been reported to be associated 
with an aggressive phenotype with increased invasiveness and higher MET expression.35-37 
Hence, we propose to target the dual arms of the VEGF/MET axis with cabozantinib in the 
hope to eliminate some of the resistance that has been encountered in the past with 
angiogenic inhibitors. 
 
4. 
In vivo activity of XL184 has been shown in the form of tumor shrinkage in RIP-Tag2 
transgenic mice29 and mice bearing MDA-MB-231 cells28. As shown in Figure 3, 
combination blockade of VEGFR and c-MET with XL184 significantly (P < 0.05) prolongs 
survival compared to treatment with vehicle or anti-VEGFR antibody alone in the RIP-
Tag2 transgenic mouse model, a spontaneous and highly vascularized pancreatic islet cell 
cancer. 
 
 
 
Figure 3: Increased survival of RIP-Tag2 transgenic mice following treatment with the 
VEGFR and c-MET inhibitor XL184 compared to treatment with anti-VEGF antibody 
or vehicle.  The extent of liver metastasis was also less in RIP-Tag2 mice treated with 
combination blockade of VEGFR and c-MET than in mice treated with anti-VEGF 
antibody alone. 
 
5. 
In the clinical arena, cabozantinib has been shown in Phase 1 study XL184-001 that 
evaluated the capsule formulation and suspension formulation to achieve SD of at least 
3 months in advanced solid tumors (including one patient each of alveolar soft part 
sarcoma and clear cell sarcoma).31  
 
By targeting the dual VEGF/c-MET pathway with cabozantinib in soft tissue sarcoma we 
propose to improve on the PFS that was established in the Phase III trial of pazopanib where it 
improved median PFS by 13 weeks compared to placebo.22 If our proposed trial is positive, we 


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would anticipate this could lead to a large randomized phase III trial comparing the two targeted 
agents pazopanib and cabozantinib in STS, thereby establishing a new standard of care in this 
population. 
 
 
3 PATIENT SELECTION 
3.1 
Eligibility Criteria  
 Patients must have histologically or cytologically confirmed soft tissue sarcoma 
that is metastatic or unresectable and for which standard treatment that prolongs 
survival does not exist or is no longer effective. 
 Patients must have measurable disease, defined as at least one lesion that can be 
accurately measured in at least one dimension (longest diameter to be recorded for 
non-nodal lesions and short axis for nodal lesions) as >20 mm with conventional 
techniques or as >10 mm with spiral CT scan, MRI, or calipers by clinical exam.   
 Patients are allowed prior VEGFR-TKI therapy.  Patients will be stratified based 
on prior VEGFR-TKI therapy. 
 Age ≥18 years.  Because no dosing or adverse event data are currently available 
on the use of cabozantinib in patients <18 years of age, children are excluded 
from this study. 
 ECOG performance status ≤1 (Karnofsky >70%, see Appendix A). 
 Life expectancy > 3 months. 
 Patients must have normal organ and marrow function as defined below: 
− leukocytes  
 
 
 
 
>3,000/mcL 
− absolute neutrophil count 
 
>1,500/mcL 
− platelets  
 
 
 
 
 
>100,000/mcL 
− total bilirubin  
 
 
 
 
≤1.5 times ULN 
− 
AST(SGOT)/ALT(SGPT) 
<2.5 X institutional upper limit of 
normal 
− creatinine  
 
 
 
 
 
within normal institutional limits 
  
OR 
− creatinine clearance  
 
>60 mL/min/1.73 m2 for patients with 
creatinine levels above institutional 
normal. 
− hemoglobin ≥9 g/dL 
− serum albumin ≥2.8g/dL 
− lipase <2.0 × ULN and no radiologic or clinical evidence of pancreatitis 
− urine protein/creatinine ratio (UPCR) ≤1 
− serum phosphorus calcium, magnesium and potassium ≥ LLN 


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 Subjects must have blood pressure (BP) no greater than 140 mmHg (systolic) and 
90 mmHg (diastolic) for eligibility.  Initiation or adjustment of BP medication is 
permitted prior to study entry provided that the average of three BP readings at 
the time of enrollment  is ≤ 140/90 mmHg 
 Patients must be able to swallow whole tablets.  Tablets must not be crushed or 
chewed. 
 The effects of cabozantinib on the developing human fetus are unknown.  For this 
reason and because receptor tyrosine kinases are known to be teratogenic, women 
of child-bearing potential and men must agree to use adequate contraception.  All 
subjects of reproductive potential must agree to use both a barrier method and a 
second method of birth control during the course of the study and for 4 months 
after the last dose of study drug(s). 
Sexually active subjects (men and women) must agree to use medically 
accepted barrier methods of contraception (e.g., male or female condom) 
during the course of the study and for 4 months after the last dose of study 
drug(s), even if oral contraceptives are also used.   
 Ability to understand and the willingness to sign a written informed consent 
document. 
3.2 
Exclusion Criteria 
 Patients who have had anticancer therapy, including kinase inhibitors or any 
investigational agent within 4 weeks or 5 half-lives (whichever is shorter) (6 
weeks for nitrosoureas or mitomycin C) prior to entering the study or those who 
have not recovered to baseline from adverse events (except alopecia and other 
non-clinically significant AEs).  Patients who have received prior cabozantinib or 
inhibitors of c-MET or HGF are ineligible. 
 The subject has received radionuclide treatment within 6 weeks of the first dose 
of study treatment 
 The subject has received radiation therapy within 4 weeks (≤ 2 weeks for 
palliative radiation therapy) 
 Patients with active brain metastases or carcinomatous meningitis or epidural 
disease are excluded from this clinical trial.  Subjects with brain metastases 
previously treated with whole brain radiation or radiosurgery or subjects with 
epidural disease previously treated with radiation who are asymptomatic and have 
remained stable for 4 weeks and do not require steroid treatment for at least 2 
weeks before starting study treatment are eligible.  Neurosurgical resection of 
brain metastases or brain biopsy is permitted if completed at least 3 months before 
starting study treatment.  Baseline brain imaging with contrast-enhanced CT or 


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MRI scans for subjects with known brain metastases is required to confirm 
eligibility. 
 Eligibility of subjects receiving any medications or substances known to affect or 
with the potential to affect the activity of cabozantinib will be determined 
following review of their cases by the Principal Investigator (see Sections 3.2.8, 
3.2.9 and 3.2.10 for further information).  Patients who are taking enzyme-
inducing anticonvulsant agents are not eligible. 
 Patients with refractory nausea and vomiting, chronic gastrointestinal diseases 
(e.g., inflammatory bowel disease), or significant bowel resection that could 
interfere with absorption. 
 Uncontrolled intercurrent illness including, but not limited to symptomatic 
congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or 
psychiatric illness/social situations that would limit compliance with study 
requirements. 
 Pregnant women are excluded from this study because cabozantinib has the 
potential for teratogenic or abortifacient effects.  Because there is an unknown but 
potential risk for adverse events in nursing infants secondary to treatment of the 
mother with cabozantinib, breastfeeding should be discontinued if the mother is 
treated with cabozantinib. 
 Strong inhibitors and inducers of CYP3A4 can affect levels of cabozantinib and 
should be avoided whenever possible or switched to alternatives.  Subjects 
requiring chronic concomitant treatment of strong CYP3A4 inducers 
(e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentin, 
phenobarbital, and St. John’s Wort) are not eligible for this study.  Because the 
lists of these agents are constantly changing, it is important to regularly consult a 
frequently-updated list such as http://medicine.iupui.edu/clinpharm/ddis/; medical 
reference texts such as the Physicians’ Desk Reference may also provide this 
information.  As part of the enrollment/informed consent procedures, the patient 
will be counseled on the risk of interactions with other agents, and what to do if 
new medications need to be prescribed or if the patient is considering a new over-
the-counter medicine or herbal product. 
 HIV-positive patients on combination antiretroviral therapy are ineligible because 
of the potential for pharmacokinetic interactions with cabozantinib.  Appropriate 
studies will be undertaken in patients receiving combination antiretroviral therapy 
when indicated. 
 The subject requires concomitant treatment, in therapeutic doses, with 
anticoagulants such as warfarin or warfarin-related agents, heparin, thrombin or 
Factor Xa inhibitors, or antiplatelet agents (e.g., clopidogrel).  Low dose aspirin 
(≤81 mg/day), low-dose warfarin (≤1 mg/day), and prophylactic low molecular 
weight heparin (LMWH) are permitted. (Please note that there may be cases in 


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which patients on study require anticoagulation for DVT/PE management; this 
does not necessitate taking the patient off study. See Section 6.1.5.) 
 The subject has experienced any of the following 
• clinically-significant gastrointestinal bleeding within 3 months before the 
first dose of study treatment; the participant must be maintained on a 
prophylactic regimen for management of an upper GI bleeding event with 
no evidence of recurrence and/or endoscopic confirmation of resolution 
of the source of a lower GI bleed. 
• hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 months 
before the first dose of study treatment 
• any other signs indicative of pulmonary hemorrhage within 3 months 
before the first dose of study treatment 
 The subject has radiographic evidence of cavitating pulmonary lesion(s). 
 The subject has tumor invading or encasing any major blood vessels 
 The subject has evidence of tumor invading the GI tract (esophagus, stomach, 
small or large bowel, rectum or anus), or any evidence of endotracheal or 
endobronchial tumor within 28 days before the first dose of cabozantinib 
 The subject has uncontrolled, significant intercurrent or recent illness including, 
but not limited to, the following conditions: 
1. Cardiovascular disorders including: 
 
a) Congestive heart failure (CHF): New York Heart Association (NYHA) Class 
III (moderate) or Class IV (severe) at the time of screening 
 
b) Concurrent uncontrolled hypertension defined as sustained BP > 140 mm Hg 
systolic, or > 90 mm Hg diastolic despite optimal antihypertensive treatment 
within 7 days of the first dose of study treatment 
 
c) Any history of congenital long QT syndrome 
 
d) Any of the following within 6 months before the first  dose of study treatment: 
• unstable angina pectoris 
• clinically-significant cardiac arrhythmias 
• stroke (including TIA, or other ischemic event) 
• myocardial infarction 
• thromboembolic event requiring therapeutic anticoagulation (Note: 
subjects with a venous filter (e.g. vena cava filter) are not eligible for this 
study) 
 
2. Gastrointestinal disorders particularly those associated with a high risk of 
perforation or fistula formation including: 
 


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a) Any of the following within 28 days before the first dose of study treatment 
• intra-abdominal tumor/metastases invading GI mucosa 
• active peptic ulcer disease, 
• inflammatory bowel disease (including ulcerative colitis and Crohn’s 
disease), diverticulitis, cholecystitis, symptomatic cholangitis or 
appendicitis 
• malabsorption syndrome 
 
b) Any of the following within 6 months before the first dose of study treatment: 
•  abdominal fistula 
• gastrointestinal perforation 
• bowel obstruction or gastric outlet obstruction 
• intra-abdominal abscess.  Note: Complete resolution of an intra-abdominal 
abscess must be confirmed prior to initiating treatment with cabozantinib 
even if the abscess occurred more than 6 months before the first dose of 
study treatment. 
 
3. Other disorders associated with a high risk of fistula formation including PEG 
tube placement within 3 months before the first dose of study therapy  
 
4. Other clinically significant disorders such as: 
 
a) serious non-healing wound/ulcer/bone fracture within 28 days before the first 
dose of study treatment 
 
b) history of organ transplant, including allogeneic bone marrow transplant 
 
c) concurrent uncompensated hypothyroidism or thyroid dysfunction within 
7 days before the first dose of study treatment 
 
d) history of major surgery as follows: 
i. 
Major surgery within 3 months of the first dose of cabozantinib if there 
were no wound healing complications or within 6 months of the first dose 
of cabozantinib if there were wound complications 
 
ii. 
Minor surgery  within 1 months of the first dose of cabozantinib if there 
were no wound healing complications or within 3 months of the first dose 
of cabozantinib if there were wound complications 
 
In addition, complete wound healing from prior surgery must be 
confirmed at least 28 days before the first dose of cabozantinib irrespective 
of the time from surgery 
 The subject is unable to swallow tablets 
 The subject has a corrected QT interval calculated by the Fridericia formula 
(QTcF) >500 ms within 28 days before enrollment.  Note: if initial QTcF is found 
to be > 500 ms, two additional EKGs separated by at least 3 minutes should be 


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performed.  If the average of these three consecutive results for QTcF is ≤500 ms, 
the subject meets eligibility in this regard. 
 The subject is unable or unwilling to abide by the study protocol or cooperate 
fully with the investigator or designee. 
 The subject has had evidence within 2 years of the start of study treatment of 
another malignancy which required systemic treatment. 
 Patients should not have any clinical evidence of an active infection at the time of 
enrollment.  
3.3 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this trial. 
3.4 
Eligibility Screening Evaluation 
 Histologic confirmation: A block or stained slides of primary tumor tissue or of 
known recurrence will be required from each participant to confirm diagnosis.  
Pathology confirmation will be performed by the Laboratory of Pathology, NIH 
for patients enrolled at the NCI or by the department of pathology at the site 
where the patient is enrolled.   
 History and physical examination: Complete history and physical examination 
(including height, weight, vital signs, and ECOG performance score) will be 
conducted within 8 days prior to enrollment.   
 Imaging Studies: All patients will be required to undergo a CT scan of the 
chest/abdomen/pelvis to evaluate sites of disease within 28 days prior to 
enrollment.  MRI or CT scan with contrast of the brain, MRI liver, MRI for other 
disease sites, or bone scan may be done as clinically indicated. 
 Laboratory Evaluation: Laboratory data are to be obtained within 8 days prior to 
enrollment: 
• Hematological Profile: CBC with differential.  
• Biochemical Profile: albumin, alkaline phosphatase, total bilirubin, 
BUN, sodium, chloride, bicarbonate, calcium, creatinine, glucose, 
phosphorus, magnesium, potassium, total protein, SGOT [AST], SGPT 
[ALT], amylase, lipase, TSH. 
• Serum or urine pregnancy test for female participants of childbearing 
potential. 
• Urinalysis for urine protein/creatinine ratio or 24-hour urine for 
proteinuria if patients have 1+ or greater urine protein. 
• EKG  
 
 


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4 REGISTRATION PROCEDURES 
Eligible participants will be entered on study by a member of the study team.   
4.1 
Registration Process 
 
Registration and status updates (e.g., when a participant is taken off protocol therapy and 
when a participant is taken off-study) will take place per CCR SOP ADCR-2, CCR 
Participant Registration & Status Updates, found here: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825 
 
Cohorts: 
Cohort 1, Soft Tissue Sarcoma 
 
Arms: 
Arm 1, Cabozantinib 
 
Arm Assignment: 
Subjects in cohort 1 will be assigned to arm 1. 
  
4.2 
Participating Site Registration 
Registration and status updates (e.g., when a participant is taken off protocol therapy and 
when a participant is taken off-study) will take place per CCR SOP ADCR-2, CCR 
Participant Registration & Status Updates, found here: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825 
 
To register a participant after they have signed the consent, complete Appendix F 
(Eligibility/Pre-Registration Worksheet) and fax (or email) it, along with all supporting 
records, to the Coordinating Center’s Research Nurse, Ashley Bruns, Phone: (240) 858-3162, 
Fax (301) 451-5625, ashley.bruns@nih.gov.  The Coordinating Center will notify you either 
by e-mail or fax that the protocol registration form has been received.  The Coordinating 
Center will register the patient and provide the participating site with the patient’s unique 
patient ID number.  This unique ID number is to be used on all research samples and data 
entry for this patient.  Questions about eligibility should be directed to the Coordinating 
Center’s Research Nurse, Ashley Bruns, Phone: (240) 858-3162, Fax (301) 451-5625, 
ashley.bruns@nih.gov. 
4.3 
Off Protocol Therapy and Off-Study Procedure 
Status updates (e.g., when a participant is taken off protocol therapy and when a participant is 
taken off-study) will take place per CCR SOP ADCR-2, CCR Participant Registration & 
Status Updates, found here: 
https://ccrod.cancer.gov/confluence/pages/viewpage.action?pageId=73203825 
 
Participating sites: When a patient is taken off protocol therapy and when a patient is taken 
off-study, the Participant Status Updates Form included in Appendix F must be completed 


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and faxed or emailed to the Coordinating Center’s Research Nurse, Ashley Bruns, Phone: 
(240) 858-3162, Fax (301) 451-5625, ashley.bruns@nih.gov. 
 
5 TREATMENT PLAN 
This is a multicenter phase II trial of patients with soft tissue sarcoma.  Treatment will be 
administered on an outpatient basis.   
 
Patient evaluations will be performed throughout the study as described below.  Baseline history, 
physical examination, laboratory evaluations, urinalysis, pregnancy test, and EKG must be 
conducted within 8 days prior to start of protocol therapy.  If protocol therapy is started within 8 
days of the eligibility screening evaluations (see Section 3.4), the results from these screening 
evaluations may be used as baseline measurements.  If >8 days have passed since the screening 
evaluations, the medical history, physical examination, laboratory evaluations, urinalysis, 
pregnancy test, and EKG must be repeated prior to starting protocol therapy.  Tumor imaging 
must be performed within 28 days prior to start of protocol therapy. 
 
History and physical examination, labs (CBC with differential; serum chemistries), serum or 
urine pregnancy test (for female participants of childbearing potential), and EKG will be 
performed at baseline and within 8 days prior to the start of each new cycle after cycle 1.  B12 
and folate are not part of the screening evaluation but will be measured at baseline (within 8 days 
prior to start of protocol therapy) and every 12 weeks (every 3 cycles; within 8 days prior to the 
start of the cycle).  Urinalysis for evaluation of urine protein/creatinine ratio should occur at 
baseline, within 8 days prior to the start of each new cycle after cycle 1, and as clinically 
indicated.   
 
CT scans will be performed at baseline (within 28 days prior to start of protocol therapy), and 
repeat imaging scans will be performed every 2 cycles (every 3 cycles for patients on study for 
more than 1 year; every 4 cycles for patients on study more than 3 years).  MRI evaluation of site 
of disease may be performed in lieu of CT evaluation at the discretion of the principal 
investigator if in the opinion of the investigator this modality would provide a more accurate 
assessment of disease than a CT would for a given site.   
 
The history and physical exam, pregnancy test, CT scan, EKG, and all other protocol-required 
labs, including blood collections for CTCs, will be done less frequently for patients on study 
more than one year (every 3 cycles after 1 year on study and every 4 cycles after 3 years on 
study).  B12 and folate (measured at baseline and then every 3 cycles) will be measured every 4 
cycles after 3 years on study. 
5.1 
Agent Administration 
Adult patients will receive cabozantinib tablets as 60 mg tablets orally once a day in a 28-day 
cycle.  A dose of 100 mg daily was tested and found to have acceptable efficacy albeit greater 
toxicity and a dose of 40 mg was also tested and found to be efficacious30,38.  Patients who 
tolerate the 60 mg dose with little or minimal toxicity may be dose escalated to 80 mg after the 
first restaging (after cycle 2) for subsequent cycles.  Dose escalation will be decided by the 
treating physician after discussion with the study PI.  Adverse events and potential risks are 
described in Section 7.  Appropriate dose modifications are described in Section 6. 


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No investigational or commercial agents or therapies other than those described below may be 
administered with the intent to treat the patient’s malignancy.  Cabozantinib will be taken on an 
empty stomach, 1 hour before or 2 hours after food.  Subjects may fast for at least 1 hour before and 
2 hours after eating.  The drug will be administered once daily at approximately the same time 
each day.  Tablets must be swallowed whole and not crushed.  A new cycle may begin up to 1 
week later than it would otherwise be scheduled based on the 28-day cycle, to allow for 
flexibility for days the clinic is closed and other unexpected events.   
 
Patients will be provided with a Study Diary (Appendix C), instructed in its use, and asked to 
bring it with them to each appointment.  After cycle 2, a cycle will be considered completed if 
90% of the prescribed doses are administered. 
 Cabozantinib 
Cabozantinib is a CYP3A4 substrate (but not a CYP2C9 or CYP2D6 substrate), based on 
data from in vitro studies using CYP-isozyme specific neutralizing antibodies. 
Concomitant medications that are inhibitors or inducers of the CYP3A4 pathway should 
be used with caution.  Strong CYP3A4 inducers such as rifampin, carbamazepine, 
phenobarbital, phenytoin, pioglitazone, rifabutin, St. John's Wort, and troglitazone should 
be avoided.  In addition, strong CYP3A4 inhibitors and other drugs that inhibit CYP3A4 
should be used with caution because these drugs have the potential to increase exposure 
(AUC) to cabozantinib (Investigators brochure, 2011).  Caution must also be used when 
discontinuing treatment with a strong CYP3A4 inducer in a subject who has been concurrently 
receiving a stable dose of Cabozantinib, as this could significantly increase the exposure to 
Cabozantinib 
 
Because there is a potential for interaction of cabozantinib with other concomitantly 
administered drugs through the cytochrome P450 system, the case report form must 
capture the concurrent use of all other drugs, over-the-counter medications, or alternative 
therapies.  The Principal Investigator should be alerted if the patient is taking any agent 
known to affect or with the potential to affect selected CYP450 isoenzymes.  Appendix B 
presents guidelines for identifying medications/substances that could potentially interact 
with cabozantinib.  Please refer to the Flockhart drug interaction tables for lists of 
substrates, inducers, and inhibitors of selected CYP450 isozyme pathways (Flockhart 
2007; http://medicine.iupui.edu/clinpharm/ddis/).  
 
Because in vitro studies only assessed the metabolizing capacity of the CYP3A4, 
CYP2C9, and CYP2D6 pathways, the potential for drugs that inhibit/induce other 
CYP450 pathways (e.g., CYP2C8, CYP2C19, CYP2B6, CYP1A2) to alter cabozantinib 
exposure is not known.  Therefore, these drugs should be used with caution when given 
with cabozantinib. 
 
Cabozantinib is highly protein bound, 99.9%.  Use caution when co-administering 
cabozantinib with medications that are highly protein-bound (e.g., diazepam, furosemide, 
dicloxacillin, and propranolol).  Administration of warfarin with cabozantinib is 
contraindicated as warfarin is highly protein-bound and has a very narrow therapeutic 
index.   
 


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Drugs Associated with QTc Prolongation:  Treatment with cabozantinib has been 
associated with a mild prolongation of the QTc interval.  Caution should be used when 
treating subjects on cabozantinib with other drugs associated with QTc prolongation (see 
http://www.qtdrugs.org).  Additional QTc monitoring is suggested for subjects who are 
treated concomitantly with QTc prolonging drugs. 
 
Other Interactions: In a relative bioavailability study in dogs, cabozantinib exposure was 
not significantly affected by drugs that alter gastric pH.  Nevertheless, drugs such as 
proton pump inhibitors (PPIs) and H2-antagonists produce profound suppression of 
gastric acid secretion and significant increases in gastric pH.  By elevating gastric pH, 
PPIs and H2-antagonists may decrease cabozantinib plasma exposure levels and its 
effectiveness in vivo, resulting in clinically significant drug interactions. 
 
Avoid concomitant use of cabozantinib with proton pump inhibitors (PPIs) and H2 -
antagonists if possible.  The PPIs and H2 –antagonists may decrease cabozantinib plasma 
exposure levels and its effectiveness in humans.  Examples of PPIs are omeprazole, 
lansoprazole, rabeprazole, pantoprazole, and esomeprazole; examples of H2 –antagonists 
are ranitidine, famotidine, and nizatidine.  Cimetidine is a moderate CYP3A4 inhibitor.  
Avoid using cimetidine with cabozantinib.  If needed, antacids are recommended for the 
initial treatment of dyspepsia or indigestion.  If antacids are not adequate, the use of H2 
blockers (other than cimetidine) is preferred over PPIs.  If antacids, H2 blockers, or PPIs 
are needed, take them at least 2 hours (preferably 4 hours) after taking cabozantinib but at 
least 14 hours before the next dose of cabozantinib if possible. 
 
Potential Food Effect 
The effect of food on the bioavailability of cabozantinib was evaluated in healthy adult 
subjects in a Phase 1; open-label, randomized, single-dose, two-treatment, and two-way 
crossover study (Study XL184-004).  Based on the preliminary PK data, a high fat meal 
did not appear to alter the terminal t1/2, but significantly increased the median tmax to 6 
hours from 4 hours (fasted).  The high fat meal also significantly increased both the 
cabozantinib Cmax and AUC values by 41% and 57%, respectively.  Based on this result, 
cabozantinib should be taken on an empty stomach (fasting is required 1 hour before, and 
2 hours after each cabozantinib dose). 
5.2 
General Concomitant Medication and Supportive Care Guidelines 
All patients will be provided with the best available supportive care.  No chemotherapeutic drugs 
other than cabozantinib will be allowed.  Because there is a potential for interaction of 
cabozantinib with other concomitantly administered drugs through the cytochrome P450 system, 
the case report form must capture the concurrent use of all other drugs, over-the-counter 
medications, or alternative therapies.  The Principal Investigator should be alerted if the patient is 
taking any agent known to affect or with the potential to affect selected CYP450 isoenzymes. 
 Anorexia 
Anorexia leading to grade 3 weight loss will be managed according to local standard of 
care including nutritional support.  Pharmacologic therapy such as megestrol acetate or 
dronabinol may be considered.  For Grade 3 weight loss dose reductions will not be done 
unless pharmacologic interventions have been tried first and fail. 


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 Diarrhea 
If diarrhea develops and does not have an identifiable cause other than study drug 
administration, anti-diarrheals such as Lomotil (diphenoxylate HCl 2.5 mg + atropine 
sulfate 0.025 mg/tablet) dosed according to package insert or loperamide 4 mg po after 
the first unformed stool with 2 mg po with every 2 hours (4 mg every 4 hours while 
asleep), till resolution of episode of at least 12 hours (no more than 16 mg of loperamide 
during a 24-hour period).  This regimen can be repeated for each diarrheal episode.  
Diarrhea will be considered refractory if it does not resolve within 24 hours to ≤ Grade 2 
with the above regimen (maximum of 16 mg of loperamide in a 24-hour period).  If the 
patient develops blood or mucus in the stool, dehydration, or hemodynamic instability, or 
fever along with the diarrhea, anti-diarrheals will be discontinued and the patient will be 
treated with IV fluids and antibiotics as medically indicated.  The dose modification 
guidance in Table 6-1 should be followed.  In addition, general supportive measures will 
be implemented including continuous oral hydration, correction of fluid and electrolyte 
abnormalities, small frequent meals; and stopping lactose-containing products, high fat 
meals, and alcohol. 
 Nausea and vomiting 
Anti-emetics will not be administered routinely prior to cabozantinib.  Anti-emetic agents 
along with supportive care are recommended as clinically appropriate at the first sign of 
nausea and vomiting.  The dose modification guidance in Table 6-1 should be followed.   
 
The 5-HT3 receptor antagonists are recommended over chronic use of NK-1 receptor 
antagonists and dexamethasone (NK-1 receptor antagonists can induce or inhibit 
CYP3A4, and glucocorticoids induce CYP3A4 and thus could lower cabozantinib 
exposure.  Caution is also recommended with the use of nabilone, which is a weak 
inhibitor of CYP3A4. 
 Myelosuppression 
The use of growth factors will be considered in accordance with ASCO guidelines. 
 Stomatitis and Mucositis 
Preventive measures may include a comprehensive dental examination to identify any 
potential complications before study treatment is initiated.  Appropriate correction of 
local factors should be instituted as indicated, such as modification of ill-fitting dentures 
and appropriate care of gingivitis.  During treatment with cabozantinib, good oral hygiene 
and standard local treatments such as non-traumatic cleansing, and oral rinses (e.g., with 
a weak solution of salt and baking soda) should be maintained.  The oral cavity should be 
rinsed and wiped after meals, and dentures should be cleaned and brushed often to 
remove plaque.  Local treatment should be instituted at the earliest onset of symptoms.  
When stomatitis interferes with adequate nutrition and local therapy is not adequately 
effective, dose reduction or temporary withholding of cabozantinib should be considered. 
5.3 
Duration of Therapy 
In the absence of treatment delays due to adverse events, treatment may continue until 
one of the following criteria applies: 


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• Disease progression 
• Intercurrent illness that prevents further administration of treatment 
• Significant toxicity occurs despite 2 dose reductions as described in Section 6 or no 
lower dose level exists 
• Patient decides to withdraw from the study 
• General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
• Necessity for treatment with other anticancer treatment prohibited by the protocol, 
• Sexually active subjects who refuse to use medically accepted barrier methods of 
contraception (e.g., male condom, female condom) during the course of the study and 
for 4 months following discontinuation of study treatment, 
• Women who become pregnant or are breast feeding, 
• Request by regulatory agencies for termination of treatment of an individual subject 
or all subjects under the protocol, or 
• Significant noncompliance with the protocol schedule in the opinion of the 
investigator. 
5.4 
Duration of Follow Up 
Patients will be followed for 30 days after the last dose is administered or until one of the 
following occurs: patient enrolls on another protocol, patient receives standard of care, or death, 
and whichever comes first.  The follow-up will consist of a phone call between Days 27-30 after 
the last dose to evaluate adverse events that were ongoing and any new events that might be 
deemed related to the therapy.  Toxicities felt to be possibly, probably, or definitely related to the 
study drugs that have not resolved or stabilized by Day 30 post-treatment will be followed until 
stabilization or resolution via biweekly phone calls. 
5.5 
Criteria for Removal from Study 
Patients will be removed from study for one of the following reasons: completed 30-day follow 
up period or toxicities are unresolved but stabilized, patient withdraws from study, and/or patient 
enrolls on another protocol.  The reason for study removal and the date the patient was removed 
must be documented in the medical record and communicated to Central Registration per Section 
4. 
 
 
6 DOSING DELAYS/DOSE MODIFICATIONS 
Treatment may be delayed for a maximum of 2 weeks for toxicities.  In case toxicities do not 
resolve as stated, the patient will not receive further therapy on this protocol and will be followed 
for resolution of toxicities.  Start of next cycle may be delayed for up to 1 week to accommodate 
scheduling conflicts.  Dose modifications are intended for within-cycle and start-of-next-cycle 
changes.  If administration of study drug is interrupted for any reason, it will not be made up, and 
counting of the cycle days continues.  A maximum of 2 dose reductions will be allowed before 
patient is taken off treatment.  Patients who require a dose reduction will not have the dose re-
escalated.   
 


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All patients begin at dose level 0.  Patients who tolerate dose level 0 with no or minimal 
toxicity may be escalated to 80 mg daily, sequentially, after the first restaging (after cycle 
2).  Dose escalation will be decided by the treating physician after discussion with the study PI.   
 
Table 3:  Dose modification 
Dose Level 
Cabozantinib Dose 
-2 
20 mg 
-1 
40 mg 
0 
60 mg 
+1 
80 mg 
6.1 
Management of Cabozantinib-related AE 
Subjects will be monitored continuously for AEs throughout the study.  Subjects must be 
instructed to notify their physician immediately for any and all toxicities. 
 General guidelines for the management of non-hematologic and hematologic 
toxicities are provided in Table 6-1 and Table 6-2, respectively. 
These algorithms should be followed unless there are specific clinical circumstances for 
which the treating physician decides an alternative treatment approach is clinically 
appropriate.  Consultation with the study chair is recommended. 
 
Table 6-1.  General Approach to the Management of Cabozantinib-Related Non-
Hematologic Adverse Events 
 
CTCAE Version 5 
Grade  
Guidelines/Intervention 
Grade 1: 
Add supportive care as indicated.  Continue cabozantinib at the current 
dose level. 
Grade 2: 
Grade 2 AEs considered 
related to cabozantinib that 
are subjectively tolerable or 
easily managed 
Add supportive care as indicated.  Continue cabozantinib at the current 
dose level.   
Grade 2 AEs considered 
related to cabozantinib that 
are intolerable to the subject 
or deemed unacceptable in 
the investigator’s judgment; 
or are not easily managed or 
corrected 
Dose reduce 
• 
If the AE dose not resolve to Grade ≤1 or baseline in 7 to 10 days 
or worsens at any time, cabozantinib dosing should then be 
interrupted.  Then upon resolution to baseline or Grade ≤ 1, the 
reduced dose should be restarted. 
• 
If the AE does resolves to resolves to Grade ≤1 or baseline without 
a dose interruption, continue the reduced dose. 
Grade 3: 
 
Grade 3 AEs considered 
related to cabozantinib 
which occurred without 
optimal prophylaxis or 
• 
Interrupt cabozantinib and add supportive care as indicated 
• 
For AEs that are easily managed (e.g., correction of electrolytes) 
with resolution to baseline or Grade ≤1 within 24 hours,  
cabozantinib may be resumed at either the same dose or with a 


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31 
 
which is easily managed by 
medical intervention or 
resolved quickly 
dose reduction at the discretion of the investigator unless this is a 
recurring event at which time the dose should be reduced 
• 
For AEs that require supportive care, the dose should be held 
while supportive care is initiated and optimized.  Then upon 
resolution of the AE to baseline or Grade ≤1,  cabozantinib may be 
resumed at either the same dose or with a dose reduction at the 
discretion of the investigator unless this is a recurring event at 
which time the dose should be reduced 
Grade 3 AEs considered 
related to study treatment 
that occurred despite 
optimal prophylaxis or is not 
easily managed by medical 
intervention  
Interrupt study treatment until recovery to ≤ Grade 1 or baseline, and 
resume treatment with a dose reduction 
Grade 4: 
Grade 4 AEs considered 
related to study treatment 
Permanently discontinue study treatment unless determined that the 
subject is unequivocally deriving clinical benefit.  In this case, upon 
recovery to Grade ≤1 or baseline, the subject may be re-treated at a 
reduced dose that is to be determined by the investigator and sponsor 
but only with sponsor approval. 
Dose reductions or delays may occur in the setting of lower grade toxicity than defined above if the 
investigator believes that it is in the interest of the subject’s safety.   
Table 6-2.  General Approach to the Management of Cabozantinib-Related Hematologic 
Adverse Events 
CTCAE Version 5 Grade 
Intervention 
Neutropenia 
Grade 3 neutropenia with 
documented infection 
Grade 3 neutropenia ≥ 5 days 
Grade 4 neutropenia  
Interrupt cabozantinib treatment until resolution to Grade ≤1, and 
resume cabozantinib treatment at a reduced dose.  
Thrombocytopenia 
Grade 3 thrombocytopenia 
with clinically significant 
bleeding or Grade 4 
thrombocytopenia 
Interrupt cabozantinib treatment until platelet count is  ≥100,000/mm3, 
and resume cabozantinib treatment at a reduced dose 
Febrile Neutropenia 
Grade 3 febrile neutropenia 
Interrupt cabozantinib treatment until recovery of ANC to Grade ≤1 
and temperature to ≤ 38.0°C and resume cabozantinib treatment at a 
reduced dose. 
Grade 4 febrile neutropenia 
Permanently discontinue study treatment unless determined that the 
subject is unequivocally deriving clinical benefit.  In this case, upon 
recovery to Grade ≤1 or baseline, the subject may be re-treated at a 
reduced dose that is to be determined by the investigator and sponsor 
but only with sponsor approval. 


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CTCAE Version 5 Grade 
Intervention 
Other Grade 4 Hematologic Toxicities 
Grade 4 hematologic 
toxicities  
other than anemia 
Permanently discontinue study treatment unless determined that the 
subject is clearly deriving clinical benefit.  In this case, upon recovery 
to Grade ≤1 or baseline, the subject may be re-treated at a reduced 
dose that is to be determined by the investigator and sponsor and only 
with approval by the sponsor. 
Grade 4 anemia 
Permanent discontinuation for Grade 4 anemia is not mandated. Dose 
reductions or dose delays for anemia should be applied as clinically 
indicated.  Supportive care such as red blood cell transfusions should 
be managed according to institutional guidelines. 
ANC, absolute neutrophil count; LLN, lower limit of normal 
Neutropenia: Grade 1 (LLN < ANC < 1.5 × 109/L; Grade 2 (1 × 109/L ≤ ANC <1.5 x 109/L),  
Grade 3 (0.5 × 109/L ≤ ANC < 1 × 109/L), Grade 4 (ANC < 0.5 × 109/L). 
Febrile Neutropenia: Grade 3 (present); Grade 4 (Life-threatening consequences; urgent intervention indicated). 
Thrombocytopenia: Grade 1 (Platelet count <LLN – 75 x 109/L); Grade 2 (Platelet count <75.0 – 50.0 x 109/L);  
Grade 3 (Platelet count <50 - 25 × 109/L); Grade 4 (Platelet count < 25 × 109/L). 
 
 Hepatobiliary Disorders 
Elevations of transaminases have also been observed during treatment with cabozantinib.  
In general, it is recommended that subjects with elevation of ALT, AST, and/or bilirubin 
have more frequent laboratory monitoring of these parameters.  If possible, hepatotoxic 
concomitant medications and alcohol should be discontinued in subjects who develop 
elevated transaminases.  Since subjects may enter the study with elevations of AST/ALT 
at baseline, the following guideline should be used for dose modifications: 
 
Transaminase 
elevation 
CTCAE v5.0 
Intervention 
Subjects with AST and ALT less than or equal to the ULN at baseline 
Grade 1  
Continue cabozantinib with weekly monitoring of liver function tests (LFTs) for at 
least 4 weeks or until LFTs return to baseline or stabilize at grade 1.  Then resume 
the standard protocol-defined monitoring of LFTs.  
Grade 2 
Continue cabozantinib with weekly monitoring of LFTs for 2 weeks or until LFTs 
return to ≤ Grade 1 or baseline.  If LFTs continue to rise within Grade 2, interrupt 
cabozantinib treatment.  Then continue with weekly LFTs for 4 weeks or until 
resolution to Grade ≤ 1.  Study treatment may then be resumed at a one dose-level 
reduction of cabozantinib 
Grade 3  
Interrupt cabozantinib treatment and monitor with at least twice weekly LFTs until 
Grade ≤ 2.  Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Cabozantinib may then be resumed at a one dose-level reduction.   
Grade 4 
Discontinue study treatment permanently.  LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1.  If the subject 
was unequivocally deriving clinical benefit, the subject may be able to resume 
treatment at a lower dose of cabozantinib as determined by the investigator and 
sponsor but only with sponsor approval. 


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Cabozantinib treatment should also be interrupted when transaminase increases are 
accompanied by progressive elevations of total bilirubin, and/or elevations of coagulation 
tests (e.g., International Normalized Ratio [INR]).  Monitoring of transaminases should 
be intensified (2–3 times per week) and cabozantinib should be held until the etiology of 
the abnormalities is determined and these abnormalities are corrected or stabilize at 
clinically acceptable levels (INR < 1.5 × ULN, total bilirubin < 1.5 × ULN, 
aminotransferases ≤ baseline grade).  
 
Subjects must have cabozantinib permanently discontinued if transaminase elevations are 
accompanied by evidence of impaired hepatic function (bilirubin elevation >2 ×ULN), in 
the absence of evidence of biliary obstruction (i.e., significant elevation of alkaline 
phosphatase) or some other explanation of the injury (e.g., viral hepatitis, alcohol 
hepatitis), as the combined finding (i.e., Hy’s Law cases) represents a signal of a potential 
for the drug to cause severe liver injury. 
 
All subjects who develop isolated bilirubin elevations of Grade 3 should have study 
treatment held until recovered to Grade ≤1 or baseline (or lower).  If this occurs within 6 
weeks of the dosing delay, study treatment may continue at a reduced dose.  In subjects 
without biliary obstruction and Grade 4 bilirubin elevation, or with recurrence of Grade 3 
bilirubin elevation after a dose reduction, study treatment must be discontinued.  
 Pancreatic Conditions 
Amylase and lipase elevations have been observed in clinical studies with cabozantinib.  
The clinical significance of asymptomatic elevations of enzymes is not known but in 
general have not been associated with clinically apparent sequelae.  It is recommended 
Transaminase 
elevation 
CTCAE v5.0 
Intervention 
Subjects with AST or ALT above the ULN  but ≤ 3.0 x ULN (i.e., Grade 1) at  baseline   
≥ 1.5 fold increase 
of AST or ALT 
from baseline 
AND both AST 
and ALT are ≤ 5.0 
x ULN 
Continue cabozantinib treatment with weekly monitoring of LFTs for 4 weeks or 
until LFTs return to baseline or stabilize, whichever occurs first.  If LFTs continue 
to rise but remain ≤5.0 x ULN continue to monitor LFTs weekly for  
4 weeks.  If LFTs continue to rise after the additional 4 weeks of monitoring, 
interrupt study treatment.  Then continue with at least weekly LFTs until resolution 
to Grade  ≤ 1.  Study treatment may then be resumed at a one dose-level reduction 
of cabozantinib. 
≥ 1.5 fold increase 
of AST or ALT 
from baseline and 
at least one of 
AST or ALT is 
Grade 3 (i.e. AST 
or ALT > 5.0 but 
≤ 20.0 x ULN) 
Interrupt study treatment and monitor with at least twice weekly LFTs until 
Grade ≤ 2.  Then continue with at least weekly LFTs until resolution to Grade ≤ 1.  
Study treatment may then be resumed at a one dose-level reduction of 
cabozantinib. 
Grade 4  
Discontinue study treatment permanently. LFTs should be monitored as clinically 
indicated, at least 2-3 times per week, until resolution to Grade ≤ 1.  If the subject 
was unequivocally deriving clinical benefit, the subject may be able to resume 
treatment at a lower dose as determined by the investigator and sponsor but only 
with sponsor approval. 


CTEP Protocol #9284 
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that subjects with lipase elevation and/or symptoms of pancreatitis have more frequent 
laboratory monitoring of lipase and/or amylase (2-3 times per week).  Subjects with 
symptomatic pancreatitis should be treated with standard supportive measures. 
 
Asymptomatic Lipase or Amylase Elevations 
 
Asymptomatic Lipase or Amylase  Elevations 
Grade 1 or Grade 2 
Continue at current dose level.  More frequent monitoring is recommended 
Grade 3 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤1 or baseline, cabozantinib may be restarted at 
the same dose or at a reduced dose provided that this occurs within 6 weeks. 
• 
If retreatment following Grade 3 lipase or amylase elevation is at the same 
dose and Grade 3 or Grade 4 elevations recur, then treatment must be 
interrupted again until lipase and amylase  levels have resolved to Grade ≤1 
or baseline and retreatment must be at a reduced dose. 
Grade 4 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤1 or baseline and if resolution occurred within 4 
days, cabozantinib may be restarted at the same dose or a reduced dose.  If 
resolution took more than 4 days, the dose must be reduced upon 
retreatment provided that resolution occurred within 6 weeks. 
• 
If retreatment following Grade 4 lipase or amylase elevation is at the same 
dose and Grade 3 or 4 elevations recur, then treatment must be interrupted 
again until lipase and amylase have resolved to Grade ≤1 or baseline and 
retreatment must be at a reduced dose. 
 
Pancreatitis 
 
Pancreatitis 
Grade 2 and 
asymptomatic 
• 
Continue at current dose level.  More frequent monitoring of lipase and 
amylase and radiographic evaluation is recommended. 
Grade 2 
symptomatic and 
Grade 3 
• 
Interrupt treatment 
• 
Monitor lipase and amylase twice weekly 
• 
Upon resolution to Grade ≤1 or baseline , cabozantinib may be restarted at a 
reduced dose if resolution occurred within 6 weeks 
Grade 4 
Permanently discontinue treatment.  However, if the subject was unequivocally 
deriving benefit from cabozantinib therapy, treatment may resume at a reduced 
at a reduced dose agreed to by the investigator and sponsor but only with 
sponsor approval. 
 Skin Disorders 
Palmar-plantar erythrodysesthesia syndrome (PPE; also known as hand-foot syndrome), 
skin rash (including blister, erythematous rash, macular rash, skin exfoliation, dermatitis 
acneiform, and papular rash), pruritus, dry skin, erythema, pigmentary changes, and 
alopecia have been reported in cabozantinib-treated subjects.  All subjects on study 
should be advised to use prophylactic measures for skin care.  These measures includes 
the use of hypoallergenic moisturizing creams, ointment for dry skin, sunscreen with SPF 
≥30; avoidance of exposure of hands and feet to hot water; protection of pressure-


CTEP Protocol #9284 
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sensitive areas of hands and feet; and use of thick cotton gloves and socks to prevent 
injury and to keep the palms and soles dry.  Subjects with skin disorders should be 
carefully monitored for signs of infection (e.g., abscess, cellulitis, or impetigo). 
 
Early signs of hand-foot syndrome can include tingling, numbness, and slight redness or 
mild hyperkeratosis.  Early manifestations include painful, symmetrical red and swollen 
areas on the palms and soles.  The lateral sides of the fingers or periungual zones may 
also be affected.  Adequate interventions are required to prevent worsening of skin 
symptoms such as blisters, desquamations, ulcerations, or necrosis of affected areas.  
Aggressive management of symptoms is recommended, including early dermatology 
referral. 
 
Treatment guidelines for PPE related to study treatment are presented in the table below. 
 
In the case of study treatment-related skin changes (e.g., rash, hand-foot syndrome), the 
investigator may request that additional assessments be conducted with the subject’s 
consent.  These assessments may include digital photographs of the skin changes and/or a 
biopsy of the affected skin and may be repeated until the skin changes resolve.  
 
Hand-Foot Skin Reaction and Hand Foot Syndrome (PPE) 
Grade 1 
Continue cabozantinib at current dose.  Start urea 20% cream twice daily AND clobetasol 
0.05% cream once daily.  Assess subject at least weekly for changes in severity.  Subjects 
should be instructed to notify investigator immediately if severity worsens.   
Grade 2 
If tolerable, continue cabozantinib at current dose.  If intolerable, reduce cabozantinib 
dose to next lower level and/or interrupt dosing.  Start/continue urea 20% cream twice 
daily AND clobetasol 0.05% cream once daily.  Add analgesics for pain control with 
NSAIDs/GABA agonists/narcotics if needed.  Assess subject at least weekly for changes 
in severity.  If treatment was interrupted (but not reduced), treatment may be restarted at 
the same dose or at one dose level lower when reaction decreases to Grade 1 or 0.  If a 
treatment interruption is again required, the dose must be reduced when treatment 
resumes.  Subjects should be instructed to notify investigator immediately if severity 
worsens.  If severity worsens at any time, or affects self-care, proceed to the management 
guidelines for Grade 3 PPE.   
Grade 3 
Interrupt study treatment until severity decreases to Grade 1 or 0.  Start/continue urea 
20% cream twice daily AND clobetasol 0.05% cream once daily.  Pain control with 
NSAIDs/GABA agonists/narcotics.  Treatment may restart at one dose level lower when 
reaction decreases to Grade 1 or 0.  Permanently discontinue subject from study if 
reactions worsen or do not improve within 6 weeks.   
 Embolism and Thrombosis  
Deep vein thrombosis and PE have been observed in clinical studies with cabozantinib; 
including fatal events (please refer to the Investigators Brochure).  Subjects who develop 
a PE or DVT should have study treatment held until therapeutic anticoagulation with 
heparins is established.  Study treatment may be resumed with a one dose-level reduction 
in subjects who have uncomplicated PE or DVT and are deriving clinical benefit from 
study treatment.  During treatment with anticoagulants, subjects need to be monitored on 
an ongoing basis for bleeding risk and signs of bleeding.  Subjects with life-threatening 
PE or DVT should have study treatment discontinued unless toxicity can be managed and 
subject is deriving clear clinical benefit as determined by the investigator and agreed by 


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36 
 
the Sponsor.  Venous filters (e.g., vena cava filters) are not recommended due to the high 
incidence of complications associated with their use.  Once a subject is fully 
anticoagulated, treatment can be restarted per investigator judgment at one dose lower.  
Subjects should permanently discontinue experimental treatment after a second 
thrombotic event.  Although routine prophylactic anticoagulation is not necessary for all 
subjects, prophylactic anticoagulation is allowed for individual subjects at the discretion 
of the investigator.  Note: lovenox will be administered as therapeutic anticoagulation; no 
data exist of an interaction between cabozantinib and lovenox.   
 
Arterial thrombotic events (e.g., transient ischemic attack, myocardial infarction) have 
been observed rarely in studies with cabozantinib.  Cabozantinib should be discontinued 
in subjects who develop an acute MI or any other clinically significant arterial 
thromboembolic complication. 
 Hypertension toxicity 
Therapeutic BP monitoring by a health care provider will occur at the beginning of every 
cycle for the duration of treatment .All patients will be required to monitor their BP at 
least once a day (preferably BID) throughout the treatment and record the readings in the 
study diary (Appendix C).  Subjects with known hypertension should be optimally 
managed prior to study entry.  Cabozantinib dosing should be interrupted in subjects with 
severe hypertension (180 mm Hg systolic or 120 mm Hg diastolic; or sustained ≥160 mm 
Hg systolic or ≥110 diastolic) who cannot be controlled with medical interventions and 
discontinued in subjects with hypertensive crises or hypertensive encephalopathy (see 
next Table 4 below). 
 
If the readings are abnormal the patient needs to have the BP reconfirmed by a health 
care provider prior to changes in study drug or antihypertensive medications are made.  
Table 4 will be used for the management, and for the determination of cabozantinib dose 
modification.  Suggested antihypertensive medications are listed in Appendix D. 
 
Table 4 
Criteria for Dose 
Modifications 
Treatment/Cabozantinib Dose Modification 
Subjects not receiving optimized anti-hypertensive therapy 
> 140 mm Hg (systolic) 
and < 160 mm Hg 
OR 
> 90 mm Hg (diastolic) 
and < 110 mm Hg 
 
• Increase antihypertension therapy  (i.e., increase dose of existing 
medications and/or add new antihypertensive medications)  
• Maintain dose of cabozantinib 
• If optimal antihypertensive therapy (usually to include 3 agents) does not 
result in blood pressure < 140 systolic or < 90 diastolic, or if the subject 
is symptomatic, the dose of cabozantinib should be reduced. 
≥ 160 mm Hg (systolic) 
and < 180 mm Hg 
OR 
≥ 110 mm Hg 
(diastolic) and < 120 
mm Hg 
• Reduce cabozantinib by one dose level. 
• Increase antihypertension therapy  (i.e., increase dose of existing 
medications and/or add new antihypertensive medications)  
• Monitor subject closely for hypotension. 
• If optimal antihypertensive therapy (usually to include 3 agents) does not 
result in blood pressure < 140 systolic or < 90 diastolic, dose of 
cabozantinib should be reduced further. 
≥ 180 mm Hg (systolic) 
• Interrupt treatment with cabozantinib Add new or additional anti-


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37 
 
Criteria for Dose 
Modifications 
Treatment/Cabozantinib Dose Modification 
OR 
≥ 120 mm Hg (diastolic ) 
hypertensive medications and/or increase dose of existing medications. 
• Monitor subject closely for hypotension. 
• When SBP < 140 and DBP < 90, restart cabozantinib treatment at  one 
dose level lower 
• If optimal antihypertensive therapy (usually to include 3 agents) does not 
result in blood pressure < 140 systolic or < 90 diastolic, dose of 
cabozantinib should be reduced further. 
Hypertensive crisis or 
hypertensive 
encephalopathy 
Discontinue all study treatment 
BP, blood pressure, SBP systolic blood pressure, DBP diastolic blood pressure 
NOTE:  If SBP and DBP meet different criteria in table, manage per higher dose-modification criteria 
 Proteinuria toxicity 
Evaluation of urine protein/creatinine ratio (UPC) should occur as follows: at baseline 
and at the start of each cycle.  Dose modification should be done according to Table 5 
below. 
 
Severity of Proteinuria 
Management of Proteinuria 
Urine Protein/Creatinine Ratio 
≤ 1 
• No change in treatment or monitoring 
> 1 and < 3.5 
• Confirm with a 24 hour urine protein excretion 
within 7 days.   
• If proteinuria of > 1 g/24 hours is confirmed, hold 
cabozantinib and continue with UPCR monitoring.  
When UPCR returns to < 1, restart cabozantinib at 
a reduced dose.  Continue monitoring UPCR once 
every week until two consecutive readings are < 1, 
then revert to UPCR monitoring frequency 
specified in the protocol. 
≥ 3.5 
• Hold cabozantinib immediately and confirm with 
24 hour urine protein excretion. 
• Evaluate for nephritic syndrome.  If present, 
discontinue cabozantinib treatment permanently, 
and monitor subject for resolution of nephritic 
syndrome. 
• If proteinuria of ≥ 3.5 g/24 hours is confirmed 
without diagnosis of nephrotic syndrome, continue 
to hold cabozantinib and monitor UPCR weekly.  If 
UPCR decreased to < 1, then revert to UPCR 
monitoring frequency specified in protocol 
UPCR, urine protein/urine creatinine ratio. 
 
 Guidelines for the Prevention of Hemorrhagic Events 
Hemorrhagic events have been reported with approved drugs that inhibit VEGF pathways 
as well as with cabozantinib.  As preventive measures, subjects should be evaluated for 
potential bleeding risk factors prior to initiating cabozantinib treatment and monitored for 


CTEP Protocol #9284 
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38 
 
bleeding events with serial complete blood counts and physical examination while on 
study.  Risk factors for hemorrhagic events may include (but may not be limited to) the 
following: 
 
• Tumor lesions with cavitations or tumor lesions which invade, encase, or abut major 
blood vessels.  The anatomic location and characteristics of primary tumors or 
metastases as well as the medical history should be carefully reviewed in the selection 
of subjects for treatment with cabozantinib. 
• Recent or concurrent radiation to the thoracic cavity.  
• Active peptic ulcer disease, ulcerative colitis, and other inflammatory GI diseases. 
• Underlying medical conditions which affect normal hemostasis (e.g., deficiencies in 
clotting factors and/or platelet function, or thrombocytopenia). 
• Concomitant medication with anticoagulants or other drugs which affect normal 
hemostasis. 
• History of clinically significant hemoptysis. 
 
Cabozantinib should be discontinued in subjects with serious and life-threatening 
bleeding events or recent hemoptysis (≥ 0.5 teaspoon (2.5 mL) of red blood).  Treatment 
with cabozantinib should be interrupted if less severe forms of clinically significant 
hemorrhage occur and may be restarted after the cause of hemorrhage has been identified 
and the risk of bleeding has subsided at a dose agreed to by the sponsor and the 
investigator.  Therapy of bleeding events should include supportive care and standard 
medical interventions.  
 
Furthermore, subjects who develop tumors abutting, encasing, or invading a major blood 
vessel or who develop cavitation of their pulmonary tumors while on study treatment 
must be discontinued from cabozantinib treatment. 
 Rectal and Perirectal Abscess 
Rectal and perirectal abscesses have been reported, sometimes in subjects with 
concurrent diarrhea.  These should be treated with appropriate local care and antibiotic 
therapy.  Cabozantinib should be held until adequate healing has taken place.  
 Guidelines for Prevention of GI Perforation/Fistula and Non-GI Fistula Formation 
GI perforation/fistula and Non-GI fistula formation have been reported with approved 
drugs that inhibit VEGF pathways as well as with cabozantinib.  Carefully monitor for 
episodes of abdominal pain, especially in subjects with known risk factors for developing 
GI perforation/fistula or non-GI fistula, to allow for early diagnosis. Such risk factors 
include (but may not be limited to) the following: 
 
GI-perforation/fistula: 
• Intra-abdominal tumor/metastases invading GI mucosa.  
• Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, 
diverticulitis, cholecystitis or symptomatic cholangitis, or appendicitis . 
• History of abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal 
abscess 


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39 
 
• Prior GI surgery (particularly when associated with delayed or incomplete healing).  
Complete healing following abdominal surgery or resolution of intra-abdominal 
abscess must be confirmed prior to initiating treatment with cabozantinib. 
 
Additional risk factors include concurrent chronic use of steroid treatment or 
non-steroidal anti-inflammatory drugs.  Constipation indicative of bowel obstruction 
should be monitored and effectively managed.  
 
Non-GI fistula: 
• Radiation therapy has been identified as a possible predisposing risk factor for non-GI 
fistula formation in subjects undergoing treatment with drugs that inhibit VEGF 
pathways.  In addition, subjects who have undergone extensive surgery may be at 
increased risk of developing a fistula of the involved organs non-GI fistula should be 
ruled out as appropriate in cases of onset of mucositis after start of therapy. 
 
Discontinue all study treatment in subjects who have been diagnosed with GI or non-GI 
perforation/fistula. 
 Wound Healing and Surgery 
VEGF inhibitors can cause wound healing complications and wound dehiscence which 
may occur even long after a wound has been considered healed.  Therefore, surgical and 
traumatic wounds must have completely healed prior to starting cabozantinib treatment 
and be monitored for wound dehiscence or wound infection while the subject is being 
treated with cabozantinib.  
 
Treatment with cabozantinib must be interrupted for any wound healing complication 
which needs medical intervention.  Treatment with cabozantinib can be resumed once 
wound healing has occurred unless otherwise prohibited in specific protocols.  
Cabozantinib should be discontinued in subjects with serious or chronic wound healing 
complications. 
 
The appropriate dose hold interval prior to elective surgery to reduce the risk for wound 
healing complications has not been determined.  In general, cabozantinib should be 
stopped at least 3 weeks (5 half-lives) prior to elective surgery.  
 Endocrine Disorders 
Prospective studies of markers of thyroid functions are currently ongoing in two single-
agent studies to characterize the effects of cabozantinib on thyroid function.  Preliminary 
data indicate that cabozantinib affects thyroid function tests (TFTs) in a high number of 
subjects (see Cabozantinib Investigator’s Brochure).  Routine monitoring of thyroid 
function and assessments for signs and symptoms associated with thyroid dysfunction is 
recommended for subjects treated with cabozantinib.  Management of thyroid 
dysfunction (e.g., symptomatic hypothyroidism) should follow accepted clinical practice 
guidelines. 
 
Other endocrine disorders such as hypocalcemia and hyperglycemia, and associated 
laboratory changes, have been observed in less than 10% of subjects.  Monitoring with 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
40 
 
standard laboratory tests for endocrine disorders and clinical examination prior to 
initiation and during treatment with cabozantinib is required.  Cabozantinib should be 
discontinued in subjects with severe or life-threatening endocrine dysfunction. 
 Guidelines for Prevention of Osteonecrosis of the Jaw 
Osteonecrosis of the jaw (ONJ) has been reported with use of antiangiogenic drugs and 
bisphosphonates and denosumab in cancer patients.  Additional risk factors for ONJ have 
been identified such as use of corticosteroids, chemotherapy, local radiotherapy, poor oral 
hygiene, smoking, dental or orofacial surgery procedures, and cancer disease itself.  
Cases of osteonecrosis have been reported in subjects treated with cabozantinib, the 
details of which are provided in the current version of Investigator’s Brochure.  As a 
preventive measure, invasive dental procedures should be avoided if possible in subjects 
who have previously been treated with or concomitantly receive bisphosphonates or 
denosumab.  In cases where dental procedures are unavoidable, the risks and benefits of a 
dental procedure and the extent of the procedure as well as the risk of developing 
osteonecrosis of the jaw need to be considered when deciding on the duration of a 
temporary treatment interruption of cabozantinib.  If clinically possible, treatment with 
cabozantinib should be held for at least 2 weeks prior to a dental procedure and resumed 
after complete wound healing occurred. 
 
Subjects with any documented case of osteonecrosis should have study treatment 
interrupted, and appropriate clinical management should be initiated.  Reinitiation of 
study treatment must be discussed with and approved by the Sponsor on a case by case 
basis. 
 Guidelines for Management of Treatment-Emergent Corrected QT (QTc) 
Prolongation 
Treatment with cabozantinib has been associated with a mild prolongation of the QTc 
interval.  Other factors which may contribute to QTc prolongation include 
• Treatment with other drugs associated with QTc prolongation (see 
http://www.qtdrugs.org). 
• Treatment with CyP 3A4 inhibitors (which may increase cabozantinib drug 
levels) 
• Electrolyte changes (hypokalemia, hypocalcemia, hypomagnesemia). 
• Medical conditions which can alter electrolyte status e.g., severe or prolonged 
diarrhea. 
 
Subjects having any of these additional risk factors while on cabozantinib must have 
EKGs performed approximately one week after the onset of these factors. 
 
If at any time on study there is an increase in QTc interval to an absolute value >500 
msec, two additional EKGs should be performed within 30 minutes after the initial EKG 
with intervals not less than 3 minutes apart.  If the average QTcF from the three EKGs is 
>500 msec, study treatment must be withheld and the following actions should be taken: 
 
• Check electrolytes, especially potassium, magnesium, and calcium.  Correct 
abnormalities as clinically indicated. 


CTEP Protocol #9284 
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41 
 
• If possible, discontinue any QTc-prolonging concomitant medications. 
• Repeat EKG triplets hourly until the average QTcF is ≤500 msec or otherwise 
determined by consultation with a cardiologist. 
 
The Sponsor should be notified immediately of any QTc prolongation event.  
 
Subjects with QTc prolongation and symptoms must be monitored closely until the QTc 
elevation has resolved.  Cardiology consultation is recommended for evaluation and 
subject management.  Symptomatic subjects must be treated according to standard 
clinical practice.  No additional study treatment is to be given to the subject until after the 
event has resolved, the subject has been thoroughly evaluated, and further treatment has 
been agreed to by the Sponsor.  If any additional study treatment is given (e.g., after 
correction of electrolyte abnormalities and normalization of QTcF), it will be at a reduced 
dose as agreed to by the investigator and the Sponsor. 
 
7 ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs (Section 7.1) and the characteristics of an observed AE (Section 7.2) will 
determine whether the event requires expedited reporting (via CTEP-AERS) in addition to 
routine reporting. 
7.1 
Comprehensive Adverse Events and Potential Risks List (CAEPR) 
 CAEPR for Cabozantinib (NSC 761968) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list 
of reported and/or potential adverse events (AE) associated with an agent using a uniform 
presentation of events by body system. In addition to the comprehensive list, a subset, the 
Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a separate column 
and is identified with bold and italicized text. This subset of AEs (SPEER) is a list of events 
that are protocol specific exceptions to expedited reporting to NCI (except as noted below).  
Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification.  Frequency is provided based on 3219 patients. Below is the CAEPR 
for XL184 (Cabozantinib). 
 
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the AE in 
the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational agents and has 
an AE listed on different SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
Version 2.4, December 17, 20181 
 
 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
  


CTEP Protocol #9284 
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42 
 
 
 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
ENDOCRINE DISORDERS 
  
 
Hypothyroidism 
 
 Hypothyroidism (Gr 2) 
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain (Gr 3) 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 3) 
 
Dry mouth 
 
 Dry mouth (Gr 2) 
 
Dyspepsia 
 
 Dyspepsia (Gr 2) 
 
 
Gastrointestinal fistula2 
  
 
 
Gastrointestinal hemorrhage3 
  
 
 
Gastrointestinal perforation4 
  
 
Mucositis oral 
 
 Mucositis oral (Gr 3) 
Nausea 
 
 
 Nausea (Gr 3) 
 
Oral pain 
 
 Oral pain (Gr 2) 
Vomiting 
 
 
 Vomiting (Gr 3) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 3) 
INFECTIONS AND INFESTATIONS 
  
 
Infection5 
 
  
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Wound complication 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase increased  
 Alanine aminotransferase increased 
(Gr 3) 
 
Aspartate aminotransferase 
increased 
 
 Aspartate aminotransferase increased 
(Gr 3) 
 
Lipase increased 
 
 Lipase increased (Gr 4) 
 
Platelet count decreased 
 
 Platelet count decreased  
(Gr 3) 
Weight loss 
 
 
 Weight loss (Gr 3) 
METABOLISM AND NUTRITION DISORDERS 
  
Anorexia 
 
 
 Anorexia (Gr 3) 
 
Dehydration 
 
  
 
Hypocalcemia 
 
  
 
Hypokalemia 
 
  
 
Hypomagnesemia 
 
  
 
Hypophosphatemia 
 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
  
 
Generalized muscle weakness 
 
  
 
Muscle cramp 
 
  
 
 
Osteonecrosis of jaw 
  
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
Dysgeusia 
 
 
 Dysgeusia (Gr 2) 
 
Headache 
 
  
 
 
Intracranial hemorrhage  
  


CTEP Protocol #9284 
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43 
 
 
 Adverse Events with Possible  
 Relationship to XL184 (Cabozantinib) 
 (CTCAE 5.0 Term) 
[n= 3219] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER) 
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
 
 
Ischemia cerebrovascular 
  
 
 
Reversible posterior 
leukoencephalopathy syndrome 
  
 
 
Stroke 
  
 
 
Transient ischemic attacks 
  
RENAL AND URINARY DISORDERS 
  
 
Hematuria 
 
  
 
 
Proteinuria 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
  
 
Dyspnea 
 
  
 
 
Pneumothorax6 
  
 
 
Respiratory fistula7 
  
 
Respiratory hemorrhage8 
 
  
 
Voice alteration 
 
 Voice alteration (Gr 3) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
  
 
Dry skin 
 
 Dry skin (Gr 2) 
 
Hair color changes 
 
 Hair color changes (Gr 1) 
Palmar-plantar erythrodysesthesia 
syndrome 
 
 
 Palmar-plantar erythrodysesthesia 
syndrome (Gr 3) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 3) 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension (Gr 3) 
 
Thromboembolic event9 
 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV. Your name, the name of the investigator, the protocol and the agent should be 
included in the e-mail. 
 
2Gastrointestinal fistula includes Anal fistula, Colonic fistula, Duodenal fistula, Esophageal fistula, 
Enterovesical fistula, Gastric fistula, Gastrointestinal fistula, Ileal fistula, Jejunal fistula, Oral cavity fistula, 
Pancreatic fistula, Rectal fistula, and Salivary gland fistula under the GASTROINTESTINAL 
DISORDERS SOC. 
 
3Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic hemorrhage, Duodenal 
hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric hemorrhage, Hemorrhoidal 
hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal hemorrhage, Lower gastrointestinal 
hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, 
and Upper gastrointestinal hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
 
4Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, Esophageal perforation, 
Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and Small intestinal 
perforation under the GASTROINTESTINAL DISORDERS SOC. 
 
5Infection includes all 75 sites of infection under the INFECTIONS AND INFESTATIONS SOC. 
 
6Pneumothorax has been observed at a higher than expected frequency (15-20%) in a study treating patients 
with relapsed Ewing sarcoma and osteosarcoma all of whom had pulmonary metastases. 


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7Respiratory fistula includes Bronchial fistula, Bronchopleural fistula, Laryngeal fistula, Pharyngeal fistula, 
Pulmonary fistula, and Tracheal fistula under the RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS SOC. 
 
8Respiratory hemorrhage includes Bronchopulmonary hemorrhage, Epistaxis, Hemoptysis, Laryngeal 
hemorrhage, Mediastinal hemorrhage, Pharyngeal hemorrhage, and Pleural hemorrhage under the 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS SOC. 
 
9Thromboembolic event includes pulmonary embolism which may be life-threatening. 
 
 
 
Adverse events reported on XL184 (Cabozantinib) trials, but for which there is insufficient evidence to 
suggest that there was a reasonable possibility that XL184 (Cabozantinib) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(pancytopenia); Disseminated intravascular coagulation; Eosinophilia; Febrile neutropenia; Hemolytic 
uremic syndrome 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block complete; Cardiac arrest; Cardiac 
disorders - Other (hypokinetic cardiomyopathy); Chest pain - cardiac; Heart failure; Left ventricular 
systolic dysfunction; Myocardial infarction; Myocarditis; Sinus bradycardia; Sinus tachycardia; 
Supraventricular tachycardia 
EAR AND LABYRINTH DISORDERS - Hearing impaired; Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (autoimmune thyroiditis); Endocrine disorders - 
Other (thyroiditis); Endocrine disorders - Other (thyrotoxicosis); Hyperthyroidism; Hypopituitarism 
EYE DISORDERS - Blurred vision; Cataract; Eye disorders - Other (corneal epithelium defect) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Anal fissure; Anal mucositis; Anal pain; Anal 
ulcer; Cheilitis; Colitis; Colonic obstruction; Duodenal ulcer; Dysphagia; Enterocolitis; Esophageal ulcer; 
Esophagitis; Flatulence; Gastric ulcer; Gastroesophageal reflux disease; Gastrointestinal disorders - Other 
(glossitis); Gastrointestinal disorders - Other (pneumoperitoneum); Gastrointestinal pain; Gingival pain; 
Hemorrhoids; Ileus; Pancreatitis; Periodontal disease; Rectal pain; Rectal ulcer; Toothache 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Chills; Death NOS; Edema 
face; Fever; Gait disturbance; General disorders and administration site conditions - Other (general physical 
health deterioration); General disorders and administration site conditions - Other (implant site 
inflammation); Hypothermia; Malaise; Multi-organ failure; Non-cardiac chest pain; Pain; Sudden death 
NOS 
HEPATOBILIARY DISORDERS - Budd-Chiari syndrome; Cholecystitis; Hepatic failure; Hepatobiliary 
disorders - Other (cholelithiasis); Hepatobiliary disorders - Other (hepatic cirrhosis); Hepatobiliary 
disorders - Other (hepatic thrombus); Hepatobiliary disorders - Other (hepatitis toxic); Hepatobiliary 
disorders - Other (hepatorenal syndrome); Portal vein thrombosis 
IMMUNE SYSTEM DISORDERS - Allergic reaction; Anaphylaxis; Autoimmune disorder 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS - Fall; Injury, poisoning and procedural 
complications - Other (post procedural hemorrhage); Injury, poisoning and procedural complications - 
Other (tendon injury); Wound dehiscence; Wrist fracture 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Blood lactate dehydrogenase 
increased; CPK increased; Cardiac troponin I increased; Creatinine increased; Ejection fraction decreased; 
Electrocardiogram QT corrected interval prolonged; GGT increased; Investigations - Other (D-dimer); 
Investigations - Other (urine ketone body present); Lymphocyte count decreased; Neutrophil count 
decreased; Serum amylase increased; Thyroid stimulating hormone increased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Glucose intolerance; Hyperglycemia; Hypernatremia; 
Hyperuricemia; Hypoalbuminemia; Hyponatremia; Metabolism and nutrition disorders - Other (failure to 
thrive); Metabolism and nutrition disorders - Other (hypoproteinemia) 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Back pain; Buttock pain; Chest 
wall pain; Flank pain; Muscle weakness lower limb; Musculoskeletal and connective tissue disorder - Other 
(muscle hemorrhage); Myalgia; Neck pain; Osteonecrosis; Osteoporosis; Rhabdomyolysis 


CTEP Protocol #9284 
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NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other (lip and/or oral cavity 
cancer); Tumor hemorrhage; Tumor pain 
NERVOUS SYSTEM DISORDERS - Ataxia; Cognitive disturbance; Concentration impairment; Dysarthria; 
Dysesthesia; Dysphasia; Encephalopathy; Lethargy; Memory impairment; Nervous system disorders - 
Other (hemiparesis); Nervous system disorders - Other (vocal cord paralysis); Peripheral motor neuropathy; 
Peripheral sensory neuropathy; Presyncope; Seizure; Somnolence; Spinal cord compression; Syncope 
PSYCHIATRIC DISORDERS - Anxiety; Confusion; Delirium; Depression; Hallucinations; Insomnia; 
Psychiatric disorders - Other (mental status changes) 
RENAL AND URINARY DISORDERS - Acute kidney injury; Chronic kidney disease; Glucosuria; Renal 
and urinary disorders - Other (hemorrhage urinary tract); Urinary tract obstruction 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Pelvic pain; Reproductive system and breast 
disorders - Other (scrotal ulcer/erythema/edema); Scrotal pain; Vaginal fistula; Vaginal inflammation; 
Vaginal perforation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome; 
Allergic rhinitis; Aspiration; Atelectasis; Hoarseness; Hypoxia; Laryngeal edema; Oropharyngeal pain; 
Pharyngeal mucositis; Pleural effusion; Pneumonitis; Productive cough; Pulmonary hypertension; 
Respiratory failure; Respiratory, thoracic and mediastinal disorders - Other (nasal septum perforation); 
Respiratory, thoracic and mediastinal disorders - Other (pneumomediastinum); Respiratory, thoracic and 
mediastinal disorders - Other (rales); Sore throat 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Erythema multiforme; Nail changes; Pain of skin; 
Pruritus; Rash acneiform; Skin and subcutaneous tissue disorders - Other (pain, sloughing of skin and 
erythema); Skin and subcutaneous tissue disorders - Other (psoriasis); Skin hypopigmentation; Skin 
ulceration 
VASCULAR DISORDERS - Hematoma; Hypotension; Superior vena cava syndrome; Vascular disorders - 
Other (bleeding varicose vein); Vasculitis 
 
 
Note: XL184 (Cabozantinib) in combination with other agents could cause an exacerbation of any adverse 
event currently known to be caused by the other agent, or the combination may result in events never 
previously associated with either agent. 
 
 


CTEP Protocol #9284 
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7.2 
CTEP Reporting Requirements  
 Adverse Event Characteristics  
• CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized until March 31, 2018 for AE reporting.  
CTCAE version 5.0 will be utilized for AE reporting beginning April 1, 2018.  All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0.  
A copy of the CTCAE version 5.0 can be downloaded from the CTEP web site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.   
 
• For expedited reporting purposes only:   
o AEs for the agent that are bold and italicized in the CAEPR (i.e., those listed 
in the SPEER column, Section 7.1.1) should be reported through CTEP-AERS 
only if the grade is above the grade provided in the SPEER. 
o Other AEs for the protocol that do not require expedited reporting are outlined 
in Section 7.2.4. 
 
• Attribution of the AE: 
1. Definite – The AE is clearly related to the study treatment. 
2. Probable – The AE is likely related to the study treatment. 
3. Possible – The AE may be related to the study treatment. 
4. Unlikely – The AE is doubtfully related to the study treatment. 
5. Unrelated – The AE is clearly NOT related to the study treatment. 
 Expedited Adverse Event Reporting 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System), accessed via the CTEP Web site (http://ctep.cancer.gov).  The 
reporting procedures to be followed are presented in the “NCI Guidelines for 
Investigators: Adverse Event Reporting Requirements for DCTD (CTEP and CIP) and 
DCP INDs and IDEs” which can be downloaded from the CTEP Web site 
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_events.htm
).  These requirements are briefly outlined in the tables below (Section 7.2.3). 
 
In the rare occurrence when Internet connectivity is lost, a 24-hour notification is to be 
made to CTEP by telephone at 301-897-7497.  Once Internet connectivity is restored, the 
24-hour notification phoned in must be entered electronically into CTEP-AERS by the 
original submitter at the site.  
 
 Distribution of Adverse Event Reports 
CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals:  Principal Investigator and Adverse Event Coordinator(s) (if 
applicable) of the Corresponding Organization or Lead Organization, the local treating 
physician, and the Reporter and Submitter.  CTEP-AERS provides a copy feature for 
other e-mail recipients 


CTEP Protocol #9284 
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 Expedited Reporting Guidelines  
Use the NCI protocol number and the protocol-specific patient ID assigned during trial 
registration on all reports. 
 
Note:  A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below.  Attribution to treatment or other cause must be 
provided. 
 
Death due to progressive disease should be reported as Grade 5 “Disease progression” 
in the system organ class (SOC) “General disorders and administration site conditions.”  
Evidence that the death was a manifestation of underlying disease (e.g., radiological 
changes suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted.  
 
Phase 1 and Early Phase 2 Studies:  Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention 1, 2 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE:  Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, whether or 
not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64) 
An adverse event is considered serious if it results in ANY of the following outcomes:   
1) Death 
2) A life-threatening adverse event  
3) An adverse event that results in inpatient hospitalization or prolongation of existing hospitalization for ≥ 24 
hours  
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require hospitalization 
may be considered serious when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
(FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 and Grade 2 Timeframes 
Grade 3-5 
Timeframes 
Resulting in Hospitalization      
≥ 24 hrs 
10 Calendar Days 
24-Hour; 5 Calendar Days 
Not resulting in Hospitalization    
≥ 24 hrs 
Not required 
NOTE:   Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
o “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-
hour report. 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  


CTEP Protocol #9284 
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Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered.  Footnote “1” 
above applies after this reporting period. 
Effective Date:  May 5, 2011 
 Additional Protocol-Specific Expedited Adverse Event Reporting Exclusions 
Lymphopenia (any grade), alopecia (any grade), anemia (grade 2), electrolytes (grade 2: 
sodium, potassium, phosphorous, and magnesium), albumin (grade 2), hyperuricemia 
(grade 3), INR (grade 2), and PTT (grade 2) will NOT be reported through CTEP-AERS 
but will be reported in the routine data submissions. 
 Routine Adverse Event Reporting 
All Adverse Events must be reported in routine study data submissions.  AEs reported 
expeditiously through CTEP-AERS must also be reported in routine study data 
submissions. 
 
 Pregnancy 
Although not an adverse event in and of itself, pregnancy as well as its outcome must be 
documented via CTEP-AERS.  In addition, the Pregnancy Information Form included 
within the NCI Guidelines for Adverse Event Reporting Requirements must be 
completed and submitted to CTEP.  Any pregnancy occurring in a patient or patient’s 
partner from the time of consent to 90 days after the last dose of study drug must be 
reported and then followed for outcome.  Newborn infants should be followed until 30 
days old.  Please see the “NCI Guidelines for Investigators: Adverse Event Reporting 
Requirements for DCTD (CTEP and CIP) and DCP INDs and IDEs” (at 
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm) for more details on 
how to report pregnancy and its outcome to CTEP.  
 
 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation, or chemotherapy).  A 
secondary malignancy is not considered a metastasis of the initial neoplasm.  CTEP 
requires all secondary malignancies that occur following treatment with an agent under 
an NCI IND/IDE be reported via CTEP-AERS.  Three options are available to describe 
the event:  
 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML])  
• Myelodysplastic syndrome (MDS)  
• Treatment-related secondary malignancy  
 


CTEP Protocol #9284 
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49 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanisms outlined in each protocol.  
 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is 
NOT a metastasis from the initial malignancy).  Second malignancies require ONLY 
routine reporting via CDUS unless otherwise specified.  
 Multicenter Guidelines for Expedited Adverse Event Reporting 
7.2.10.1 
Expedited Adverse Event Reporting for Participating Sites 
Adverse Event Reporting via CTEP-AERS: 
Follow sponsor expedited AE reporting requirements in Section 7.2 and copy Ashley 
Bruns  (ashley.bruns@nih.gov) and Dr. Alice Chen (chenali@mail.nih.gov) on all CTEP-
AERS reports.   
 
Adverse Event Reporting to NIH IRB: 
The Coordinating Center will review CTEP-AERS reports and submit to the NIH-IRB 
via iRIS (https://iris.nci.nih.gov/iMedris/).  The site PI must immediately report to the 
Coordinating Center PI any serious adverse event, whether or not considered drug 
related, including those listed in the protocol or investigator brochure and must include an 
assessment of whether there is a reasonable possibility that the drug caused the event 
within 24 hours of PI awareness of the event.  The site PI must also report any protocol 
deviations or violations to the Coordinating Center PI within 7 days of PI awareness.  
Participating centers must also submit the report to their IRB in accordance with their 
institutional policies. 
 
Follow NIH IRB expedited AE reporting requirements in this section.  Complete the NIH 
IRB Expedited AE form supplied by the Coordinating Center.  Send the completed form 
to Ashley Bruns either by e-mail to ashley.bruns@nih.gov or by fax to (301) 451-5625. 
7.3 
NIH Reporting Requirements 
 Definitions 
Please refer to definitions provided in Policy 801: Reporting Research Events 
(https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs). 
 
 OHSRP Office of Compliance and Training / IRB Reporting  
Please refer to the reporting requirements in Policy 801: Reporting Research Events and 
Policy 802 Non-Compliance Human Subjects Research found at 
https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs 
 
Note: Only IND Safety Reports that meet the definition of an unanticipated problem will 
need to be reported per these policies. 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
50 
 
 IRB Requirements for PI Reporting at Continuing Review 
Please refer to the reporting requirements in Policy 801: Reporting Research Events 
found at https://irbo.nih.gov/confluence/display/IRBO/Policies+and+SOPs  
 
 NCI Clinical Director Reporting  
Problems expeditiously reviewed by the OHSRP/IRB in the NIH eIRB system will also 
be reported to the NCI Clinical Director/designee; therefore, a separate submission for 
these reports is not necessary. 
 
In addition to those reports, all deaths that occur within 30 days after receiving a research 
intervention should be reported via email unless they are due to progressive disease.   
 
To report these deaths, please send an email describing the circumstances of the death to 
the NCI Clinical Director or their designee atNCICCRQA@mail.nih.gov within one 
business day of learning of the death. 
 
8 PHARMACEUTICAL INFORMATION 
A list of the adverse events and potential risks associated with cabozantinib can be found in 
Section 7.1. 
8.1 
Cabozantinib (NSC 761968) 
Chemical Name: N-{4-[(6,7-dimethoxyquinolin-4-yl)oxy]phenyl}-N’-(4-fluorophenyl) 
cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutanedioate  
 
Other Names: XL184, EXEL-7184, EXEL-02977184 
 
Classification: Receptor Tyrosine Kinases Inhibitor (RTK) 
 
CAS Registry Number: 1140909-48-3  
 
Molecular Formula: C28H24FN3O5.C4H6O5 
Molecular Weight: 635.6  
 
Mode of Action: Cabozantinib inhibits multiple RTKs implicated in tumor growth, metastasis, 
and angiogenesis, and targets primarily MET and VEGFR2.  Other targets are RET, AXL, KIT, 
TIE-2, and FLT-3.  
 
How Supplied: Cabozantinib is supplied by Exelixis and distributed by the DCTD.  
Cabozantinib is available in 20-mg and 60-mg tablets.  The tablets are yellow film coated 
containing cabozantinib malate equivalent to 20 mg and 60 mg of cabozantinib.  The 20-mg 
tablets have a round shape and the 60-mg tablets have an oval shape, and they are packaged 30 
tablets per bottle.  
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
51 
 
Cabozantinib Tablet Components and Composition 
Ingredient  
Function 
% w/w 
Cabozantinib malate (25% drug load as cabozantinib) 
Active Ingredient 
31.7 
Microcrystalline Cellulose (Avicel PH-102) 
Filler 
38.9 
Lactose Anhydrous (60M) 
Filler 
19.4 
Hydroxypropyl Cellulose (EXF) 
Binder 
3.0 
Croscarmellose Sodium (Ac-Di-Sol) 
Disenegrant 
6.0 
Colloidal Silicon Dioxide, 
Glidant 
0.3 
Magnesium Stearate 
Lubricant 
0.75 
Opadry Yellow Film Coating which includes: 
HPMC 2910 / Hypromellose 6 cp  
Titanium dioxide  
Triacetin  
Iron Oxide Yellow 
Film Coating 
4.00 
 
Storage:  Store intact bottles at controlled room temperature, 20° to 25°C (68° F to 77° F); 
temperature excursions are permitted between 15° C and 30° C (59° F to 86° F) [see USP 
Controlled Room Temperature]. 
If a storage temperature excursion is identified, promptly return cabozantinib to 20° to 
25°C (68° to 77° F) and quarantine the supplies.  Provide a detailed report of the excursion 
(including documentation of temperature monitoring and duration of the excursion) to 
PMBAfterHours@mail.nih.gov for determination of suitability. 
 
Stability:  Stability testing of the intact bottles is ongoing.  Cabozantinib is stable up to 24 hours 
when dispensed in an open container such as a pill cup, and up to 7 days when dispensed in a 
closed container such as a pharmacy bottle other than the original container.  
 
Route of Administration: Oral cabozantinib should be taken on an empty stomach, 1 hour 
before or 2 hours after food.  Do not crush or chew.   
 
Potential Drug Interactions: See Section 5.1.1 
8.2 Agent Ordering 
 
NCI-supplied agents may be requested by the responsible investigator (or their authorized 
designee) at each participating institution.  Pharmaceutical Management Branch (PMB) 
policy requires that agent be shipped directly to the institution where the patient is to be 
treated.  PMB does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  The CTEP-assigned protocol number must be used for 
ordering all CTEP-supplied investigational agents.  The responsible investigator at each 
participating institution must be registered with CTEP, DCTD through an annual 
submission of FDA Form 1572 (Statement of Investigator), Biosketch, Agent Shipment 
Form, and Financial Disclosure Form (FDF).  If there are several participating 
investigators at one institution, CTEP-supplied investigational agents for the study should 
be ordered under the name of one lead investigator at that institution. 
 


CTEP Protocol #9284 
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Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx).  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://ctepcore.nci.nih.gov/iam) and the maintenance of an “active” 
account status and a “current” password.  For questions about drug orders, transfers, 
returns, or accountability, call (240) 276-6575 Monday through Friday between 8:30 am 
and 4:30 pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
8.3 
Agent Accountability 
Agent Inventory Records – The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the receipt, dispensing and final 
disposition of all agents received from the PMB using the appropriate NCI 
Investigational Agent (Drug) Accountability Record (DARF) available on the CTEP 
forms page.  Store and maintain separate NCI Investigational Agent Accountability 
Records for each agent, strength, formulation and ordering investigator on this protocol. 
8.4 
Investigator Brochure Availability 
The current versions of the IBs for the agents will be accessible to site investigators and 
research staff through the PMB Online Agent Order Processing (OAOP) application.  
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account and the maintenance of an “active” account status and a “current” 
password.  Questions about IB access may be directed to the PMB IB coordinator via 
email. 
8.5 
Useful Links and Contacts 
• CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/ 
• NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov  
• PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm  
• PMB Online Agent Order Processing (OAOP) application: https://eapps-
ctep.nci.nih.gov/OAOP/pages/login.jspx  
• CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam 
• CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov  
• PMB email:  PMBAfterHours@mail.nih.gov 
• IB Coordinator: IBCoordinator@mail.nih.gov 
• PMB phone and hours of service: (240) 276-6575 Monday through Friday between 
8:30 am and 4:30 pm (ET) 
 


CTEP Protocol #9284 
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9 CORRELATIVE STUDIES 
9.1 
Pharmacodynamics  
Blood will be obtained from all patients for PD assessment as described in Section 9.1.1.    
Optional blood samples will also be collected for isolation of CTCs as defined in Section 
9.1.2.     
 
Record the date, planned time, and actual time of collection for each specimen on the PK/PD 
Sample Collection Sheet in Appendix H, the CTEP tracking number (P9284), unique patient 
accession number, and 3-digit sample number should be included on this form.  In addition, 
the date and exact time when study drug was administered should be recorded on the form. 
 
At the NCI,  at least 24 hours prior to blood sample collection, the research nurse will contact 
the NCI Phase I/II PK/PD Support Group in NIH Building 10: E-mail NCIPK-
PDsupportgroup@mail.nih.gov Pager: 102-12798 Phone: 301-451-1169 Fax: 301-480-5871.   
 Blood Samples (mandatory at the NCI but optional at participating sites) 
Assays to be performed: sMET, HGF, VEGF-A, and sVEGFR2.  These research blood 
tests are mandatory at the NCI but optional at participating sites:  
 
Samples will be obtained at the following time points:  
 
• Before drug administration on study (baseline) 
• Cycle 1 day 1; 3-6 hours post dose 
• Cycle 2 day 1; 3-6 hours post-dose 
 
1. Blood samples should be obtained using EDTA as an anticoagulant; the minimum 
volume of blood needed for analysis of all four markers is 3 mL 
2. Plasma should be prepared from the blood samples within 1 hour (with interim 
storage and handling at 4oC). 
3. Plasma should be transferred to a sterile screw cap cryovial (silicon gasket); pre-
labeled with bar code is preferred. 
4. Plasma should be frozen and stored at -80°C within 1 hour of blood processing. 
5. Samples should be shipped on dry ice in batches at periodic intervals (if local storage 
is limiting or interim analysis is performed) or after all samples have been collected. 
 
Samples should be shipped to: 
 
Donald P. Bottaro, PhD 
Urologic Oncology Branch 
National Cancer Institute 
Bldg 10, Rm 1W-5832 
10 Center Drive MSC 1210 
Bethesda, MD  20892-1210 
301-496-6353 (UOB Office & paging) 
301-402-6499 (direct & voice mail) 
301-402-0922 (fax) 


CTEP Protocol #9284 
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54 
 
bottarod@mail.nih.gov 
 
Participating sites should e-mail the research nurse, Ashley Bruns, at 
ashley.bruns@nih.gov prior to sending samples to obtain a FedEx account number to use 
for shipment.   
 Blood Collection for Circulating Tumor Cells (optional) 
Whole blood will be collected aseptically by venipuncture or from a venous port into one 
6-mL sodium heparin tube.   
 
Blood samples for CTCs (optional) will be collected at the following times:  
• cycle 1 prior to drug administration (baseline) 
• cycle 1 day 1 4 hours (+/- 1 hour) after drug administration  
• day 1 of every subsequent cycle prior to drug administration (every 3 cycles after 
1 year on study and every 4 cycles after 3 years on study) 
• one additional blood sample will be collected at time of disease progression   
 
 
Testing and data analysis will be performed by Dr. Bob Kinders (PADIS/FNLCR).   
 
Samples should be shipped to: 
Attention: Dan Danner 
NCI-F/FNLCR 
1073 Beasley Street, Building 1073 
Fort Detrick 
Frederick, MD 21701 
Phone: 301-846-5748 
NCI_PD_Support_CellSearch@mail.nih.gov 
 
Blood for CTC analysis will be shipped to the PADIS laboratory on the day it is 
collected.  Shipping arrangements will be made by sending an email to 
NCI_PD_Support_CellSearch@mail.nih.gov.   
For NCI Clinical Center specimens only: arrangements will be made for pickup with 
the CSP courier service (301-846-5893) 
 
 Sample Collection and Processing 
Biospecimens will be collected and processed using validated SOPs that will ensure both 
specimen quality and patient confidentiality pursuant to informed consent provisions.  
 
Using a computerized inventory system and a backup hardcopy process, all specimen 
collection and processing steps will be documented and the specific location of each 
specimen will be tracked.  Each new specimen collected will be assigned a unique 
barcode identifier that can be linked to the original specimen collected and other relevant 
information within the inventory system.  To ensure patient confidentiality, only 
containers used for the initial specimen collections will be labeled with patient identifiers.  


CTEP Protocol #9284 
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55 
 
Only the barcode identifier will be applied to all subsequent specimen containers.  When 
specimens are processed and aliquoted, no patient information will be included on the 
new containers.  Original specimen containers will be discarded.  Only barcode-labeled 
specimens without patient identifiers will be shipped for analysis and/or storage.  
Specimen labels will indicate: CTEP protocol number, unique patient accession number, 
3-digit sample number (see list below), collection time, and total volume collected, as 
appropriate.  Samples from sets of at least three patients will be grouped for scientific 
analysis. 
 
Standardized 3-digit sample collection numbers: 
300 series: blood for PD 
400 series: blood for circulating tumor cells (CTCs) 
 
The inventory process contains other security provisions sufficient to safeguard patient 
privacy and confidentiality.  Access to the inventory system and associated documents 
will be restricted to appropriate individuals.  Requests to use specimens stored in the 
repository must be approved.  The only patient information available in the inventory 
system will be the patient sex, diagnosis, and level of informed consent given.  SOPs 
ensure that any changes in informed consent made by a patient and relayed to the PI will 
be reflected in the inventory system to ensure that specimens are destroyed as 
appropriate.  All laboratory personnel will be trained to adhere to SOPs and will be 
monitored for high-quality performance. 
 
Any new use of these samples will require prospective IRB review and approval.  Access 
to these samples will only be granted following IRB approval of an additional protocol, 
granting the rights to use the material. 
 
 
 
If at any time, a patient withdraws from the study and does not wish for their existing 
samples to be utilized, the individual must provide a written request.  Following receipt 
of this request, the samples will be destroyed (or returned to the patient, if so requested), 
and reported as such to the IRB.  Any samples lost (in transit or by a researcher) or 
destroyed due to unknown sample integrity (i.e., broken freezer allows for extensive 
sample thawing, etc.) will be reported as such to the IRB. 
 
 Human Data Sharing Plan 
What data will be shared?  
We will share human data generated in this research for future research as 
follows: 
X De-identified data in an NIH-funded or approved public repository  
X Identified data in BTRIS (automatic for activities in the Clinical Center)  
X De-identified or identified data with approved outside collaborators under 
appropriate agreements  
 
How and where will the data be shared?  
Data will be shared through:  
X An NIH-funded or approved public repository: clinicaltrials.gov 
X BTRIS (automatic for activities in the Clinical Center)  


CTEP Protocol #9284 
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X Approved outside collaborators under appropriate individual agreements  
X Publication and/or public presentations  
 
When will the data be shared?  
X At the time of publication or shortly thereafter 
 
 


CTEP Protocol #9284 
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57 
 
10 STUDY CALENDAR 
Eligibility screening evaluations are to be conducted within 8 days prior to enrollment, with the 
exception of informed consent and tumor imaging scans, which must be done within 28 days 
prior to enrollment (see Section 3.4).  Baseline history, physical examination, laboratory 
evaluations, urinalysis, pregnancy test, and EKG are to be conducted within 8 days prior to the 
start of protocol therapy.  If protocol therapy is started within 8 days of the eligibility screening 
evaluations, values from the screening evaluations may be used as baseline measurements; if > 8 
days have passed since the screening evaluations, the medical history, physical examination, 
laboratory evaluations, urinalysis, pregnancy test, and EKG must be repeated prior to starting 
protocol therapy.  Baseline imaging scans and must be done within 28 days prior to the start of 
protocol therapy.   
 
A new cycle may begin up to 1 week later than it would otherwise be scheduled based on the 28-
day cycle, to allow for flexibility for days the clinic is closed and other unexpected events.  In the 
event that the patient’s condition is deteriorating, laboratory evaluations should be repeated 
within 48 hours prior to initiation of the next cycle of therapy. 
 
 
 


CTEP Protocol #9284 
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58 
 
Pre-Study 
Screening 
C1 
W1 
C1 
W2 
C1 
W3 
C1 
W4 
C2 
W1 
C2 
W2 
C2 
W3 
C2 
W4 
C3 
W1 
C3 
W3 
Off 
Treatment 
Cabozantiniba 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Archival tumorb 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
Concurrent meds 
X 
    X-----------------------------------------------------------------------------X 
 
Physical examc,m 
X 
Xn 
 
 
 
X 
 
 
 
X 
 
Vital signsd,m 
X 
Xn 
 
 
 
X 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
Weightm 
X 
Xn 
 
 
 
X 
 
 
 
X 
 
Performance 
statusm 
X 
Xn 
 
 
 
X 
 
 
 
X 
 
CBC w/diff, 
pltse,m 
X 
Xn 
 
 
 
X 
 
 
 
X 
 
Serum  
chemistrye,m 
X 
Xn 
 
 
 
X 
 
 
 
X 
 
B12, folateo 
 
X 
 
 
 
 
 
 
 
 
 
Urine protein/ 
creatinine ratiof,m 
X 
Xn 
 
 
 
X 
 
 
 
X 
 
Adverse event 
evaluation 
 
   X-----------------------------------------------------------------------------X 
 
Tumor 
measurementsg,m 
X 
Tumor measurements as indicated below.  Documentation (radiologic) must 
be provided for patients removed from study for progressive disease. 
 
EKGh,m 
X 
Xn 
 
 
 
X 
 
 
 
X 
 
 
B-HCGi,m 
X 
Xn 
 
 
 
X 
 
 
 
X 
 
 
PD blood 
samplingj 
 
   X 
 
 
 
X 
 
 
 
 
 
 
TSHk,m 
X 
Xn 
 
 
 
X 
 
 
 
X 
 
 
Blood for CTCsl,m 
 
X 
 
 
 
X 
 
 
 
X 
 
X 
a: Cabozantinib once daily at 60 mg po daily.  A new cycle may begin up to 1 week later than it would otherwise 
be scheduled based on the 28-day cycle, to allow for flexibility for days the clinic is closed and other unexpected 
events. 
b:  Archival tumor specimens will be requested to confirm diagnosis and is mandatory for eligibility in the trial. 
c: Physical examination should be performed at baseline and within 8 days prior to the start of each new cycle. 
d:  BP monitoring by a health care provider should be performed within 8 days prior to the start of each new cycle.  
Patients should measure and record their blood pressure at home at least once per day for the duration of the 
study. 
e: Serum chemistry (albumin, alkaline phosphatase, total bilirubin, BUN, sodium, chloride, bicarbonate, calcium, 
creatinine, glucose, amylase, lipase, phosphorus, magnesium, potassium, total protein, SGOT [AST], SGPT 
[ALT]) and CBC w/diff, platelets at baseline and within 8 days prior to the start of each new cycle. 
 


CTEP Protocol #9284 
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11 MEASUREMENT OF EFFECT 
11.1 
Antitumor Effect – Solid Tumors 
For the purposes of this study, patients should be re-evaluated for response every 8 weeks or 2 
cycles (every 3 cycles for patients on study for more than 1 year; every 4 cycles for patients on 
study more than 3 years).  In addition to a baseline scan, confirmatory scans should also be 
obtained 4 weeks following initial documentation of objective response.  Bone scans will be 
done at baseline for patients with known bone tumors and at restaging if clinically needed. 
 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) [Eur J Ca 45:228-247, 2009].  Changes in the largest diameter (unidimensional 
measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph 
nodes are used in the RECIST criteria. 
 Definitions 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with cabozantinib. 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received at least one cycle of therapy, and have had their disease 
re-evaluated will be considered evaluable for response.  These patients will have their 
response classified according to the definitions stated below.  (Note:  Patients who exhibit 
objective disease progression prior to the end of cycle 1 will also be considered 
evaluable.) 
 
f:   Evaluation of urine protein/creatinine ratio should occur at baseline, within 8 days prior to the start of each new 
cycle, and as clinically indicated.  If patient has urine protein/creatinine ratio >1+, obtain a 24 hour urine for 
protein and creatinine clearance.  
g:  Tumor measurements are repeated every 2 cycles (every 3 cycles for patients on study for more than 1 year; 
every 4 cycles for patients on study more than 3 years). 
h: EKG will be performed at baseline and within 8 days prior to the start of each new cycle. 
i:   Serum or urine pregnancy test (women of childbearing potential) at baseline and within 8 days prior to the start 
of each new cycle. 
j: Blood samples will be obtained at the following time points: at baseline, on C1D1 3-6 hours after dose of 
cabozantinib and C2D1 3-6 hours post drug (mandatory at the NCI but optional at participating sites). 
k:  TSH at baseline and within 8 days prior to the start of each new cycle. 
l:   Blood for circulating tumor cells (CTCs) will be collected (optional) as described in Section 9.1.2.  
m: The history and physical exam, pregnancy test, CT scan, EKG, TSH, and all other protocol-required labs and 
CTC blood collections will be done every 3 cycles after 1 year on study and every 4 cycles after 3 years on 
study. 
n:  Eligibility screening results may be used for these baseline measurements if conducted within 8 days prior to the 
start of protocol therapy. See Sections 3.4 and 5. 
o:  B12 and folate at baseline and every 12 weeks (every 3 cycles, within 8 days prior to the start of the cycle; every 
4 cycles after 3 years on study). 


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60 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received at 
least one cycle of therapy, and have had their disease re-evaluated will be considered 
evaluable for non-target disease.  The response assessment is based on the presence, 
absence, or unequivocal progression of the lesions.  
 Disease Parameters 
Measurable disease.  Measurable lesions are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as >20 mm by chest 
x-ray or as >10 mm with CT scan, MRI, or calipers by clinical exam.  All tumor 
measurements must be recorded in millimeters (or decimal fractions of centimeters). 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
Malignant lymph nodes.  To be considered pathologically enlarged and measurable, a 
lymph node must be >15 mm in short axis when assessed by CT scan (CT scan slice 
thickness recommended to be no greater than 5 mm).  At baseline and in follow-up, only 
the short axis will be measured and followed. 
 
Non-measurable disease.  All other lesions (or sites of disease), including small lesions 
(longest diameter <10 mm or pathological lymph nodes with ≥10 to <15 mm short axis), 
are considered non-measurable disease.  Bone lesions, leptomeningeal disease, ascites, 
pleural/pericardial effusions, lymphangitis cutis/pulmonitis, inflammatory breast disease, 
and abdominal masses (not followed by CT or MRI), are considered as non-measurable. 
 
Note:  Cystic lesions that meet the criteria for radiographically defined simple cysts 
should not be considered as malignant lesions (neither measurable nor non-measurable) 
since they are, by definition, simple cysts. 
 
‘Cystic lesions’ thought to represent cystic metastases can be considered as measurable 
lesions, if they meet the definition of measurability described above.  However, if non-
cystic lesions are present in the same patient, these are preferred for selection as target 
lesions. 
 
Target lesions.  All measurable lesions up to a maximum of 2 lesions per organ and 5 
lesions in total, representative of all involved organs, should be identified as target 
lesions and recorded and measured at baseline.  Target lesions should be selected on the 
basis of their size (lesions with the longest diameter), be representative of all involved 
organs, but in addition should be those that lend themselves to reproducible repeated 
measurements.  It may be the case that, on occasion, the largest lesion does not lend itself 
to reproducible measurement in which circumstance the next largest lesion which can be 
measured reproducibly should be selected.  A sum of the diameters (longest for non-
nodal lesions, short axis for nodal lesions) for all target lesions will be calculated and 
reported as the baseline sum diameters.  If lymph nodes are to be included in the sum, 
then only the short axis is added into the sum.  The baseline sum diameters will be used 


CTEP Protocol #9284 
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61 
 
as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
 
Non-target lesions.  All other lesions (or sites of disease) including any measurable 
lesions over and above the 5 target lesions should be identified as non-target lesions and 
should also be recorded at baseline.  Measurements of these lesions are not required, but 
the presence, absence, or in rare cases unequivocal progression of each should be noted 
throughout follow-up.  
11.2 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation using a ruler or calipers.  All 
baseline evaluations should be performed as closely as possible to the beginning of treatment and 
never more than 4 weeks before the beginning of the treatment. 
 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.  Imaging-based evaluation is 
preferred to evaluation by clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as assessed using calipers 
(e.g., skin nodules).  In the case of skin lesions, documentation by color photography, including a 
ruler to estimate the size of the lesion, is recommended.  
 
Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are clearly 
defined and surrounded by aerated lung.  However, CT is preferable.  
 
Conventional CT and MRI: This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less.  If CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness.  
MRI is also acceptable in certain situations (e.g. for body scans).   
 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which greatly 
impact image quality, lesion conspicuity, and measurement.  Furthermore, the availability of 
MRI is variable globally.  As with CT, if an MRI is performed, the technical specifications of the 
scanning sequences used should be optimized for the evaluation of the type and site of disease.  
Furthermore, as with CT, the modality used at follow-up should be the same as was used at 
baseline and the lesions should be measured/assessed on the same pulse sequence.  It is beyond 
the scope of the RECIST guidelines to prescribe specific MRI pulse sequence parameters for all 
scanners, body parts, and diseases.  Ideally, the same type of scanner should be used and the 
image acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT: At present, the low dose or attenuation correction CT portion of a combined PET-CT is 
not always of optimal diagnostic CT quality for use with RECIST measurements.  However, if 
the site can document that the CT performed as part of a PET-CT is of identical diagnostic 


CTEP Protocol #9284 
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62 
 
quality to a diagnostic CT (with IV and oral contrast), then the CT portion of the PET-CT can be 
used for RECIST measurements and can be used interchangeably with conventional CT in 
accurately measuring cancer lesions over time.  Note, however, that the PET portion of the CT 
introduces additional data which may bias an investigator if it is not routinely or serially 
performed.   
 
Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement.  Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next.  If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised.  If there is concern about radiation exposure at CT, MRI may be used instead 
of CT in selected instances. 
 
Endoscopy, Laparoscopy: The utilization of these techniques for objective tumor evaluation is 
not advised.  However, such techniques may be useful to confirm complete pathological 
response when biopsies are obtained or to determine relapse in trials where recurrence following 
complete response (CR) or surgical resection is an endpoint. 
 
Cytology, Histology: These techniques can be used to differentiate between partial responses 
(PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor types, such as 
germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or worsens 
during treatment when the measurable tumor has met criteria for response or stable disease is 
mandatory to differentiate between response or stable disease (an effusion may be a side effect of 
the treatment) and progressive disease. 
 
FDG-PET:  While FDG-PET response assessments need additional study, it is sometimes 
reasonable to incorporate the use of FDG-PET scanning to complement CT scanning in 
assessment of progression (particularly possible 'new' disease).  New lesions on the basis of 
FDG-PET imaging can be identified according to the following algorithm:  
a. Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up:  If the positive FDG-
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD.  If the 
positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT  scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal FDG-
PET scan).  If the positive FDG-PET at follow-up corresponds to a pre-existing site of 
disease on CT that is not progressing on the basis of the anatomic images, this is not PD. 
c. FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in 
cases where a residual radiographic abnormality is thought to represent fibrosis or 
scarring.  The use of FDG-PET in this circumstance should be prospectively described in 
the protocol and supported by disease-specific medical literature for the indication.  
However, it must be acknowledged that both approaches may lead to false positive CR 
due to limitations of FDG-PET and biopsy resolution/sensitivity. 
 


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63 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater 
than twice that of the surrounding tissue on the attenuation corrected image. 
11.3 
Response Criteria 
 Evaluation of Target Lesions 
Complete Response (CR): 
Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have 
reduction in short axis to <10 mm. 
 
Partial Response (PR): 
 
At least a 30% decrease in the sum of the diameters of 
target lesions, taking as reference the baseline sum 
diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study 
(this includes the baseline sum if that is the smallest on 
study).  In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 
mm.  (Note:  the appearance of one or more new lesions is 
also considered progressions). 
 
Stable Disease (SD):  
 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum diameters while on study. 
 
 Evaluation of Non-Target Lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization 
of tumor marker level.  All lymph nodes must be non-
pathological in size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper 
normal limit, they must normalize for a patient to be 
considered in complete clinical response. 
 
Non-CR/Non-PD:  
 
 
Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal 
limits. 
 
Progressive Disease (PD): 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.  Unequivocal 
progression should not normally trump target lesion status.  
It must be representative of overall disease status change, 
not a single lesion increase.     


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Although a clear progression of “non-target” lesions only is exceptional, the opinion of 
the treating physician should prevail in such circumstances, and the progression status 
should be confirmed at a later time by the review panel (or Principal Investigator). 
 Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence (taking as reference for progressive disease the 
smallest measurements recorded since the treatment started).  The patient's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 
Target 
Lesions 
Non-
Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks.  Confirmation** 
CR 
Non-CR/ 
Non-PD 
No 
PR 
>4 wks.  Confirmation** 
CR 
Not 
evaluated 
No 
PR 
PR 
Non-
CR/Non-
PD/not 
evaluated 
No 
PR 
SD 
Non-CR/ 
Non-PD/ 
not 
evaluated 
No 
SD 
Documented at least once >4 
wks.  from baseline** 
PD 
Any 
Yes or 
No 
PD 
no prior SD, PR or CR 
Any 
PD*** 
Yes or 
No 
PD 
Any 
Any 
Yes 
PD 
* 
See RECIST 1.1 manuscript for further details on what is evidence of a new 
lesion. 
** 
Only for non-randomized trials with response as primary endpoint. 
*** 
In exceptional circumstances, unequivocal progression in non-target lesions 
may be accepted as disease progression. 
Note: Patients with a global deterioration of health status requiring discontinuation 
of treatment without objective evidence of disease progression at that time 
should be reported as “symptomatic deterioration.”  Every effort should be 
made to document the objective progression even after discontinuation of 
treatment. 
 


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For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
not evaluated 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
*  ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign this 
category when no lesions can be measured is not advised 
11.4 
Duration of Response 
Duration of overall response:  The duration of overall response is measured from the time 
measurement criteria are met for CR or PR (whichever is first recorded) until the first 
date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded since the treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease is objectively documented. 
 
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression are met, taking as reference the smallest measurements 
recorded since the treatment started, including the baseline measurements.  
11.5 
Progression-Free Survival 
PFS is defined as the duration of time from start of treatment to time of progression or 
death, whichever occurs first. 
 
 
12 DATA REPORTING / REGULATORY REQUIREMENTS 
Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 7.0 
(Adverse Events: List and Reporting Requirements). 
12.1 
Data Reporting 
 Method 
Data will be collected in the Center for Cancer Research C3D database.  This study will 
be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
protocol- and patient-specific CDUS data will be submitted electronically to CTEP on a 
quarterly basis, either by FTP burst of data or via the CDS web application.  Reports are 
due January 31, April 30, July 31, and October 31.  Instructions for submitting data using 
the CDUS can be found on the CTEP Web site 
(http://ctep.cancer.gov/reporting/cdus.html).  
 


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Note:  All adverse events that have occurred on the study, including those reported 
through CTEP-AERS, must be reported via the monitoring method identified above. 
 Responsibility for Data Submission 
Study participants are responsible for submitting CDUS data and/or data forms to the 
Coordinating Center quarterly to allow time for Coordinating Center compilation, 
Principal Investigator review, and timely submission to CTEP.  The Coordinating Center 
is responsible for compiling and submitting CDUS data to CTEP for all participants and 
for providing the data to the Principal Investigator for review.   
 
12.2 
Data Safety and Monitoring Plan 
The investigators at each participating center will be responsible for the collection, 
maintenance, and quality control of the study data.  Adverse events observed in patients 
enrolled on the trial will be monitored in real time by the Principal and Associate 
Investigators, and attribution of these events to the research will be determined at the end 
of each treatment cycle in each subject.  The clinical research team (PI, adjunct PI, 
research nurses, data managers) will meet weekly when patients are being actively treated 
on the trial to discuss each patient in detail and ensure that all events are graded 
appropriately, and that the attribution to study drug is correct.  The Coordinating Center 
is responsible for establishing conference calls between participating sites at least on a 
monthly basis to discuss the observed toxicities and protocol issues.  
 
All SAEs will be reported through CTEP-AERS to CTEP, to the Coordinating Center PI 
at NCI, and forwarded to the IRB per Section 7.0.  In all cases where the dose of the 
study treatment has been reduced/modified or the patient withdrawn due to unusual or 
unusually severe toxicity considered related to the study treatment, the investigator must 
contact and inform the Coordinating Center PI.  All sites will be monitored by the CTEP 
drug monitor, who will receive data from all participating sites. 
 
Data will be monitored regularly by the PI in order to identify significant toxicity trends.  
Any new significant finding that may affect the patient’s willingness to continue in the 
study will be shared with patients.   
 
Confidentiality will be maintained as much as possible, consistent with applicable 
regulations.  Names of participants or identifying material will not be released without 
patient permission, except when such release is required by law.  No patient’s name or 
identifying information will be released in any publication or presentation.  Records are 
maintained according to current legal requirements, and are made available for review 
according to the requirements of the FDA or other authorized user, only under guidelines 
established by the Federal Privacy Act.  
 
Safety Monitoring Committee: 
Because this is a multi-institutional protocol for which the NCI CCR is the Coordinating 
Center, it will be monitored by the DTC Safety Monitoring Committee, NCI.  
 


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12.3 
Multicenter Guidelines  
This protocol opened initially at the NCI.  The NIH IRB will be notified once the 
participating centers’ IRBs have approved the studies to open.  This protocol will follow 
the CCR’s Clinical Research Operations’ SOPs for multicenter trials.  
 
 IRB Approvals  
As the Coordinating Center for a trial, it is the PI’s responsibility to ascertain that no 
patients are entered on the trial at a participating institution without full IRB approval.  
Thus, the NIH IRB must approve the addition of each participating institution to the 
protocol and will require a copy of the local IRB approval from each participating 
institution before NIH IRB approval will be granted. 
  
The PI will provide the NIH IRB with a copy of the participating institution’s approved 
yearly continuing review.  Registration will be halted at any participating institution in 
which a current continuing approval is not on file at the NIH IRB.  
 
 Amendments and Consents  
The NCI PI will provide the NIH IRB with copies of all amendments, consents, and 
approvals from each participating institution. 
 
 Data Collection 
The investigators will be responsible for the collection, maintenance, and quality control 
of the study data.  All data collected for each study subject will be entered into the Cancer 
Central Clinical Database (C3D), an NCI electronic case report form/database, every 
2 weeks.  The participating sites will be able to enter the data remotely into the web-
based C3D system.  Each site investigator is also responsible for maintaining all source 
documentation related to the study, including any films, tracings, computer discs or tapes.  
NCI will be responsible for data management, data analysis, and reporting.  Data 
collection forms will be provided to the participating institutions.  Required data include, 
not exclusively: prior disease-related therapies with dates, disease type, stage, disease 
sites, with measurements, and concurrent medications.  
 
 Data and Center Audits 
Audits will be conducted yearly to ensure data integrity and provide quality control.  
These audits will be conducted by the NCI research team.  Selected patient charts should 
be audited as well as the participating institution’s Standard Operating Procedures (SOP) 
at the time of the visit.  Data from participating institutions should be available when the 
protocol is audited at the NCI.  
 


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 CTEP Multicenter Guidelines  
This protocol will adhere to the policies and requirements of the CTEP Multicenter 
Guidelines.  The specific responsibilities of the Principal Investigator and the 
Coordinating Center (Study Coordinator) and the procedures for auditing are presented in 
Appendix E. 
 
• The Principal Investigator/Coordinating Center is responsible for distributing all IND 
Action Letters or Safety Reports received from CTEP to all participating institutions 
for submission to their individual IRBs for action as required. 
 
• Except in very unusual circumstances, each participating institution will order 
DCTD-supplied agents directly from CTEP.  Agents may be ordered by a 
participating site only after the initial IRB approval for the site has been forwarded 
by the Coordinating Center to the CTEP PIO (PIO@ctep.nci.nih.gov) (except for 
Group studies). 
 
12.4 
Collaborative Agreements Language 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the NCI 
under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis.  Therefore, the following obligations/guidelines, in addition to the 
provisions in the “Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
 
1. 
Agent(s) may not be used for any purpose outside the scope of this protocol, nor 
can Agent(s) be transferred or licensed to any party not participating in the clinical 
study.  Collaborator(s) data for Agent(s) are confidential and proprietary to 
Collaborator(s) and shall be maintained as such by the investigators.  The protocol 
documents for studies utilizing Agents contain confidential information and should 
not be shared or distributed without the permission of the NCI.  If a copy of this 
protocol is requested by a patient or patient’s family member participating on the 
study, the individual should sign a confidentiality agreement.  A suitable model 
agreement can be downloaded from: http://ctep.cancer.gov. 
 
2. 
For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NCI, the design of the proposed combination protocol, and the existence of 
any obligations that would tend to restrict NCI's participation in the 
proposed combination protocol. 
 


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b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to 
allow said other Collaborator to develop, obtain regulatory approval or 
commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these 
trials must agree in writing prior to the commencement of the trials that it 
will use the Multi-Party Data solely for development, regulatory approval, 
and commercialization of its own Agent. 
 
3. 
Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described in the IP Option to Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm).  
Additionally, all Clinical Data and Results and Raw Data will be collected, used 
and disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. 
When a Collaborator wishes to initiate a data request, the request should first be 
sent to the NCI, who will then notify the appropriate investigators (Group Chair for 
Cooperative Group studies, or PI for other studies) of Collaborator's wish to contact 
them. 
 
5. 
Any data provided to Collaborator(s) for Phase 3 studies must be in accordance 
with the guidelines and policies of the responsible Data Monitoring Committee 
(DMC), if there is a DMC for this clinical trial. 
 
6. 
Any manuscripts reporting the results of this clinical trial must be provided to 
CTEP by the Group office for Cooperative Group studies or by the principal 
investigator for non-Cooperative Group studies for immediate delivery to 
Collaborator(s) for advisory review and comment prior to submission for 
publication.  Collaborator(s) will have 30 days from the date of receipt for review.  
Collaborator shall have the right to request that publication be delayed for up to an 
additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are 
protected.  Copies of abstracts must be provided to CTEP for forwarding to 
Collaborator(s) for courtesy review as soon as possible and preferably at least three 
(3) days prior to submission, but in any case, prior to presentation at the meeting or 
publication in the proceedings.  Press releases and other media presentations must 
also be forwarded to CTEP prior to release.  Copies of any manuscript, abstract 
and/or press release/ media presentation should be sent to:  
Email: ncicteppubs@mail.nih.gov  
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of 
Collaborator’s confidential/ proprietary information. 


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13 STATISTICAL CONSIDERATIONS 
13.1 
Study Design/Endpoints 
The study will be conducted as a dual-endpoint two-stage Phase II trial to target objective tumor 
response rate (CR+PR) of 30% against an unacceptably low rate of 10%, and 6-month PFS rate 
of 65% against an unacceptably low rate of 45% (corresponding to median PFS of 9.6 vs. 5.2 
months).  
 
The trial is designed to accrue up to 50 evaluable patients and judge the agent as promising if 
either tumor response rate or 6-month PFS rate is promising.  If at least 11 objective responses 
(at least 22%), or at least 27 instances of 6-month PFS (at least 54%), are observed among the 50 
evaluable patients, this agent will be considered worthy of further testing in this disease.  If no 
more than 3 objective responses (12%), and no more than 12 instances of 6-month PFS (no more 
than 48%), are observed among the initial 25 patients, the study will be terminated early and 
declared negative.  This design yields at least 90% power to detect a true objective response rate 
of at least 30%.  It yields at least 92% power to detect a true 6-month PFS rate of at least 65% 
(median PFS of 9.6 months).  It yields at least .89 probability of a negative result if the true 
objective response rate is no more than 10% and the true 6-month PFS rate is no more than 45% 
(median PFS of 5.2 months), with approximately .53 probability, at least, of early negative 
stopping in this case.  These last two probabilities (of a negative result and early negative 
stopping, both under the null hypothesis) are calculated assuming that tumor response rate and 
PFS rate are uncorrelated.  If they are positively correlated, as is likely, the probabilities will be a 
bit higher.   
13.2 
Sample Size/Accrual Rate 
The study will accrue 50 evaluable patients at the rate of 2-3 patients per month.  To allow for a 
small number of unevaluable patients, the accrual ceiling has been set at 55 patients. 
13.3 
Stratification Factors 
 
Patients will be stratified based on prior VEGF/TKI therapy.  In order to ensure accrual of 
multiple different histological types of STS to this trial (including histologic types that are felt to 
be driven by angiogenesis or the MET pathway), following accrual of the first 20 patients, 
discussions will be held with CTEP to review which other histologic types of STS should be 
enrolled. 
13.4 
Analysis of Secondary Endpoints 
• Determine and compare circulating levels of HGF, soluble MET (sMET), VEGF-A, and 
soluble VEGFR2 (sVEGFR2) prior to and following administration of cabozantinib. 
• All PD changes from baseline will be assessed descriptively by calculating the mean and 
the 95% confidence interval of the change.  PD measures derived from blood samples 
will be used to assess the change from baseline 3-6 hours after the first dose of the first 
cycle of treatment and 3-6 hours after the first dose of the second cycle of treatment. 


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13.5 
Reporting and Exclusions 
 Evaluation of toxicity – All patients will be evaluable for toxicity from the time of 
their first treatment with cabozantinib. 
 Evaluation of response – All patients included in the study will be assessed for 
response to treatment, even if there are major protocol treatment deviations or if 
they are ineligible.  Each patient will be assigned one of the following categories:  
1) complete response, 2) partial response, 3) stable disease, 4) progressive 
disease, 5) early death from malignant disease, 6) early death from toxicity, 7) 
early death because of other cause, or 9) unknown (not assessable, insufficient 
data).  [Note:  By arbitrary convention, category 9 usually designates the 
“unknown” status of any type of data in a clinical database.] 
All of the patients who met the eligibility criteria (with the possible exception of 
those who received no study medication) will be included in the main analysis of 
the response rate.  Patients in response categories 4-9 will be considered to have a 
treatment failure (disease progression).  Thus, an incorrect treatment schedule or 
drug administration does not result in exclusion from the analysis of the response 
rate.  Precise definitions for categories 4-9 will be protocol specific.  
 
All conclusions will be based on all eligible patients.  Subanalyses may then be 
performed on the basis of a subset of patients, excluding those for whom major 
protocol deviations have been identified (e.g., early death due to other reasons, 
early discontinuation of treatment, major protocol violations, etc.).  However, 
these subanalyses will not serve as the basis for drawing conclusions concerning 
treatment efficacy, and the reasons for excluding patients from the analysis will 
be clearly reported.  The 95% confidence intervals will also be provided.  
 
 
14 HUMAN SUBJECTS PROTECTIONS 
14.1 
Justification for Subject Selection 
This study will be open to all individuals regardless of gender, ethnicity, or race, provided that 
the aforementioned inclusion and exclusion criteria are met.  Patients for this study will be 
recruited through internal referral, our physician referral base, and through various cancer 
information hotlines (i.e., Clinical Studies Support Center, 1-800-4Cancer).  To date, there is no 
information that suggests that differences in drug metabolism or effect on tumor would be 
expected in one ethnic group compared to another.  Efforts will be made to extend accrual to 
each representative population, but a balance must be struck between participant safety 
considerations and limitations on the number of individuals exposed to potentially ineffective 
treatments on the one hand and the need to explore racial/ethnic aspects of clinical research on 
the other hand.  If differences in outcome that correlate to ethnic identity are noted, a follow-up 
study may be written to investigate those differences more fully. 
 
Due to lack of knowledge of the effects of cabozantinib on the fetus or infants, as well as the 
possibility of teratogenic effects, pregnant and nursing women will be excluded from this trial.  
Patients with unstable or serious medical conditions are excluded due to the possibility that 


CTEP Protocol #9284 
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cabozantinib may worsen their condition and the likelihood that the underlying condition may 
obscure the attribution of adverse events with respect to cabozantinib.  HIV-positive patients on 
combination antiretroviral therapy are excluded from the study because of possible interactions 
with cabozantinib 
 Participation of Children 
This study includes patients 18 years of age and older.  Because insufficient dosing or 
adverse event data are currently available on the use of cabozantinib in patients <18 years 
of age, children are excluded from this study, but may be eligible for future pediatric 
trials.  Studies will be performed in patients <18 years of age when it is appropriate to do 
so.  
14.2 
Evaluation of Benefits and Risks/Discomforts 
There may or may not be any clinical benefit to a patient from participation in this trial.  Their 
participation will benefit future cancer patients.  Potential risks include the possible occurrence 
of any of a range of side effects that are listed in the consent document.  The procedure for 
protecting against or minimizing risks will be to medically evaluate patients as described in 
Sections 5 and Section 6.  Although no compensation is available, any injury will be fully 
evaluated and treated in keeping with the benefits or care to which participants are entitled under 
applicable regulations.  
14.3 
Consent and Assent Process and Documentation 
An associate or principal investigator on the trial will inform patients of the purpose, alternatives, 
drug administration plan, research objectives, and follow-up of this trial.  The patient will be 
provided an IRB-approved consent for review and signature and his/her questions will be 
answered.  After a decision is made to enroll into the study, a signature will be obtained from the 
patient.  The original signed consent goes to Medical Records; a copy will be placed in the 
research record.  Patients will not be consented by telephone. 
 
All patients must have a signed informed consent form and an on-study (confirmation of 
eligibility) form filled out and signed by a participating investigator before entering on study. 
 
Adults unable to give consent are excluded from enrolling in the protocol.  However, re-consent 
may be necessary, and there is a possibility, though unlikely, that subjects could become 
decisionally impaired. For this reason, and because there is a prospect of direct benefit from 
research participation (i.e., long-term stabilization and/or improvement in the pain and physical 
impairment caused by soft tissue sarcoma), all subjects ≥ age 18 at the NCI only will be offered 
the opportunity to fill in their wishes for research and care, and assign a substitute decision 
maker on the “NIH Advance Directive for Health Care and Medical Research Participation” 
form so that another person can make decisions about their medical care in the event that they 
become incapacitated or cognitively impaired during the course of the study. Note: The PI or AI 
will contact the NIH Ability to Consent Assessment Team for evaluation.  For those subjects that 
become incapacitated and do not have pre-determined substitute decision maker, the procedures 
described in NIH OHSRP Policy 403 for appointing a surrogate decision maker for adult subjects 
who are (a) decisionally impaired, and (b) who do not have a legal guardian or durable power of 
attorney, will be followed. 


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14.4 
Procedure for Protecting Against or Minimizing Any Potential Risks 
All care will be taken to minimize side effects, but they can be unpredictable in nature and 
severity.  This study may involve risks to patients, which are currently unforeseeable.  All 
patients will be monitored for side effects from taking study medication.  This research 
represents a greater than minimal risk to participants, but presents the prospect of direct benefit 
to individual subjects. 
 
14.5 
Patient Advocate 
The patients’ rights representative is available to patients receiving treatment on this protocol at 
the NIH Clinical Center at (301) 496-2626 in Building 10 of the Clinical Research Center, Room 
1-3521, on the Bethesda NIH campus.  Patients will be informed that they can contact the study 
PI or RN at any time with questions about their medical care, and that the patients’ rights 
representative is also available to answer non-medical questions about the study.  


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in situ hybridization study. Cancer Res 54:560-4, 1994 
 19. 
Verschraegen CF, Arias-Pulido H, Lee SJ, et al: Phase IB study of the combination of 
docetaxel, gemcitabine, and bevacizumab in patients with advanced or recurrent soft tissue 
sarcoma: the Axtell regimen. Ann Oncol, 2011 
 20. 
Park MS PS, Ludwig JA et al.  : Combination therapy with temozolomide and 
 bevacizumab in the treatment of hemangiopericytoma/malignant solitary fibrous 
 tumor. J Clin Oncol 26(Suppl): 10512., 2008 
 21. 
Sleijfer S, Ray-Coquard I, Papai Z, et al: Pazopanib, a multikinase angiogenesis inhibitor, 
in patients with relapsed or refractory advanced soft tissue sarcoma: a phase II study from the 
European organisation for research and treatment of cancer-soft tissue and bone sarcoma group 
(EORTC study 62043). J Clin Oncol 27:3126-32, 2009 
 22. 
al WTVDGe: J Clin Oncol suppl; abstr LBA10002, 2011 
 23. 
Trusolino L, Comoglio PM: Scatter-factor and semaphorin receptors: cell signalling for 
invasive growth. Nat Rev Cancer 2:289-300, 2002 
 24. 
Birchmeier C, Birchmeier W, Gherardi E, et al: Met, metastasis, motility and more. Nat 
Rev Mol Cell Biol 4:915-25, 2003 
 25. 
Rong S, Jeffers M, Resau JH, et al: Met expression and sarcoma tumorigenicity. Cancer 
Res 53:5355-60, 1993 
 26. 
Gao CF, Xie Q, Zhang YW, et al: Therapeutic potential of hepatocyte growth 
factor/scatter factor neutralizing antibodies: inhibition of tumor growth in both autocrine and 
paracrine hepatocyte growth factor/scatter factor:c-Met-driven models of leiomyosarcoma. Mol 
Cancer Ther 8:2803-10, 2009 
 27. 
Davis IJ, McFadden AW, Zhang Y, et al: Identification of the receptor tyrosine kinase c-
Met and its ligand, hepatocyte growth factor, as therapeutic targets in clear cell sarcoma. Cancer 
Res 70:639-45, 2010 
 28. 
Yakes FM, Chen J, Tan J, et al: Cabozantinib (XL184), a Novel MET and VEGFR2 
Inhibitor, Simultaneously Suppresses Metastasis, Angiogenesis, and Tumor Growth. Mol 
Cancer Ther 10:2298-308, 2011 
 29. 
Sennino B NR, Tabruyn SP, You W-K, Aftab DT, McDonald, DM.: Reduction of tumor 
invasiveness and metastasis and prolongation 
 of survival of RIP-Tag2 mice after inhibition of VEGFR plus c-Met 
 by XL184. . Mol Cancer Ther ;8(12 Suppl):A13, 2009 
 30. 
Lee R: Investigator-sponsored trial of efficacy and tolerability of cabozantinib (cabo) at 
lower dose: A dose-finding study in men with castration-resistant prostate cancer (CRPC) and 
bone metastases. J Clin Oncol 2012 
 31. 
Kurzrock R, Sherman SI, Ball DW, et al: Activity of XL184 (Cabozantinib), an oral 
tyrosine kinase inhibitor, in patients with medullary thyroid cancer. J Clin Oncol 29:2660-6, 
2011 
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Athauda G, Giubellino A, Coleman JA, et al: c-Met ectodomain shedding rate correlates 
with malignant potential. Clin Cancer Res 12:4154-62, 2006 


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Cecchi F, Rabe DC, Bottaro DP: Targeting the HGF/Met signalling pathway in cancer. 
Eur J Cancer 46:1260-70, 2010 
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Shojaei F, Lee JH, Simmons BH, et al: HGF/c-Met acts as an alternative angiogenic 
pathway in sunitinib-resistant tumors. Cancer Res 70:10090-100, 2010 
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di Tomaso E, Snuderl M, Kamoun WS, et al: Glioblastoma recurrence after cediranib 
therapy in patients: lack of "rebound" revascularization as mode of escape. Cancer Res 71:19-
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Ebos JM, Lee CR, Cruz-Munoz W, et al: Accelerated metastasis after short-term 
treatment with a potent inhibitor of tumor angiogenesis. Cancer Cell 15:232-9, 2009 
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Paez-Ribes M, Allen E, Hudock J, et al: Antiangiogenic therapy elicits malignant 
progression of tumors to increased local invasion and distant metastasis. Cancer Cell 15:220-31, 
2009 
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MR S: Cabozantinib (XL184) in chemotherapy-pretreated metastatic castration resistant 
prostate cancer (mCRPC): Results from a phase II nonrandomized expansion cohort (NRE). J 
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trials of anticancer agents for pharmacodynamic evaluation. Clin Cancer Res 7:2971-6, 2001 
 
 
 
 


CTEP Protocol #9284 
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APPENDIX A:PERFORMANCE STATUS CRITERIA 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, 
able to carry on all pre-
disease performance without 
restriction. 
100 
Normal, no complaints, no evidence of 
disease. 
90 
Able to carry on normal activity; minor 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory.  
Restricted in physically 
strenuous activity, but 
ambulatory and able to carry 
out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
80 
Normal activity with effort; some signs 
or symptoms of disease. 
70 
Cares for self, unable to carry on normal 
activity or to do active work. 
2 
In bed <50% of the time.  
Ambulatory and capable of 
all self-care, but unable to 
carry out any work activities.  
Up and about more than 50% 
of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  
Capable of only limited self-
care, confined to bed or chair 
more than 50% of waking 
hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on 
any self-care.  Totally 
confined to bed or chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, fatal processes progressing 
rapidly. 
5 
Dead. 
0 
Dead. 
 
 
 


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APPENDIX B: POTENTIAL DRUG INTERACTIONS 
 
Because the lists of these agents are constantly changing, frequently-updated lists available at 
http://medicine.iupui.edu/clinpharm/ddis/table.asp will be consulted. 
 
CYP3A4 Inhibitors 
Acetazolamide 
Amiodarone 
Amlodipine 
Amprenavir 
Anastrozole 
Aprepitant 
Atazanavir 
Atorvastatin 
Azelastine 
Azithromycin 
Betamethasone 
Bortezomib 
Bromocriptine 
Caffeine 
Cerivastatin 
Chloramphenicol 
Chlorzoxazone 
Cimetidine 
Ciprofloxacin 
Cisapride 
Clarithromycin 
Clemastine 
Clofazimine 
Clotrimazole 
Clozapine 
Cocaine 
Conivaptan 
Cyclophosphamide 
Cyclosporine 
Danazol 
Dasatinib  
Delavirdine 
Desipramine 
Dexmedetomidine 
Diazepam 
Diclofenac 
Dihydroergotamine 
Diltiazem 
Disulfiram 
Docetaxel 
Doxorubicin 
Doxycycline 
Drospirenone 
Efavirenz 
Enoxacin 
Entacapone 
Ergotamine 
Erythromycin 
Ethinyl estradiol 
Etoposide 
Felodipine 
Fentanyl 
Fluconazole 
Fluoxetine 
Fluvastatin 
Fluvoxamine 
Fosamprenavir 
Glyburide 
Grapefruit juice  
Haloperidol 
Hydralazine 
Ifosfamide 
Imatinib 
Indinavir 
Irbesartan 
Isoniazid 
Isradipine 
Itraconazole 
Ketoconazole 
Lansoprazole 
Lidocaine 
Lomustine 
Losartan  
Lovastatin 
Mefloquine 
Mestranol 
Methadone 
Methimazole 
Methoxsalen 
Methylprednisolone 
Metronidazole 
Miconazole 
Midazolam 
Mifepristone 
Mirtazapine 
Mitoxantrone 
Modafinil 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nisoldipine 
Nizatidine 
Norfloxacin 
Olanzapine 
Omeprazole 
Orphenadrine 
Oxybutynin 
Paroxetine 
Pentamidine 
Pergolide 
Phencyclidine 
Pilocarpine 
Pimozide 
Pravastatin 
Prednisolone 
Primaquine 
Progesterone 
Propofol  
Propoxyphene 
Quinidine 
Quinine 
Quinupristin 
Rabeprazole 
Ranolazine 
Risperidone 
Ritonavir 
Saquinavir 
Selegiline 
Sertraline 
Sildenafil 
Sirolimus 
Sulconazole 
Tacrolimus 
Tamoxifen 
Telithromycin 
Teniposide 
Testosterone 
Tetracycline 
Ticlopidine 
Tranylcypromine 
Trazodone 
Troleandomycin 
Valproic acid 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Voriconazole 
Zafirlukast 
Ziprasidone 
 
 
CYP3A4 Inducers 
Aminoglutethimide 
Carbamazepine 
Fosphenytoin 
Nafcillin  
Nevirapine 
Oxcarbazepine 
Pentobarbital 
Phenobarbital 
Phenytoin 
Primidone 
Rifabutin 
Rifampin  
Rifapentine 
St. John’s wort 
 
 
 
 
 


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CYP3A4 Substrates 
Albuterol 
Alfentanil 
Alprazolam 
Amlodipine 
Amprenavir 
Aprepitant 
Aripiprazole 
Atazanavir 
Atorvastatin 
Benzphetamine 
Bisoprolol 
Bortezomib 
Bosentan 
Bromazepam 
Bromocriptine 
Buprenorphine 
Buspirone 
Busulfan 
Carbamazapine 
Cerivastatin 
Chlordiazepoxide 
Chloroquine 
Chlorpheniramine 
Cisapride 
Citalopram 
Clarithromycin 
Clobazam 
Clonazepam 
Clorazepate 
Cocaine 
Colchicine 
Cyclophosphamide 
Cyclosporine 
Dantrolene 
Dapsone 
Delavirdine 
Diazepam 
Digitoxin 
Dihydroergotamine 
Diltiazem 
Disopyramide 
Docetaxel 
Doxepin 
Doxorubicin 
Doxycycline 
Efavirenz 
Eletriptan 
Enalapril 
Eplerenone 
Ergoloid mesylates 
Ergonovine 
Ergotamine 
Erythromycin 
Escitalopram 
Estradiol 
Estrogens, conj., 
synthetic 
Estrogens, conj., 
equine 
Estrogens, conj., 
esterified 
Estrone 
Estropipate 
Ethinyl estradiol 
Ethosuximide 
Etoposide 
Felbamate 
Felodipine 
Fentanyl 
Flurazepam 
Flutamide 
Fosamprenavir 
Fulvestrant 
Gefitinib 
Halofantrine 
Haloperidol 
Ifosfamide 
Imatinib 
Indinavir 
Irinotecan 
Isosorbide dinitrate 
Isosorbide mononitrate 
Isradipine 
Itraconazole 
Ketamine 
Ketoconazole 
Lansoprazole 
Letrozole 
Levomethadyl acetate 
    hydrochloride 
Levonorgestrel 
Lidocaine 
Losartan 
Lovastatin 
Medroxyprogesterone 
Mefloquine 
Mestranol 
Methadone 
Methylergonovine 
Methysergide 
Miconazole 
Midazolam 
Miglustat 
Mirtazapine 
Modafinil 
Montelukast 
Moricizine 
Nateglinide 
Nefazodone 
Nelfinavir 
Nevirapine 
Nicardipine 
Nifedipine 
Nimodipine 
Nisoldipine 
Nitrendipine 
Norethindrone 
Norgestrel 
Ondansetron 
Paclitaxel 
Pergolide 
Phencyclidine 
Pimozide 
Pioglitazone 
Primaquine 
Progesterone 
Quetiapine 
Quinidine 
Rabeprazole 
Repaglinide 
Rifabutin 
Rifampin 
Ritonavir 
Saquinavir 
Sertraline 
Sibutramine 
Sildenafil 
Simvastatin 
Sirolimus 
Sufentanil 
Tacrolimus 
Tamoxifen 
Tamsulosin 
Telithromycin 
Teniposide 
Terbinafine 
Tetracycline 
Theophylline 
Tiagabine 
Ticlopidine 
Tolterodine 
Toremifene 
Trazodone 
Triazolam 
Trimethoprim 
Trimipramine 
Troleandomycin 
Vardenafil 
Venlafaxine 
Verapamil 
Vinblastine 
Vincristine 
Vinorelbine 
Zolpidem 
Zonisamide 
Zopiclone 
 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
80 
 
APPENDIX C: STUDY DIARY 
 
Today’s date _____________________ 
 
 
    Agent:  Cabozantinib  
Patient Name_____________________(initials acceptable) Patient Study ID ___________________ 
 
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each cycle of treatment. 
2. 
Cabozantinib should be taken with water at least 1 hour before or 2 hours after a meal. The drug 
tablets should be swallowed whole with water and may not be crushed or broken. 
3. 
Do not chew the tablets.  If the tablet is broken and the powder of the tablets gets on skin, wash the 
exposed area with as much water as necessary.  Inform investigator or nurse if that occurs. 
3. 
Record the date and times when you took the tablet/s.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column.   
5. 
Please bring this form and your bottle of cabozantinib when you return for your Day 28 
appointment.  
6. 
In case of errors, please place a single slash mark through the error and initial it.  Please do 
not white out any error or scribble it out with ink.  Please do not write the correct 
information directly over the error, but on a separate line next to the error. 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
81 
 
Day 
Date 
Cabozantinib 
tablet strength 
20 mg     60mg 
Time of 
Cabozantinib 
dose 
Blood Pressure 
Morning                     Evening 
Comments 
Side effects / missed 
dose 
1 
 
 
 
 
 
 
 
2 
 
 
 
 
 
 
 
3 
 
 
 
 
 
 
 
4 
 
 
 
 
 
 
 
5 
 
 
 
 
 
 
 
6 
 
 
 
 
 
 
 
7 
 
 
 
 
 
 
 
8 
 
 
 
 
 
 
 
9 
 
 
 
 
 
 
 
10 
 
 
 
 
 
 
 
11 
 
 
 
 
 
 
 
12 
 
 
 
 
 
 
 
13 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
17 
 
 
 
 
 
 
 
18 
 
 
 
 
 
 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
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19 
 
 
 
 
 
 
 
20 
 
 
 
 
 
 
 
21 
 
 
 
 
 
 
 
22 
 
 
 
 
 
 
 
23 
 
 
 
 
 
 
 
24 
 
 
 
 
 
 
 
25 
 
 
 
 
 
 
 
26 
 
 
 
 
 
 
 
27 
 
 
 
 
 
 
 
28 
 
 
 
 
 
 
 
 
Patient’s signature  ________________________________________________________________ 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
83 
 
APPENDIX D: DRUG INTERACTIONS 
 
Oral Antihypertensive Medications: Agents in bold characters are suggested as optimal choices to avoid 
or minimize potential drug-interactions with cabozantinib through CYP450. 
Agent 
class 
Agent 
Initial 
dose 
Intermediate 
dose 
Maximum 
dose 
Hepatic 
metabolism 
Dihydro-pyridine 
Calcium-Channel 
Blockers 
(DHP CCB) 
nifedipine 
XL 
30 mg daily 
60 mg daily 
90 mg daily 
CYP 3A4 
substrate 
amlodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate 
felodipine 
2.5 mg daily 
5 mg daily 
10 mg daily 
CYP 3A4 
substrate and 
inhibitor 
Selective 
β Blockers 
(BB) 
metoprolol 
25 mg twice 
daily 
50 mg twice 
daily 
100 mg twice 
daily 
CYP 2D6 
substrate 
atenolol 
25 mg daily 
50 mg daily 
100 mg daily 
No 
acebutolol 
100 mg twice 
daily 
200-300 mg 
twice daily 
400 mg 
twice daily 
Yes (CYP450 
unknown) 
bisoprolol 
2.5 mg daily 
5-10 mg daily 
20 mg daily 
Yes (CYP450 
unknown) 
Angiotensin 
Converting 
Enzyme 
Inhibitors 
(ACEIs) 
 
captopril 
12.5 mg 3x 
daily 
25 mg 3x daily 50 mg 3x daily 
CYP 2D6 
substrate 
enalapril 
5 mg daily 
10-20 mg daily 40 mg daily 
CYP 3A4 
substrate 
ramipril 
2.5 mg daily 
5 mg daily 
10 mg daily 
Yes (CYP450 
unknown) 
lisinopril 
5 mg daily 
10-20 mg daily 40 mg daily 
No 
fosinopril 
10 mg daily 
20 mg daily 
40 mg daily 
Yes (CYP450 
unknown) 
Rarely used: 
perindopril 
4 mg daily 
none 
8 mg daily 
Yes, but not 
CYP450 
Rarely used: 
quinapril 
10 mg daily 
20 mg daily 
40 mg daily 
No 
Angiotensin II 
Receptor 
Blockers 
(ARBs) 
losartan 
25 mg daily 
50 mg daily 
100 mg daily 
CYP 3A4 
substrate 
candesartan 
4 mg daily 
8-16 mg daily 
32 mg daily 
CYP 2C9 
substrate 
irbesartan 
75 mg daily 
150 mg daily 
300 mg daily 
CYP 2C9 
substrate 
telmisartan 
40 mg daily 
none 
80 mg daily 
Yes, but not 
CYP450 
valsartan 
80 mg daily 
none 
160 mg daily 
Yes, but not 
CYP450 
α and β 
Blocker 
labetolol 
100 mg twice 
daily 
200 mg twice 
daily 
400 mg twice 
daily 
CYP 2D6 
substrate and 
inhibitor 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
84 
 
APPENDIX E: CTEP Multicenter Guidelines 
 
If an institution wishes to collaborate with other participating institutions in performing a CTEP 
sponsored research protocol, then the following guidelines must be followed. 
 
Responsibility of the Protocol Chair  
• 
The Protocol Chair will be the single liaison with the CTEP Protocol and Information Office 
(PIO).  The Protocol Chair is responsible for the coordination, development, submission, and 
approval of the protocol as well as its subsequent amendments.  The protocol must not be 
rewritten or modified by anyone other than the Protocol Chair.  There will be only one 
version of the protocol, and each participating institution will use that document.  The 
Protocol Chair is responsible for assuring that all participating institutions are using the 
correct version of the protocol. 
• 
The Protocol Chair is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements to CTEP are the 
responsibility of the Protocol Chair.  
• 
The Protocol Chair is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
• 
The Protocol Chair will be responsible for the review of and timely submission of data for 
study analysis. 
 
Responsibilities of the Coordinating Center 
• 
Each participating institution will have an appropriate assurance on file with the Office for 
Human Research Protection (OHRP), NIH.  The Coordinating Center is responsible for 
assuring that each participating institution has an OHRP assurance and must maintain copies 
of IRB approvals from each participating site.  
• 
Prior to the activation of the protocol at each participating institution, an OHRP Form 310 
(documentation of IRB approval) must be submitted to the CTEP PIO. 
• 
The Coordinating Center is responsible for central patient registration.  The Coordinating 
Center is responsible for assuring that IRB approval has been obtained at each participating 
site prior to the first patient registration from that site. 
• 
The Coordinating Center is responsible for the preparation of all submitted data for review 
by the Protocol Chair. 
• 
The Coordinating Center will maintain documentation of AE reports.  There are two options 
for AE reporting: (1) participating institutions may report directly to CTEP with a copy to 
the Coordinating Center, or (2) participating institutions report to the Coordinating Center 
who in turn report to CTEP.  The Coordinating Center will submit AE reports to the 
Protocol Chair for timely review. 
• 
Audits may be accomplished in one of two ways:  (1) source documents and research 
records for selected patients are brought from participating sites to the Coordinating Center 
for audit, or (2) selected patient records may be audited on-site at participating sites.  If the 
NCI chooses to have an audit at the Coordinating Center, then the Coordinating Center is 
responsible for having all source documents, research records, all IRB approval documents, 
NCI Drug Accountability Record forms, patient registration lists, response assessments 
scans, x-rays, etc. available for the audit. 
 


CTEP Protocol #9284 
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85 
 
Inclusion of Multicenter Guidelines in the Protocol 
• 
The protocol must include the following minimum information:  
• 
The title page must include the name and address of each participating institution and the 
name, telephone number and e-mail address of the responsible investigator at each 
participating institution. 
• 
The Coordinating Center must be designated on the title page. 
• 
Central registration of patients is required.  The procedures for registration must be stated in 
the protocol. 
• 
Data collection forms should be of a common format.  Sample forms should be submitted 
with the protocol.  The frequency and timing of data submission forms to the Coordinating 
Center should be stated. 
• 
Describe how AEs will be reported from the participating institutions, either directly to 
CTEP or through the Coordinating Center. 
• 
Describe how Safety Reports and Action Letters from CTEP will be distributed to 
participating institutions.  
 
Agent Ordering 
Except in very unusual circumstances, each participating institution will order DCTD-supplied 
investigational agents directly from CTEP (See Section 8).  Investigational agents may be 
ordered by a participating site only after the initial IRB approval for the site has been forwarded 
by the Coordinating Center to the CTEP PIO.  
 
 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
86 
 
 
Appendix F: Eligibility/Pre-Registration Worksheet 
Coordinating Center: NCI 
 
 
 
Bethesda, MD 20892 
 
PI: A. P. Chen, MD 
Contact: Ashley Bruns 
 
240-781-3320 
Tel: (240) 858-3162 
 
chenali@mail.nih.gov 
Fax: (301) 451-5625 
 
 
ashley.bruns@nih.gov 
 
 
 
 
 
 
Patient’s Name: (FML)   
 
 
Institution:   
 
Medical Record Number:  
  
 
Investigator:  
  
Patient’s Birth date:  
 
  
Signature of  Treating 
Physician 
  
Sex: ______male ______female   
IRB approval valid until (date):  
Date Informed Consent was 
signed:  
  
Race:  
Ethnicity:  
Projected start date of treatment:  
  
_____ Black  
___Hispanic  
_____ Caucasian  
___Non-Hispanic  
_____ Asian  
___Other: 
_____ American Indian  
 
 _____ Native Hawaiian/Pacific 
Islander  
  
_____ 
Other_________________  
  
 
 
 
Continued next page 
 
 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
87 
 
INCLUSION CRITERIA: All responses must be YES.  A NO response will make the 
subject ineligible. 
 
Does the patient have histologically or cytologically confirmed soft 
tissue sarcoma that is metastatic or unresectable and for which 
standard treatment that prolongs survival does not exist or is no 
longer effective? 
Yes 
No 
N/A 
 
 
  
Does the patient have measurable or evaluable disease? 
 
 
 
Has the diagnosis of malignancy been confirmed by the department 
of pathology at the institution where the patient is being enrolled? 
 
 
 
Has the patient completed any previous anticancer therapy, 
including kinase inhibitors or any investigational agent, at least 4 
weeks or 5 half-lives (whichever is shorter) (6 weeks for 
nitrosoureas or mitomycin C) prior to entering the study and 
recovered to baseline from adverse events (except alopecia and 
other non-clinically significant AEs)?  Patients who have received 
prior cabozantinib or inhibitors of c-MET or HGF are ineligible. 
 
 
 
Does the subject have blood pressure (BP) no greater than 140 
mmHg (systolic) and 90 mmHg (diastolic)? 
 
 
 
Age ≥ 18 years? 
 
 
 
Karnofsky score > 70% (see Appendix A) score______  
or ECOG ≤ 1? 
 
 
 
Life expectancy > 3 months? 
 
 
 
Has the patient, if a woman of childbearing potential or a man, 
agreed to use adequate birth control? 
 
 
 
Has a signed informed consent/assent been obtained? 
 
 
 
Able to swallow whole tablets? 
 
 
 
 
 
 
 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
88 
 
EXCLUSION CRITERIA: Responses should be NO 
Does the patient have any clinically significant illnesses which would 
compromise participation in the study, including, but not limited to 
known HIV infection requiring combination antiretroviral therapy, 
symptomatic congestive heart failure, uncontrolled hypertension, 
unstable angina pectoris, myocardial infarction within the past 6 
months, uncontrolled cardiac arrhythmia, gastrointestinal disorders 
associated with a high risk of perforation or fistula formation, or 
psychiatric illness/social situations that would limit compliance with 
study requirements? 
Yes 
No 
N/A 
 
 
 
Does the patient have known brain metastases, carcinomatous 
meningitis, or epidural disease?  Patients whose brain metastatic 
disease status has remained stable for 4 weeks after treatment and do 
not require steroid treatment for at least 2 weeks before starting the 
study are eligible.   
 
 
 
Is the patient taking enzyme-inducing anticonvulsant agents? 
 
 
 
Does the patients have refractory nausea and vomiting, chronic 
gastrointestinal diseases (e.g., inflammatory bowel disease), or 
significant bowel resection that could interfere with absorption? 
 
 
 
Does the subject require concomitant treatment, in therapeutic doses, 
with anticoagulants such as warfarin or warfarin-related agents, 
heparin, thrombin or Factor Xa inhibitors, or antiplatelet agents (e.g., 
clopidogrel)?  Low dose aspirin (≤81 mg/day), low-dose warfarin (≤1 
mg/day), and prophylactic low molecular weight heparin (LMWH) 
are permitted. 
 
 
 
Has the subject experienced any of the following 
• clinically-significant gastrointestinal bleeding within 3 months 
before the first dose of study treatment; the participant must be 
maintained on a prophylactic regimen for management of an 
upper GI bleeding event with no evidence of recurrence and/or 
endoscopic confirmation of resolution of the source of a lower GI 
bleed? 
• hemoptysis of ≥0.5 teaspoon (2.5 mL) of red blood within 3 
months before the first dose of study treatment? 
• any other signs indicative of pulmonary hemorrhage within 3 
months before the first dose of study treatment? 
 
 
 
Does the subject have a corrected QT interval calculated by the 
Fridericia formula (QTcF) >500 ms? 
Note: if initial QTcF (within 28 days before enrollment) is found to 
be >500 ms, two additional EKGs separated by at least 3 minutes 
should be performed.  If the average of these three consecutive 
 
 
 


CTEP Protocol #9284 
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89 
 
results for QTcF is ≤500 ms, the subject meets eligibility in this 
regard. 
Pregnant? 
 
Pregnancy Test Date: 
 
 
 
 
Radiographic evidence of cavitating pulmonary lesion(s)? 
 
 
 
Does the subject have tumor invading or encasing any major blood 
vessels? 
 
 
 
Breastfeeding? 
 
 
 
Receiving any other investigational agents? 
 
 
 
 
Pre Study Evaluations: 
Date Done: 
History and Physical Exam  (within 8 days prior to starting drug) 
 
Height, weight, vital signs, EKG, and performance status (within 8 days 
prior to starting study drug) 
 
CBC, Diff, Plts; biochemical profile: albumin, alkaline phosphatase, 
total bilirubin, BUN, sodium, chloride, bicarbonate, calcium, creatinine, 
glucose, phosphorus, magnesium, potassium, total protein, SGOT 
[AST], SGPT [ALT], amylase, lipase, TSH: Send actual lab results 
 
Urinalysis within 8 days prior to starting study drug 
 
Diagnostic imaging studies (within 28 days prior to starting study drug) 
 
Pregnancy test within 8 days prior to starting study drug 
 
 


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DESCRIPTIVE FACTORS: 
Primary:                                                                       Histology: 
 
 
Other Chronic Diseases: Y / N (If yes, please explain):  
 
 
 
PRIOR THERAPY (Please specify date, procedure, agent, and dose, response; date of last 
treatment is required.) 
YES  NO 
 
 
 
1. Surgery/Biopsy: 
 
 
2. Chemotherapy: 
 
 
3. Radiotherapy: 
 
 
4. Hormonal Therapy: 
 
 
5. Immunotherapy: 
Physician’s Signature: ____________________________  Date: _________________ 
Printed Name of Physician: ________________________ 
To be completed by participating center when registering a patient: 
Date Registered with NCI ______/_______/_______ 
Spoke With: ______________________________________ 
Study ID: _________________________________________ 
Eligibility Checklist Completed By: ___________________ 
Assigned CRA / Data Manager: ______________________ 
 
A confirmation of registration will be sent to you by the NCI. 
 
 


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Participant Status Updates Form 
Complete form and send via encrypted email to:   
NCI Central Registration Office (HOIS) at ncicentralregistration-l@mail.nih.gov 
and fax or email to the Coordinating Center Research Nurse 
(Fax: 301-451-5625, ashley.bruns@nih.gov) 
Patient Information: 
First name 
 
 
Last name 
Middle initial 
 
ID number:________________________________________ 
 
Local Protocol Number (P9284):_______________________ 
 
Off Study Date (mm/dd/yy): _________________________ 
 
Choose one of the following off-study reasons: 
 
C: Completed Study 
 
L: Lost to follow-up 
 
R: Refused Further Treatment 
 
T: Toxicity 
 
D: Death 
 
P: Progressive Disease  
 
O: Other 
 
Death Date: (mm/dd/yy): ______________________________ 
 
Choose one or more of the following DOD Sources: 
Social Security Death Index SS#:____________________ 
http://ssdi.rootsweb.com/ 
Obituaries Document:_________________ http://www.legacy.com/washingtonpost/DeathNotices 
Cause of Death__________________________________________________________ 
Place of Death:__________________________________________________________ 
Family/staff member name notifying DOD:____________________________________ 
 
Registrar:  
Name:___________________________________________ 
Work Phone:________________________ 
Today's Date: ___________________________ 
 
 
Comments: 
 
 
 


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APPENDIX G: Informed Consent Template for Multicenter 
 
Study Title: A Phase 2 Study of Cabozantinib (XL184), a Dual Inhibitor of MET and VEGFR, 
in Patients With Metastatic Refractory Soft Tissue Sarcoma 
Introduction 
We invite you to take part in a research study.   
First, we want you to know that: 
Taking part in this research is entirely voluntary.  
You may choose not to take part, or you may withdraw from the study at any time.  In either 
case, you will not lose any benefits to which you are otherwise entitled.   
You may receive no benefit from taking part.  The research may give us knowledge that may 
help people in the future. 
 
Second, some people have personal, religious or ethical beliefs that may limit the kinds of 
medical or research treatments they would want to receive (such as blood transfusions).  If you 
have such beliefs, please discuss them with your doctors or research team before you agree to the 
study. 
Now we will describe this research study.  Before you decide to take part, please take as much 
time as you need to ask any questions and discuss this study with family, friends or your personal 
physician or other health professional.   
 
Why is this study being done?  
We are doing this study to try to develop better treatments for cancer.  In this study, the 
experimental drug cabozantinib will be given to you.  The purpose of this study is to find out if 
the drug is effective in a particular type of tumor called soft tissue sarcoma, which is what your 
doctor has diagnosed you with.  We are trying to understand how these drugs work in soft tissue 
sarcomas.  For that, this study will look at how cabozantinib may affect the levels of certain 
proteins in your tumor.   
 
The use of cabozantinib in soft tissue sarcoma is experimental.  Cabozantinib works by two 
mechanisms.  Firstly, it acts by blocking the formation of new blood vessels in tumors, a process 
called angiogenesis.  New blood vessels provide oxygen and nutrients to growing cancers, and 
blocking this process can cause cancer cells or the supporting blood vessels to stop growing.  A 
drug that works by the same mechanism, pazopanib, has already been approved by the FDA for 
the treatment of patients with sarcoma.  In laboratory studies, some drugs that block angiogenesis 
increase the production of c-MET in tumors, which helps cancer cells adapt to not having enough 
oxygen, so the tumor can keep growing.  Cabozantinib also blocks c-MET in tumors.  By both 
these mechanisms the ability of the sarcoma tumor cells to survive may be markedly reduced by 
the drug.   
Although we hope this drug will decrease the size of your tumor, we cannot promise or predict 
the benefits of the treatment at this time.  The drug used in this study has known side effects that 
will be reviewed with you by your medical team before you sign the consent form.  
 
 
 


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Why are you being asked to take part in this study? 
You are being asked to take part in this research study because you have advanced cancer that 
has progressed after receiving standard treatment, or for which no effective therapy exists.   
 
Have these drugs been given to other people?  
Cabozantinib has been studied in many different cancer types like prostate cancer.  So far, more 
than 1300 patients have received cabozantinib in clinical trials for different types of cancers.  
 
How many people will take part in this study?  
Up to 55 patients will take part in this study at 4 centers across the United States. 
 
Description of Research Study 
What will happen if you take part in this research study?   
Before you begin the study 
You will need to have the following examinations, tests, or procedures to find out if you can be 
in the study.  These tests are part of your regular cancer care and should be done by your health 
care team even if you do not join the study.  If you have had them recently, they may not need to 
be repeated.  This will be up to your study doctor. 
 
If you decide that you would like to participate in this study, you will be asked to sign this 
consent form.  You will then have the examinations, tests, and procedures listed below done to 
see if you can take part in the study (this is called the screening/baseline evaluation).  
• 
Complete medical history. 
• 
Physical examination, including height, weight, blood pressure, pulse, and temperature. 
• Standard blood tests (requiring about 1 tablespoon of blood in total), which include 
measurement of your white blood cells, red blood cells, platelets, blood sugar and 
electrolytes, how your liver and kidneys work, and how well your blood clots. 
• Pregnancy test in women who are able to become pregnant. 
• Urine tests: A urine test will be done every 4 weeks to check the level of protein 
excreted by your kidneys.  Depending on the results of blood tests, you may be asked to 
collect your urine for 24 hours for further testing. 
• EKG to check your heart. 
• CT scans (a computerized x-ray examination) of your chest, abdomen, and pelvis to 
measure your tumor(s).  Other imaging tests may be done as needed. 
• Pathology slides:  Before starting on the study, we will request tumor slides or blocks to 
confirm your diagnosis.   
 
During the study 
If you are accepted and choose to take part, you will begin taking the study drug cabozantinib.  
Cabozantinib is taken by mouth.  The study drug will be given in cycles.  All cycles are 4 weeks 
(28 days) long.   
Cabozantinib is taken 1 hour before or 2 hours after food.  Each day that you take study drug, 
you will be asked to fill in a diary to show when you took the study drugs, how many pills you 
took, and report any side effects you may have had.   
 
For some study procedures we will need you to come to the ________________[name of center]  
You will also have tests performed because you are in the study to see how the study drug is 


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affecting your body and to find out how your body handles the study drug.  This will include 
imaging studies (for example, CT scans) to find out if your cancer has responded.   
 
We will ask that you come to the __________________[name of center] for at least 2 days 
during the first cycle, and then at the beginning of each cycle after that (less often if you have 
been on study for more than one year).  During the first cycle, you may be admitted for the first 2 
days of drug administration to make it easier to perform study test and procedures to see how the 
drugs are affecting your body.  If you develop any side effects, you may be asked to visit more 
often.  Please see the study chart for more details.  
 
Standard procedures being done because you are in this study; these may be done more often 
because you are in the study: 
 
• Clinic visit to ask how you are feeling and to evaluate you with a physical examination at 
the beginning of each cycle (up to 8 days before the start of each cycle; less often if you 
have been on study for more than one year). 
• Vital signs and physical examination: will be performed during the clinic visits. 
We will ask that you buy a blood pressure monitor (the cost of may be reimbursed to you; 
discuss with your study team) and measure your own blood pressure at home at least once a 
day (preferably twice a day) throughout the study.  You will record the readings in a diary.  
If your systolic blood pressure (top number) is ever more than 150 or your diastolic blood 
pressure (bottom number) more than 90, you should re-measure your blood pressure 1 to 4 
hours later.  If your systolic pressure is still greater than 150 or your diastolic blood 
pressure is still greater than 90, please contact your study team for instructions.  You 
should also call the research team if you experience any symptoms of high blood pressure, 
such as chest pain, shortness of breath, headache, blood in the urine, or double vision. 
• Blood tests: Measurement of your white blood cells, red blood cells and platelets, and 
measurements of your blood sugar, electrolytes, and how your liver and kidneys work will 
be done each time you are seen in the outpatient clinic.  All of these blood tests combined 
will require 1-2 tablespoons (20-30 mL) of blood each time. 
• Urine test to check urine protein will be done during the first cycle and then before you 
start each new cycle (less often if you have been on study for more than one year).  You 
may need it more frequently if the study doctor thinks it is needed to check for signs of 
possible damage to your kidneys.  Depending on the results of urine tests, you may be 
asked to collect your urine for 24 hours for further testing.   
• CT scans or other imaging tests such as ultrasound (an examination using sound waves) or 
MRI (an examination using magnetic field and radio waves) that detect your tumor will be 
done every 2 cycles (about every 8 weeks; every 12 weeks if you have been on study for 
more than 1 year or every 16 weeks if on study for more than 3 years) while you are 
receiving treatment.  This is done so that any benefit of the treatment can be determined, 
and so that if your cancer is not responding to the treatment, the study team can tell you 
and help you move to a different treatment program (discussed further below). 
 
Tests and procedures being done to see how the drug is affecting your body: 
• Research blood samples (optional): We may collect blood samples to help us find out if 
cabozantinib affects the levels of certain proteins.  Blood will be collected before you first 


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take the drug and on the first day of cycles 1 and 2 only.  Please see the study chart for more 
details.  The total blood for all these tests will be about 2 teaspoons.   
• We will also be collecting optional blood samples to find out the effects of the drug on any 
tumor cells in your blood.  Blood samples will be collected before you first take the drug, on 
the first day of cycle 1, and on the first day of every cycle for as long as you are on study 
(every 3 cycles if you have been on study for more than one year or every 4 cycles if more 
than 3 years).  Each blood collection is about 2 teaspoons.   
 
Study Chart 
The treatment is given over periods called cycles.  All cycles are 4 weeks long.  Treatment cycles 
will be repeated as long as you are tolerating the drugs and your cancer is either stable or getting 
better.  Each cycle is numbered in consecutive order.  The chart below shows what will happen 
during Cycle 1 and future cycles.  The left-hand column shows the day in the cycle, and the 
right-hand column tells you what will happen on that day.  This schedule shows what will 
happen to you after you sign the consent and start the study.   
Cabozantinib should be taken with water at least 1 hour before or 2 hours after a meal.  
The drug tablets should be swallowed whole with water and may not be crushed or broken. 
 
Day 
What to do and what will happen to you 
Before starting 
study drugs 
• Check in at __________________________[name of center] 
• Get routine blood and urine tests 
• Pregnancy test for women who are able to become pregnant 
• Have a history taken of how you feel and undergo a physical 
examination including vital signs by a Health Care Provider (can be 
completed up to 8 days before the start of the study) 
• CT or MRI scan will be done 
• EKG will be done 
• Research blood samples (optional) may be taken 
Cycle 1,  
Day 1 
• Admitted to __________________________[name of center] 
• Begin taking cabozantinib 60 mg PO by mouth each day 
• Research blood samples will be taken  
• You will be asked to keep a record of pill consumption and any new 
symptoms 
• Receive study diary 
Cycle 1,  
Day 2-28 
• Continue taking cabozantinib by mouth each day 
Cycles 2 and 3, 
Day 1 
• Check in at __________________________[name of center] 
• Return study diary 
• Have a history taken of how you feel and undergo a physical 
examination including vital signs by a Health Care Provider (can be 
completed up to 8 days before the start of each new cycle) 
• Pregnancy test for women who are able to become pregnant  
• Get routine blood and urine tests (up to 8 days before) 
• Get a routine EKG (up to 8 days before) 
• Research blood samples (optional) may be taken 


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Day 
What to do and what will happen to you 
• Continue taking cabozantinib by mouth each day 
Cycles 2 and 3, 
Day 2-28 
• Continue taking cabozantinib by mouth each day 
Cycle 4 onwards, 
D1 
 
Clinic visits on D1 
will be every 3 
cycles (every 12 
weeks) if you have 
been on study for 
more than one 
year or every 4 
cycles (every 16 
weeks) if you have 
been on study for 
more than 3 years 
• Continue taking cabozantinib by mouth each day 
• Check in at __________________________[name of center] 
• Return study diary  
• Research blood samples (optional) may be taken on the first day of 
each cycle 
• Have a history taken of how you feel and undergo a physical 
examination including vital signs by a Health Care Provider (can be 
completed up to 8 days before the start of each new cycle) 
• Pregnancy test for women who are able to become pregnant 
• Get routine blood and urine tests (up to 8 days before) 
• EKG tests (up to 8 days before) 
• CT scans to determine how your tumor is responding to the treatment 
will be done every 2 cycles (every 8 weeks; every 12 weeks if you 
have been on study for more than one year or every 16 weeks if more 
than 3 years) 
 
 
Risks or Discomforts of Participation 
What side effects or risks can I expect from being in this study?  
 
If you choose to take part in this study, there is a risk that the XL184 (cabozantinib) may not be 
as good as the usual approach for your cancer or condition at shrinking or stabilizing your 
cancer. 
 
You also may have the following discomforts: 
• Spend more time in the hospital or doctor’s office. 
• Be asked sensitive or private questions about things you normally do not discuss. 
• May not be able to take part in future studies. 
 
The XL184 (cabozantinib) used in this study may affect how different parts of your body work 
such as your liver, kidneys, heart, and blood.  The study doctor will test your blood and will let 
you know if changes occur that may affect your health. 
 
There is also a risk that you could have side effects from the study drug(s)/study approach. 
 
Here are important things to know about side effects: 
• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, and some may never go 
away. 
• Some side effects may make it hard for you to have children. 
• Some side effects may be mild.  Other side effects may be very serious and even result in 
death. 


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You can ask your study doctor questions about side effects at any time.  Here are important ways 
to make side effects less of a problem: 
• If you notice or feel anything different, tell your study doctor.  He or she can check to see 
if it is a side effect. 
• Your study doctor will work with you to treat your side effects. 
• Your study doctor may adjust the study drugs to try to reduce side effects. 
 
The tables below show the most common and the most serious side effects doctors know about.  
Keep in mind that there might be other side effects doctors do not yet know about.  If important 
new side effects are found, the study doctor will discuss these with you. 
 
High blood pressure is one common side effect of cabozantinib.  Your blood pressure will be 
closely watched while you are taking this drug.  You will also be checking your blood pressure at 
home at least once a day (preferable twice a day) for the entire study.  If you have high blood 
pressure while taking cabozantinib, your study doctor may recommend follow-up with your 
primary care physician and/or starting or increasing medication to lower your blood pressure. 
 
Some patients on this study have experienced blood clots in the lungs, possibly related to the 
study drug.  Let your doctor know immediately if you experience any shortness of breath or 
chest pain. 
 
In addition, some patients on this study have experienced sepsis, or an infection in the 
bloodstream, possibly related to the study drug.  This condition can cause fever, increased heart 
rate, increased breathing rate, and confusion.  Sepsis can be life-threatening. 
 
Grapefruit juice has been shown to affect how the body handles some drugs by blocking the 
activity of the body’s cytochrome P450 (CYP450) system.  CYP450 is important in breaking 
down substances in the body, including cabozantinib.  Do not take grapefruit/ grapefruit juice or 
Seville oranges while participating in this trial.  Inform physician and study healthcare team about 
current medications including over the counter drugs, herbals, or natural medicines.  We do not 
know if taking cabozantinib will cause other drugs you may be taking to work differently.  It is 
very important that you talk to a member of the research team before beginning any new 
drugs, over-the-counter medications, vitamins, or alternative therapies. 
 
Risks and side effects related to cabozantinib may include: 
 
COMMON, SOME MAY BE SERIOUS   
In 100 people receiving XL184 (cabozantinib), more than 20 and up to 100 may have: 
• 
Diarrhea, nausea, vomiting 
• 
Tiredness 
• 
Weight loss, loss of appetite 
• 
Changes in taste  
• 
Redness, pain or peeling of palms and soles 
• 
High blood pressure which may cause headaches, dizziness, blurred vision 
 
 
 
 


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OCCASIONAL, SOME MAY BE SERIOUS   
In 100 people receiving XL184 (cabozantinib), from 4 to 20 may have: 
• 
Anemia which may require blood transfusion 
• 
Pain 
• 
Constipation, heartburn 
• 
Dry mouth, skin 
• 
Sores in the mouth which may cause difficulty swallowing 
• 
Swelling of arms, legs 
• 
Infection 
• 
Bruising, bleeding 
• 
Dehydration 
• 
Muscle weakness 
• 
Dizziness, headache 
• 
Cough, shortness of breath 
• 
Internal bleeding which may cause black tarry stool, blood in vomit, coughing up blood, or 
blood in urine 
• 
Bleeding from multiple sites including the nose 
• 
Changes in voice 
• 
Hair loss, rash 
• 
Change in hair color 
• 
Blood clot which may cause swelling, pain, shortness of breath 
RARE, AND SERIOUS 
In 100 people receiving XL184 (cabozantinib), 3 or fewer may have: 
• 
A tear or hole in internal organs that may require surgery 
• 
Non-healing surgical site 
• 
Damage to the jawbone which may cause loss of teeth 
• 
Bleeding in the brain which may cause confusion 
• 
Stroke which may cause paralysis, weakness 
• 
Brain damage which may cause headache, seizure, blindness (also known as Reversible 
Posterior Leukoencephalopathy Syndrome) 
• 
Lung collapse 
 
 
Reproductive Risks: 
If you are a woman who is breast feeding or pregnant, you may not take part in the study because 
we don’t know how cabozantinib would affect your baby or your unborn child.  If you are a 
woman who can become pregnant, or are the partner of a woman who can become pregnant, you 
will need to practice two effective forms of birth control before starting study treatment, during 
study treatment, and for 4 months after you finish study treatment.  Your study team will talk 
with you about the kinds of birth control that can be used in this study.   
If you think that you or your partner is pregnant, you should tell your study doctor or nurse at 
once.   
Effective forms of birth control include: 
• abstinence  
• intrauterine device (IUD) 
• hormonal [injections, or implants]: estrogen containing pills are not allowed due to the 
risk of blood clotting 


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• tubal ligation 
• vasectomy 
 
Side Effects of Blood Draw: 
Infrequent (occurs in 1 to 10 out of 100 people): persistent pain and discomfort at the injection 
or needle insertion site as well as possible infection, bleeding, bruising, and soreness.  
 
Potential Benefits of Participation 
Are there benefits to taking part in this study?  
Taking part in this study may or may not make your health better.  We do not know if you will 
receive personal, medical benefit from taking part in this study.  These potential benefits could 
include shrinking of your tumor or lessening of your symptoms, such as pain, that are caused by 
the cancer.  You should discuss other treatment options with the study team and your home 
doctor before deciding to take part in this study.  We do know that information from this study 
will help doctors learn more about these study drugs.  This information will also help future 
cancer patients. 
 
Alternative Approaches or Treatments 
What other choices do I have if I do not take part in this study?  
Instead of being in this study, you have these options  
• Getting treatment or care for your cancer without being in a study 
• Taking part in another study 
• 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.  Instead, it tries to improve how you feel.  Comfort care tries to keep 
you as active and comfortable as possible. 
 
Please talk to your doctor about these and other options. 
 
Research Subject’s Rights 
 
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 
this study.  If you decide to take part, 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 if you are eligible and choose to participate in another trial.  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. 
 
 
 
 
What are the costs of taking part in this study?  


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You and/or your health plan/insurance company will need to pay for some or all of the costs of 
treating your cancer in this study.  Some health plans will not pay these costs for people taking 
part in studies.  Check with your health plan or insurance company to find out what they will pay 
for.  Taking part in this study may or may not cost your insurance company more than the cost of 
getting regular cancer treatment. 
 
The NCI will supply cabozantinib at no charge while you take part in this study.  Even though it 
is unlikely, there is a possibility that at some point the supply of study agents may run out, 
necessitating taking you off-study. 
 
[If applicable, inform the patient of any tests, procedures, or agents for which there is no charge.  
The explanation, when applicable, should clearly state that there are charges resulting from 
performance of the test or drug administration that will be billed to the patient and/or health 
plan.  For example, “The NCI is supplying (drug) at no cost to you.  However, you or your 
health plan may need to pay for costs of the supplies and personnel who give you the (drug).”]  
 
You will not be paid for taking part in this study. 
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. 
 
Stopping Therapy 
Your doctor may decide to stop your therapy for the following reasons: 
• if he/she believes that it is in your best interest 
• if your disease comes back during treatment 
• if you have side effects from the treatment that your doctor thinks are too severe 
• if new information shows that another treatment would be better for you 
• if too many patients in the study experience severe side effects 
• if you become pregnant 
 
In this case, you will be informed of the reason therapy is being stopped.  You can stop taking 
part in the study at any time.  However, if you decide to stop taking part in the study, we would 
like you to talk to the study doctor and your regular doctor first.   
If you decide at any time to withdraw your consent to participate in the trial, we will not collect 
any additional medical information about you.  However, according to FDA guidelines, 
information collected on you up to that point may still be provided to the Cancer Therapy 
Evaluation Program (CTEP) at the National Cancer Institute (NCI) or designated representatives.  
If you withdraw your consent and leave the trial, any samples of yours that have been obtained 
for the study and stored at the NCI can be destroyed upon request.  However, any samples and 
data generated from the samples that have already been distributed to other researchers or placed 
in the research databases cannot be recalled and destroyed. 
 
 
Follow-up  


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You will be followed for 30 days after taking the last dose of study drug.  We will call you after 
about 30 days to ask about any side effects that were ongoing when you stopped therapy, or any 
new side effects that might be related to the study therapy.  If you have side effects that might be 
related to the study drugs that have not gotten better after 30 days, we will call you every 2 
weeks until the side effects have become stable or gotten better.  The follow-up period will end if 
you enroll on another protocol or start receiving standard therapy.   
 
What happens if I am injured because I took part in this study? 
It is important that you tell your study doctor, __________________ [investigator’s name(s)], 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 at __________________ [telephone number]. 
You will get medical treatment if you are injured as a result of taking part in this study.  You 
and/or your health plan will be charged for this treatment.  The study will not pay for medical 
treatment. 
 
Will my medical information be kept private? 
We will do our best to make sure that the personal information in your medical record will be 
kept private.  However, we cannot guarantee total privacy.  Your personal information may be 
given 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, including research records, for 
research, quality assurance, and data analysis include: 
• 
The National Cancer Institute (NCI) and other government agencies, like the Food and 
Drug Administration (FDA), involved in keeping research safe for people. 
• 
Qualified representatives from the pharmaceutical collaborator may also review the 
medical records. 
• 
Designated investigators from other cancer centers participating in this study, including 
the University of Southern California/Norris Comprehensive Cancer Center; the 
University of California, Davis, Cancer Center; and Stanford University Medical Center  
 
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. 
[Note to Local Investigators: The NCI has recommended that HIPAA regulations be addressed 
by the local institution.  The regulations may or may not be included in the informed consent 
form depending on local institutional policy.] 
 
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 
this study.  If you decide to participate, 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 center.  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? 


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You can talk to your study doctor about any questions or concerns you have about this study.  
Contact your study doctor __________________ [name(s)] at __________________ [telephone 
number]. 
For questions about your rights while taking part in this study, call the 
________________________ [name of center] Institutional Review Board (a group of people 
who review the research to protect your rights) at __________________ (telephone number). 
[Note to Local Investigator: Contact information for patient representatives or other individuals 
in a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can be listed here.] 
 
Where can I get more information? 
You may call the National Cancer Institute’s Cancer Information Service at: 1-800-4-CANCER 
(1-800-422-6237).  You may also visit the NCI Web site at http://cancer.gov/ 
• For NCI’s clinical trials information, go to: http://cancer.gov/clinicaltrials/ 
• For NCI’s general information about cancer, go to http://cancer.gov/cancerinfo/ 
You will get a copy of this form.  If you want more information about this study, ask your study 
doctor.  
 
Use of Specimens and Data for Future Research 
To advance science, it is helpful for researchers to share information they get from studying 
human samples.  They do this by putting it into one or more scientific databases, where it is 
stored along with information from other studies.  A researcher who wants to study the 
information must apply to the database and be approved.  Researchers use specimens and data 
stored in scientific databases to advance science and learn about health and disease.   
We plan to keep some of your specimens and data that we collect and use them for future 
research and share them with other researchers. We will not contact you to ask about each of 
these future uses.  These specimens and data will be stripped of identifiers such as name, address 
or account number, so that they may be used for future research on any topic and shared broadly 
for research purposes.  Your specimens and data will be used for research purposes only and will 
not benefit you.  It is also possible that the stored specimens and data may never be used.  
Results of research done on your specimens and data will not be available to you or your doctor.  
It might help people who have cancer and other diseases in the future.   
My specimens and data may be kept for use in research to learn about, prevent, or treat 
cancer or other health problems.   
 
Yes              No               Initials_________ 
Signature 
 
I have been given a copy of all _____ [insert total of number of pages] pages of this form.  I 
have read it or it has been read to me.  I understand the information and have had my questions 
answered.  I agree to take part in this study. 
 
Participant ________________________________ 
Date ______________________________________ 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
103 
 
APPENDIX H: PD Collection Worksheets  
 
Date:  
PD SAMPLE COLLECTION SHEET: Cycle 1 Day 1 
Protocol: 9284 
Ht:  
Page ______________for 
Sample Pick-up 
Lab phone:  
Research Nurse:   
Dose level: 
XL184 Dose:  
Wt:   
Phone:                     Pager:   
Patient ID: 
BSA:   
PI:  
Phone:  
  
Diagnosis/subtype: 
 
PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION 
Day 
Time 
Instructions 
Ideal 
Time 
Actual 
Time 
Record comments (i.e., if collection missed), and 
sign each time you collect a sample 
Day 1 
Prior to drug 
PD 300 K2 EDTA 3 mL x1 
Label tube: sample number, date and time 
----- 
  
Day 1 
Prior to drug 
PD 400 6 mL NaHep x1 
Label tube: sample number, date and time 
------ 
 
 
Administer XL184, Time: 
Day 1 
3-6 hours post 
dose 
PD 301 K2 EDTA 3 mL x1 
Label tube: sample number, date and time 
 
 
 
Day 1 
4 hours post 
dose 
PD 401 6 mL NaHep x1 
Label tube: sample number, date and time 
 
 
 
 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
104 
 
Date:  
PD SAMPLE COLLECTION SHEET: Cycle 2 Day 1 
Protocol: 9284 
Ht:  
Page ______________for 
Sample Pick-up 
Lab phone:  
Research Nurse:   
Dose level: 
XL184 Dose:  
Wt:   
Phone:                     Pager:   
Patient ID: 
BSA:   
PI:  
Phone:  
 
Diagnosis/subtype: 
 
 PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION 
Day 
Time 
Instructions 
Ideal 
Time 
Actual 
Time 
Record comments (i.e., if collection missed), and 
sign each time you collect a sample 
Day 1 
Prior to drug 
PD 402 6 mL NaHep x1 
Label tube: sample number, date and time 
------ 
 
 
Administer XL184, Time: 
Day 1 
3-6 hours post 
dose 
PD 302 K2 EDTA 3 mL x1 
Label tube: sample number, date and time 
 
 
 
 
 
 


CTEP Protocol #9284 
Clinical Center Protocol #13-C-0044 
 
 
 
105 
 
 
Date:  
PD SAMPLE COLLECTION SHEET: Day 1 each cycle/determined by PI 
Protocol: P9284 
Ht:  
Page ______________for 
Sample Pick-up 
Lab phone:  
Research Nurse:   
Dose level: 
XL184 Dose:  
Wt:   
Phone:                     Pager:   
Patient ID: 
BSA:   
PI:  
Phone: 
 
Diagnosis/subtype: 
  
PLEASE LABEL EACH TUBE WITH ACTUAL DATE AND TIME OF SAMPLE COLLECTION 
Day 
Time 
Instructions 
Ideal 
Time 
Actual 
Time 
Record comments (i.e., if collection missed), and 
sign each time you collect a sample 
Day 1 
Prior to drug 
PD 40X 6 mL NaHep x1 
Label tube: sample number, date and time 
------ 
 
 
Administer XL184, Time: