Clinical trial NCT00436956
Conditions: Prostate Cancer
Keywords: VEGF Angiogenesis Hormone-Refractory Bone Metastases Docetaxel-Resistant Prostate Cancer
Sponsor: National Cancer Institute (NCI)
Start date: 2006-10-16; Completion date: 2014-02-05
Enrollment: 59 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* AZD2171 (Cediranib) is an experimental drug that inhibits formation of new blood vessels.
* Tumors need new blood vessels to grow. Preventing the growth of new blood vessels with AZD2171 may inhibit tumor growth.

Objectives:

-To determine the effectiveness and side effects of AZD2171 in patients with prostate cancer that has metastasized (spread beyond the primary site).

Eligibility:

* Males 18 years of age and older with androgen-independent prostate cancer that has metastasized.
* Patients must have received prior treatment with docetaxel.

Design:

Patients take one AZD2171 by mouth every day in 28-day treatment cycles and undergo the following procedures:

* 1- to 2-day hospitalization at the start of the study for biopsies and blood measurements to determine the level of AZD2171 in the bloodstream. Blood is drawn immediately before the first dose, and 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr, 24 hr, and 48 hours after the dose is taken.
* Blood tests before starting treatment and then monthly to determine the level of vascular endothelial growth factor receptor ( VEGFR), a protein involved in blood vessel formation.
* Magnetic resonance imaging (MRI) scans once a month to evaluate blood flow.
* Tumor biopsies (optional) both before and after the second and sixth treatment cycles.
* Clinic visits every 4 weeks, including various routine and research blood tests, urine test and electrocardiogram.
* Computed tomography (CT) scan of the chest, abdomen, and pelvis every 8 weeks
* Bone scan every 8 weeks

Patients record all doses of AZD2171 taken or missed in a pill diary. They record their blood pressure at least once daily in a blood pressure diary.

Treatment may continue as long as the patient tolerates the AZD2171 and the cancer does not worsen.

...

Detailed description:
Background:

* AZD2171 (Cediranib) is an oral potent inhibitor of receptor tyrosine kinases which impact vascular endothelial growth factor-A (VEGF).
* VEGF appears important in blood vessel formation and disease progression in prostate cancer.
* No known effective therapy in patients with progressive androgen-independent prostate cancer after treatment with docetaxel.

Objectives:

* Primary objective of this study is to determine if AZD2171 is associated with a 30% 6 month probability of progression free survival in patients with metastatic androgen independent prostate cancer (AIPC) as determined by clinical and radiographic criteria.
* Secondary objective of this study will be demonstration of biologic effect by the drug in the patient and on the tumor (when possible). Correlative studies will be conducted on serially obtained tissue biopsies and white blood cell collections.
* Laboratory correlates will include elucidation of activation of components of the VEGFR2 and angiogenesis pathways and evaluation of endothelial cell adhesion molecules (released by damaged cells) using enzyme-linked immunosorbent assay (ELISA), pharmacogenetic analysis of kinase insert domain receptor (KDR) variants and single nucleotide polymorphisms, and pharmacokinetic characterization of AZD2171 activity.

Eligibility:

* Metastatic progressive androgen-independent prostate cancer.
* Prior treatment with docetaxel.
* May not have corrected QT interval (QTc ) greater than 470 msec or greater than 1+ proteinuria on 2 consecutive dipsticks no less than 1 week apart.

Design:

* Phase II trial with a two stage design. 12 patients enrolled in first cohort, if 2 or more are progression free at 6 months than enroll up to 35 evaluable patients. The ceiling will be set at 37 to allow for inevaluable patients.
* Starting dose 20 mg QD (every day) for all patients.
* Once two stage design is complete then prednisone 10 mg once per day will be given in combination with AZD2171. The total number of patients will be 23 for this portion of the protocol.

Arms: arm 1: Cohort 1 (n=35) received 20 mg AZD2171 (Cediranib) orally daily. Cohort 2 (n=23) received prednisone 10 mg orally daily with 20 mg AZD2171.
Interventions: intervention 1: Magnetic Resonance Imaging (DCE-MRI) intervention 2: AZD2171 intervention 3: Prednisone
Intervention descriptions: intervention 1: Scans evaluate tumor tissue and blood flow. intervention 2: 20 mg oral daily for 28 days intervention 3: 10mg orally daily in combination with AZD2171 20mg daily.

Protocol documents:
ICF_001.pdf: 
 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE: 
National Cancer Institute 
 
 
STUDY NUMBER: 
07-C-0059 
PRINCIPAL INVESTIGATOR:  William L. Dahut, M.D. 
 
 
STUDY TITLE: 
A Phase II Study of AZD2171 in Metastatic Androgen Independent Prostate Cancer 
 
 
Continuing Review Approved by the IRB on 7/20/09 
Amendment Approved by the IRB on 12/4/09 (H) 
 
 
 
Date Posted to the Web: 12/18/09 
Standard 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (7-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
Taking part in NIH 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.  However, to receive care at the NIH, you must be taking 
part in a study or be under evaluation for study participation. 
 
 
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 NIH 
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 anyone at NIH, or with family, friends or your personal physician or other health 
professional. 
 
 
This is a clinical trial, a type of research study.  Your study team will explain the clinical trial to you.  Clinical trials include 
only people who choose to take part.  Please take your time to make your decision about taking part.  You may discuss 
your decision with your friends and family or your referring physician.  You can also discuss it with your study team.  If 
you have any questions, you can ask your study doctor for more explanation.  
 
You are being asked to take part in this study because you have a cancer that has not responded to standard treatments 
or for which no standard treatments have been identified.  


 
 
  
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STUDY NUMBER: 
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CONTINUATION:  page  2  of  12  pages 
 
 
 
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Description of Research Study 
 
Why is this study being done? 
The purpose of this study is to determine what effects, good and/or bad AZD2171, an unproven anticancer drug, has on 
you and your prostate cancer.  This study will also help to determine how AZD2171 works in patients who have prostate 
cancer.  AZD2171 is an experimental drug, not yet approved by the Food and Drug Administration.  This study is being 
done in collaboration with Astra Zeneca, the makers of AZD2171, in an effort to understand the utility of this drug. The 
drug is an oral inhibitor of angiogenesis, the process of creating new blood vessels.  All solid tumors require new blood 
vessels to grow.  We hope to inhibit tumor growth with AZD2171 by preventing the growth of new blood vessels. 
 
How many people will take part in the study? 
About 23 people will take part in this study.  
 
What will happen if you take part in this research study?   
This drug is a medicine you take by mouth and give to yourself every day.  You will start by taking 1 tablet once daily.  
You are to swallow the tablet whole with about 8 oz. of water each morning, on an empty stomach, one hour before or 
two hours after meals.  You should record the number of pills you consume and the time of consumption in a diary which 
will be provided to you by your study team.  If you miss doses, that should also be recorded in the diary. If you remember 
your missed dose within three hours of the time you usually take a dose, you may take a pill to make up for the missed 
dose; otherwise do not make up the missed dose. The dose will be adjusted if you experience any significant problems.  
This will be determined by your study team.  AZD2171 can be taken while you are an outpatient.  To help us to 
understand how the drug is working, a number of tests will be done, including tests to determine the level of vascular 
endothelial growth factor receptor (VEGFR), the target of AZD2171, in your blood prior to cycle 1 and monthly thereafter, 
as well as a special type of MRI (dynamic contrast-enhanced MRI, DCE-MRI, lasting approximately one hour) to evaluate 
blood flow, and tumor biopsies (optional), both before and after 2 and 6 cycles of treatment.  You will be watched very 
closely as an outpatient and every 4 weeks return to the NIH to see a doctor who will monitor your response to the 
experimental treatment.  At the outset of the study you may be hospitalized for 24 to 48 hours to complete research 
studies including your biopsies and blood measurements to determine the level of drug in your bloodstream.  During this 
hospitalization, blood will be drawn immediately prior to your first dose, and 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 
hr, 24 hr, and 48 hours after ingestion.  You will also have blood drawn at each clinic visit to measure the level of drug in 
your body.  Each blood draw will consist of approximately one tablespoon of blood.  In addition, you will be asked to take 
your blood pressure twice daily (once in the morning while resting quietly, once in the evening) and record it in a log 
which will be provided to you. Furthermore, all study participants will be invited to provide a blood sample (approximately 
one tablespoon) for retrospective evaluation of genetic variants possibly playing a role in how the drug acts.  Participation 
in pharmacogenetic studies will be optional for all patients entering the study. 
 
In addition, you will also take prednisone 10 mg per day. This drug is prescribed with FDA approved 
prostate cancer regimens. Our experience with this drug as well as at other institutions in individual 
patients demonstrates a possible benefit in decreasing some of the side effects from AZD-2171. At our 
institution , we have had four patients who have tried this combination and may have tolerated the 
AZD2171 better. 


 
 
  
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Before you begin the study …  
You will need to have the following exams, tests, and procedures to find out if it is safe for you to be in the study.  The 
exams, tests, and procedures are part of regular cancer care and may be done even if you do not join the study.  If you 
recently had some of the tests, they may not need to be repeated.  This will be up to your study team. 
• 
Blood tests: measurements of how your liver and kidneys work, measurement of your white blood cells, red blood 
cells and platelets, your blood sugar and blood electrolytes.   
• 
Computerized Tomography  scan of the chest, abdomen, and pelvis within the past 4 weeks 
• 
Bone scan within the past 4 weeks 
• 
Chest x-ray within the past 4 weeks 
• 
Blood counts and chemistries (within 16 days before enrollment) 
• 
PSA (Prostate Specific Antigen); if PSA is less than 4 ng/ml:  PAP (prostate acid phosphatase) within 7 days of 
enrollment 
• 
Tumor biopsy (optional) 
• 
Electrocardiogram 
• 
Echocardiogram 
 
During the study …  
If the exams, tests and procedures show that you can be in the study, and you choose to take part, then you will need 
the following tests and procedures.  Some are part of regular cancer care; other tests are specific to the drug you will be 
taking. 
• 
Blood tests including blood counts, chemistries, Thyroid Stimulating Hormone, and serum troponin. 
• 
Electrocardiogram 
• 
PSA measurements 
• 
Urinalysis for protein. 
 
You will need these tests and procedures that are also part of regular cancer care.  They are being done more often 
because you are in this study.   
• 
Computerized Tomography scan of the chest, abdomen, and pelvis and Echocardiogram after cycles 2 and 4, then 
every 3 months. 
• 
Bone scan after cycles 2 and 4, then every 3 months. 
 
You will need these tests and procedures that are either being tested in this study or being done to see how the study 
drug is affecting your body. 
• 
Pharmacokinetic sampling- this is determination of the amount of AZD2171 in your bloodstream at different 
amounts of time after having consumed the drug by mouth. 
• 
Optional tumor biopsies before AZD2171 and after 2 and 6 cycles of experimental treatment. 
 
Continue to record all doses of AZD2171 taken and / or missed in your pill diary.  Record your blood pressure at least 
once daily in a blood pressure diary, which will be provided to you.  We will also provide you with a blood pressure 
monitor. 
 
When you are finished taking AZD2171 
Your participation in this study will continue until either you or your study team decides that this medication is not 
beneficial to you.  Your participation is voluntary; so you may stop taking AZD2171 at any time, but we ask that you 
speak to your study team before stopping the study drug.  Your study team will be monitoring you and your cancer while 


 
 
  
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you are taking AZD2171.  If your prostate cancer is clearly worsening, then your study team will stop treatment with 
AZD2171.  At the end of the study, no additional testing will be required. 
 
Study Chart 
The treatment is given over 28-day periods of time called cycles.  The 28 day treatment cycle will be repeated as long as 
you are tolerating the AZD2171 and your cancer is either steady or getting better.  Each cycle is numbered in consecutive 
order.  The chart below shows what will happen to you 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 indicates what will 
happen to you after you sign consent and start the study. 
Cycle 1 
Day  
What to do and what will happen to you 
Before 
starting 
AZD2171 
Get routine blood tests. 
Provide a history of how you feel and undergo a physical examination by a Health Care Provider. 
Research blood samples will be taken. 
Optional tumor biopsy (if there is a site that is safe as determined by your study team).  You may 
require overnight admission to the hospital for the biopsy; the decision whether to admit will be 
discussed with you by your heath care team. 
Day 1 
Begin taking AZD2171 once a day, and continue unless told to stop by your health care team. 
• 
Blood draws for research will be obtained on days 1 and 2 including a series of blood draws at 
pre, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr, 24 hr, and 48 hr after drug administration 
to monitor the level of AZD2171 in your bloodstream.  You may be hospitalized overnight for 
these blood tests. 
Day 2 
Do not take AZD2171 on Day 2 (because of the blood draws described above). 
Obtain weekly blood pressure checks at a healthcare facility. 
Check your blood pressure at home twice daily (once in the morning while resting quietly, and once 
in the evening) for the next 27 days. 
If you were admitted for biopsies and other testing, you will be discharged from the hospital. 
Day 3 
Bring AZD2171.  Begin taking drug after your 48-hour blood draw. 
Day 29 
(also Cycle 
2 day 1) 
Get routine blood tests and exams including PSA measurement. 
Return to the NIH clinic (OP12 outpatient clinic) to see your doctor. Provide a history of how you feel 
and undergo a physical examination by a Health Care Provider. 
If you are tolerating the drug well, the first dose of cycle 2 will be given at the NIH Clinical Center. 
Future cycles 
Day 
 
What to do and what will happen to you 
Days 1-28 
Keep taking AZD2171 once a day if you have no bad side effects and cancer is not getting worse.  
Call the research nurse, , or your study doctor if you do not know what to do. 
Get routine X-rays,  
Computerized Tomography  scans, Echocardiograms and/or bone scan cycles 2 and 4, then 
every 3 months (more if your doctor tells you to). 
MRIs cycles 2 and 4, then every 4 months 
Optional tumor biopsy after cycles 2 and 6; biopsy may require overnight admission. 
Day 29 
Return to your doctor’s office for your next exam and to begin the next cycle. 
 


 
 
  
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How long will you be in the study? 
You will be invited to continue to take AZD2171 until your study team advises you that the medication is not helping your 
cancer, you are experiencing significant toxicity from the therapy, or you decide that you no longer wish to participate in 
the study. 
 
Can I stop being in the study? 
Yes.  You can decide to stop at any time.  Tell your study team if you are thinking about stopping or decide to stop.  He 
or she will tell you how to stop safely.  
 
It is important to tell your study team if you are thinking about stopping so any risks from AZD2171 can be evaluated by 
your study team.  Another reason to tell your study team that you are thinking about stopping is to discuss what follow-up 
care and testing could be most helpful for you. 
 
Your study team may stop you from taking part in this study at any time if they believe it is in your best interest, if you do 
not follow the study rules, or if the study is stopped. 
 
Alternative Approaches or Treatments  
 
What other choices do I have if I do not take part in this study? 
To make an informed decision about whether or not to participate in this study, you need to know your options.  
Alternative treatments to this study, in general, include:   
1) no further treatment of the cancer, but treatment of any symptoms that may be causing discomfort, 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. 
2) chemotherapy and/or hormonal therapy with commercially available drugs. Recent studies have shown that a 
drug known as docetaxel or taxotere in combination with prednisone has survival benefit in prostate cancer.  This 
is now recognized as the standard treatment of prostate cancers that are no longer sensitive to hormonal 
therapies. You are required to have at least one attempt at cytotoxic therapy for your prostate cancer before 
enrolling on this study; you remain eligible for this study after several attempts at different types of cytotoxic 
therapy. 
3) ketoconazole 
4) other experimental therapies,  
5) radiation therapy to shrink tumor masses or relieve pain, and  
6) surgery to remove tumor masses.   
All of these options may not apply to your particular situation, but it is important that you have explored these options 
with your regular doctor.  
 
Risk or Discomforts of Participation 
What side effects or risks can you expect from being in the study?  
You may have side effects while you are taking the study drug.  Everyone taking part in the study will be watched 
carefully for any side effects.  However, doctors don’t know all the side effects that may happen so it is important to 
report changes that you may notice, even if your study team does not ask specifically about them.  Side effects may be 
mild or very serious.  Your study team may give you medicines to help lessen side effects.  Many side effects go away 
with those medicines and others can go away soon after you stop taking AZD2171. In some cases, side effects can be 


 
 
  
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serious, long lasting, or may never go away.  There are no known long-lasting toxicities from AZD2171 at this time.  You 
should talk to your study team about all side effects that you have while taking part in the study.  
Preliminary studies have shown hypertension, or elevated blood pressure, to be one common side effect of AZD2171.  
Your blood pressure will be closely monitored while you are taking AZD2171.  If your blood pressure becomes elevated 
while taking AZD2171, your physicians may recommend follow-up with your primary care physician, starting or increasing 
medication to lower blood pressure, and / or home blood pressure monitoring. 
Grapefruit juice has been shown to interact with a number of drugs by blocking the activity of the body’s cytochrome P450 
(CYP450) system. CYP450 is important in breaking down substances in the body, including many drugs.  Since the degree 
to which grapefruit juice interacts with AZD2171 in the body is not fully known, please avoid grapefruit juice while taking 
AZD2171.  As other drugs may also interact with the CYP450 system, please contact the study team prior to starting any 
new medication. 
 
Risks and side effects related to AZD2171 are detailed in the table on the following page. “Common” side effects as those 
occurring in greater than 20% of patients and “Uncommon” side effects as those occurring in ≤ 20% of patients. 
Risks and side effects related to AZD2171 include those which are: 
Side Effect 
Mild 
Severe, but not life threatening 
Life threatening 
Common 
High blood pressure 
(Hypertension) 
Diarrhea (can be 
severe in some cases) 
Fatigue 
Loss of appetite 
(Anorexia) 
Hoarseness, loss or 
alteration in voice, 
throat irritation 
(laryngitis) 
 
 
Uncommon 
Red peeling rash 
affecting the hands 
and feet (hand-foot 
syndrome) 
Abnormal blood tests 
related to liver 
function 
Dry mouth 
Headache (can be 
severe in some cases) 
Constipation 
Weight loss 
Cough 
Sweating 
Low thyroid function 
(with associated 
inreased thyroid 
stimulating hormone 
 
 
 


 
 
  
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and decreased 
thyroxine levels) 
Dehydration 
Proteinuria (protein in 
the urine) 
Difficulty swallowing 
(dysphagia) 
Mouth ulcers 
(mucositis) 
Muscle pain 
Fever , Back pain, 
Joint pain, Muscle pain 
Nausea 
Vomiting 
Shortness of breath 
Dry Skin 
Abdominal Pain 
Decreased platelets  
Bladder spasms  
Low red blood cells 
causing anemia  
Low blood pressure  
Rare 
Hypokalemia* 
Duodenal ulcer (stomach ulcer)* 
Aphasia (inability to speak)* 
Hepatic hemorrhage (bleeding into the liver)* 
Abnormal EKG (prolonged QT corrected)* 
Muscle weakness* 
Transient ischemic attack (“ministroke”)* 
Deep vein thrombosis (blood clots)* 
Left ventricular systolic dysfunction (decrease in 
heart function) 
Formation or presence of a blood clot inside an artery 
Leukoencephalopathy syndrome including reversible 
posterior leukoencephalopathy syndrome (RPLS). 
RPLS is a medical condition related to leakiness of 
blood vessels in the brain and can cause confusion, 
blindness or vision changes, seizure and other 
symptoms, as well as changes in brain scans.  This 
condition is usually reversible, but in rare cases it is 
potentially life-threatening and may have long-term 
effect on brain function. 
Low blood sugar* 
Stroke* 
Hypertensive crisis 
(severe high blood 
pressure) 
Lung 
infection/pneumonia*  
Bleeding into you 
spine or brain(Central 
Nervous System 
Hemorrhage)*  
Death*  
Kidney Failure(Renal 
Failure)*  
 
 
*Duodenal ulcer (stomach ulcer), Hepatic hemorrhage (bleeding into the liver), transient ischemic attack (ministroke), 
deep vein thrombosis (blood clots), low blood sugar, abnormal EKG (prolonged QT corrected), muscle weakness,  aphasia 
(inability to speak), Low Potassium (Hypokalemia), Lung infection/pneumonia, Bleeding into you spine or brain(Central 
Nervous System Hemorrhage)* , Death, Kidney Failure (Renal Failure) and stroke are classified as rare side effects of 


 
 
  
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AZD2171.  These events have occurred on AZD2171 trials but it has not yet been determined whether the events were 
caused by AZD2171. 
 
Reproductive risks:  You should not father a baby while on this study because the drugs in this study can affect an  
unborn baby.  It is important you understand that you must refrain from intercourse or need to use birth control while on 
this study.  Check with your study doctor about what kind of birth control methods to use and for how long you should 
use them after you are no longer receiving the study drug.  Typical birth control methods include abstinence from 
intercourse, barrier contraceptives (condoms, diaphragms), or hormonal agents (oral contraceptive pills). 
 
For more information about risks and side effects, ask your study team. 
 
AZD2171 can cause hypertension that can become significant.  For the first 4 weeks of the study you will be required to 
have your blood pressure checked at a healthcare facility.  This should be recorded in your first study diary and reported 
to the research team. 
 
You will also begin taking prednisone by mouth at a dose of 10 mg on the first day of each cycle but you will continue to 
take it daily throughout the cycle. The side effects that have been associated with prednisone include: 
•gastric hyperacidity(increased stomach acid), increased appetite, insomnia or nervousness occurring in > 10% of 
patients 
•hyperglycemia (high blood sugar level), fluid retention, mood swings, dizziness, headaches, muscle weakness, 
osteoporosis (bone thinning), and cataracts with long-term use, occurring in about 1% - 10% of patients 
 
*Hypertension occurring in < 1% of patients but this risk may be higher in combination with AZD2171. 
In addition,this combination of prednisone and AZD-2171 has not been studied before so unknown side effects may also 
occur. 
 
The DCE-MRI involves intravenous injection with a special non-radioactive dye (gadolinium chelate) to examine blood flow 
in a certain part of the body. An intravenous injection involves a needle stick into a vein in the arm.  Several attempts may 
be necessary to place the needle into the vein.  In addition to the pain associated with the needle stick there may be 
some bruising after the needle is removed. Experience with a large number of patients who have received commercially 
available gadolinium has shown it is without side effects in a large majority of patients.  When side effects do occur, they 
are usually mild and last a short time.  These include coolness in the arm during injection, headache, and nausea.  More 
severe reactions (shortness of breath, wheezing, or lowering of blood pressure) have occurred in an extremely small 
number of patients. 
 
Side effects may be mild or very serious.  Many side effects go away soon after you stop taking AZD2171. In some cases 
side effects may be long lasting or may never go away.  There also is a risk of death. 
 


 
 
  
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Potential Benefit 
 
Are there benefits to taking part in the study? 
Taking part in this study may or may not make your health better.  While doctors hope AZD2171 will be more useful 
against cancer compared to currently available treatments, there is not yet any proof that this is so.  We do know that the 
information from this study will help doctors learn more about AZD2171 as a treatment for cancer.  The information will 
help future cancer patients. 
 
Cost and Reimbursement 
What are the costs of taking part in this study? 
While you are on study at the National Cancer Institute, we will pay for the medications and treatments associated with 
the study.  We cannot, however, assume the cost of your overall medical care.  Any studies done outside of the NCI may 
require you or your insurance company to cover the cost of the service. 
 
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. 
 
What happens if you injured because you took part in this study? 
It is important that you tell your study team, Principal Investigator Dr. William Dahut at (301) 435-5613) if you feel that 
you have been injured because of taking part in this study.  You will get medical treatment if you are injured as a direct 
result of taking part in this study at the NIH. 
 
What are your rights if you take part in this study? 
Taking part in this study is your choice.  You may choose either to take part or to not take part in the study.  If you 
decide to take part in this study, you may leave the study at any time.  No matter what decision you make, there will be 
no penalty to you and you will not lose any of your regular benefits.  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.   
 
Communication 
Who can answer my questions about the study? 
You can talk to your study doctor about any questions or concerns you have about this study.  Contact your study team 
(Principal Investigator Dr. William Dahut) at (301) 435-5613,  
If you have any complications when you are not in the Clinical Center (e.g., at home or in a local hotel), you may call the 
page operator at (301) 496-1211 and ask for the NCI Medical Oncology Branch physician on call or the NIH Patients’ 


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-C-0059 
CONTINUATION:  page  10  of  12  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Rights Representative who will be available to answer questions concerning your involvement in this study or your rights 
as a research subject.  She is not directly associated with this study and can be contacted at (301) 496-2626. 
Research Subjects’ Rights 
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.  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 for research, quality assurance, and data analysis 
include: 
• 
The National Cancer Institute (NCI) and other government agencies, like the Food and Drug Administration (FDA), 
which are involved in keeping research safe for people. 
• 
Qualified representatives from AstraZeneca Pharamceuticals, the pharmaceutical drug sponsors who produce 
AZD2171. 
 
Please note:  This section of the informed consent form is about additional research studies that are being done with 
people who are taking part in the main study.  You may take part in these additional studies if you want to.  You can still 
be a part of the main study even if you say ‘no’ to taking part in any of these additional studies. 
You can say “yes” or “no” to each of the following studies.  Please mark your choice for each study.   
 
About Using Tissue for Research  
We encourage all patients on this study to agree to tumor biopsies for research purposes, at intervals as described in this 
consent.  Participating in biopsies is optional; study eligibility is not contingent on agreeing to tumor biopsy. If you agree 
to biopises, your doctor will remove some body tissue do some tests.  None of the data gained by the biopsy will affect 
your participation in the study.  The intention of obtaining the tissue is solely scientific and will not be used to direct your 
care. 
Reports about research done with your tissue will not be given to you or your doctor.  These reports will not be put in 
your health record.  The research will not have an effect on your care.  
Things to Think About  
If you decide now that your tissue can be kept for research, you can change your mind at any time.  Just contact us and 
let us know that you do not want us to use your tissue.  Then any tissue that remains will no longer be used for research.  
In the future, people who do research may need to know more about your health.  While the NCI may give them reports 
about your health, it will not give them your name, address, phone number, or any other information that will let the 
researchers know who you are.  
Your tissue will be used only for research and will not be sold.  The research done with your tissue may help to develop 
new products in the future.  
Benefits  
 
The benefits of research using tissue include learning more about what causes cancer and other diseases, how to prevent 
them, and how to treat them.  


 
 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
07-C-0059 
CONTINUATION:  page  11  of  12  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Risks  
The greatest risk to you is the release of information from your health records.  We will do our best to make sure that 
your personal information will be kept private.  The chance that this information will be given to someone else is very 
small.  
 
Making Your Choice  
Please read each sentence below and think about your choice.  After reading each sentence, circle "Yes" or "No".  If you 
have any questions, please talk to your doctor or nurse, or call the NIH Clinical Center Patient Representative at (301) 
496-2626.  No matter what you decide to do, it will not affect your care. 
1. My tissue may be kept for use in research to learn about, prevent, or treat cancer.  
Yes 
No 
2. My tissue may be kept for use in research to learn about, prevent or treat other health problems (for example: 
diabetes, Alzheimer's disease, or heart disease).  
Yes 
No 
3. Someone may contact me in the future to ask me to take part in more research.  
Yes 
No 
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) or TTY: 1-800-332-8615 
 
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.


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
07-C-0059 
CONTINUATION:  page  12  of  12  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (7-09) 
 
P.A.: 09-25-0099 
 
 
FAX TO:  (301) 480-3126 
 
File in Section 4:  Protocol Consent 
 
 
OTHER PERTINENT INFORMATION 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any information about 
your research involvement without your written permission.  However, if you sign a release of information form, for 
example, for an insurance company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you should know that the Act 
allows release of some information from your medical record without your permission, for example, if it is required by the 
Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital accreditation 
organizations. 
 
2. Policy Regarding Research-Related Injuries.  The 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 National Institutes of Health, the Clinical Center, or the Federal 
Government.  However, you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National Institutes of Health policies.  In 
general, patients are not paid for taking part in research studies at the National Institutes of Health. Reimbursement of 
travel and subsistence will be offered consistent with NIH guidelines. 
 
4. 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, William L. Dahut, M.D. at (301) 435-
5613;  Building 10, Room 12N226. 
 
You may also call the Clinical Center Patient Representative at 301-496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby consent to take 
part in this study. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby give permission 
for my child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/Legal Representative 
Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
 
  
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM JULY 20, 2009 THROUGH JULY 19, 2010.  
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name 
 
 

Prot_000.pdf: 


NCI Protocol #: CTEP LOI 7395 
 
Local Protocol #: 07C0059 Amendment I 
TITLE:  A Phase II Study of AZD2171 in metastatic androgen independent prostate cancer 
 
Abbreviated Title: Phase II AZD2171in Prostate Cancer 
 
Coordinating Center: 
 
Medical Oncology Branch 
National Cancer Institute 
 
Principal Investigator:
 
William L. Dahut, MD 
                                                Medical Oncology Branch 
                                                National Cancer Institute 
 
 
Building 10, Rm 12N226 
 
 
9000 Rockville Pike 
 
 
Bethesda, MD 20892 
 
 
301-435-8143 
 
 
FAX: 301-435-3854 
 
 
dahutw@mail.nih.gov 
 
Associate Investigators:  
David E. Adelberg, M.D. OD/CCR/NCI/NIH 
Joyson Karakunnel, M.D. OD/CCR/NCI/NIH
James Gulley, M.D., Ph.D., LTIB/CCR/NCI 
Philip M. Arlen, M.D., LTIB/CCR/NCI 
Howard Parnes, M.D., DCP/PUCR/NCI 
David Kohler, Pharm.D., PD/CCR/NIH 
Peter Choyke, M.D., CC/NIH 
Douglas K. Price, PhD CTB/CCR/NCI 
John Wright, MD, CTEP 
Ramaprasad Srinivasan, MD, UOB/CCR/NCI 
Marcia Mulquin, RN MOB/CCR/NCI/NIH 
Ann Pierpoint RN MOB/CCR/NCI/NIH 
David Draper, RN MOB/CCR/NCI/NIH 
Seth Steinberg, PhD, BDMS/CCR/NCI/NIH 
 
Drug Monitor:          Percy Ivy, MD 
 
Drug Sponsor:        Cancer Therapy and Evaluation Program, NCI 
 
Statistician:
Protocol Chair:
Seth Steinberg, PhD
William D. Figg, PharmD 
Biostatistics and Data Management Section 
Clinical Pharmacology Research Core 
National Cancer Institute 
National Cancer Institute 
6116 Executive Blvd, Rm 702 
Bldg 10, Rm 5A01 
Bethesda, MD 20892 
9000 Rockville Pike 
301-496-9502                                                     Bethesda, MD 20892 
Fax: 301-402-1259                                             301-402-3622 
steinbes@mail.nih.gov 
 
 
 
 
 
 
Fax: 301-402-8606 
 
 
 
 
 
 
 
wdfigg@helix.nih.gov 
 
NCI Supplied Agent: 
 AZD2171 (NSC 732208) IND # 72740 
 
 
Protocol Version Date: 
 March 17, 2010 
 
 
 


 
 Schema (All times are approximated): 
 
Frequent blood pressure monitoring  
Renal function monitoring 
Troponin T or troponin I monitoring 
Enzymes monitoring monthly 
             
 
Cycles repeat every 28 days with AZD2171 20 mg, oral administration, once daily. 
 
 
Prior to C1D1 
Baseline Evaluation 
 
 
 
 
Technetium-99 Bone Scintigraphy, Chest X-ray, CT scan of                      
                       chest, abdomen and pelvis (within 4 wk prior to enrollment) 
 
 
 
 
Laboratory Evaluation (within 16 days prior to enrollment) 
 
 
 
 
Tumor Markers (within 16 days prior to enrollment) 
History and Physical Exam, with vital sign (Within 1 week prior to 
enrollment) 
PSA (baseline – within 7 days prior to enrollment) 
Cardiac evaluation (baseline– obtained within 16 days prior to enrollment) 
 
 
 
 
 
 
C1D1  
 
AZD2171 tablets equal to 20 mg, oral administration, with 250 ml water, 
taken in empty stomach 
 
 
 
 
 
           Pharmacokinetic samples will be drawn at pre, 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 
hr, 6 hr, 8 hr, 12 hr, 24 hr, and 48 hours after drug administration 
 
 
 
C1D2  
 
Pharmacokinetic samples will be drawn at 24 hr 
 
                                
                                           Pharmacokinetic samples will be drawn at each following clinic visit 
                                  
 
 
Approximately every subsequent 4 weeks, 
           Follow-up Evaluation 
           Laboratory Evaluation 
           Tumor Markers 
           History and Physical Exam 


ii
PRECIS
Background:
* AZD2171 is an oral potent inhibitor of receptor tyrosine kinases which impact vascular endothelial growth 
factor-A (VEGF) 
* VEGF appears important in blood vessel formation and disease progression in prostate cancer 
* No known effective therapy in patients with progressive androgen-independent prostate cancer after 
treatment with docetaxel 
 
Objectives: 
* Primary objective of this study is to determine if AZD2171 is associated with a 30% 6 month probability 
of progression free survival in patients with metastatic AIPC as determined by clinical and radiographic 
criteria  
* Secondary objective of this study will be demonstration of biologic effect by the drug in the patient and on 
the tumor (when possible).  Correlative studies will be conducted on serially obtained tissue biopsies and 
white blood cell collections.   
 * Laboratory correlates will include elucidation of activation of components of the VEGFR2 and 
angiogenesis pathways and evaluation of endothelial cell adhesion molecules (released by damaged 
cells) using ELISA, pharmacogenetic analysis of KDR variants and single nucleotide polymorphisms, and 
pharmacokinetic characterization of AZD2171 activity. 
   
 
Eligibility: 
* Metastatic progressive androgen-independent prostate cancer. 
* Prior treatment with docetaxel. 
* May not have QTc > 470 msec  
or >1+ proteinuria on 2 consecutive dipsticks no less than 1 week apart 
Design:
* Phase II trial with a two stage design.  12 patients enrolled in first cohort, if 2 or more are progression 
free @ 6 months than enroll up to 35 evaluable patients. The ceiling will be set at 37 to allow for 
inevaluable patients. 
* Starting dose 20 mg QD for all patients 
* Once two stage design is complete then prednisone 10 mg once per day will be given in combination 
with AZD2171. The total number of patients will be 23 for this portion of the protocol. 
 


iii
TABLE OF CONTENTS 
SCHEMA (ALL TIMES ARE APPROXIMATED): ........................................................................................... I 
PRECIS ......................................................................................................................................................... II 
1. 
OBJECTIVES ....................................................................................................................................... 1 
1.1. 
Primary ........................................................................................................................................ 1 
1.2.     Secondary ..................................................................................................................................... 1 
2. 
BACKGROUND ................................................................................................................................... 1 
2.1 
 Androgen-independent Prostate Cancer ................................................................................ 1 
2.2 
 AZD2171 ..................................................................................................................................... 1 
2.3 
 Rationale .................................................................................................................................... 6 
3. 
PATIENT SELECTION ......................................................................................................................... 8 
3.1 
 Eligibility Criteria ...................................................................................................................... 8 
3.2 
 Exclusion Criteria ..................................................................................................................... 9 
3.3 
 Inclusion of Women and Minorities ...................................................................................... 10 
3.4 
 Baseline evaluation ................................................................................................................ 10 
3.5 
 REGISTRATION PROCEDURES ............................................................................................ 10 
4. 
TREATMENT PLAN ........................................................................................................................... 10 
4.1 
 AZD2171-Prednisone Administration ................................................................................... 10 
4.2 
 General Concomitant Medication and Supportive Care Guidelines ................................ 101 
4.3 
 Duration of Therapy ................................................................................................................ 12 
4.4         Follow-up Criteria ................................................................................................................... 12 
4.5         Off-Study Criteria .................................................................................................................... 12 
5. 
DOSING DELAYS/DOSE MODIFICATIONS ..................................................................................... 12 
5.1 
 Management of Hypertension ................................................................................................ 13 
6. 
ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS .................................................. 17 
6.1      Comprehensive Adverse Events and Potential Risks List (CAEPR) .................................... 18 
6.2      Expedited Adverse Event Reporting to Sponsor .................................................................... 20 
6.3      NCI-IRB Expedited Adverse Event Reporting Requirements: ............................................... 22 
6.4      NCI-IRB Requirements for PI Reporting of Expected and Unexpected Adverse Events         
          at Continuing Review ................................................................................................................. 22 
6.5      Routine Adverse Event Reporting ............................................................................................ 22 
6.6      Secondary AML/MDS ................................................................................................................. 22 
7. 
PHARMACEUTICAL INFORMATION ............................................................................................... 23 
8. 
CORRELATIVE/SPECIAL STUDIES ................................................................................................. 25 
8.1 
Tissue Studies .......................................................................................................................... 25 
8.2 
Imaging Studies ....................................................................................................................... 28 
8.3        Assessment of the pharmacokinetic parameters of AZD2171 ............................................ 30 
9. 
STUDY CALENDAR .......................................................................................................................... 31 
10. 
MEASUREMENT OF EFFECT ...................................................................................................... 32 
10.1 
Definitions ................................................................................................................................ 32 
10.2 
Guidelines for Evaluation of Measurable Disease ................................................................ 32 
10.3 
Response Criteria .................................................................................................................... 33 


iv
10.4 
Confirmatory Measurement/Duration of Response .............................................................. 34 
10.6 
Progression-Free Survival ...................................................................................................... 35 
11. 
DATA REPORTING / REGULATORY CONSIDERATIONS ......................................................... 35 
11.1 
Data Reporting ......................................................................................................................... 35 
11.2 
CTEP Multicenter Guidelines .................................................................................................. 35 
11.3 
Cooperative Research and Development Agreement (CRADA)/Clinical   Trials Agreement 
(CTA) ......................................................................................................................................... 36 
11.4    Data and Safety Monitoring Plan .............................................................................................. 37 
12. 
STATISTICAL CONSIDERATIONS .............................................................................................. 37 
12.1 
Sample Size/Accrual Rate ....................................................................................................... 38 
12.2 
Stratification Factors ............................................................................................................... 38 
12.3 
Analysis of Secondary Endpoints .......................................................................................... 38 
    12.4     Reporting and Exclusions………..……………………………………………………
38
12.5 
Statistical Analysis with prednison ........................................................................................ 38 
13. 
HUMAN SUBJECTS PROTECTIONS ........................................................................................... 39 
13.1 
Rationale for subject selection ............................................................................................... 39 
13.2 
Evaluation of benefits and risks/discomforts ....................................................................... 39 
13.3 
Consent process ...................................................................................................................... 39 
13.4 
Patient Records and Quality Assurance ................................................................................ 39 
APPENDIX A ............................................................................................................................................... 41 
Performance Status Criteria ................................................................................................................ 41 
APPENDIX B .............................................................................................................................................. 42 
PATIENT’S PILL DIARY ........................................................................................................................ 42 
APPENDIX C ............................................................................................................................................... 43 
PATIENT’S BLOOD PRESSURE DIARY .............................................................................................. 43 
REFERENCES ............................................................................................................................................ 44 
 
 
 
 
 


1
1. OBJECTIVES 
 
1.1. Primary 
The primary objective of this study is to determine if AZD2171 is associated with a 30% 6 month 
probability of progression free survival in patients with metastatic AIPC as determined by clinical and 
radiographic criteria.  
 
1.2.     Secondary  
1.2.1 
Measurement of overall response rate and overall survival. Response and progression will be 
evaluated in this study using the new international criteria proposed by the Response Evaluation 
Criteria in Solid Tumors (RECIST) Committee. 
1.2.2 
Document survival from the point of PSA progression in the absence of radiologic or clinical 
progression.  
1.2.3 
Demonstration of biologic effect by AZD2171 in the patient and on the tumor (when possible) via 
correlative studies will be conducted on serially obtained tissue biopsies, and dynamic contrast 
enhanced-magnetic resonance imaging (DCE-MRI).  Laboratory correlates will include 
determining serum and tissue concentrations of Vascular Endothelial Growth Factor Receptor 
(VEGFR) as well as tissue microvessel density count.   
1.2.4 
Measurement of the pharmacokinetics of AZD2171 in human patients with prostate cancer. 
1.2.5 
Description of the prostate specific antigen (PSA) response rate to therapy with AZD2171 
 
 
2. BACKGROUND 
 
2.1  
Androgen-independent Prostate Cancer 
Prostate adenocarcinoma is the most common malignancy in American men and the second leading 
cause of cancer related deaths (Rini 2002; Jemal 2003).  According to the SEER database, 42% of 
patients have either metastatic disease or will eventually progress following local therapy. Whereas 
androgen ablation therapy is an effective initial modality in patients with metastatic disease, androgen 
independence and progression of disease eventually occurs in all. (Goktas 1999; Klotz 2000).  The 
utilization of second line hormonal agents is generally associated with low response rates, and has no 
documented survival benefit. Data from previous trials of NCI patients with similar eligibility requirements 
demonstrated a 2.1 month median progression free survival when using thalidomide (n=63) (Figg 2001). 
 Median progression free survival on ketoconazole alone is expected to be 4 months based on previous 
trials (Oh 2002; Figg 2005). 
 
Chemotherapies have been extensively evaluated in patients with metastatic androgen independent 
prostate cancer (AIPC) since the 1970s.  The initial studies showed low response rates and high 
toxicities.  Recently, however, with the development of new agents targeting prostate cancer both on the 
cellular and molecular level, promising results have been emerging. The agents, including docetaxel, 
mitoxantrone, estramustine, vinblastine and etoposide, either as a single agent or as a combination 
therapy, have produced significant PSA responses in 30-80% of patients with median progression free 
survival of 3-5 months (Beedassy 1999). Recently, two regimens containing docetaxel and either 
prednisone or estramustine have shown to have a significant increase in overall survival when 
compared to standard mitoxantrone/prednisone (Petrylak 2004; Tannock 2004). There is no standard 
therapy for patients who have progressed following docetaxel therapy. Plasma VEGF levels are 
significantly higher in patients with AIPC than in those with localized disease (Duque 1999); in patients 
with AIPC, elevated pretreatment plasma VEGF inversely correlates with survival (George 2001).  A 
recent study found an increasing plasma VEGF level gradient when healthy patients were compared to 
those with localized and metastatic disease (Shariat 2004). New therapeutic modalities are needed in 
patients with advanced AIPC.  Siegal demonstrated that microvessel density was higher in prostate 
cancer tissue than the adjacent hypoplastic or benign tissue (Siegal 1995).  Angiogenesis also has been 
shown to play an important role in prostate cancer progression (Sokoloff 1999, Choy 2001).  
Antiangiogenic therapy directed at the VEGF signaling axis may therefore be helpful in advanced AIPC. 
 
 
2.2  
AZD2171 


2
 
AZD2171 (NSC 732208), an orally available small molecule, is a potent inhibitor of receptor tyrosine 
kinases (RTKs) which influence a key angiogenic factor, vascular endothelial growth factor-A (VEGF).  
VEGF is implicated in tumor blood vessel formation and in disease progression in a wide range of solid 
tumor malignancies.  Expression of this factor is increased by diverse stimuli which include proto-
oncogene activation and hypoxia, with the hypoxic state frequently occurring in solid tumors because of 
inadequate perfusion.  In addition to its angiogenic role, VEGF also profoundly increases the 
permeability of the vasculature and thereby potentially contributes to tumor progression – a leaky tumor 
endothelium enhances nutrient and catabolite exchange and represents less of a barrier to tumor cell 
migration during metastasis.  With the goal of suppressing neovascularization and thus inhibiting tumor 
growth and metastasis, numerous antiangiogenic agents have been developed.  In contrast to many of 
these intravenously-administered antiangiogenic agents, a recently emerging class of novel orally-
administered VEGF TK inhibitors including AZD2171 has been developed (Hennequin 1999; Wedge 
2000, 2002).   
 
Two high-affinity receptors for VEGF with associated TK activity have been identified on human vascular 
endothelium, KDR (kinase insert domain-containing receptor = VEGFR2) and Flt-1 (fms-like tyrosine 
kinase 1 = VEGFR1).  Although the relative contributions of KDR and Flt-1 signaling in mediating tumor 
progression have not been elucidated, a number of studies suggest that KDR performs a predominant 
role.  AZD2171 is a potent inhibitor of both KDR (IC50 <0.002 microM) and Flt-1 (IC50 = 0.005 microM) 
and shows activity versus c-kit, platelet-derived growth factor receptor beta (PDGFRȕ),ѽ and Flt-4 at 
nanomolar concentrations, but is selective against other serine/threonine kinases studied.  It has been 
shown that AZD2171 potently and selectively inhibits VEGF-stimulated human umbilical cord vascular 
endothelial cell (HUVEC) proliferation with an IC50 of 4 nM (Ogilvie 2004).  These authors have also 
demonstrated the agent’s profound inhibitory effect on vessel area, length, and branching at 
subnanomolar concentrations using a modified fibroblast/endothelial cell co-culture system.  AZD2171’s 
effects on hemodynamic parameters have been studied in an athymic rat xenograft model of human 
colorectal carcinoma (SW620) using perfusion-permeability dynamic contrast-enhanced magnetic 
resonance imaging (pp-DCE-MRI) (Bradley 2004).  This method clearly demonstrated that in this model, 
AZD2171 significantly reduced vascular permeability by 80% (P<0.005) and vascular volume by 68% 
(P<0.05). 
 
Nonclinical Efficacy 
The effect of AZD2171 was studied in athymic nu/nu mice bearing established subcutaneous human 
tumor xenografts of diverse histologies [SW620 (colon), PC-3 (prostate), Calu-6 (lung), SKOV-3 
(ovarian), and MDA-MB-231 (breast)]  (Wedge 2005).  Animals were administered AZD2171 orally (PO) 
at doses from 0.75 to 6 mg/kg/day (2.25-18 mg/m2/day) in a constant volume of 0.1 mL/10 g body weight 
for 24-28 days.  AZD2171 produced a statistically significant inhibition of tumor growth in all human 
tumor types examined when dosed at 1.5 mg/kg/day (4.5 mg/m2/day) or higher (Wedge 2005).   
 
Angiogenesis and VEGF signaling play central roles in endochondral ossification.  AZD2171 cased a 
dose-dependent increase in the hypertrophic chondrocyte zone of the epiphyseal growth plates in 
growing rats when dosed for 28 days. The effect was reversed upon withholding AZD2171. These 
results are consistent with the drug’s ability to inhibit VEGF signaling and angiogenesis in this model 
(Wedge 2005). 
 
The murine renal cell carcinoma (RENCA) model, which rapidly (generally within 10 days) metastasizes 
to the lung and abdominal lymph nodes, has also been used for AZD2171 efficacy studies (Drevs 2004). 
 In experiments incorporating a vehicle control, AZD2171 (at a dose of 6.3 mg/kg/day PO) reduced 
primary tumor growth, metastasis, and microvessel density more potently than any other previously-
studied VEGF RTK inhibitor reported in the literature. 
 
Using a transgenic mouse model in which multiple mammary tumors spontaneously develop after two 
pregnancies, investigators studied the temporal effects of AZD2171 administration (Klinowska 2004).  
When dosed with AZD2171 (0.75 to 6 mg/kg/day PO) at the time early lesions start to develop, the 
number of tumor foci was not affected, but their growth was inhibited.  When tumors were well 
established before AZD2171 was given (at doses of 3 and 6 mg/kg/day), dose-dependent growth 
inhibition occurred as well as tumor regression. 
 
In another model, athymic nu/nu mice bearing human MCF-7 breast cancer xenografts were exposed to 
AZD2171.  In this model, drug administration resulted in significant inhibition of tumor growth. This 


3
inhibition was at least partially dependent on VEGF expression, as the drug effect was transient in 
tumors expressing VEGF (Miller 2006). 
 
 
Nonclinical Pharmacology and Toxicology 
Nonclinical pharmacology and toxicology company-sponsored AZD2171 studies have been conducted 
in rats, dogs, and cynomolgus monkeys.  In rats and dogs, oral bioavailability is high, but absorption is 
relatively slow, with peak plasma concentration (Cmax) of the agent seen 4-6 hours after PO dosing.  
Plasma concentrations and exposure are generally linear over the dose ranges studied in rats.  
AZD2171 is excreted in the feces (>70% of the dose) of rats, dogs, and cynomolgus monkey after both 
PO and intravenous administration.   Fecal excretion was the predominant route of elimination (>70% of 
the dose) in both rat, dog and cynomolgus monkey after both oral and intravenous administration.  
Elimination was rapid in rats and monkeys with over 75% of the dose being recovered in the first 
48 hours; in dogs excretion was slightly slower but again substantially complete by 7 days. 
 
Over the dose ranges examined in the rat, plasma concentrations and exposure generally increased in 
proportion to dose; however, in monkeys, plasma AZD2171 concentration-time profiles obtained 
following a single oral dose indicated that systemic exposure increased in a greater than dose-
proportional manner over the dose range 0.05 to 2.5 mg/kg. 
 
Protein binding of AZD2171 (90 to 95%) was relatively high across all species examined and was 
independent of concentration (range: 0.03 to 10 mcg/mL) and gender.  AZD2171 was approximately 
95% bound to human plasma proteins, with human serum albumin and Į1-acid glycoprotein accounting 
for most of this binding.   
 
VEGF has three major biological activities in endothelial cells of rats and primates of the age groups 
used in the nonclinical studies.  It is an important angiogenic factor, a potent physiological mediator of 
vascular tone (specifically of vasodilation), and a potent modulator of capillary permeability inducing 
endothelial cell fenestrations.  VEGF receptor inhibition was therefore considered to be the cause of 
many of the pathophysiological changes encountered. 
 
Vascular (myocarditis, choroid plexus) and renal (glomerulosclerosis and tubular degeneration) 
pathologies have been seen in rat, dog, and primate dosed with AZD2171 which are considered to be 
consistent with lesions induced by hypertension, although a direct effect by AZD2171 on these tissues 
cannot be excluded.  Pathological findings were also seen in the adrenal glands (degenerative cortical 
changes), pancreas (acinar epithelial cell necrosis), thyroid (follicular epithelial cell atrophy), liver 
(hepatocyte necrosis), and biliary system (cholangitis and bile duct proliferation and bile duct cholangitis) 
of the rat.  In addition in the primate, changes were seen in the gallbladder (mucosal hypertrophy) and 
bile duct (hyperplasia/hypertrophy). 
 
AZD2171 did not induce rat hepatic microsomal P450 activity but caused a 40 to 60% reduction in 
CYP1A activity at the 2.5 mg/kg dose level.  Inhibition studies in vitro using human hepatic microsomal 
protein gave IC50 values for AZD2171 against CYP2D6, CYP3A4 testosterone, and CYP3A4 midazolam 
of 32.9, 16.2, and 21.4 mcg/mL, respectively.  For CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, 
and CYP2E1, the IC50 values were outside the concentration range of AZD2171 examined.  As the 
clinically relevant plasma concentration of AZD2171 has not yet been determined, any possible effect on 
compound clearance and drug interaction is currently unknown.  
 
 
Clinical Studies 
The safety, tolerability, efficacy, and pharmacokinetics (PK) of AZD2171 are currently being evaluated in 
three phase 1 monotherapy studies in patients with solid tumors and metastatic liver disease (Study 
2171IL/0001), in relapsed or refractory acute myeloid leukemia (Study 2171IL/0002), and in elderly 
patients with metastatic prostate adenocarcinoma (Study 2171IL/0003). In addition, an ongoing 
company-sponsored phase 1 study is currently assessing the safety and tolerability of AZD2171 in 
combination with gefitinib (IRESSA) in patients with advanced cancer (Study 2171IL0004). 
 
In Study 2171IL/0001, patients have received AZD2171 at doses ranging from 0.5 to 60 mg.  Patient 
cohorts receive a single dose of AZD2171 followed by a 7-day washout period then start a 28-day cycle 
of daily doses of the agent at the same dose level they received initially.  The company reports that 
preliminary safety data from this study show that AZD2171 appears to be well tolerated at doses up to 


4
and including 45 mg/day.  The 60 mg dose of AZD2171 appears to be less well tolerated and is 
associated with increased adverse events, dose interruptions, and increases in serum thyroid 
stimulating hormone (TSH).  The most frequently reported adverse events (AEs) in Study 2171IL/0001 
were fatigue (13/36 [36%]), nausea (13/36 [36%]), diarrhea (10/36 [28%]), and vomiting (10/36 [28%]).  
Three serious adverse events (SAEs) including an abnormal liver function test, hypertension, and 
hypoglycemia were considered to be related to AZD2171.  The company reported that the patients 
reporting the incidences of hypertension and hypoglycemia recovered, while the patient with an 
abnormal liver function test improved while on trial.  Increases in mean arterial blood pressure (MAP) 
were observed for at least one time point in several patients across all of the AZD2171 doses studied.  
No clinically relevant changes in electrocardiogram parameters, heart rate, or laboratory parameters 
have been observed.  The company reports that while only limited and preliminary safety data are 
currently available from the other three studies, those data also suggest that AZD2171 is well tolerated. 
 
Preliminary AZD2171 PK data from two ongoing phase 1 clinical studies (Study 2171IL/0001 and 
2171IL/0003) have established that following a single dose, AZD2171 is orally available with Cmax 
ranging from 1 to 8 hours post dosing.  Concentrations declined in an apparent bi-exponential manner 
thereafter with a t½lz ranging from 12.5 to 35.4 hours.  Steady-state plasma concentrations were 
predicted by the single dose PK with the grand arithmetic mean temporal change parameter value being 
1.07.  This observation supports the concept that there are no time-dependent PK changes.  Dose 
proportionate increases in Cmax, Cmax,ss, AUC, and AUCss provide no evidence to reject linear PK for 
single and multiple AZD2171 doses ranging from 0.5 to 60 mg.  The PK profile of AZD2171 supports 
once-daily oral dosing. 
 
The metabolism of AZD2171 is not fully clear.  It appears to be metabolized slowly and to a limited 
extent in microsomes.  However, radiolabeled AZD2171 was metabolized by hepatocytes by a number 
of species to several metabolites.  Isozymes involved have not been fully identified.  AZD2171 has 
shown no inhibition of CYP1A2, CYP2A6, CYP2C8, CYP2C9, CYP2C19, and CYP2E1.  One 
experiment showed a 40-60% reduction in CYP1A1 activity in animals.   
 
Initial assessments from the ongoing phase 1 study in patients with solid tumors and metastatic liver 
disease (Study 2171IL/0001) have produced encouraging indications of potential biological efficacy in 
the patient population studied.  Reductions in blood flow in hepatic metastases have been detected by 
dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), and initial biomarker assessments 
(VEGF and VEGF-R2) have been encouraging.  In addition, the company reports that one ovarian 
cancer patient had a minor-partial response in lung and liver metastases, while a colorectal cancer 
patient had a minor response.   
 
A phase I study of AZD2171 in 24 patients with hormone-refractory prostate cancer was recently 
reported (Ryan 2006).  Doses d 10 mg caused only mild, CTCAE Grade 1 and 2 adverse events (AEs) 
were fatigue, anorexia, and nausea.   In cohorts receiving 20 and 30 mg, grade 3 AEs considered to be 
possibly drug-related were hypertension (n = 2), fatigue, muscular weakness, myalgia, and transient 
ischemic attack (n = 1 each). PK data supported once-daily dosing, with a mean effective half-life of 
about 20 hours.  One patient in the 20 mg cohort had a PSA decline of 30% from baseline; PSA fell > 
50% from baseline in a second patient in the same cohort with resolution of adenopathy for > 6 months 
without further antitumor therapy.  The authors conclude that AZD2171 is well-tolerated in doses d 20 
mg/day in this patient population, and that PSA changes and off-study objective response suggests 
further investigation of treatment of this patient population with AZD2171 is warranted (Ryan 2006). 
 
Based on evidence from animal data with AZD2171 (vascular and renal pathology) and results in the 
ongoing phase 1 clinical studies, it is possible that the agent will produce hypertension in man.  Because 
hypertension seen in animals has been abrogated by nifedipine, the change is thought to be 
mechanistically related to inhibition of VEGF signaling, although a direct toxicologic effect on the blood 
vessels and kidneys cannot be ruled out.  The potential for hypertensive changes following AZD2171 
administration is additionally supported by evidence from use of other antiangiogenic agents in the clinic. 
 For these reasons, patients should be monitored frequently for changes in blood pressure and renal 
function (blood urea nitrogen, creatinine, and urinary protein).  The potential for myocardial injury 
indicates that patient levels of troponin T or troponin I should also be measured. 
 
Certain physiologic processes other than endothelial cell growth are dependent on VEGF signaling, so 
inhibition of that growth factor may have implications for use of AZD2171 in selected patient populations. 


5
 Pediatric studies with AZD2171 should be undertaken with caution because the agent increases the 
zone of hypertrophy in the epiphyseal growth plates thus preventing ossification during long bone 
growth.  AZD2171 interferes with normal reproductive processes and completely prevents fetal 
development in rats at a dose of 2.5 mg/kg/day.  For this reason, women of childbearing potential should 
have a negative pregnancy test before treatment with AZD2171 is initiated.   In rat studies, AZD2171 
significantly inhibited endochondral ossification and corpora lutea formation (Wedge 2004).  
 
Reversible Posterior Leukoencephalopathy Syndrome (RPLS) or similar leukoencephalopathy 
syndrome: RPLS or clinical syndromes related to vasogenic edema of the white matter have been rarely 
reported in association with AZD2171 therapy (<3%).  Clinical presentations are variable and may 
include altered mental status, seizure and cortical visual deficit. Hypertension is a common risk factor 
and was present in most (though not all) patients on cediranib who developed RPLS.  MRI scans are 
key to diagnosis and typically demonstrate vasogenic edema (hyperintensity in T2 and FLAIR images 
and hypointensity in T1 images) predominantly in the white matter of the posterior parietal and occipital 
lobes' less frequently, the anterior distributions and the gray matter may also be involved.  RPLS should 
be in the differential diagnosis in patients presenting with unexplained mental status change, visual 
distrubance, seizure or other CNS findings. RPLS is potentially reversible, but timel correction of the 
underlying causes, including control of blood pressure and interruption of the offending drug, 
is important in order to prevent progression to irreversible tissue damage. 
 
Clinical Experience with Prednisone 
 
As of June 2008, there have been 28 patients treated on this protocol. There have been several signs 
that the drug has tumor activity. To date, the event free survival at 6 months has been 38% which has 
exceeded our initial goal of 30% with tumor shrinkage in several patients. Although the current results 
have been exciting, the limiting factor for the AZD-2171 appears to be constitutional side effects (fatigue, 
weight loss, anorexia) which have occurred as at least a Grade 2 toxicity in 19 of 28 patients.  There 
have been a total of 10 dose reductions of which 40% have been for fatigue, weakness or weight loss. 
These side effects are similar to that seen in other AZD-2171 protocols in other solid tumors (verbal 
communication at AZD-2171 Investigator meeting and with Dr Percy Ivy, CTEP). In addition, Ryan et al. 
found similar dose limiting toxicities in the Phase 1 trial in prostate cancer that established the current 
dose. The prostate dose of 20 mg/day is lower than is used in many other trials, thus maintaining this 
relatively low dose may be important. 
In prostate cancer, prednisone has been used as a complimentary treatment to therapies such as 
docetaxel and mitoxantrone. In addition, a trial combining prednisone with docetaxel and AZD-2171 in 
metastatic prostate cancer is currently ongoing. In discussions with Dr. Ivy and other investigators it 
appears that low dose corticosteroids can potentially decrease the constitutional symptoms associated 
with this agent (although the mechanism remains cryptogenic). In our current trial, we have anecdotal 
evidence that prednisone can lead to the improvement of symptoms. There have been 4 patients that 
have been treated to date with prednisone for clinical symptoms. The four patients are briefly described 
below: 
 
Patient 1 
70 y/o male with CRPC with metastatic disease in bone and soft tissue who began to have worsening 
symptoms of fatigue during cycle 1 about 2-3 weeks after initiating therapy. The patient was on 
prednisone prior to this for his docetaxel and prednisone (10 mg) chemotherapeutic regimen. He was 
tapered over approximately 2-3 weeks. His fatigue gradually worsened till he was not able to continue 
with some of his ADL’s. He was then started on prednisone 10 mg per day. AZD-2171 was not held. 
After the prednisone his activity level and fatigue began to improve within 24 hours.  
 
Patient 2 
73 y/o male with CRPC with metastatic disease in bone and soft tissue who began to have worsening 
symptoms of fatigue and weight loss during cycle 16 who was doing well prior to that. The patient 
indicated that he had loss of appetite. He stated that his activities had begun to decrease and most 
recently he was unable to continue with work. It was decided to hold AZD-2171 and begin the patient on 
prednisone 10 mg per day for 7 days. The patient by the third day was eating much better, restarted to 
work and continued his yard work. The patient was restarted on AZD-2171 at a reduced dose and did 
well during the rest of his therapy. 
 
Patient 3 
59 y/o male with CRPC with metastatic disease to bone and soft tissue who experienced worsening 


6
fatigue after cycle 1 which resulted in delay of cycle 2. The patient also was given 7 days of prednisone 
10 mg per day. The patient reported that after 3 days he had improvement in his symptoms but 
developed symptoms of UTI. The prednisone was discontinued after 5 dyas of therapy and the patient 
was given antibiotics. The patient restarted AZD-2171. He continued on therapy to be taken off therapy 
due to clinical deterioration from a ureteral obstruction. 
 
Patient 4 
72 y/o male with CRPC with metastatic disease to bone and soft tissue who experienced worsening 
fatigue after cycle 2 and decreased in appetite that began to interfere with his quality of life. The patient 
was given prednisone 10 mg for 7 weeks concurrently with his AZD-2171. The patient did indicate that 
during his 7 days that he did have some improvement in his symptoms. The patient eventually due to 
symptoms withdrew himself from the study.  
 
As mentioned three of the patients appeared to have benefit from the prednisone and one patient 
appeared to have adrenocorticol insufficiency although a cortisol level was not drawn. Our experiences 
with these patients have led us to further explore the potential to use prednisone in combination with 
AZD. The drug has biologic activity and appears to be limited mainly due to side effects which have 
been observed in other trials using the same agent.  
 
 
2.3  
Rationale 
 
In 1971, Dr. Folkman proposed that angiogenesis is important for tumor progression (Folkman 1971). 
He has gone on to hypothesize that angiogenesis plays an important role in determining the possibility 
of metastasis and patient prognosis (Folkman 1995).  His group has put forward the idea of an 
“angiogenic switch” that is required to “turn on” angiogenesis in the tumor.  Basic fibroblast growth factor 
(bFGF), vascular endothelial growth factor (VEGF) and tumor necrosis factorD (TNF-D) are among the 
most important angiogenic proteins found in tumors (Folkman 1995).  Malignant cells can alter 
endogenous angiogenic pathways and retard antiangiogenic factors, thus providing an imbalance in 
blood vessel formation (Nicholson 2004).  VEGF has been shown to be upregulated in new blood vessel 
formation, although the exact mechanism by which this occurs remains a mystery (Nicholson 2004).  
VEGF121, VEGF165, and VEGF189 are the three most commonly found isoforms of VEGF that are 
secreted.  VEGF121 is found most often in circulation, whereas VEGF165 is found in malignant cells and 
the extracellular matrix and VEGF189 is located within the extracellular matrix exclusively (Nicholson 
2004).  Mutations in the tumor suppressors p53, a ubiquitous tumor suppressor gene, and PTEN, which 
is found in a minority of prostate cancer patients, have been correlated to VEGF over-expression 
(Nicholson 2004). 
 
In order to elucidate its effects on cell proliferation, VEGF must bind to a receptor.  There have been at 
least three VEGF receptors (VEGF R) reported to date; VEGF R1 (Flt-1), VEGF R2 (Flk-1/KDR) and 
VEGF R3 (Flt-4) (Chevalier 2002).  It has been reported that all three VEGF isoforms, in addition to 
VEGF R1 and R2 have been detected in Dunning tumors, when grown in Copenhagen and Copenhagen 
x Fisher rats (Haggstrom 2000).  VEGF expression was highest in the AT-3 subline of the Dunning 
tumor, which is the most metastatic subline (Haggstrom 2000).  There was a statistically relevant 
correlation between VEGF concentration and microvessel density (MVD) (p<0.05) (Toi 1995; Haggstrom 
2000; Seo 2000; Straume 2001).  Balbay and coworkers reported increased VEGF expression in a 
highly metastatic variant of LNCaP cells, when compared to normal LNCaPs or slightly metastatic 
LNCaPs (Balbay 1999).  They also reported that the LNCaP-LN3 cells had a statistically higher MVD 
and Flt-1 expression than the less metastatic forms of LNCaP (Balbay 1999).  Hahn and colleagues 
reported on the expression of Flt-1 in various human prostatic tissues (Hahn 2000).  This group reported 
that Flt-1 was expressed by endothelial cells from benign, premalignant and malignant prostate tissues, 
which was confirmed by Kollermann and Helpap (Kollermann 2001).  Hahn showed that there was a 
progressive loss of Flt-1 expression as the tissue decreased in differentiation, from normal to malignant, 
within the same patient biopsy samples (Hahn 2000).  The reasons for decreasing Flt-1 expression as 
the cells dedifferentiate are not fully understood, but a theory could be that as the malignant 
transformation occurs, Flt-1-mediated signaling is progressively turned off.   
 
Data has been presented that suggests angiogenesis is a crucial step in the progression of prostate 
cancer from early to advanced disease (Sokoloff 1999; Choy 2001).  Microvessel density is an indicator 
of biological aggressiveness and metastatic potential in many primary tumors (Weidner 1993).  
Interruption of this process would halt the progression of cancers that are dependent upon angiogenesis 


7
for advancing pathology by eliminating their potential for growth.  Inhibition of angiogenesis is expected 
to augment the effects of other therapies such as chemotherapy or radiation by limiting the tumor to a 
dormant state of low metastatic potential (McNamara 1998).  Prostate cancer progression from primary 
neoplasia to advanced disease requires the acquisition of microcirculation to support the developing 
neoplastic mass (Izawa 2001). Hypoxia induces angiogenesis and HIF-1D.  HIF-1D activates genes 
regulating cell growth, vascular remodeling, and cell survival (Siegal 1995; Bergers 2003).  
Immunohistochemical analysis of specimen from high-grade prostate intraepithelial neoplasia shows 
HIF-1D upregulation compared with normal epithelium, stromal cells, and benign prostatic hyperplasia 
(BPH) tissue samples (Zhong 2004). HIF-1D has been shown to induce VEGF up-regulation in LNCaP 
cells (Mabjeesh 2003) and hypoxia induces VEGF in human prostate cancer (Cvetkovic 2001).  VEGF 
has been associated with progression to a malignant phenotype in prostate cancer (Soker 2001).  The 
dependence of prostate tumors on androgens for induction of tumor growth and metastasis is unique to 
this cancer (Choy 2001).  Androgens have been implicated in the induction of VEGF expression, 
supporting the hypothesis that androgen ablation affects prostate tumors at least in part through 
inhibition of angiogenesis (Choy 2001).   
 
A growing body of literature implicates VEGF as a tumor promoter, and VEGF R3 over expression is 
related to lymphangitic spread of prostate cancer (Li 2004; Lissbrant 2004; Zeng 2004).  Biopsy samples 
from 640 patients, including normal prostate, benign prostatic hyperplasia (BPH) and prostate cancer, 
were analyzed by microarray (Li 2004).  VEGF R3 was expressed in all three tissue types, but 
expressed to a greater extent in prostate cancer.  VEGF R3 expression was also correlated to pre-
operative PSA, Gleason score and the possibility of lymph node metastasis (Li 2004).  Patients with 
lower VEGF R3 expression had a better 5-year overall survival (77.3% vs 69.6%, p=0.037).  Li’s paper 
suggests that increased VEGF R3 expression results in higher incidence of aggressive disease and a 
poorer overall survival (Li 2004).  Zeng and colleagues confirmed that expression of VEGF R3 is 
associated with advanced disease, lymph node metastasis, extracapsular extension, and surgical 
margin status (Zeng 2004).  Lissbrant showed that, while inhibiting VEGF receptors resulted in a 
decreased epithelial cell proliferation when testosterone was reintroduced into castrated mice, the tumor 
was still able to respond to testosterone(Lissbrant 2004). 
 
Vascular endothelial growth factor and its receptors appear as a likely therapeutic target in the treatment 
of cancer.  The Food and Drug Administration (FDA) recently approved the first anti-VEGF compound, 
bevacizumab.  Bevacizumab is a humanized monoclonal antibody that binds VEGF and prevents it from 
attaching to the VEGF receptor (Zondor 2004).  Bevacizumab binds all isoforms of VEGF and blocks 
tumor growth in xenografts (Zondor 2004). Currently, at least three small molecule agents are in various 
stages of development, which act by antagonizing the VEGF receptor.  CEP-7055, a pan-VEGFR 
inhibitor, has shown activity in a variety of preclinical tumor models (Ruggeri 2003). CEP-7055 showed a 
dose-dependent reduction in neovascularization, when tested in the rat aorta assay and the HUVEC 
assay.  In LNCaP cells tested in nude mice, there was a decrease in the metastatic potential as well as 
significant antitumor activity (Ruggeri 2003).  ZD6474, a KDR tyrosine kinase inhibitor, has been shown 
to decrease tumor vascular permeability on dynamic contrast-enhanced magnetic resonance imaging 
(DCE-MRI) (Checkley 2003). 
 
AZD2171 has been shown to inhibit VEGF signaling by inhibiting KDR and Flt-1 kinase activity 
(Hennequin 2004; Ogilvie 2004; Wedge 2004).  This compound, when tested in athymic mice with 
various tumor xenografts, showed a dose-dependent inhibition of tumor growth in each model (Ogilvie 
2004).  When tested in murine renal cell carcinoma model (RENCA), primary tumor volume was reduced 
by 58% and primary tumor vessel density by 70%, after 10 days of therapy (Drevs 2004).  Preliminary 
pharmacokinetic and safety analysis shows AZD2171 can be safely administered once-daily (Medinger 
2004).  AZD2171 was well tolerated up to 10mg daily, with a terminal half-life of 20 hours, following 
linear pharmacokinetics (Medinger 2004).   
 
Parallel observations with respect to molecular determinants of angiogenesis in prostate and other 
cancers suggest that antiangiogenic therapeutic strategies are relevant to prostate cancer.  
Antiangiogenic agents have demonstrated efficacy in the treatment of prostate cancer in various clinical 
trials (Macpherson 2002).  Based on the knowledge that prostate cancer proliferation and progression is 
directly related to VEGF expression, and that MVD and VEGFR expression denotes more advanced 
disease, as well as the fact that AZD2171 has been shown to antagonize the VEGF R1 and VEGF R2 
receptors, it is with great interest that we wish to study this drug in patients with androgen-independent 
prostate cancer. 
 


8
The Genitourinary Clinical Research Section has had a long history of success in developing 
antiangiogenic compounds for use in treating advanced stage adenocarcinoma of the prostate.  
Beginning with 92-C-0265, combining aminoglutithimide with suramin, and high-dose ketoconazole in 
combination with alendronate, through a phase II trial evaluating thalidomide alone and in combination 
with docetaxel, hundreds of patients have benefited from the unique trials designed by our group.  More 
recently, we have begun studying small-molecule inhibitors including sorafenib, which may provide 
additional benefit to this patient population. It has become increasingly clear that PSA decline rates of 
50% alone may not be adequate to asses activity with many of these agents. In an exploratory fashion, 
we have incorporated time to progression as the primary endpoint in trials of small molecules.  Although 
time to progression can be problematic in single-arm phase II trials, the objective nature of PSA 
eliminates a significant portion of investigator bias.  
 
In a study presented at this year’s ASCO, a randomized phase II trial studied patients with 
taxane-resistent androgen-independent prostate cancer treated with prednisone and irofulven, a 
novel DNA binding agent and a semisynthetic derivative of the natural product illudin S, in the 
presence or absence of capecitabine.  When compared with a control arm treated with 
mitoxantrone and prednisone, both experimental arms demonstrated a median time to 
progression (TTP) of 2.1 months, compared with a 1.1 month TTP in the control arm. (Hart 
2006) 
In a large unpublished study provided to CTEP by the Memorial Sloan Kettering Cancer Center, 10% of 
patients experienced a progression free survival of 6 months. (Ivy 2006) 
 
3. PATIENT SELECTION 
 
3.1  
Eligibility Criteria 
 
3.1.1 
Patients must have histopathological confirmation of prostate cancer by the Laboratory of 
Pathology of the NCI, Pathology Department of the National Naval Medical Center or 
Pathology Department of Walter Reed Army Medical Center prior to entering this study.  
Patients whose pathology specimens are no longer available may be enrolled in the trial if 
the patient has a clinical course consistent with prostate cancer and available 
documentation from an outside pathology laboratory of the diagnosis.  In cases where 
original tissue blocks or archival biopsy material is available, all efforts should be made to 
have the material forwarded to the research team for use in correlative studies. 
 
3.1.2   Patients must have metastatic progressive androgen-independent prostate cancer.  There 
must be radiographic evidence of disease that has continued to progress despite hormonal 
agents.  Progression requires that a measurable lesion is expanding, new lesions have 
appeared, and/or that PSA is continuing to rise on successive measurements.  Patients on 
flutamide must have disease progression at least 4 weeks after withdrawal.  Patients on 
bicalutamide or nilutamide must have progression at least 6 weeks after withdrawal.   
3.1.3 
Patients must have received prior therapy with docetaxel for androgen-independent prostate 
cancer.  Any number of prior treatments are acceptable. 
 
3.1.4 
Age >18 years  
 
3.1.5 
Life expectancy of greater than 3 months. 
 
3.1.6 
ECOG performance status < 2 (Karnofsky > 60%; see Appendix A). 
 
3.1.7 
Patients must have normal organ and marrow function as defined below: 
 
Absolute neutrophil count 
>1,500/mcL 
Platelets 
 
>100,000/mcL 
Hemoglobin > 8 g/dL 
Total bilirubin 
  1.5 x institutional upper normal institutional limits 
(unless with clinical Gilbert’s syndrome) 
AST(SGOT)/ALT(SGPT) 
d 2.5 × institutional upper limit of 
 
 
 
 
 
 
 
 
 
normal 


9
Creatinine  1.5 x 
 institutional upper normal institutional limits 
 
OR 
Creatinine clearance > 40 mL/min/1.73 m2 for patients with creatinine levels above 
institutional normal. as calculated by the Cockcroft Gault formula. 
 
3.1.8 
Patients must have recovered from any acute toxicity related to prior therapy, including 
surgery.  Toxicity should be < grade 1 or returned to baseline. 
 
3.1.9 
All patients who have not undergone bilateral surgical castration must continue suppression 
of testosterone production by appropriate usage of GnRH agonists or antagonists. 
 
3.1.10 Patients must not have other invasive malignancies (within the past three years with the 
exception of non-melanoma skin cancers or non-invasive bladder cancer). 
 
3.1.11 AZD2171 has been shown to terminate fetal development in the rat, as expected for a 
process dependent on VEGF signaling.  Enrolled patients must agree to use adequate 
contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, 
the duration of study participation and 3 months after the end of the treatment.  
 
3.1.12 Ability to understand and the willingness to sign a written informed consent document. 
 
3.1.13 Patients must have a blood pressure of <140/90 at the time of enrollment. Details of 
antihypertensive treatment, if required, will be left up to the primary care physician. 
 
3.2  
Exclusion Criteria 
 
3.2.1 
Patients who have had chemotherapy, radiotherapy, or major surgery within 4 weeks (6 
weeks for nitrosoureas or mitomycin C) prior to entering the study. 
  
3.2.2 
Patients may not be receiving any agents not approved by the FDA within the past four 
weeks. 
 
 
3.2.3 
Patients with known brain metastases should be excluded from this clinical trial because of 
their poor prognosis and because they often develop progressive neurologic dysfunction 
that would confound the evaluation of neurologic and other adverse events. 
 
3.2.4 
Mean QTc >470 msec (with Bazett’s correction) in screening electrocardiogram or history of 
familial long QT syndrome. 
 
3.2.5 
Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart. 
 
3.2.6 
Uncontrolled intercurrent illness including, but not limited to hypertension, ongoing or active 
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac 
arrhythmia, or psychiatric illness/social situations that would limit compliance with study 
requirements.  
 
3.2.7 
HIV-positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with AZD2171.   
 
3.3 
Inclusion of Women and Minorities
Men of all races and ethnic groups are eligible for this trial.  Women are excluded by the nature of 
the disease. 
  
 
3.4 
Baseline evaluation 
3.4.1 
Imaging studies (baseline – obtained within one month prior to enrollment): Technetium-99 
Bone Scintigraphy, Chest X-ray, CT scan of chest, abdomen and pelvis.
3.4.2 
Laboratory evaluation (baseline – obtained within 16 days prior to enrollment)
3.4.2.1 
Hematological profile: CBC with differential and platelet count, PT, aPTT, fibrinogen.


10
3.4.2.2 
Biochemical profile: electrolytes, BUN, creatinine, AST, ALT, total  bilirubin, calcium, 
phosphorus, albumin, magnesium, uric acid, C-reactive protein, albumin, amylase, 
lipase, testosterone level, TSH, and troponin.
3.4.2.3  Tumor marker profile: PSA (baseline – within 7 days prior to                  enrollment), acid 
phosphatase (if PSA <4ng/mL, for research               purposes only).
3.4.2.4  History and physical exam with vital signs.
3.4.3 
Cardiac evaluation (baseline – obtained within 16 days prior to enrollment)
3.4.3.1  Electrocardiogram
3.4.3.2  Laboratory evaluation – troponin
3.4.3.3  Echocardiogram
3.5 
REGISTRATION PROCEDURES 
3.5.1 
Authorized staff must register an eligible candidate with NCI Central Registration Office (CRO) 
within 24 hours of signing consent. A registration Eligibility Checklist from the web site 
(http://camp.nci.nih.gov/ccr/welcome.htm) must be completed and faxed to 301-480-0757. After 
confirmation of eligibility at Central Registration Office, CRO staff will call pharmacy to advise 
them of the acceptance of the patient on the protocol prior to the release of any investigational 
agents. Verification of Registration will be forwarded electronically via e-mail. Please note, it is 
very important for all registrars to acquire encrypted e-mail from NIH Help Desk, since the 
verification of registration includes patient’s information. A recorder is available during non-
working hours. 
3.5.2 
Off-Study Procedure: Authorized staff must notify Central Registration Office (CRO) when a 
patient is taken off-study. An off-study form from the web site 
(http://camp.nci.nih.gov/ccr/welcome.htm) main page must be completed and faxed to 301-480-
0757. 
4. TREATMENT PLAN 
4.1  
AZD2171-Prednisone Administration 
At the outset of the study, the patient may be admitted to the inpatient service for a period of 
approximately 24 hours to complete research studies including biopsies and PK measurements.  
Otherwise, treatment will be administered on an outpatient basis. Reported adverse events (AEs) 
and potential risks are described in Section 6.  Appropriate dose modifications for AZD2171 are 
described in Section 5.  No investigational or commercial agents or therapies other than those 
described below may be administered with the intent to treat the patient’s malignancy. 
 
AZD2171 is supplied in a matched series of beige film-coated tablets containing 10 mg or 15 mg of 
AZD2171 free base.  Patients are to swallow tablets to equal 20 mg without crushing with 
approximately 250ml (8 oz.) of water, once daily.  AZD2171 tablets should be taken on an empty 
stomach, 1 hour before or 2 hours after meals.  AZD2171 will be given as self-administered oral 
doses of 20 mg once daily continuously throughout the 28 day cycle.   
 
Patients will be provided with a pill diary (Appendix B), instructed in its use, and asked to bring it 
with them to each appointment.  A new copy of the Pill Diary will be given to patients whose dose is 
reduced due to adverse events. Pill counts will also be maintained be study personnel. 
 
The combination of treatment of AZD with prednisone may help to alleviate some of the 
constitutional symptoms and allow us to maintain therapeutic dosing. All patients will receive 
Prednisone 10 mg orally daily and AZD2171 20 mg orally daily. Both drugs should be taken 
together in the morning. In addition, we will also check cortisol levels in patients who are not on 
steroids at the time of enrollment. 
 
 
4.2  
General Concomitant Medication and Supportive Care Guidelines
4.2.1 
Frequent blood pressure monitoring is important in patients receiving AZD2171. Experience to date 


11
suggests that increases in blood pressure may occur following dosing with AZD2171 for a number 
of weeks and that these increases may occur relatively quickly.  Patients will be provided with a 
blood pressure monitoring device and a log in which to record their twice-daily blood pressure 
readings (Appendix C).  If two successive systolic readings are >140 mmHg OR two successive 
diastolic readings are >90 mmHg OR any combination of elevated systolic and diastolic blood 
pressure are observed, patients will be instructed to contact their physician as soon as possible.  
Patients should seek medical advice if their BP exceeds 180 mmHg (systolic) or 105 mmHg 
(diastolic) at any time and should also be encouraged to contact their physician if they are 
concerned about any symptoms that may be associated with high blood pressure (e.g., headache). 
Section 5.1 includes specific guidelines on the management and, if appropriate, dose modifications 
for treatment-emergent hypertension. 
4.2.2 
Renal function (creatinine and urinary protein) should be frequently monitored as suggested by 
the pathologic changes noted in animal studies and evidence from studies of other 
antiangiogenic agents.  Patients will have a monthly chemistry panel and urinalysis. 
Management of Proteinuria 
Proteinuria Value 
Monitoring 
Dose modification 
>1+ (dipstick or equivalent 
routine laboratory analysis) 
Perform the following tests: 
x 
24-hour urine collection for total 
protein and creatinine 
x 
microscopic examination of fresh 
urine 
x 
urine protein electrophoresis (at 
first occurrence of >1+ proteinuria 
only) 
See below. 
Based on results of the 24-hour urine collection: 
 1g protein 
(24-hour collection) 
Continue dipstick or equivalent routine 
laboratory analysis 
Continue planned dose. 
> 1g but  2g protein  
(24-hour collection) 
Perform 24-hour urine collection (total 
protein, creatinine) prior to day 1 of each 
subsequent cycle of therapy (q4wk) until 
total protein is <500mg/24 hours. 
Decrease one dose level; 
continue treatment. 
> 2g protein 
(24-hour collection) 
Perform 24-hour urine collection (total 
protein, creatinine) weekly unitl proteinuria 
is <2g/24 hours. 
Hold AZD2171. 
 
When protein is < 2g/24 
hours, resume treatment at 
one lower dose level. 
Perform 24-hour urine collection (total 
protein, creatinine) prior to day 1 of each 
subsequent cycle of therapy (q4wk). 
Continue until patient is off 
study. 
 
4.2.3 
Because of the potential for myocardial injury with AZD2171, patients will undergo 
electrocardigram testing and measurement of serum of troponin levels at each clinic visit.  
4.2.4 
Because there is a potential for interaction of AZD2171 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 P450 isoenzymes; these agents/drugs should be documented along 
with any associated AEs that occur. 
4.2.5 
No premedications will be used with the initiation of therapy 


12
4.2.6 
Concurrent use of bisphosphonates will be allowed for patients with known bone metastases 
4.2.7 
Patients who require hematopoietic growth factor support (e.g. epogen, darbepoetin), NSAIDs 
and other maintenance medications prior to study entry will be allowed to continue their 
supportive therapies. 
 
 
4.3 Duration of Therapy 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of the 
following criteria applies: 
x 
Radiographic disease progression, 
x 
Intercurrent illness that prevents further administration of treatment, 
x 
Unacceptable adverse event(s), 
x 
Patient decides to withdraw from the study, or 
x 
General or specific changes in the patient’s condition render the patient unacceptable 
for further treatment in the judgment of the investigator. 
x 
Patients who meet the criteria for PSA progression (See Section 10.5) may continue on 
study unless they meet the above criteria. 
4.4 Follow-up Criteria 
All study subjects will be followed for overall survival only once active treatment has been completed 
(as indicated above). 
Follow-up will be annual telephone contact to assess survival status. Every attempt will be made to 
contact patient/subject including: contacting referring physician, contacting emergency contact 
patient identified on admission, checking SSDI (Social Security Death Index) 
All attempts will be noted in the medical record. 
4.5 Off-Study Criteria 
x 
Discretion of the principle investigator 
x 
Patient Choice 
x 
Patient Death 
 
5. DOSING DELAYS/DOSE MODIFICATIONS 
Toxicities will be described using CTCAE v3.0.  The following adjustments will only apply if the toxicities 
reported are attributed by the investigators to be related to AZD2171 therapy. 
 
AZD2171 should be held in patients with symptoms/signs suggestive of RPLS, pending work-up and 
management, including control of blood pressure.  Cediranib should be discontinued upon diagnosis of 
RPLS.  After Consultation with the principal investigator and the NCI, consideration of restarting the 
study may be evaluated in light of any clinical benefit. 
 
For Grade 1 toxicity, treatment with AZD2171 need not be interrupted.  For symptoms that last more 
than 7 days and have been found to be intolerable to the patient, the dose of AZD2171 may be reduced 
to 15mg/day. 
 
For Grade 2 toxicity 
For nausea, vomiting, and diarrhea, maintain dosing with symptomatic treatment.  The dose of 
AZD2171 may be repeated if emesis occurs within 30 minutes of taking the tablets or all the tablets 
are seen in the emesis. 
 
For persistant nausea, vomiting or diarrhea despite symptomatic treatment that remains 
unacceptable (intolerable) to the patient, reduce dose to 15 mg/day, as indicated in the table below. 
 


13
For other grade 2 toxicities, the dose does not need to be reduced unless side effects become 
intolerable to the patient. 
 
Patients with intolerable or limiting toxicity while taking 10 mg/day will be removed from study 
 
 
 
 For Grade 3 nonhematologic toxicity, or Grade 4 hematologic toxicity 
Hold AZD2171 and reevaluate the patient at least weekly until toxicity improves to < Grade 1 or pre-
treatment baseline.  Reduce dose of AZD2171 by one dose level, as indicated in the table below 
except for grade 3 hypertension (follow chart found below).  Treatment will be discontinued in 
patients who experience toxicity > grade 3 or 4 that does not resolved to < grade 1 or baseline 
within 3 weeks. Hypophosphotemia, hypokalemia, and hypomagnesimia that can be corrected 
within 48 hours to grade 2 or less will not require a dose reduction. 
 
Patients with intolerable or limiting toxicity while taking 10 mg/day will be removed from study 
 
 
 
For Grade 4 non-hematologic toxicity 
Patients who had clinical grade 4 non-hematologic toxicity (except pulmonary embolism without 
significant hypoxia and hemodynamic instability) will be taken off study permanently. 
 
Dose level 
AZD2171 Dose 
-2 
10 mg qd 
-1 
15 mg qd 
1 
20 mg qd 
 
As this trial allows patients to receive treatment indefinitely, patients may have the doses of any or all 
drugs (AZD-2171 and prednisone) temporarily withheld (maximum of 21days at which time the patient 
will be taken off study), and potentially resume treatment as long as they do not fulfill the off-study 
criteria outlined in section 4.5. 
 
 
5.1 
Management of Hypertension 
Increases in blood pressure and cases of hypertension have been associated with many drugs acting on 
the VEGF pathway.  The proposed mechanism for this increase is through inhibition of VEGF-induced 
peripheral vasodilation.  Hypertension following AZD2171 treatment has been seen in animal studies as 
well as clinical trials.  Blood pressure will be measured by a health professional at the time of enrollment, 
and at each clinic visit.  In addition, patients will be asked to monitor their blood pressure at home on a 
twice daily basis, consisting of a a morning resting blood pressure and an evening blood pressure, and 
to log blood pressure values in a blood pressure diary (Appendix C).  Patients will be asked to call their 
research nurse with any abnormal values (CTCAE v3.0 Grade 1 or above) or if they experience new 
headache or dizziness.Specific guidance for management of this AE is provided below. 
BP monitors for patients enrolled in the study may be ordered from 
Andrea R. Dickerson, MS 
AstraZeneca Pharamceuticals 
1800 Concord Pike / C2B-701 
Wilmington, DE 19850-5437 
Andrea.dickerson@astrazeneca.com 
Phone: (302) 885-9873 


14
 
Grade
(CTCAE
v3.0) 
Antihypertensive  
Therapy 
Blood Pressure 
 Monitoring 
AZD2171 Dose 
1 
None 
Consider increased 
monitoring 
No change 
2 
Initiate monotherapy 
(suggest dihydropyridine 
calcium-channel 
blocker) 
Increase frequency 
and monitor (by health 
professional) every 2 
days until stabilized. 
No change 
3 
Add agent(s): Ca++ 
channel blocker (if not 
already used), K+ 
channel opener, beta-
blocker, thiazide 
diuretic) 
Increase frequency 
and monitor (by health 
professional) every 2 
days until stabilized; 
continue q2d 
monitoring to 
stabilization after 
dosing restarted. 
Hold dose until symptoms 
resolve and diastolic BP 
<100 mm Hg.  Restart at 
same dose (investigator 
discretion). 
 
If diastolic BP not controlled to <100 mm Hg on 
therapy when dose restarted … 
Hold dose until symptoms 
resolve and diastolic BP 
<100 mm Hg.  Restart at 
next lower dose level. 
4 
Manage symptoms per 
local practice. 
Continue frequent BP 
monitoring until 
stabilization. 
Discontinue AZD2171* 
* 
If patient is considered to be benefiting from AZD2171 treatment, dosing may continue 
at the next lower dose level provided the responsible study sponsor (DCTD, NCI) 
physician concurs after discussion of the case.
 
CTCAE v3.0 hypertension grade definitions  
  
Grade 1: asymptomatic, transient (<24 hours) increase by >20 mm Hg (diastolic) or to 
>150/100 if previously WNL; intervention not indicated 
Grade 2: recurrent or persistent (>24 hours) or symptomatic increase by >20 mm Hg 
Grade 3: requiring more than one drug or more intensive therapy than previously 
Grade 4: life-threatening (e.g., hypertensive crisis) 
Notes: 
x 
While patients are receiving treatment with AZD2171, the early initiation of antihypertensive 
treatment for grade 1 or 2 hypertension to minimize more severe or persistent hypertension is 
not considered a grade 3 adverse event. 
x 
Decisions to hold or decrease the AZD2171 dose during treatment must be based on BP 
readings taken in the clinic by a medical professional. 


15
Table 1. Dihydropyridine calcium-channel blockers (DHP CCB)
 
Agent 
Initial dose 
Intermediate dose 
Maximum dose 
Hepatic metabolism 
 
Nifedipine XL 
Amlodipine
Felodipine 
 
30 mg po qd 
2.5 mg po qd 
2.5 mg po qd 
 
60 mg po qd 
5 mg po qd 
 
90 mg po qd 
10 mg po qd 
10 mg po qd 
 
CYP 3A4 substrate 
CYP 3A4 substrate 
CYP 3A4 substrate + inhibitor 
 
Table 2: Selective E blockers (BB)
 
Agent 
Initial dose 
Intermediate dose 
Maximum 
dose 
Hepatic metabolism 
 
Metoprolol 
Atenolol
Acebutolol 
Bisoprolol 
 
 
25 mg po bid 
25 mg po qd 
100 mg po bid 
2.5 mg po qd 
 
50 mg po bid 
50 mg po qd 
200mg-300 mg po bid 
5-10 mg po bid 
 
100 mg po bid 
100 mg po qd 
400 mg po bid 
20 mg po qd 
 
CYP 2D6 substrate 
No
Yes(CYP450 unknown) 
Yes(CYP450 unknown) 
 
Table 3. Angiotensin Converting Enzyme Inhibitors (ACEIs)
 
Agent  
Initial dose 
Intermediate dose 
Maximum dose 
Hepatic metabolism 
 
Captopril 
Enalapril 
Ramipril 
Lisinopril
Fosinopril 
Rarely used: 
Perindopril
Quinapril
 
12.5 po tid 
5 mg po qd 
2.5 mg po qd 
5 mg po qd 
10 mg po qd 
 
4mg po qd 
10mg po qd 
 
25 mg po tid 
10-20 mg po qd 
5 mg po qd 
10-20 mg po qd 
20 mg po qd 
 
none 
20 mg po qd 
 
50 mg po tid 
40 mg po qd 
10 mg po qd 
40 mg po qd 
40 mg po qd 
 
8mg po qd 
40 mg po /qd 
 
CYP 2D6 substrate 
CYP 3A4 substrate 
Yes (CYP450 unknown) 
No
Yes (CYP450 unknown) 
 
Yes but not CYP450 
No 
Table 4. Angiotensin II Receptors Blockers (ARBs)
 
Agent 
Initial dose 
Intermediate dose 
Maximum dose 
Hepatic metabolism 
 
Losartan 
Candesartan 
Irbesartan 
Telmisartan
Valsartan 
 
25mg po qd 
4mg po qd 
75mg po qd 
40 mg po qd 
80 mg po qd 
 
50 mg po qd 
8-16 mg po qd 
150 mg po qd 
none 
none 
 
100 mg po qd 
32mg po qd 
300 mg po qd 
80 mg po qd 
160mg po qd 
 
CYP 3A4 substrate 
CYP 2C9 substrate  
CYP 2C9 substrate 
Yes but not CYP450 
Yes but not CYP450
Table 5. D and E blocker
 
Agent 
Initial dose 
Intermediate dose 
Maximum dose 
Hepatic metabolism? 
 
Labetolol 
 
 
100 mg po bid 
 
200 mg po bid 
 
400 mg po bid 
 
CYP 2D6 substrate and inhibitor 
 
Agents in bold characters above are suggested as optimal choices to avoid or minimize potential drug-
interactions with AZD2171 through CYP450. 
5.2 Management of LVEF 
 
There have been reports of VEGF inhibitors leading to decreases in ejection fraction.  In support of this, recent 
trials have shown asymptomatic decreases in ejection fraction with different VEGF inhibitors. Specifically, a 
reduced LVEF (left ventricular ejection fraction) has been observed with sunitinib in up to 5–11% of patients, and 
5% of patients treated with bevacizumab (Motzer 2006, Karp 2004, Motzer RJ, Rini 2006).  Recent data from 
breast cancer trials using AZD-2171 and doxorubicin at the NCI have identified two patients’ who experienced 


16
asymptomatic ejection fraction decreases that were reversible upon withdrawal of AZD-2171.  Since it is difficult 
to differentiate whether this is a toxicity that is associated with VEGF inhibitor monotherapy or concurrent 
regimens including VEGF inhibitors, further investigation is needed. These questions that arise because of the 
safety of AZD-2171, in regards to cardiac function have prompted us to obtain echocardiograms for patients 
concurrently with CT scans and bone scans. As there are currently no guidelines on evaluation and 
management of ejection fraction in the setting of AZD-2171 use, similar criteria to that previously used for 
trastuzumab, which is known to decrease ejection fraction, and the NCI breast cancer trials will be employed 
(Tan-Chiu 2005). 
 
Continuation Guidelines for AZD based on Echocardiogram**
 
 
Asymptomatic Decrease in LVEF from baseline 
Relationship of LVEF to 
the LLN 
Decrease of < 10 
percentage points 
Decrease of 10 to 15 
percentage points 
Decrease of  15 
percentage points 
Within radiology facility’s 
normal limits 
Continue AZD-2171 
Continue AZD-2171 
Hold AZD-2171 and 
repeat Echo in 4 weeks 
and reevaluate 
1 to 5 percentage points 
below the LLN 
Continue AZD-2171 
Hold AZD-2171 and 
repeat Echo in 4 weeks 
and reevaluate 
Hold AZD-2171 and 
repeat Echo in 4 weeks 
and reevaluate 
 6 percentage points 
below the LLN 
Continue AZD-2171 
Hold AZD-2171 and 
repeat Echo in 4 weeks 
and reevaluate 
Hold AZD-2171 and 
repeat Echo in 4 weeks 
and reevaluate 
  
**Please note that reevaluation should be conducted as per the table above. 
 
 
6. ADVERSE EVENTS:  LIST AND REPORTING REQUIREMENTS  
The following adverse event management guidelines are intended to ensure the safety of each patient while 
on the study. Adverse events occurring during the study will be graded according to the NCI Common 
Terminology Criteria for Adverse Events version 3.0 (CTCAE v3.0).  
 
Definition of an Adverse Event (AE) 
 
An adverse event is defined as any reaction, side effect, or untoward event that occurs during the course of 
the clinical trial, whether or not the event is considered related to the treatment or clinically significant. For 
this study, AEs will include events reported by the patient, as well as clinically significant abnormal findings 
on physical examination or laboratory evaluation. A new illness, symptom, sign or clinically significant 
laboratory abnormality or worsening of a pre-existing condition or abnormality is considered an AE.  All AEs 
must be recorded on the AE case report form.  
 
All AEs, including clinically significant abnormal findings on laboratory evaluations, regardless of severity, 
will be followed until satisfactory resolution. AEs should be reported up to 30 days following the last dose of 
study drug.  AEs that are considered treatment related, expected, continuing, but not resolvable by 30 days 
after treatment completion (e.g., alopecia) will not be followed after the 30-day period.  
 
An abnormal laboratory value will be considered an AE if the laboratory abnormality is characterized by any 
of the following: 
x 
Results in discontinuation from the study 
x 
Is associated with clinical signs or symptoms  
x 
Requires treatment or any other therapeutic intervention 
x 
Is associated with death or another serious adverse event, including hospitalization.  
x 
Is judged by the Investigator to be of significant clinical impact 
x 
If any abnormal laboratory result is considered clinically significant, the investigator will provide 
details about the action taken with respect to the test drug and about the patient’s outcome. 
 
If a laboratory abnormality is one component of a diagnosis or syndrome, then only the diagnosis or 
syndrome should be recorded on the AE page of the CRF. If the abnormality was not a part of a diagnosis or 
syndrome, then the abnormality should be recorded as the AE. 
 


17
x 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 will be 
utilized for AE reporting.  All appropriate treatment areas should have access to a copy of the 
CTCAE version 3.0.  A copy of the CTCAE version 3.0 can be downloaded from the CTEP web 
site (http://ctep.cancer.gov/reporting/ctc.html). 
 
 
x 
Attribution of the AE: 
- 
Definite – The AE is clearly related to the study treatment. 
- 
Probable – The AE is likely related to the study treatment. 
- 
Possible – The AE may be related to the study treatment. 
- 
Unlikely – The AE is doubtfully related to the study treatment. 
- 
Unrelated – The AE is clearly NOT related to the study treatment. 
6.1 Comprehensive Adverse Events and Potential Risks List (CAEPR) 
The Comprehensive Adverse Event and Potential Risks list (CAEPR) was developed to provide a 
single, complete list of reported and/or potential adverse events associated with an agent using a 
uniform presentation of adverse events by body system.  In addition to the comprehensive list, the 
subset of those events that are “expected” [i.e., the Agent Specific Adverse Event List (ASAEL)] is 
presented in a separate column and identified with bold and italicized text.  This subset is used to 
guide expedited reporting requirements.  The CAEPR for AZD2171 is shown on the next page. 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
Cediranib (AZD2171, NSC 732208) 
 
The Comprehensive Adverse Event 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 Agent Specific Adverse Event List (ASAEL), appears in a 
separate column and is identified with bold and italicized text. This subset of AEs (ASAEL) contains events that 
are considered 'expected' for expedited reporting purposes only. Refer to the 'CTEP, NCI Guidelines: Adverse 
Event Reporting Requirements' 
http://ctep.info.nih.gov/protocolDevelopment/default.htm#adverse_events_adeers for further clarification. 
Frequency is provided based on 681 patients. Below is the CAEPR for cediranib (AZD2171). 
Version 2.9, February 19, 20101 
 Adverse Events with Possible  
 Relationship to Cediranib (AZD2171) 
 (CTCAE 4.0 Term) 
[n= 681] 
 
 
 EXPECTED AEs FOR 
ADEERS REPORTING
Agent Specific Adverse 
Event List 
(ASAEL)
 
Likely (>20%) 
Less Likely (<=20%)
Rare but Serious (<3%)
 
Expected
CARDIAC DISORDERS 
  
 
 
Left ventricular systolic 
dysfunction 
  
ENDOCRINE DISORDERS 
  
 
Hyperthyroidism 
 
 
Hypothyroidism 
 
 Hypothyroidism
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
 Abdominal pain
 
Anal mucositis 
 
 Anal mucositis
 
Constipation 
 
 Constipation
Diarrhea 
 
 
 Diarrhea 
 
Dry mouth 
 
 Dry mouth 
 
Dysphagia 
 
 Dysphagia 
 
Mucositis oral 
 
 Mucositis oral


18
 
Nausea 
 
 Nausea 
 
Rectal mucositis 
 
 Rectal mucositis
 
Small intestinal mucositis 
 
 Small intestinal mucositis
 
Vomiting 
 
 Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
Fatigue 
 
 
 Fatigue 
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
 Aspartate aminotransferase 
increased 
 
 
  
 
 Investigations - Other  
(increased blood 
erythropoietin) 
 
 
 
Investigations - Other 
(increased thyroid 
stimulating hormone) 
 
 Investigations - Other 
(increased thyroid 
stimulating hormone)
 
Neutrophil count decreased  
  
 
Platelet count decreased 
 
 
Weight loss 
 
Weight loss 
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia 
 
Dehydration 
 
 Dehydration
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
 Dizziness 
 
Headache 
 
 Headache 
 
 
Leukoencephalopathy 
  
 
 
Reversible posterior 
leukoencephalopathy 
syndrome 
  
RENAL AND URINARY DISORDERS 
  
 
Proteinuria 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough 
 
Dyspnea 
 
 Dyspnea 
 
Laryngeal mucositis 
 
 Laryngeal mucositis
 
Pharyngeal mucositis 
 
 Pharyngeal mucositis
 
Tracheal mucositis 
 
 Tracheal mucositis
 
Voice alteration 
 
 Voice alteration
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Palmar-plantar 
erythrodysesthesia 
syndrome 
 
 Palmar-plantar
erythrodysesthesia
syndrome 
VASCULAR DISORDERS 
  
Hypertension 
 
 
 Hypertension
 
 
Vascular disorders - Other 
(arterial thrombosis) 
  
This 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. 
 
Also reported on cediranib (AZD2171) trials but with the relationship to cediranib (AZD2171) still 
undetermined: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Anemia; Leukocytosis 


19
CARDIAC DISORDERS - Acute coronary syndrome; Chest pain - cardiac; Myocardial infarction 
EAR AND LABYRINTH DISORDERS - Tinnitus; Vertigo 
ENDOCRINE DISORDERS - Endocrine disorders - Other (thyrotoxicosis) 
GASTROINTESTINAL DISORDERS - Abdominal distension; Ascites; Colitis; Dyspepsia; Enterocolitis; 
Esophagitis; Flatulence; Gastric perforation; Ileus; Oral pain; Rectal hemorrhage 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Edema limbs; Fever; Non-cardiac 
chest pain 
HEPATOBILIARY DISORDERS - Hepatic failure; Hepatic hemorrhage; Hepatic pain 
IMMUNE SYSTEM DISORDERS - Allergic reaction 
INFECTIONS AND INFESTATIONS - Gum infection; Lung infection; Sepsis; Skin infection; Soft tissue infection; 
Urinary tract infection 
INVESTIGATIONS - Alkaline phosphatase increased; Blood bilirubin increased; Cardiac troponin T increased; 
Creatinine increased; Electrocardiogram QT corrected interval prolonged; GGT increased; Investigations - Other 
(decreased thyroxine); Lymphocyte count decreased; White blood cell decreased 
METABOLISM AND NUTRITION DISORDERS - Hyperglycemia; Hyperkalemia; Hypertriglyceridemia; 
Hypoalbuminemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Hyponatremia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Arthralgia; Back pain; Bone pain; Chest 
wall pain; Generalized muscle weakness; Muscle weakness lower limb; Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - Tumor pain 
NERVOUS SYSTEM DISORDERS - Dysgeusia; Encephalopathy; Intracranial hemorrhage; Ischemia 
cerebrovascular; Lethargy; Peripheral motor neuropathy; Peripheral sensory neuropathy; Seizure; Somnolence; 
Transient ischemic attacks 
PSYCHIATRIC DISORDERS - Confusion; Insomnia 
RENAL AND URINARY DISORDERS - Acute kidney injury; Hematuria 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Bronchopulmonary hemorrhage; Epistaxis; 
Hypoxia; Pharyngolaryngeal pain; Pleural effusion; Pneumonitis; Pneumothorax 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin; Hyperhidrosis; Nail loss; Pruritus; Purpura; 
Rash maculo-papular 
VASCULAR DISORDERS - Hematoma; Hypotension; Thromboembolic event 
 
 
Note: Cediranib (AZD2171) 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. 
Precautions:  Hypertension is an expected adverse event with agents that inhibit VEGF signaling.  In cediranib 
(AZD2171) studies, increases in blood pressure have been observed and cases of hypertension have been 
reported, including CTC grade 4 hypertension and end-organ damage related to hypertension.  Clinical 
experience with cediranib (AZD2171) has shown that hypertension occurs at doses of 20 mg and higher.  
Cediranib (AZD2171) studies include monitoring of blood pressure and renal function, and a hypertension 
monitoring and management protocol has been developed which will be appended to all future study protocols. 
 
6.2 Expedited Adverse Event Reporting to Sponsor 
6.2.1 Expedited AE reporting for this study is via AdEERS (Adverse Event Expedited Reporting System) 
accessed via the secure CTEP web site 
https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers_main$.startup).  The reporting procedures to 
be followed are presented in the “CTEP, NCI Guidelines: Adverse Event Reporting Requirements” which 
can be downloaded from the CTEP web site (http://ctep.cancer.gov/reporting/adeers.html). 
 
6.2.2 AEs that require notification to the Investigational Drug Branch (IDB) within 24 hours should be 
made via the AdEERS web site: 
https://webapps.ctep.nci.nih.gov/openapps/plsql/gadeers_main$.startup. 
 
6.2.3 All AEs reported via AdEERS must be copied to the Study Coordinator wdfigg@helix.nih.gov 
using the copy feature of AdEERS.  The Study Coordinator will submit AE reports to the Principal 
Investigator for timely review. 
 


20
6.2.4 Expedited Reporting Guidelines – AdEERS Reporting Requirements for Adverse Events that occur 
within 30 Days1 of the Last Dose of the Investigational Agent on Phase 2 and 3 Trials 
 
 
Grade 1 Grade 2 Grade 2
Grade 3 
Grade 3 
Grades
4 & 52
Grades
4 & 52
Unexpect
ed
and
Expected 
Unex-
pected Expect
ed 
Unexpected 
Expected 
Unex-
pected
Expecte
d
with  
Hospital
i-zation
without 
Hospitali
- zation
with  
Hospita
li-
zation
without 
Hospitali
-
zation
Unrelated
Unlikely 
Not 
Required 
Not 
Require
d 
Not 
Require
d 
10 
Calendar
Days 
Not 
Required
10 
Calenda
r 
Days 
Not 
Required 
10 
Calendar
Days 
10 
Calenda
r 
Days 
Possible
Probable
Definite
Not 
Required 
10 
Calenda
r 
Days 
Not 
Require
d 
10 
Calendar
Days 
10 
Calendar
Days 
10 
Calenda
r 
Days 
Not 
Required 
24-Hour;
5 
Calendar
Days 
10 
Calenda
r 
Days 
1 Adverse events with attribution of possible, probable, or definite that occur greater than 30 
days after the last dose of treatment with an agent under a CTEP IND require reporting as 
follows: 
AdEERS 24-hour notification followed by complete report within 5 calendar days for: 
x Grade 4 and Grade 5 unexpected events  
 
AdEERS 10 calendar day report: 
x Grade 3 unexpected events with hospitalization or prolongation of hospitalization 
x Grade 5 expected events 
2 Although an AdEERS 24-hour notification is not required for death clearly related to progressive 
disease, a full report is required as outlined in the table. 
December 15, 2004
 
Note:  All deaths on study must be reported using expedited reporting regardless of causality.  
Attribution to treatment or other cause should be provided. 
x 
Expedited AE reporting timelines defined:  
¾ “24 hours; 5 calendar days” – The investigator must initially report the AE via AdEERS 
within 24 hours of learning of the event followed by a complete AdEERS report within 5 
calendar days of the initial 24-hour report. 
¾ “10 calendar days” - A complete AdEERS report on the AE must be submitted within 10 
calendar days of the investigator learning of the event.  
x 
 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates hospitalization 
(or prolongation of existing hospitalization) must be reported regardless of designation as 
expected or unexpected and attribution with the exception of events listed in Section 7.3.5 
(Protocol-Specific Expedited Adverse Event Reporting Exclusions).Any event that results in 
persistent or significant disabilities/incapacities, congenital anomalies, or birth defects must be 
reported via AdEERS if the event occurs following treatment with an agent under a CTEP IND.  
x 
Use the NCI protocol number on all reports. 
x 
Events that are clearly consequences of the “main” event may be noted in the Description of 
Event in the AdEERS report, and do not require separate AdEERS reports. 
The possibility of the contribution of comorbid conditions to the event should be considered when reporting AEs. 
 
6.3 NCI-IRB Expedited Adverse Event Reporting Requirements: 
The PI will report: 
x 
All serious adverse events (SAEs) that are not in the consent form, but are possibly, 
probably or definitely related to the research.  A SAE is defined as an untoward medical 
occurrence that 
 resulted in a death; 


21
 was life-threatening; 
 required or prolonged hospitalization; 
 caused persistent or significant disability/incapacity; 
 resulted in congenital anomalies or birth defects; or 
 required intervention to prevent permanent impairment or death. 
x 
All other deaths.  
x 
All grade 3 and 4 (CTCAE) events that are not in the consent and that are possibly, 
probably or definitely related to the research.  
 
Reports must be received by the NCI-IRB within 7 calendar days of the investigator’s notification of 
the event.   
A copy of the current NCI IRB Adverse Event Form can be downloaded from the following URL: 
http://home.ccr.cancer.gov/irb/adverse.html 
 
NCI IRB Contact Information: 
x 
E-mail- nciirbadmin@mail.nih.gov 
x 
Mail- Building 82/Room 115, 9030 Old Georgetown Road, Bethesda, MD, 20892 
x 
FAX- 301-480-0106 
 
6.4 NCI-IRB Requirements for PI Reporting of Expected and Unexpected Adverse Events at 
Continuing Review 
The NCI-IRB requires a summary report of adverse events that have occurred on the protocol since the 
previous continuing review. The method of presentation should provide the NCI-IRB with the information 
necessary to clearly identify risks to participants and to make a risk:benefit determination. The summary 
report is based on the following guidance: 
 
Any unexpected severity and/or unexpected frequency of expected events needs to be reported and 
interpreted in relation to the risk:benefit of study participants in the narrative. 
 
1. Grade 1 events are not required. 
2. Grade 2 unexpected events related to the research that are not in the consent  is required. 
3. Grade 3 and 4 events related to the research are required. 
4. All Serious Events regardless of attribution are required. 
4. All Grade 5 events are required regardless of attribution. 
   
Based on protocol associated risks to participants, the NCI-IRB retains the authority to establish more 
frequent Continuing Review periods than the customary annual review period.    
 
6.5 Routine Adverse Event Reporting 
Those AEs that do not require expedited reporting must be reported in routine (CDUS) study data 
submissions.  AEs reported through AdEERS must also be reported in routine study data 
submissions. 
 
6.6 Secondary AML/MDS 
Investigators are required to report cases of secondary AML/MDS occurring on or following 
treatment on NCI-sponsored chemotherapy protocols using the NCI/CTEP Secondary AML/MDS 
Report Form.  This form can be downloaded from the CTEP web site 
(http://ctep.cancer.gov/reporting/index.html). Second malignancies and non-AML/MDS secondary 
malignancies (e.g., endometrial cancer in a breast cancer patient receiving tamoxifen) should NOT 
be reported via AdEERS but should be submitted as part of the study results via routine CDUS 
reporting. 
7. PHARMACEUTICAL INFORMATION 
 
AZD2171 (NSC 732208) IND # 72740 
 
Chemical Name:  
 4-[(4-Fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(3-pyrrolidin-1- 


22
ylpropoxy) quinazoline maleate 
 
Other Names: 
AZD2171 maleate,  Recentin™ 
CAS Registry Number:
288383-20-0 (for the free base)  
 
Molecular Formula: 
C25H27FN4O3 · C4H4O4
 
Molecular Weight:
566.59 as maleate salt (450.52 as free base)  
Approximate Solubility:
The aqueous solubility of AZD2171 has been measured as 0.0006 
mg/mL for the free base (distilled water, pH 8.1 at 25°C) and 1.9 
mg/mL for the maleate salt (distilled water, pH 4.4 at 25°C).  
Mode of Action:
AZD2171 is a highly potent inhibitor of vascular endothelial growth 
factor receptor (VEGFR) tyrosine kinase activity, which may inhibit 
vascular endothelial growth factor-A (VEGF) driven angiogenesis and, 
as a consequence, constrain solid tumor growth.  
 
How Supplied: 
Until September, 2007, NCI will distribute AZD2171 as 9 mm round, 
beige film-coated tablets containing 10 mg or 15 mg of AZD2171 free 
base in bottles of 100.  
 
In addition to the active ingredient, tablets contain mannitol, dibasic 
calcium phosphate anhydrous, sodium starch glycollate, and magnesium 
stearate with a film coat coating hypromellose 606, polyethylene glycol 
400, red iron oxide, yellow iron oxide, black iron oxide, and titanium 
dioxide.  Sites can use these tablets to their expiration dates.  
 
In September 2007, NCI will distribute AZD2171 as round, beige film-
coated tablets containing 10 mg and 15 mg of AZD2171 free base.  The 
10 mg and 15 mg tablets are 6 mm and 7 mm in diameter, respectively.  
Each bottle contains 35 tablets.  
 
In addition to the active ingredient, the tablets contain mannitol, dibasic 
calcium phosphate anhydrous, sodium starch glycollate, microcrystalline 
cellulose, and magnesium stearate with a film coat coating hypromellose 
606, polyethylene glycol 400, red iron oxide, yellow iron oxide, black iron 
oxide, and titanium dioxide.  
Storage:
Store intact bottles at controlled room temperature [20°C-25°C, (68-
77°F)] and protect from light.  
Stability: 
Stability studies are ongoing.  
 
Route of Administration:  Oral.  AZD2171 tablets should be taken either 1 hour before or 2 hours after 
meals.  
Adverse Events and Potential Risks 
A list of the AEs and potential risks associated with AZD2171 can be found in Section 5. 
 
Availability 
AZD2171 is an investigational agent (IND 72740) supplied to investigators by the Division of Cancer 
Treatment and Diagnosis (DCTD), NCI. 
 
AZD2171 is provided to the NCI under a Clinical Trials Agreement (CTA) between  Astra Zeneca 
International and the DCTD, NCI (see Section 11.3). 


23
Agent Ordering 
NCI-supplied agents may be requested by the Principal Investigator (or their authorized designees) 
at each participating institution.  Pharmaceutical Management Branch (PMB) policy requires that the 
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).  Completed 
Clinical Drug Requests (NIH-986) should be submitted to the PMB by fax (301) 480-4612 or mailed 
to the Pharmaceutical Management Branch, CTEP, DCTD, NCI, 9000 Rockville Pike, EPN Rm. 
7149, Bethesda, MD 20892. 
Agent Accountability 
The Investigator, or a responsible party designated by the investigator, must maintain a careful 
record of the inventory and disposition of all agents received from DCTD using the NCI Drug 
Accountability Record Form.  See the CTEP web site for Policy and Guidelines for Accountability 
and Storage of Investigational Drugs (http://ctep.cancer.gov/requisition/storage.html), as well as the 
CCR Standard Operating Procedure: Conducting and Documenting Drug Accountability for Oral 
Investigational Agents that are Self Administered by Patients 
(http://ccrintra.cancer.gov/clin_ops/policies/SOPCLIN1.pdf). 
Prednisone
a) 
Chemical formula: 17a, 32-Dihydroxy-1,4-pregnadiene-       3,11,20-trione 
¾ 
Chemical Formula: C21H26O5 Molecular weight of 358.4 
b) 
Classification: Glucocoticorticoids 
 
c) 
Mechanism of Action:  Multiple mechanisms leading to anti-inflammatory and immune 
suppression outcomes 
 
d) 
How supplied: Prednisone is supplied as a tablet or suspension.  We will use commercially 
available 5 mg tablets for this study. 
 
e) 
Storage:  Prednisone should be stored in original containers at room temperature, out of direct 
sunlight. 
 
f) 
Stability:  Prednisone tablets are stable for three years from date of manufacture 
 
g) 
Route of administration: Oral 
 
h) 
Toxicities: Anemia, eosinopenia, leukocytosis, lymphopenia, thrombocytopenia, leukocytosis, 
hypertensive crisis, hypertension, psychosis, schizophrenic psychosis, extrapyramidal effects, 
pseudotumor cerebri, hyperglycemia, hyperuricemia, hypercalcemia, adrenal suppression, 
Cushing’s syndrome, porphyria, lipid abnormalities, hypokalemia, peptic ulcers, pancreatitis, 
abdominal pain, nephrotoxicity, proteinuria, cataracts, papilledema, acne, osteonecrosis, 
osteoporosis, myopathy, and superinfections. 
 
i) 
Availability: Prednisone will be obtained from commercial stock purchased by the NIH CC 
Pharmacy Department. 
8. CORRELATIVE/SPECIAL STUDIES 
Given the nature of this pharmacologic intervention, characterization of the actual biological manipulation will 
be critical in understanding the biological effects seen following drug administration.  Blood and tissue 
samples will be analyzed to achieve this goal.   
 
The collection of correlative studies is designed to characterize a baseline molecular profile as well as a 
treatment-induced molecular profile.  VEGFR mutational analysis will allow for retrospective analysis of 
responsiveness in the presence or absence of mutations.  Pharmacokinetic analysis will provide insight into 
dosing efficacy as it relates to both biological activity and clinical response. 


24
 
Correlative laboratory studies for this trial will be conducted in the Clinical Pharmacology Research Core and 
the  Molecular Pharmacology Section, both under the direction of Dr. William D. Figg.  All patients will have 
leukocyte collections by standard buffy coat preperation to evaluate for tumor and gene expression 
alterations related to drug therapy.   
 
Proposed correlative studies follow.  Other studies may be performed as further data is developed both 
within the study and from other investigators. 
 
8.1 
Tissue Studies 
 
8.1.1 
Soluble KDR  
The Molecular Pharmacology Section will utilize an ELISA assay to determine VEGF R 
concentration, as previously described (Belgore 2001; Neulen 2001; Robak 2003; Wierzbowska 
2003).  Patients will have serum drawn for VEGF R concentration analysis prior to cycle one, 
and subsequently prior to each cycle there after.  Vascular endothelial growth factor receptor 
concentrations will be correlated to response and disease progression. 
 
8.1.2 
Adhesion Molecules 
Endothelial cell-specific adhesion molecules (VCAM-1, E-selectin, ICAM-1) are released by 
damaged endothelial cells; ELISA analysis of these markers will assess the level of cell 
dysfunction. 
 
8.1.3 
Biopsies 
If tissue is obtained from biospies, the expression of of KDR & phospho-KDR will be assessed 
via immunohistochemical staining.  Although KDR is expressed on endothelial cells, there are 
reports that it can also be expressed on epithelial tissues (tumor tissues)  REF.  The assay will 
provide information as to whether drug targets the endothelium or the tumor itself. 
Biopsies are optional and will be limited to those that are easily accessible and involve minimal 
risk.  The procurement of tissue samples will be discussed with patients at enrollement in the 
protocol.  Biopsies will be obtained prior to initiating AZD2171 (0 months), and after cycles 2 
and 6, and every six months thereafter. Participation in the phase II study is in no way 
contingent on consent to biopsy.  
 
8.1.4 Pharmacogenetic Analyses 
 
Rationale 
Knowledge of variation in kdr/flk-1 (the target of AZD2171) as well as other genes in this 
pathway will assist in the interpretation of biomarker data.  The proteins encoded by these other 
genes are either biomarkers themselves (VEGF-A) or they regulate the expression of 
biomarkers (Hif1 alpha ,microvessel density).  Additionally, other genes regulated by this 
pathway include candidates for genetic factors predisposing to the development of hypertension 
in response to anti-angiogenic therapy.   
 
Two common (>10% allele frequency) variants of the kdr/flk-1 gene were discovered and 
validated by an AstraZeneca polymorphism screen and have subsequently been reported in 
public domain data bases.  Both of the polymorphic amino acid residues (Val/Ile 297; Gln/His 
472) are located in the external domain of the receptor.  Single nucleotide polymorphisms have 
also been described in the promoter region of the kdr/flk-1 gene and may correlate with 
expression levels of the receptor.  While somatic mutations in the kdr/flk-1 gene have been 
described in colorectal tumors (Bardelli 2003), there are no data on the functional consequences 
of these mutations and there are no reports of mutations in the kdr/flk-1 gene in other tumor 
types. 
 
Although no decrease in circulating VEGF was detected in a study with bevacizumab in rectal 
cancer (Willett 2004), VEGF-A levels may be modulated by AZD2171.  There is a wide inter-
individual variation in VEGF-A levels, and an understanding of the factors influencing basal 
levels of VEGF-A may aid the interpretation of results.  Polymorphisms in the VEGF-A gene 
have been shown to affect expression levels of the protein both in vitro and in vivo (Watson 


25
2000; Renner 2000; Stevens 2003).  
 
Analysis of the HIF1D gene should be included in studies where microvessel density (MVD) is 
being analyzed as a biomarker. HIF1D is a key regulator of cellular response to hypoxia and is 
thought to play an important role in tumor progression and metastasis through activation of 
genes that are involved in the regulation of angiogenesis, energy metabolism and other 
functions (reviewed by Semenza 2002).  Tanimoto et al. (2003) have demonstrated a correlation 
between two polymorphic variants of HIF1D ҏand MVD in head and neck cancer.  
 
The development of hypertension has been reported in ~11% of patients treated with 
bevacizumab plus chemotherapy compared to 2% in patients treated with chemotherapy alone 
(Hurwitz 2004), indicating that a proportion of patients on antiangiogenic therapy may be 
susceptible to the development of hypertension.  If hypertension is observed in patients treated 
with AZD2171, analysis of candidate genes such as endothelial nitric oxide synthase gene 
(eNOS) could be undertaken. Variants of eNOS have been associated with essential 
hypertension and renal disease (reviewed by Wattanaitayakul 2001) and may correlate with the 
development of hypertension in patients treated with antiangiogenic therapy.  Nitric oxide 
release is mediated via the activation of kdr/flk-1 through downstream signaling mechanisms, 
and components of these pathways could provide additional candidates (Duval 2003).  
 
All study participants will be invited to provide a blood sample for retrospective genotyping.  
Participation in pharmacogenetic studies will be optional for all patients entering the study and 
will involve a separate consent procedure.  A patient’s acceptance of pharmacogenetic analyses 
will not be a requirement of their participation in this study.  
 
8.1.5 Blood Sample Collection for Tumor Biomarker Studies 
 
NCI, Dr. William D Figg’s laboratory is the designated laboratory, (POC, Mr. Gareth Peters, 
10/5A09, 102-11964, 301-402-3622).  
 
Collection
x 
Samples for tumor biomarkers will be drawn at baseline, 24 hours after starting 
daily oral dosing, and at each clinic visit prior to the start of the next cycle. 
x 
Collect blood in two 10 mL polypropylene tubes containing the anticoagulant 
Heparin 
- SARSTEDT Monovette® EDTA KE (9 mL), Part # 02.1333.001 or 
- Becton-Dickinson VacutainerTM K2E (10 mL), Part # 367525 or 
- Greiner Bio-One Vacuette® K3E EDTA K3 (9 mL), Part 455036 
x 
Blood tubes must be gently inverted several times after collection to ensure 
thorough mixing of EDTA with the sample to prevent clotting. 
x 
Glass tubes MUST NOT be used as they may break during transport and freeze-
thaw cycles. 
x 
x 
After collection, blood samples must be refrigerated (+ 4°C) or frozen (see chart 
below) at the site of collection and transported to the central reference laboratory or 
designated DNA processing laboratory as soon as possible. 
 
Option
Storage
Temperature
at Treatment 
Site
Maximum
Duration of 
Storage at 
Treatment
Site
Transport
Temperature
Delivery 
Time
1 
+ 4°C (fridge) 
24 hours 
0 - 4°C (ice 
blocks) 
24 hours
2 
+ 4°C (fridge) 
24 hours 
Less than -20°C 
(dry ice) 
24-72 
hours 
3 
-20°C 
Up to 1 month 
Less than -20°C 
24-72 


26
(freezer) or -
70°C 
(dry ice) 
hours 
 
x 
If blood samples are to be frozen for storage at -20°C or less, non-frost free 
freezers must be used to prevent repeated freeze-thaw of blood which may reduce 
yield and quality of the DNA obtained. 
Samples must not be thawed and then re-frozen at any point. 
 
Labeling, Storage, and Tracking 
x 
All labels used must be freezer-proof. 
x 
Barcode labels will be used in this study.  
x 
Label each collection tube with the following information: 
- unique sample I.D.  
- study I.D. (CTEP protocol number, local protocol number, etc.) 
- date of sample collection 
x 
All data associated with samples is entered into the Clinical Pharmacology 
Program’s “Patient Sample Database Management System” (PSDMS) - Labrador. 
This is a secure program that can only be accessed by authorized users in Dr. 
Figg’s lab. PSDMS creates a unique barcode ID for every sample and sample box 
which cannot be traced back to patients without PSDMS access 
x 
The data recorded for each sample includes the patient ID, name, trial 
name/protocol number, time drawn, cycle time point, dose, material type, as well as 
box and freezer location. There are patient demographics that can be obtained to 
correlate with the samples through the PSDMS system.  For each sample, there are 
associated processing notes (i.e., delay in sample processing, storage conditions 
on the ward, etc.).  Bar-coded samples are stored in bar-coded boxes in a locked 
freezer at either -20 or -85qC according to stability requirements.  These freezers 
are located onsite in Dr. Figg’s lab and offsite at NCI Frederick Central Repository 
Services (Fisher Bioservices) in Frederick, MD. Samples will be stored until 
requested by the researcher assigned to the protocol (however, those requests 
must come from a member of Dr. Figg’s laboratory with PSDMS access/clearance). 
 All requests are monitored and tracked in the PSDMS system. All researchers are 
required to sign a form stating that the samples are only to be used for research 
purposes associated with this trial (as per the IRB approved protocol – that protocol 
is stored in the PSDMS system) and that any unused samples must be returned to 
Dr. Figg’s laboratory.  
 
 
Protocol Completion/Sample Destruction 
x 
Once primary research objectives for the protocol are achieved, intramural 
researchers can request access to remaining samples providing they have an IRB 
approved protocol and patient consent. 
x 
Samples, and associated data, will be stored permanently unless the patient 
withdraws consent. If researchers have samples remaining once they have 
completed all studies associated with the protocol, they must be returned to Dr. 
Figg’s laboratory. 
x 
The PI will report destroyed samples to the IRB if samples become unsalvageable 
because of environmental factors (ex. broken freezer or lack of dry ice in a shipping 
container) or if a patient withdraws consent. Samples will also be reported as lost if 
they are lost in transit between facilities or misplaced by a researcher.  Dr. Figg’s 
laboratory will report any freezer problems, lost samples or other problems 
associated with samples to the IRB, the NCI Clinical Director, and the office of the 
CCR, NCI. 
 
8.2 
Imaging Studies 
 
8.2.1 
Dynamic Contrast Enhanced – Magnetic Resonance Imaging (DCE-MRI) 
Dynamic Contrast Enhanced Magnetic Resonance Imaging (DCE-MRI) has been used 
extensively with novel antiangiogenic agents in Phase 1/2 to monitor their effect on tumor 


27
vasculature through parameters reflecting both tumor perfusion and permeability.  This
protocol is limited to DCE-MRI using T1 weighted studies with low molecular weight 
gadolinium (Gd) chelates.
Other MRI techniques (which are not covered by this protocol) 
include the following:  DCE-MRI using T2* weighted images; contrast-enhanced MR with high 
molecular weight contrast agents; and non-contrast enhanced MRI techniques such as 
diffusion-weighted MRI, T2* weighted MRI or BOLD. 
DCE-MRI studies will be interpreted by Dr. Peter Choyke, MD, Chief, NCI Molecular Imaging 
Department, 301.435.4046, 10/1B40. Other members of the clinical imaging program may 
contact Dr. Choyke for information purposes regarding the imaging protocol and data capture 
methodology. 
 
8.2.1.1 DCE-MRI End Points  
x 
The primary end points of these DCE-MRI studies are the Initial Area Under the Gd 
Curve measured over 60 seconds (IAUC60) and the Transport Constant (Ktrans). 
x 
IAUC (initial area under the gadolinium concentration time curve) does not require a 
model but does not have a simple relationship to physiology. It is a relatively robust and 
simple technique.  Each institution participating in this DCE-MRI study should measure 
the initial area under the curve (IAUC, mMGd/sec) over the first 60 seconds from a 
region of interest (ROI) analysis averaged over the whole tumor volume (3D 
techniques) or over the tumor area (2D techniques) to provide a basic measurement for 
collation of DCE-MRI data across studies. 
x 
Transport Constant (Ktrans) should ideally be provided by each institution participating in 
this DCE-MRI study from a region of interest (ROI) analysis averaged over the whole 
tumor volume (3D techniques) or over the tumor area (2D techniques). 
x 
Both Ktrans and IAUC60 require calculation of instantaneous tumor Gd concentration 
based on the change in relaxivity due to contrast uptake ǻR1.  The basic requirements 
for these calculations are: 
- 
An estimate of contrast agent relaxivity in tumor vasculature and tissue 
- 
Measurement of tumor T1 immediately prior to contrast uptake 
- 
An accurate T1 measurement method verified for all spatial locations, coils and 
scanners used 
- 
Cardiac output (or arterial input function) for Ktrans (population based estimates 
may be appropriate) 
- 
Reproducible injection (ideally power injector) 
x 
All data including ROI definition and analysis should be recorded and traceable to 
support external review. 
x 
Additional end points may be generated at a study / protocol level in addition to these 
primary end points.  The production of the primary DCE-MRI end points for comparison 
between studies does not preclude other end points within studies such as parametric 
maps of IAUC/Ktrans, blood volume (Vb), extravascular space (Ve), Kep (a function of 
Ktrans and Ve), etc. 
 
8.2.1.2 Tumor Type and Location 
x 
Current guidance for AZD2171 studies is that lesions within the lung are excluded 
from DCE-MRI studies due to “breathing” artifacts which make image data difficult 
to analyze reliably. 
x 
Recommendations for lesion selection: 
- 
Exclude lung lesions.   
- 
If possible, exclude lesions in close proximity to the heart or major vascular 
structures. 
- 
If possible, choose lesions towards the center of the image volume. 
- 
If possible, choose lesions towards the center of the image plane. 
- 
Lesions should be at least 1.5 cm and preferably > 2 cm in longest in plane 
diameter. 
- 
Lesions preferably should be < 7 cm in the z plane [the entire lesion(s) 
should be within the volume scanned].   
- 
Lesions should be well defined on standard CT or MR imaging. 
 
8.2.1.3 Schedule of CT/Bone scan and DCE-MRI Assessments 


28
x 
Preliminary results in AZD2171 phase 1 studies indicate that reduction in DCE-MRI 
parameters reflecting tumor “blood flow” (IAUC60) and permeability (Ktrans) can be seen 
after a single dose of the agent as well as after daily dosing over 28 and 56 days. Then 
DCE-MRI will be scheduled every 4 months after cycle 4. 
x 
CT Bone scans, Echo should be obtained at 0, 2, and 4 months after enrollment, then 
every 3 months thereafter.  If CTs show no evidence of soft tissue disease, subsequent 
CTs may be omitted. Echo guidelines should be followed as per Section 5.2. 
x 
DCE-MRI scans should be obtained: 
- 
prior to treatment (preferably within 7 days of treatment start) 
- 
24-36 hours after starting daily oral dosing  
- 
28 +/- 2 days after starting daily oral dosing 
- 
56 +/- 2 days after starting daily oral dosing, depending on the study design 
- 
further follow-up scans, depending on the study design 
 
8.2.1.4 Data to be Collected 
The following information on a per patient basis should be supplied to the NCI with the final 
study manuscript. 
x 
Study identifier (NCI protocol number) 
x 
Subject identifier (patient I.D.) 
x 
AZD2171 dosing information 
- 
Date of first dose of AZD2171 
- 
Date of last dose of AZD2171 
- 
Dose of AZD2171 
- 
Any relevant dosing information, e.g., drug holidays 
x 
Tumor type 
x 
For each DCE-MRI scan 
- 
Location of lesion studied, e.g., liver metastases 
- 
Date of DCE-MRI scan 
- 
Tumor IAUC60 
- 
Tumor Ktrans 
x 
For each RECIST response assessment 
- 
Date of each RECIST assessment 
- 
Response assessment (if progression is recorded, then it should be 
specified whether the progression is in the lesion assessed by DCE-MRI) 
 
 
8.3  Assessment of the pharmacokinetic parameters of AZD2171 
Samples should be sent to NCI, Dr. William D Figg’s  laboratory, (POC, Mr. Gareth Peters, 10/5A09, 
102-11964, 301-402-3622).  
Each PK sample requires that at least 4ml blood be collected in Lavender-top tube containing EDTA. 
After collection, each tube should be completely and gently inverted ten times, placed on ice and 
subsequently refrigerated until picked up the point of contact noted above.  Pickup should ocurr within 
30 minutes of collection to ensure prompt processing as described below.  During the first cycle, blood 
samples will be obtained serially from prior to ingestion until 48 hours post-dose at the following time 
points: immediately pre-dose, and 0.25 hr, 0.5 hr, 1 hr, 2 hr, 4 hr, 6 hr, 8 hr, 12 hr, 24 hr, and 48 hours 
after ingestion, and then a trough sample at each clinic visit.  Patients will be asked to refrain from taking 
their dose prior to trough levels being obtained. Patients will not take drug on day 2, and will resume 
taking drug on day 3 after the 48 hour PK timepoint.  Patients may have PKs done on either an inpatient 
or outpatient basis.The Clinical Pharmacology Research Core of Dr. William D. Figg will coordinate 
rapid acquisition and evaluation of patient samples. The maximum concentration, time to maximum 
concentration, the area under the curve extrapolated to infinity, and the apparent terminal half-life will be 
calculated.  Pharmacodynamic study will address any correlation in AZD2171 concentration with 
disease response and/or toxicities.    
Each PK sample requires that at least 4ml blood be collected in Lavender-top tube containing EDTA. 
After collection, each tube should be completely and gently inverted ten times, then centrifuged within 30 
minutes for 10 minutes at 1500 x g. The supernatant/plasma (2ml) will be transferred into a 4ml Corning 
cryovial and frozen upright at -20oC until samples can be sent to Quest Diagnostics for further analysis. 
Samples should be shipped on dry ice.  If samples are sent to Quest the same day of collection, 
cryovials should be sent to Quest Diagnostics on dry ice for analysis.  Each sample should be labeled 


29
with labels provided by Quest, and shipped to the following address: 
Quest Diagnostics Clinical Trials 
Attn: Specimen Processing 
7600 Tyrone Avenue 
Van Nuys, CA 91405 USA 
 
Quest contacts for PK samples are as follows: 
US and Canada Toll-Free:  
800-877-7004 
Direct Line: 
818-830-2200 
Fax – General Inquiries: 
818-891-7780 
Fax – Reorder Supplies: 
818-895-6803 
 
For study-specific questions, press “1” and extension below: 
Ben Delect 
x2237 
ben.b.delact@questdiagnostics.com 
George Negron 
x2272 
george.x.negron@questdiagnostics.com 
 
For general information, supplies and results, press “2” for the Client Response Center. 
 
Client Response: 
5:00 AM – 6:00 PM (Pacific Time) Monday-Friday 
Center Hours: 
6:00 AM – 2:30 PM (Pacific Time) Saturday, Sunday, and Holidays* 
 
*On Christmas and New Year’s Day, outbound critical calls only 
 
 
or send inquiries to crc.us@questdiagnostics.com 
 
Please refer to the document “ Investigator Manual for US and Canda, AstraZeneca Study ID Z6C, 
General Manual for AstraZeneca, AZD2171/NCI Collaboration, Version 2.0, September 21, 2006, for 
detailed information regarding PK sample processing. 
 


30
9. 
STUDY CALENDAR 
Baseline evaluations are to be conducted within 16 days prior to administration of protocol therapy.  Scans and 
x-rays must be done 4 weeks prior to the start of therapy.  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. All patients will receive AZD2171 20 mg po daily and prednisone 10mg po daily. AZD-2171. AZD-2171 
dose reductions will be made in 5 mg increments; the lowest dose level is dose level -2, or 10 mg. All baseline 
and follow up evaluations can be done on the last week of the prior cycle. 
 
 
 
Pre-
Study
C1D1 
C2D1 
C3D1
C4D1 
C5D1 
Off 
Study 
AZD2171a
 
X 
X 
X 
X 
X 
 
Prednisonea 
 
X 
X 
X 
X 
X 
 
Informed consent 
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Med List 
X 
X 
X 
X 
X 
X 
X 
Physical exam 
X 
X 
X 
X 
X 
X 
X 
Vital signsg 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
Weight 
X 
X 
X 
X 
X 
X 
X 
Performance status 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff, plts, PSA 
X 
X 
X 
X 
X 
X 
X 
Serum chemistryb 
X 
X 
X 
X 
X 
X 
X 
Serum PAP 
X 
 
 
 
 
 
 
PKsh 
X 
X 
X 
X 
X 
X 
 
Serum Troponin Td 
X 
X 
X 
X 
X 
X 
 
TSH, free T4e 
X 
X 
X 
 
 
 
 
EKG  
X 
X 
X 
X 
X 
X 
 
Urine dipstick for protein f 
X 
X 
X 
X 
X 
X 
 
Imaging studiesc 
X 
 
X 
 
X 
 
X 
Biomarkers 
X 
X 
X 
X 
X 
X 
X 
 
a: AZD2171 and prednisone: Dose as assigned.  Administered orally, daily at a fixed dose.  
Please keep a pill diary (Appendix B).  Cycles = 28 days.  
b: Albumin, alkaline phosphatase, total bilirubin, bicarbonate, BUN, calcium, chloride, 
creatinine, glucose, LDH, phosphorus, potassium, total protein, SGOT[AST], SGPT[ALT], 
sodium. 
c: CT, Bone scan, Echo, DCE-MRI and/or 18 FDG-PET.  See Section 8.2.1.3 for the 
frequency of Imaging studies.  
d: Serum Troponin is to be obtained pre-study andonce a cycle thereafter. 
e: TSH and free T4 is to be obtained pre-study, once a cycle for the first two cycles, then 
only if clinically indicated. 
f: 
if patient has significant proteinuria, obtain a 24-hour urine for protein and creatinine 
clearance. 
g: Blood pressure will be measured at each clinic visit.  In addition, patients will be asked to 
measure their blood pressure twice daily at home, as follows: a resting morning blood 
pressure and an evening blood pressure.  Any abnormal blood pressure measurements 
should be reported to the research nurse within 24 hours.  Furthermore, the patient will be 
asked to record blood pressure readings in a blood pressure diary (Appendix C).  
h 
See Section 8.3 for details as to pharmacokinetic timepoints to be drawn Pre-study.  At 
the beginning of each cycle, a trough level will be drawn at each clinic visit prior to 
ingesting the first dose of drug for that cycle. 
 
 


31
10. MEASUREMENT OF EFFECT 
 
For the purposes of this study, patients should be reevaluated for response after 8 weeks.  In addition to a 
baseline scan, confirmatory scans should also be obtained 4 weeks following initial documentation of 
objective response. 
 
10.1 
Definitions 
Response and progression will be evaluated in this study using the new international criteria 
proposed by the Response Evaluation Criteria in Solid Tumors (RECIST) Committee [J Nat Cancer 
Inst 92(3):205-216, 2000].  Changes in only the largest diameter (unidimensional measurement) of 
the tumor lesions are used in the RECIST criteria. Note:  Lesions are either measurable or non-
measurable using the criteria provided below. The term “evaluable” in reference to measurability will 
not be used because it does not provide additional meaning or accuracy. 
 
10.1.1 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 with conventional techniques (CT, 
MRI, x-ray) or as >10 mm with spiral CT scan.  All tumor measurements must be recorded 
in millimeters (or decimal fractions of centimeters). 
 
10.1.2 Non-measurable disease 
All other lesions (or sites of disease), including small lesions (longest diameter <20 mm with 
conventional techniques or <10 mm using spiral CT scan), are considered non-measurable 
disease.  Bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusions, 
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses (not followed 
by CT or MRI), and cystic lesions are all non-measurable. 
 
10.1.3 Target lesions 
All measurable lesions up to a maximum of five lesions per organ and 10 lesions in total, 
representative of all involved organs, should be identified as target lesions and recorded 
and measured at baseline.  Target lesions should be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate repeated measurements 
(either by imaging techniques or clinically).  A sum of the longest diameter (LD) for all target 
lesions will be calculated and reported as the baseline sum LD.  The baseline sum LD will 
be used as reference by which to characterize the objective tumor response. 
 
10.1.4  Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and 
should also be recorded at baseline.  Non-target lesions include measurable lesions that 
exceed the maximum numbers per organ or total of all involved organs as well as non-
measurable lesions.  Measurements of these lesions are not required, but the presence or 
absence of each should be noted throughout follow-up.  
10.2 
Guidelines 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 when both methods have been used to assess the 
antitumor effect of a treatment. 
 
Clinical lesions. Clinical lesions will only be considered measurable when they are superficial 
(e.g., skin nodules and palpable lymph nodes).  In the case of skin lesions, documentation by color 
photography, including a ruler to estimate the size of the lesion, is recommended.  


32
 
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.  These techniques should be performed with cuts of 10 mm or less in 
slice thickness contiguously.  Spiral CT should be performed using a 5 mm contiguous 
reconstruction algorithm.  This applies to tumors of the chest, abdomen, and pelvis.  Head and neck 
tumors and those of extremities usually require specific protocols. 
 
Ultrasound (US).  When the primary endpoint of the study is objective response evaluation, US 
should not be used to measure tumor lesions.  It is, however, a possible alternative to clinical 
measurements of superficial palpable lymph nodes, subcutaneous lesions, and thyroid nodules.  US 
might also be useful to confirm the complete disappearance of superficial lesions usually assessed 
by clinical examination. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor evaluation has 
not yet been fully and widely validated.  Their uses in this specific context require sophisticated 
equipment and a high level of expertise that may only be available in some centers.  Therefore, the 
utilization of such techniques for objective tumor response should be restricted to validation 
purposes in reference centers. However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained. 
 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers are initially 
above the upper normal limit, they must normalize for a patient to be considered in complete clinical 
response.  Specific additional criteria for standardized usage of prostate-specific antigen (PSA) and 
CA-125 response in support of clinical trials are being developed. 
 
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. 
 
10.3 
Response Criteria 
10.3.1 Evaluation of target lesions 
 
Complete Response (CR): Disappearance of all target lesions 
 
Partial Response (PR): 
 
At least a 30% decrease in the sum of the longest diameter 
(LD) of target lesions, taking as reference the baseline sum 
LD 
 
Progressive Disease (PD):  
At least a 20% increase in the sum of the LD of target 
lesions, taking as reference the smallest sum LD recorded 
since the treatment started or the appearance of one or 
more new lesions 
 
Stable Disease (SD): 
 
 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest 
sum LD since the treatment started 
10.3.2 
Evaluation of non-target lesions 
 
 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization 
of tumor marker level 
 
Incomplete Response/ 


33
Stable Disease (SD): 
 
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 
 
Although a clear progression of “non-target” lesions only is exceptional, in such 
circumstances the opinion of the treating physician should prevail, and the progression 
status should be confirmed at a later time by the review panel (or study chair). 
Note:  If tumor markers are initially above the upper normal limit, they must normalize for a 
patient to be considered in complete clinical response. 
 
10.3.3 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 
(see Sections 10.1, 10.2, and 10.3). 
 
 
Target Lesions 
 
Non-Target Lesions 
New Lesions 
Overall Response 
 
CR 
 
CR 
No 
CR 
 
CR 
 
Incomplete 
response/SD 
No 
PR 
 
PR 
 
Non-PD 
No 
PR 
 
SD 
 
Non-PD 
No 
SD 
 
PD 
 
Any 
Yes or No 
PD 
 
Any 
 
PD 
Yes or No 
PD 
 
Any 
 
Any 
Yes 
PD 
 
Note: 
 
x 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be classified as 
having “symptomatic deterioration.”  Every effort should be made to document the objective 
progression, even after discontinuation of treatment. 
 
x 
In some circumstances, it may be difficult to distinguish residual disease from normal tissue. 
 When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
 
10.4 
Confirmatory Measurement/Duration of Response 
 
10.4.1 Confirmation 
 
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be 4 weeks after the criteria for response are first met.  
In the case of SD, follow-up measurements must have met the SD criteria at least once 
after study entry at a minimum interval of 8 weeks (see section 10.3.3). 
 
10.4.2 Duration of overall response 


34
 
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 recurrent disease is objectively documented. 
 
10.4.3 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.  
 
10.5 
Biochemical Response Criteria –PSA measurements (PSA Consensus Criteria) (Bubley et al. 
1999)
10.5.1 
PSA Decline of 50% 
 
A decline of PSA of at least 50% (confirmed by a second value at least 4 weeks after the 
first) with no other evidence of disease progression. 
10.5.2.  PSA Progression (all progression dates require to be confirmed by a second value after the 
first no sooner than 4 weeks after the initial measurement) 
A 50% increase in PSA over nadir (confirmed by a second reading four weeks later) in 
patients whose PSA has fallen by at least 50%. PSA increase must be at least 5ng/ml. 
10.5.2.1 
A 25% increase in PSA over nadir (confirmed by a second reading) in 
patients whose PSA has not fallen by at least 50%.  PSA increase must 
be at least 5ng/ml. 
10.5.2.2 
A 25% increase in PSA over baseline in patients whose PSA has not 
decreased.  PSA increase must be at least 5ng/ml. 
10.5.3 
Time to PSA Progression 
The time between the first day of treatment to the day of PSA progression as described in 
9.5.2.   the day of progression is defined as the first study day when the PSA level meets 
progression criteria (not the day of verification). 
10.5.4 Patients will not be taken off trial for changes in PSA alone.  
 
10.6 
Progression-Free Survival 
 
The primary objective of this study is to determine whether AZD2171, when used to treat metastatic 
androgen-independent prostate cancer, is associated with > 30% of patients’ progression free at 6 
months by radiographic and clinical criteria.  Patient monitoring studies and definitions of response 
are defined above.  Please refer to the statistics section for further details. 
 
Clinical evidence of progression even in the absence of clear radiographic or biochemical evidence 
of progression will be grounds for terminiation of study continutation for a given patient.  
Radiographic evidence of progression (progression or development of new measurable disease on 
CT scan or appearance of  at least 2 new lesions on bone scan) without concurrent PSA rises 
meeting progression criteria will be considered grounds for termination of study for a given patient.   
 
11. 
DATA REPORTING / REGULATORY CONSIDERATIONS 
Note: Adverse event lists, guidelines, and instructions for AE reporting can be found in Section 6.0 
(Adverse Events: List and Reporting Requirements). 
 
11.1 
Data Reporting 
 


35
For ease of reporting, this trial will utilize reporting guidelines as outlined by CTEP (available at 
http://ctep.info.nih.gov/reporting/index.html). These reporting guidelines have been formally adopted 
by the NCI IRB.   This study will use C3D to capture data and report to CDUS and will be monitored 
by the Clinical Data Update System (CDUS) version 3.0.  Cumulative CDUS data will be submitted 
quarterly to CTEP by electronic means.  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). 
 
11.2 
CTEP Multicenter Guidelines 
  
 
 
 
This is not a multicenter trial. 
 
11.3 
Cooperative Research and Development Agreement (CRADA)/Clinical Trials Agreement 
(CTA)
 
The agent(s), supplied by CTEP, DCTD, NCI, used in this protocol is/are provided to the NCI under 
a Collaborative Agreement (CTA) between the Pharmaceutical Company [hereinafter referred to as 
“Collaborators”] 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” contained within the terms of award, apply to the use of 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 investigational 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 participating on the study or patient’s 
family member, 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 
investigational 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 must provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NIH, 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. 
 
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 investigational 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 investigational agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will 
be made available exclusively to Collaborator(s), the NCI, and the FDA, as appropriate unless 
additional disclosure is required by law or court order.  Additionally, all Clinical Data and Results 
and Raw Data will be collected, used and disclosed consistent with alll 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 Principal Investigator for other studies) of Collaborator's wish to contact them. 
 


36
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 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: 
 
Regulatory Affairs Branch, CTEP, DCTD, NCI 
 
 
 
 
6130 Executive Boulevard, Suite 7111 
Rockville, MD  20852 
 
 
 
FAX 301-402-1584 
 
 
 
E-mail: anshers@ctep.nci.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. 
 
     11.4    Data and Safety Monitoring Plan 
The PI, protocol chairperson and the research nurse will meet at least           monthly to review all 
adverse events.  Unexpected adverse events and/or serious adverse events will be reported to the 
NCI IRB and CTEP.  If trends are noted and/or risks warrant it, accrual will be interrupted and/or the 
protocol and/or the consent will be modified accordingly.  MedWatch reporting will be used to report 
adverse events not previously associated with non-IND drugs to the FDA.  Adverse events thought 
to be associated with AZD2171 will be reported via AdEERS. 
 
 
12. STATISTICAL CONSIDERATIONS 
 
The primary objective of this study is to determine whether AZD2171, when used to treat metastatic AIPC, is 
associated with having 30% of patients progression free at 6 months by clinical andradiographic criteria.  If this is 
found to be the case, then this agent will be considered potentially useful when combined with other anticancer 
agents to be tested in later trials.  Data from previous trials of NCI patients with similar eligibility requirements 
demonstrated a 2.1 month median progression free survival when using thalidomide (n=63).  Median 
progression free survival on ketoconazole alone is expected to be 4 months based on previous trials. 
Ketoconazole is recognized as a standard therapy alterative to cytotoxic chemotherapy in the setting of failure of 
primary hormonal therapy with GnRH agonists and anti-androgen therapy.  The Eastern Cooperative Oncology 
Group sponsored a phase III clinical trial comparing ketoconazole to the combination of estramustine and 
docetaxel. (closed recently due to poor accrual).  Median progression free survival on ketoconazole alone was 
expected to be 4 months based on previous trials  Based on these results, it would be useful to demonstrate 
whether AZD2171 is able to induce progression free survival in 30% of patients at the 6 month (approximately 
day 180 evaluation) time point. 
The study will be conducted as a two-stage optimal design (Simon 1989). With alpha=0.10 and beta=0.10 as 
acceptable error probabilities, the trial will target 30% as the desirable proportion of patients who are still without 
progression by clinical and radiographic criteria by the 6th monthly evaluation (p1=0.30), and will be considered 
inadequate if only a fraction consistent with 10% are without progression by the same evaluation time (p0=0.10). 
Initially 12 patients will be enrolled and followed for progression. If 0-1 of the 12 is progression free at 6 months, 
then no further patients will be enrolled. The enrollment will be temporarily halted after the 12th patient unless we 
know that 2 patients have passed the 6 month point without progression.   If 2 or more of the first 12 reach 6 
months without progression, then enrollment will continue until a total of 35 evaluable patients have been 
entered. If 2-5 of 35 are able to get to 6 months without progression, this is not adequate responsiveness to 
treatment, while if 6 or more of 35 are progression free at 6 months, this will indicate results consistent with an 


37
adequate progression free survival probability worthy of further investigation. Under the null hypothesis (10% 
progression free at 6 months), the probability of early termination after 12 patients have been evaluated at 6 
months would be 66%. 
 
 
Given the difficulties in interpreting progression free rates in our patients compared to historical data, the 
response rate will be included as a secondary clinical endpoint.  In addition to evaluation of the proportion 
progression free at 6 months, the progression free survival will also be analyzed via a Kaplan-Meier curve.  This 
will be done for both progression free survival evaluated by clinical, radiographic and PSA criteria, as well as 
secondarily based only on clinical and radiographic criteria. This latter, secondary, evaluation will be based on all 
patients who are able to be assessed by these criteria in either the first (retrospectively) or second stage of 
accrual.  
 
 
12.1 
Sample Size/Accrual Rate 
Based on previous efforts in recruiting patients with this disease onto trials at the NCI, it is 
anticipated that 20-30 patients per year may be able to enroll onto this protocol.  To allow for up to 2 
inevaluable patients, the accrual ceiling will be set at 37. Thus, it is expected that accrual to this trial 
can be completed in approximately 1.5 years if all 37 patients are to be enrolled. 
 
12.2 
Stratification Factors 
There are no stratification factors.  
 
12.3 
Analysis of Secondary Endpoints 
PSA, pharmacokinetic, and molecular endpoints will be evaluated on the protocol in all available 
enrolled patients.  These will all be considered exploratory analyses, and will not have their 
statistical results adjusted for multiple comparisons. However, all interesting findings will be carefully 
interpreted as hypothesis generating.  
 
12.4 
Reporting and Exclusions 
12.4.1 
Evaluation of toxicity.   
All patients will be evaluable for toxicity from the time of their first treatment with AZD2171.  
12.4.2 
Evaluation of response.  
All patients included in the study must 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) should be included in the main analysis of the response rate.  Patients in 
response categories 4-9 should be considered as failing to respond to treatment (disease 
progression).  Thus, an incorrect treatment schedule or drug administration does not result in 
exclusion from the analysis of the response rate.   
 
12. 5 Statistical Analysis with prednisone 
 
As of June 2008, protocol 07-C-0059 has enrolled 28 evaluable patients, of whom 19 have experienced at least 
grade 2 fatigue, anorexia, and/or weight loss (68%). Since this incidence of constitutional symptoms tends to 
limit the ability to provide treatment which may be associated with improvement in disease outcome, the protocol 
will be amended following completion of the initial enrollment of 35 patients to include prednisone in combination 
with AZD2171. 
 
This amendment will permit 23 additional evaluable patients to enroll onto this trial and receive prednisone and 
AZD2171.  Using a one-sided 0.05 alpha level Fisher’s exact test, 23 patients will provide 80% power to detect a 
difference between the currently identified 19/28=68% of patients with grade 2 or worse fatigue, anorexia, and/or 
weight loss and 30% with the same level and type of symptoms.  The final comparison will be based on up to 35 
evaluable patients from the first part of the trial, and thus this power calculation may remain approximately 


38
correct based upon the findings at that time. 
 
An event free survival curve based on the initial 28 patients indicated  that the 3 month EFS probability was  
57% with a lower one-sided 90% CI bound of 43%, and the 6 month EFS probability was 38%, with a lower one-
sided 90% CI bound of 25%.  As a stopping rule, after 10 patients have been enrolled onto the amended 
protocol and potentially followed for at least 6 months, a Kaplan-Meier probability estimate of EFS will be 
constructed. If either the 3 month or the 6 month observed probability estimates are less than the corresponding 
lower one-sided 90% CI bounds (43% or 25% at 3 and 6 months respectively), then no further patients will be 
enrolled onto this amended version of the trial. Furthermore, at the conclusion of the trial, if final Kaplan-Meier 
estimated results are below those same lower bounds (43% or 25% at 3 and 6 months respectively), the 
combination will be considered to be inferior to that of AZD alone and will not be recommended for further 
consideration, even if constitutional symptoms improve dramatically. 
 
It is anticipated that approximately 1 to 1.5 years will be required to enroll 23 additional evaluable patients.  In 
order to allow for a small number of potentially inevaluable patients, the accrual ceiling for the protocol will be 
revised to be 62 patients (up to 37 for the first portion and 25 for the second). 
 
13. 
HUMAN SUBJECTS PROTECTIONS 
13.1 
Rationale for subject selection 
Subjects treated on this study, will be individuals with metastatic prostate cancer, which has 
recurred (or persisted) after appropriate standard treatment.  Individuals of any race or ethnic 
group will be eligible for this study.  Eligibility assessment will be based solely on the patient’s 
medical status.  Recruitment of patients onto this study, will be through standard CCR 
mechanisms.  No special recruitment efforts will be conducted. 
13.2 
Evaluation of benefits and risks/discomforts 
The potential benefit to a patient that goes onto study, is a reduction in the bulk of their tumor 
and improvement in their bony lesions, which may or may not have favorable impact on 
symptoms and/or survival.  Potential risks include the possible occurrence of any of a range of 
side effects, that are listed in the Consent Document (Please refer to 
http://ctep.cancer.gov/reporting/adeers.html to review the up-to-date expected adverse event list 
for AZD2171).  The procedure for protecting against or minimizing risks, will be to medically 
evaluate patients on a regular basis as described in Section 9. 
13.3 
Consent process 
Patients will meet with an associate or principal investigator on the trial in the Prostate Cancer 
Clinic, during the initial evaluation for this study.  During that meeting, the investiagor will inform 
patients of the purpose, alternatives, treatment plan, research objectives and follow-up of this 
trial.  The investigator will then provide a copy of the IRB-approved informed consent document 
that is included in this protocol.  The patient will be allowed to take as much time as he wishes, 
in deciding whether or not he wishes to participate.  If a prolonged period of time expires during 
the decision making process (several weeks, as an example), it may be necessary to reassess 
the patient for protocol eligibility. The original signed consent goes to Medical Records; copy 
placed in research record (NIH policy). 
 
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 the study. 
13.4 
Patient Records and Quality Assurance 
13.4.1 Drug Accountability  
          The unused AZD2171 (partial bottles, empty bottles, and full bottles) will be returned for drug 
accountability at each clinic visit.   Protocol related data will be entered into the NCI C3D 
database. Research records will be maintained to include but not limited to: 
o 
Signed, Dated Consent Form 
o 
Completed Eligibility Checklist 
o 
Source documents verifying eligibility criteria 
o 
Pre-study lab, radiology, pathology reports, histopathological results 
o 
Interim monitoring test results 


39
o 
Physician notes/progress notes documenting physical evaluations, PS, history, prior 
therapy 
o 
Physician/Nursing notes documenting vital signs, adverse event assessment, 
o 
Treatment administration forms-In-patient/Out-patient 
o 
PK Collection Forms 
o 
Study diary/record of self administered medication schedule/compliance 
o 
Response evaluation- results/tumor measurements 
o 
Research PET Scan/biologic correlate sample collection/analysis 
o 
Off study summary 
See also the CCR Standard Operating Procedure: Conducting and Documenting Drug 
Accountability for Oral Investigational Agents that are Self Administered by Patients 
(http://ccrintra.cancer.gov/clin_ops/policies/SOPCLIN1.pdf).
13.4.2 
Patients will use a diary to document daily drug intake, blood pressure, and adverse events 


40
 
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. 
 
 
 
 
 
 
 
 


41
APPENDIX B 
CTEP-assigned Protocol # 7395 
Local Protocol # 07-C-0059 
PATIENT’S PILL DIARY 
Cycle #_____________________ 
Patient Name________________________________   
INSTRUCTIONS TO THE PATIENT: 
1. 
Complete one form for each Cycle. 
2. 
You will take ___ pills each day.  You must take the pills on an empty stomach, one hour before or two hours after 
meals. 
3. 
Record the date, the number of pills you took, and when you took them.   
4. 
If you have any comments or notice any side effects, please record them in the Comments column. 
3. 
Please bring your pill bottle and this form to your physician when you go for your next appointment. 
4.Total dose: ___mg per day.  Number of pills each day: ___.  Effective date of dosage:___ 
 
Date
Day 
# pills, 
when 
taken
# pills
missed 
Comments 
Date 
Day 
# pills, 
when 
taken
# pills
missed 
Comments 
 
1 
 
 
 
 
17 
 
 
 
 
2 
 
 
 
 
18 
 
 
 
 
3 
 
 
 
 
19 
 
 
 
 
4 
 
 
 
 
20 
 
 
 
 
5 
 
 
 
 
21 
 
 
 
 
6 
 
 
 
 
22 
 
 
 
 
7 
 
 
 
 
23 
 
 
 
 
8 
 
 
 
 
24 
 
 
 
 
9 
 
 
 
 
25 
 
 
 
 
10 
 
 
 
 
26 
 
 
 
 
11 
 
 
 
 
27 
 
 
 
 
12 
 
 
 
 
28 
 
 
 
 
13 
 
 
 
 
 
 
 
 
 
14 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
16 
 
 
 
 
 
 
 
 
Patient’s Signature: ___________________________________  Date: ____________________ 
 
 
 


42
APPENDIX C 
CTEP-assigned Protocol # 7395 
Local Protocol #07-C-0059_ 
PATIENT’S BLOOD PRESSURE DIARY 
Cycle # _________ 
Patient Name________________________________ 
INSTRUCTIONS TO THE PATIENT: 
1. Your blood pressure readings have two numbers.  The first number is the pressure in your blood vessels during a 
heart beat (systolic), and the second number is the pressure in the vessels when the heart rests in between beats 
(diastolic).  These numbers are usually written with a slash in between them (for example, normal blood pressure 
is 120/80). 
2. Record the date, then record your blood pressure twice each day using a home blood pressure monitor:  
x each morning after sitting quietly for 30 minutes or reading (not while you are active:  dressing, making 
breakfast, etc.) 
x each evening at bedtime or while you are relaxing during the evening 
3. If you take your blood pressure at other times of the day, please record the numbers and time under “Other 
readings.”  
4. If your systolic pressure is greater than 150 or your diastolic blood pressure is greater than 90 twice in a row 
measured several hours apart, please contact your research nurse at NIH for instructions.  
5. Patients should seek medical advice immediately if their BP exceeds 180 mmHg (systolic) or 105 mmHg 
(diastolic) at any time and should also be encouraged to contact their physician if they are concerned about any 
symptoms that may be associated with high blood pressure (e.g., headache). 
6. Please bring this form to every clinic visit or appointment.  
 
Date 
AM 
reading
s
PM
reading
s
Other readings 
(include time of day) 
Date 
AM 
reading
s
PM
reading
s
Other readings 
(include time of day) 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
 
/ 
/ 
 
/
/
 
Patient’s Signature: _____________________________________________  Date:  
 


43
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