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UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
CONSENT TO PARTICIPATE IN A RESEARCH STUDY
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Study Title: A phase I/II study of sunitinib (SU11248) in combination with metronomic and methotrexate for patients with metastatic breast cancer Phase 1 Consent Form Version 7.0 11 pages
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August 28, 2008

Consent for Phase I Study

This is a clinical trial, a type of research study. Your study doctor(s) Dr. Hope Rugo and associates from the University of California, San Francisco (UCSF) Comprehensive Cancer Center, will explain the clinical trial to you.
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Clinical trials include only people who choose to take part. Please take your time to make your decision about participating. You may discuss your decision with your family and friends and with your health care team. If you have any questions, you may ask your study doctor.

You are being asked to take part in this study because you have metastatic breast cancer that has not responded to one chemotherapy treatment.
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Why is this study being done?

This study will have two parts, also known as phase I and phase II. You are being asked to participate in this phase I study. The purpose of this study is to test the safety of sunitinib, a new cancer drug, at different dose levels. Sunitinib has already been approved by the Food and Drug Administration for the treatment of kidney cancer and a rare kind of sarcoma.
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Sunitinib will be given with two other chemotherapy drugs, cyclophosphamide and methotrexate. These two drugs are already approved for the treatment of breast cancer.
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However, they will be given daily, in lower doses than the doses that are typically used to treat patients with breast cancer. This dosing schedule is called "metronomic."
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Unlike standard cancer treatment, where large doses of chemotherapy drugs are given in a cyclical fashion, metronomic dosing involves giving low doses of chemotherapy every day, without a break. In animal studies, metronomic chemotherapy can be effective at treatingt tumors that do not respond to standard, cyclical chemotherapy.
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We believe that using sunitinib in combination with metronomic dose cyclophosphamide and methotrexate targets new blood vessels that are formed by tumors, and that damaging these blood vessel or preventing the new tumor blood vessels from developing may be an effective way to treat cancer.
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We want to find out what the optimal dose of sunitinib is to use with these other drugs. We also want to learn more about what effects, good and/or bad, that this combination of drugs has on you and your breast cancer.
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This study is being sponsored by Pfizer, Inc., the manufacturer of sunitinib.
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How many people will take part in this study?
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Between 6 and 18 people will take part in this study. At the beginning of the study, 3 patients will be treated with a low dose of the drug. If this dose does not cause bad side effects, it will slowly be made higher as new patients take part in the study. You can ask your study doctor what dose you will receive. A total of 18 patients is the most that would be able to enter the study. This study will only be open at the UCSF Comprehensive Cancer Center.
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What will happen if I take part in this research study?

Before you begin the main part of the study:

You will need to have the following exams, tests or procedures to find out if you will be in the main part of the study. These exams, tests or procedures are part of regular cancer care and may be done even if you do not join the study.
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If you have had some of them recently, they may not need to be repeated. This will be up to your study doctor.

1. Complete medial history and physical
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2. Blood drawing (venipuncture); A blood sample will be drawn by inserting a needle into a vein in your arm. About 4 teaspoons will be taken to check blood counts and chemistry levels.
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3. Pregnancy test for women of child-bearing potential. This test will require removal of 1 teaspoon of blood.
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4. CT scan, you will need to lie still on a table with your body inside a large doughnut-shaped machine. The table will move and the machine will make clicking and whirring noises as the pictures are taken. An iodine dye (contrast material) will first be injected into a vein and given to your orally. The dye may make tissue and organs more visible in the pictures. Each CT scan will take about 15 minutes to a half hour.
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5. Bone scan (patients with known bone metastases): A bone scan is a test where a small amount of radioactive substance is injected in your vein followed 3 hours later by you lying under a machine which will develop an image of your bones. This image of your bones may alert your doctors of any possibility of spread of your cancer to the bones. The test itself will take about 1 hour, but the whole process takes up to 4 hours.
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6. Echocardiogram: As part of the screening procedures you will have an echocardiogram to make sure your heart is functioning properly. This examination uses sound waves to make pictures of your heart, which helps determine how well your heart pumps blood. You will be asked to lie on your left side while a technician places a probe with gel on your chest to creart images of your heart to determine the function and size. The procedure is done in the cardiology department and will take approximate 60 minutes.

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During the main part of the study:

If the exams, tests and procedures show that you can be in the main part of the study, and you choose to take part, then you will need the following tests and procedures. They are part of regular cancer care.

1. Medical history and physical exam at the start of each new cycle of treatment.
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2. Blood drawing (venipuncture): At the start of each new cycle of treatment, a blood sample will be drawn by inserting a needle into a vein in your arm to measure your blood counts and chemistry levels. Each sample will be approximately 2 teaspoons, a total of about 4 tablespoons will be drawn for the whole study however some subjects may have more total blood drawn if they receive study treatment for more than 5 cycles.

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You will also need the following tests and procedures that are part of regular cancer care, but they will be done more often because you are in this study.

1. CT scan: You will have a computer tomography (CT) scan of your chest/ abdomen/ pelvis every 6 weeks to see what the effects the study treatment is having on your breast cancer.
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2. Bone scan: If you had breast cancer in the bones at the start of this study, you will have a bone scan every 6 weeks to see what the effects of the study treatment is having on your breast cancer.

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You will also need the following tests and procedures done that are either being tested in this study or being done to see how the study if affecting your body.

1. Blood draw (venipuncture) to remove a sample of blood to monitor the effects of the study treatment on the levels of 2 types of cells in your blood. The cell types are circulating tumor cells (CTCs) and circulating endothelial cells (CECs). We are looking at these levels to see if they may help us predict which patients will have a response to the study treatment. This blood sample can be taken at the same time as the other blood tests. About 3 teaspoons of blood will be removed at the start of each cycle of chemotherapy and approximately 4 tablespoons of blood will be drawn for the whole study.

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When you are finished receiving the study treatment:

You will come back to the clinic for a follow up visit within 30 days after the last dose of your treatment. At this visit, you will have a complete medical history and physical exam and a blood draw to check blood counts, chemistry levels. You will also have a blood sample taken for measurement of levels of CTCs and CECs; this test is part of the study and not standard of care. If you continue to have side effects from the study treatment, you will continue to have follow up visits to monitor these symptoms until they are improved or stable.
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You will be contacted by the study coordinators every 2 months for up to one year from the last dose of study treatment to check on your health status. This may be done during clinic visits or on the phone.

1. Study location: All study procedures will be done at the UCSF Comprehensive Cancer Center.

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Study Chart

Cycle 1

Day -- What you do
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Day 1 of treatment

Get routine blood tests as well as a blood sample taken to test for CTC and CECS.

Begin taking Sunitinib once a day. Keep taking this medication until the end of study, unless told to stop by your health care team. ..
Day 15 Return to your doctor's office for a follow up visit to see what side effects you may be having
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Get routine blood tests as well as a blood samples taken to test for CTCs and CECs.
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If you have not been having serious side effects from the sunitinib, you will start taking cyclophosphamide and methotrexate on this day. The cyclophosphamide should be taken everyday. The methotrexate is taken twice a day for 2 days in a row each week. ..
Day 37 Return to your doctor's office for you next exam and to begin the next cycle. ..
Future Cycles

Day -- What you do
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Days 1-21

Keep taking the study treatment if you have no bad side effects and your breast cancer is not getting worse. Call the doctor at (415) 353-7070 if you do not know what to do.
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Get routine blood tests and exams every cycle (more if your doctor tells you to).
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Get blood sample taken for measurement of CTCs and CECs at the start of the second and third cycle, then every other cycle.
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Get routine CT scans every other cycle (more if your doctor tells you to).
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If you have breast cancer in your bones, you will also have routine bone scans done every other cycle. ..
Day 22

Return to your doctor's office for your next exam and to begin the next cycle. ..
Study Plan

Another way to find out what will happen to you during the study is to read the chart below. Start reading at the and read down the list, following the liens and arrows.
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Start Here

Take sunitinib by mounth every day for 14 days
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If you do not have serious side effects from sunitinib, the you will start taking cyclophosphamide by mouth every day and methotrexate twice a day for 2 days in a row each week. ..
How long will I be in the study?

You will be asked to take sunitinib, cyclophosphamide, and methotrexate every day until your physician believes the treatment may not be beneficial to you. If you develop serious side effects or your breast cancer does not respond to the study treatment, you will stop the study treatment at that time.
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After you are finished taking the study medications, the study doctor will ask you to visit the office for a follow up visit 30 days after you have stopped the treatment. You will have a medical history and physical exam performed, as well as a blood test.
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If you do develop side effects from the study medications, you will have regular follow up in the clinic until your symptoms have improved or stabilized.
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You will be contacted by a member of the study team every 2 months to check on your health status for up to year from the day that you started taking the study medication. These follow up contacts can be done in clinic visits or over the phone. Keeping in touch with you and checking on your condition helps us look at the long-term effects of the study.
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Can I stop being in the study?

Yes. You can decide to stop at any time. Tell the study doctor if you are thinking about stopping or decide to stop. He or she will tell you how to stop your participation safely.
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It is important to tell the study doctor if you are thinking about stopping so any risks from the study medication can be evaluated by your doctor. Another reason to tell your doctor that you are thinking about stopping is to discuss what follow-up care and testing could be most helpful for you.

The study doctor may stop you from taking part in this study at any time if he/she believes it is in your best interest, if you do not follow the study rules, or if the study is stopped.
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What side effects or risks can I expect from being in the study?

You may have side effects while on the study. Everyone taking part in the study will be watched carefully for any side effects. However, doctors don't know all the side effects that may happen.
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Side effects may be mild or serious. Your health care team may give you medicines to help lessen side effects. Many side effects go away soon after you stop taking the study medications. In some cases side effects can be serious, long lasting, or may never go away. There is also a risk of death.

You should talk to your study doctor about any side effects you experience while taking part in the study.
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Risks and side effects related to sunitinib are listed below. These side effects occurred in patients with metastatic beast cancer who were taking a higher dose of sunitinib than the doses that are being tested in this study. The potential risks and side effects include those which are:
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Likely between (10-50%):

1. Fatigue, which can limit your activities
2. High blood pressure, which may require need for medication
3. Diarrhea
4. Nausea
5. Loss of appetite
6. Upset stomach
7. Vomiting
8. Increase lipase level (a digestive enzyme)
9. Yellowing of the skin
10. Hair color changes
11. Headache
12. Shortness of breath
13. Inflammation of mucous membranes (including mouth sores)
14. Altered taste
15. Swelling
16. Constipation
17. Muscle aches
18. Joint/back pain
19. Dermatitis

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Less Likely (1-10%)

1. Nosebleeds
2. Insomnia
3. Cough
4. Fever
5. Increased eye tearing
6. Increased heart muscle enzyme levels
7. Decreased heart muscle function
8. Increased levels of liver enzymes (may indicate liver damage)
9. Decreased kidney function
10. Decreased white blood cells infection fighting cells; this problem may lead to increased risk of infection)
11. Decreased red blood cells (may make you feel tired or short of breath
12. Decreased platelet count (may lead to increased bleeding)

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Rare but serious

1. Dysfunction of adrenal gland (which would cause lowered blood pressure and fatigue)
2. Weakness of the heart muscle; irregular heartbeat
3. Clots in blood vessels
4. Decreased thyroid gland function
5. Infection
6. Decreased blood flow to the brain
7. Bleeding requiring transfusion

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A subject on this study fell down and hit her head. This caused bleeding around her brain (similar to a stroke) that was very serious. It is unknown if being on this study contributed to her bleeding
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Risks and side effects related to cyclophosphamide include those which are:
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Likely (more than 10%)

1. Nausea
2. Infertility

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Less Likely (between 1-10%)

1. Skin rash
2. Headache
3. Dizziness
4. Increased liver enzyme tests (may indicate liver damage)

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Rare but serious

1. Development of another type of cancer
2. Steven-Johnson syndrome (can be a life-threatening skin disorder)
3. Interstitial pneumonitis (inflammation of the lung which can affect your breathing)

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Risks and side effect related to methotrexate include those which are:
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Likely (more than 10%)

1. Elevated liver function tests (?)
2. Nausea
3. Vomiting

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Less Likely (between 1-10%)

1. Mouth sores
2. Decreased platelet count (may increase risk of bleeding)
3. Skin rash
4. Diarrhea
5. Hair loss or thinning
6. Decreased white blood cell counts (infection fighting cells; this problem may lead to increased risk of infection_
7. Decreased red blood cells (may make you feel tired or short of breath)
8. Dizziness

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Rare but serious

1. Interstitial pneumonitis (a serious inflammation in the lung
2. which can affect your breathing)

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Other Risks:

1. Blood drawing (venipuncture) risks; Drawing blood may cause temporary discomfort from the needle stick, bruising, and infection.
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2. Radiation (x-ray) risks:
   
   The amount of radiation you will be exposed to is relatively small. Such doses of radiation may be potentially harmful, but the risks are so small that they are difficult to measure. If you have already had many x-rays, you should discuss this was the researchers before agreeing to be in the study.
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3. CT scan risks: CT scans involve the risks of radiation (see above).
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   In addition, if contrast material (iodine dye) is used, there is a slight risk of developing an allergic reaction, from mild (itching, rash) to severe (difficulty breathing, shock, or rarely, death).
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   The contrast material may also cause kidney problems, especially if you are dehydrated or have poor kidney function. The study doctors will asked you about any allergies or related conditions before the procedure. If you have any of these problems, you may not be allowed to have a CT scan or continue in the study.
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   Having a CT scan may mean some added discomfort for you. In particular, you may be bothered by feelings of claustrophobia when placed inside the CT scanner, or by lying in one position for a long time.
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   If contrast material is used, you may feel discomfort when it is injected. You may feel warm and flushed and get a metallic taste in your mouth.
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   Rarely, the contrast material may cause nausea, vomiting or a headache.
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4. Bone Scan risks: You may develop bruising when a needle is placed in your veins to administer the radioactive substance through your veins. You may be uncomfortable lying flat.
   
   
5. Reproductive risks: You should not become pregnant or father a baby while on this study because the drugs in this study can affect an unborn baby. You will be asked to have a pregnancy test prior to entering this study, if you have child-bearing potential, to ensure that you are not pregnant. Women should not breast feed a baby while on this study. Check with your study doctor about what kind of birth control methods to use and how long to use them. Some methods might not be approved for use in this study. Some of the drugs used in the study may make you unable to have children in the future.
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6. Unknown Risks: The experimental treatment may have side effects that no one knows about yet. The researchers will let you know if they learn anything that might make you change your mind about participating in the study.

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For more information about risks and side effects, ask your study doctor.
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Are there benefits to taking part in the study?

Taking part in this study may or may not make you health better. Although doctors hope the study medication (sunitinib, cyclophosphamide, and methotrexate) will be more useful against cancer compared to the usual treatment, there is no proof of this yet. We do know that the information from this study will help doctors learn more about the study medications as a treatment for cancer. This information could help future cancer patients.
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What other choices do I have if I do not take part in this study?

You other choices may include:

1. Getting standard therapy for care for your cancer without being in a study.
2. Taking part in another study.
3. Getting no treatment

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Please talk to your doctor about your choices before deciding if you will take part in this study.
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Will my medical information be kept private?

We will do our best to make sure that the personal information in your medical record is kept private. However, we cannot guarantee total privacy. Your personal information may be given 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.
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Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include:

1. UCSF's Committee on Human Research
2. Pfizer, Inc., the study sponsor
3. The National Cancer Institute (NCI) and other government agencies, e.g., the Food and Drug Administration (FDA), involved in keeping research safe for people.
4. Insurance companies

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What are the costs of taking part in this study?

You and/or health plan/insurance company will need to pay for some or all of the costs treating your cancer in this study. Some health plans will not pay these costs for taking part in studies. Check with you health plan/insurance company to find out what they will pay for. Taking part in this study may or may not cost you or your insurance company more than the cost of getting regular cancer treatment.
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The study sponsor, Pfizer, Inc., is providing one of the study drugs, sunitinib, at no cost to you. Any study- related tests or procedures outside of the standard of care are also covered by the study sponsor. You or your health plan will have to pay for other costs which are not covered by the sponsor. If, during the study, sunitinib becomes approved for use in your cancer, you and/or you health plan may have to pay for the drug needed to complete this study.
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For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute's Web site a 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.
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Will I be paid for taking part in this study?

You will not be paid for taking part in this study.
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What happens if I am injured because I took part in this study?

It is important that you tell your study doctor, Dr. Hope Rugo, if you feel that you have been injured because of taking part in this study. You can tell the doctor in person or call him/her at (415) 353-7070. Treatment and Compensation for Injury: If you are injured as a result of being in this study, treatment will be available. The costs of the treatment may be covered by the University of California or the study sponsor, Pfizer, Inc., depending on a number of factors. The University and the study sponsor do not normally provide any other form of compensation for injury. For further information about this, you may call the office of the Committee on Human Research at 415-476-1814.
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What are my rights if I take part in this study?

Taking part in this study in your choice. You may choose either to take part or not to take part in the study. If you decide to take part in this study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our institution.
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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 our legal right to seek ______________________________
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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 doctor(s) Dr. Hope Rugo and associates (415) 353-7070.

For questions about your rights while taking part of this study, call the office of the Committee on Human Research, UCSFs Institutional Review Board (a group of people who review the research to protect your rights) at 415-476-1814.
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CONSENT

You have been given copies of this consent form and the Experimental Subject's Bill of Rights to keep. You will be asked to sign a separate form authorizing access, use, creation, or disclosure of health information about you.
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PARTICIPATION IN RESEARCH IS VOLUNTARY. You have the right to decline to participate or to withdraw at any point in this study without penalty or loss of benefits to which you are otherwise entitled.

If you wish to participate in this study, you should sign below.
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Date Participant's Signature for Consent


Date Person Obtaining Consent


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IRB Approval Number H6961-28991

University of California
Permission to Use Personal Health Information for Research

Study Title (or IRB Approval Number if study title may breach subject's privacy): Phase I/II Study of SU 11248 (Sutent) in combination with metronomic dosing of Cyclophosphamide and methotrexate in patients with metastatic breast cancer. ..
Principal Investigator: Hope Rugo, MD
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Sponsor/Funding Agency (if funded): Pfizer

1. What is the purpose of this form?
   
   State and federal privacy laws protect the use and release of your health information. Under these laws, the University of California San Francisco (UCSF) or your health care provider cannot release your health information to the research team unless you give your permission. The research team includes the researchers and people hired by the University or the sponsor to do the research. If you decide to give your permission and to participate in the study, you must sign this form, as well as the Consent Form. This form described the different ways that the researcher, research team and research sponsor may use your health information for the research study. The research team will use and protect your information as described in the attached Consent Form. Once your health information is released it may not be protected by these privacy laws and might be shared with others. However, other laws protecting your confidentiality may still apply. If you have questions, please ask a member of the research team.
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2. What Personal Health Information will be released?
   
   If you give your permission and sign this form, you are allowing ___________________ to release the following medical records containing your Personal Health Information. Your Personal Health Information includes health information in your medical records and information that can identify you.
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   For example, Personal Health Information may include your name address, phone number or social security number.
   1. Entire Medical Records
   2. Outpatient Clinic Records
   3. Progress Notes
   4. Consultations
   5. History & Physical Exams
   6. EKG
   7. Radiology Reports
   8. Radiology Images
   9. Diagnostic Imaging Reports
   10. Operative Reports
   11. Pathology Reports
   12. Emergency Medicine Center Reports
   13. Laboratory Reports
   14. Psychological Tests
   15. Dental Records
   16. Discharge Summaries
   17. Health Care Billing
   18. Other: _____________________________________________
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3. Do I have to give my permission for certain specific uses?
   
   Yes. The following information will only be released if you give your specific permission by putting your initial on the line(s)
   1. __ I agree to the release of information pertaining to drug and alcohol abuse, diagnosis or treatment.
   2. __I agree to the release of HIV/AIDS testing information.
   3. __ I agree to release of genetic testing information
   4. __ I agree to the release of information pertaining to mental health diagnosis or treatment as follows: _______________________________________________________
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4. How will my Personal Health Information be used?
   
   You Personal Health Information may be released to these people for the following purposes:
   1. To the research team for the research described in the attached Consent Form;
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   2. To others at UC who are required by law to review the research
      
      
   3. To others who are required by law to review the quality and safety of the research, including: U.S. government agencies, such as the Food and Drug Administration, the research sponsor or the sponsor's representatives, or government agencies in other countries. These organizations and their representatives may see your Personal Health Information. They may not copy or take it from your medical records unless permitted or required by law.
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5. How will my Personal Health Information be used in a research report:
   
   If you agree to be in this study, the research team may fill out a research report. (This is sometimes called a "case report.") The research report will not include your name, address, or telephone or social security number. The research report may include your date of birth, initials, dates you received medical care, and a tracking code. The research report will also include information the research team collects in the study. The research team and the research sponsor may use the research report and share it with others in the following ways:
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   1. To perform more research;
   2. Share it with researchers in the U.S. or other countries;
   3. Place it into research databases;
   4. Use it to improve the design of future studies;
   5. Use it to publish articles or for presentations to other researchers;
   6. Share it with business partners of the sponsor; or
   7. File applications with U.S. or foreign government agencies to get approval for new drugs or health care products.
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6. Does my permission expire?
   
   This permission to release your Personal Health Information expires when the research ends and all required study monitoring is over. Research reports can be used forever.
   
   
7. Can I cancel my permission?
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   You can cancel your permission at any time. You can do this in two ways. You can write to the researcher or you ask someone on the research team to give you a form to fill out to cancel your permission. If you cancel your permission, you may no longer be in the research study. You may want to ask someone on the research team if canceling will affect your medical treatment. If you cancel, information that was already collected and disclosed about you may continue to be used. Also, if the law requires it, the sponsor and government agencies may look at your medical records to review the quality or safety of the study.
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8. Signature
   
   If you agree to the release and use of your Personal Health Information, please sign below. You will be given a signed copy of this form.
   
   
   

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Name of Subject (Print)


Signature of Subject

Date


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Note: If the subject is a minor, an individual signing with a "X", an adult incapable of giving consent, or is unable to read the authorization, fill out and attached the "special signatures" page (sections "I" and "J").