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KAISER FOUNDATION HOSPITALS
THE PERMANENTE MEDICAL GROUP, INC.

CONSENT TO PARTICIPATE IN A MEDICAL RESEARCH STUDY
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FORMAL TITLE:

A RANDOMIZED PHASE III TRIAL OF PACLITAXEL VERSUS PACLITAXEL PLUS BEVACIZUMAB (RHUMAB BEFG) AS FIRST-LINE THERAPY FOR LOCALLY RECURRENT OR METASTATIC BREAST CANCER (CTSU E2100)
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Researchers at Kaiser Permanente are conducting a research study. To decide whether or no you want to be part of this research, you should understand the risks and benefits in order to make an informed decision. You have the right to know what the purpose of the study is, how participats are selected, what procedures will be used, what the potential risks and benefits and possible alternateive treatmenst are, and what is expected of you as a study participant. This process is called "informed consent." This consent form gives information about the research study, which the study doctor will discuss with you.
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This consent form may contain words or phrases that you do not understand. Please ask the study doctor or thestudy staff to explain any words or information that you do not clearly understand. You may take home an unsigned copy of this consent form to think about or discuss the study with family or friends before making your decision. Once you are satisfied that you understand the study, you will be asked to sign and date this consent if you choose to participte. You will be given a copy of the signed and dated consent form.
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This study is being conducted by the Cancer Trials Support Unit (CTSU). CTSU is research group sponsored by the National Cancer Insitute to provide greater access to cancner trials. Your doctor is a memeber of CTSU or another group that is participating in ths study.
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About 685 people will take part in this study.


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STUDY PURPOSE
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You are being asked to take part in this study because you have breast cancer that has spread. This research is being done because current treatment does not help everyone with breast cancer that has spread or recurred. Cancers must stimulate the growth of new bloodvessels in order to continue growing. This process is called "angiogenesis." New drugs may treat cancers by blocking these new blood vessels from growing in the tumor.
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The purpose of this study is to evaluate and compare the effectivenss of treatment wtih paclitaxel (Taxol) in combintation with bevacizumab (rhuMab VEGF), an investigational agent, (an angiogensis inhibitor) compared to treatment with paclitaxel alone in women with breast cancer that has spread. The Food and Drug Administration (FDA) considers an investigational drug to be a drug that is being tested and not approved for genneral use; therefore it is not commercially available. Paclitaxel has been approved by the FDS and is one of the most effective chemotherapy drugs for the treatment of breast cancer and is commonly used when breast cancer has spread beyond the breast or axillary lymph nodes.


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STUDY PROCEDURES

If you decide to partricipate in this study, the following will occur:
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Before receiving treatment, you will undergo various tests and procedures to determine if you are eligible to participate in this study, including, but not limited to the following: a quality-of-life assessment, collection of information about yoru medical history, physical examination, including vital signs (blood pressure, pulse, temperature, weight, and height), computerized tomography (CT) scan or magnetic resonance imaging (MRI), blood and urine tests. If you are a woman of childbearing potential, a pregnancy test will be performed. Some these tests would done even if yuou do not take part in the study.
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It if is determined that you are elegible to participate in this study, you will be randomly assigned (by chance, like flipping a coin) to one of the two treatment groups: paclitaxel plus bevacizumab (Group A) or paclitaxel (Group B). You will have an equal chance of being placed in either group. You and your doctor will not be able to choose which treatment you receive.
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Treatment will be carried out as follows:
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Group A: You will receive paclitaxel as an infusion in the vein every week for three weeks followed by one week rest period. You will not receive any treatment during the one week rest period. In addition you will receive bevcizumab as an infusion in the vein once every two weeks. Each 4-week period will be considered one cycle. All treatment will done in a clinic or doctor's office. You may a receive a maximum of 18 cycles (72 weeks) of treatment.
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Group B: You will receive paclitaxel as an infusion in the vein every week for three weeks followed by one week rest period. You will not receive any treatment during the one week rest period. Each 4-week period will be considered one cycle. All treatment will done in a clinic or doctor's office. You may a receive a maximum of 18 cycles (72 weeks) of treatment.


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LENGTH OF PARTICIPATION
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You will be in the study for a maximum of 72 weeks or until your disease progresses or side effects of therapy would make it unsafe for you to continue. You medical condition will be tracked for five years from the time you begin treatment on this study to look at the long-term effects of the treatment. Your doctor may decide to take you off this study if your desease does not improve or if side effects of treament would make it unsafe to continue.
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You may stop participating at any tie. However, if you decide to stop participating in the study, we encourage you to talk to your doctor first.


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POSSIBLE RISKS AND SIDE EFFECTS
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While on the study, you are at risk for the following side effects. Paclitaxel and bevacizumab my cause some, all or none of the side effects listed. You should discuss these with your doctor. There may also be other side effects that we cannot predict. Other drugs will be given to make side effects less serious and less uncomfortable. Many side effects go away shortly after the drugs are stopped, but in some cases side effects can be serioud, long-lasting, permanent, or life threatening. Death is rare, but possible. There have been patients who have been treated withy bevacizumab for lung cancer who have experienced fatal hemorrhage.


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Paclitaxel (Taxol)

More Likely:

• Lowering of your blood cell counts that could cause infection, easy bruising and bleeding, or anemia
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• Mild to sever allergic reaction
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• Numbness and pain of the hands and feet that sometimes worsens with additional treatment and may not disappear after the drug is stopped
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• Hair loss
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• Muscle weakness and muscle loss
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• Muscle and joint aches
  
  

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Less likely:

• A slowing of the heart rate
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• Irregular heartbeats
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• Nausea and/or vomiting
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• Diarrhea
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• Sores in the mouth or throat
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• Fatigue
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• Lightheadness
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• Headaches
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• A sensation of flashing light or spots
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• Changes in kidney function tests
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• An increase in triglyceride (blood lipid) levels
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• Changes in liver enzymes
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• Confusion; mood changes
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• Skin irritation and swelling if the drug leaks from the vein into which it is being injected into the surrounding skin.
  
  

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Rare:

• Liver damage or failure
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• Seizure
  
  

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Bevacizumab (rhuMab VEGF):

• Bleeding from the lungs, stomach or colon
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• Blood clots in the arteries or veins of the legs, lung (pulmonary embolism) or abdomen
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• Stroke
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• Hypersensitivity associated with the infusion (fever, chills, rash itching)
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• High or low blood pressure
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• Increase in heart rate
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• Shortness of breath
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• Chest pain
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• Loss of protein in the urine
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• Muscle pain
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• Sores in the mouth or throat
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• Delay in wound healing or breakdown of a wound that had healed
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• Nose bleeds
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• Headaches
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• Fertiity impariment; unknow duration
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• Nausea and vomiting
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• Nephrodic syndrome (loss of protein in urine, swelling of tissues, loss of albumin in blood)
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• Fever
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• Chills, shivering
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• Rash
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• Inflammation of the mucous lining of the mouth and/or throat
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• Infection
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• Intensinal obstruction
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• Inflammation of the colon
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• Blood leaking from the heart
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• Fluid leaking from the lungs
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• A few patients have experienced "bowel perforation" and "bowel anastomotic hehisence". Bowel performation occurs when an opening exists in the bowel wall allowig bowel contents to spill into the abdomen. Bowel anastomotic dehisence is a breakdown in the surgical connection between two pieces of bowel. These events can be life threatening. In addition, there have also been a few reports of surgical wounds healing slowly or poorly. We do not know at thtis time if these side effects are related to treatment with bevacizumab or if they are due to other factors such as worsening of the patient's cancer, chemotherapy, or previous surgery or radiation's.
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• Reversible and marked elevations of liver function tests have been reported (rarely) when bevacizumab is used in combination with chemotheapy or concurrently with other drugs that are potentially toxic to your liver. It is currently unclear what causes this liver toxicity and whether or not bevacizumab alone could be the cause.
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• Congestive hear failure (CHF) or decrease in heart function.
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• NOTE: Blood clots or bleeding could be life threatening or fatal.

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Other risks: the risks of drawing blood include mild pain, bruising and/or bleeding at the needle stick site, and in rare cases, dizziness or fainting, or infection.


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PREGNANCY/CONTRACEPTION
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Because the drugs in this study can affect an unborn child, women who are pregnant, will be not able to participate in this study. If you are of childbearing age and choose to be sexually active during the course of this study, you must use effective birth control while participating in this study. If you become pregnant while you re participating in this study, you must notify your doctor or nurse immediately and you will be removed from the study. If you have any questions about the reproductive issues or about preventing pregnancy, please discuss them with your doctor or a member of the Study Team.


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POSSIBLE BENEFITS
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It is not possible to predict whether or not you will receive any personal benefit form participating in this study. The possible benefits of taking part in the sutyd are the same as receiving paclitaxel without bein in the study. It is hoped that the information learned from this study will beneift other women with breast cancer in the future.


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ALTERNATIVES

Instead of being in this study, you have these options:

• Standard chemotherapy or hormonal therapy.
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• Standard agents includ, but are not limited to paclitaxel, docetaxel, doxorubicin or anastrazole
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• No therapy at this time, with care to help you feel more comfortable.

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Please talk to your doctor about these and other options.


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INJURY
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Any injury or condition experiencedby a member of Kaiser Foundation Health Plan (KFHP), as a result of being in this study, will be treated in accordance with the member's Health Plan coverage, as described in the Service Agreement.
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If you experience any symptoms that you think may be related to other medical problems, or have any questions about the research compensation, or your rights as a participant in this study, call Louis Fehrenbacher, MD or his associates at telephone number (707) 651 2797.


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COSTS/PAYMENT
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Tests and services used in this study, and the drug paclitaxel will be provided as described under your KFHP member Services Agreement. The Division of Cancer Treatment and Diagnosis, National Cancer Institute will provide you with the investigational agent bevacizumab free of charge for this study. Should bevacizumab become commercially available during your participation in this study, it will be provided as described under your Member Services Agreement.
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You will not receive any payment or other compensation for participating in this study.


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VOLUNTARY PARTICIPATOIN/TERMINATION

Participation in this study is completely voluntary. You are free to refuse to participate in this study. Your decision whether or not to participate in the study will not affect your medical dare. If you decide to participate, you are free to change your mind and discontinue participation at any time without any effect on your medical care or elegibiity for future care or memebership in KFHP.
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You will be informed of new developments that may become available that might affect your willingness to continue treatment, or willingness to stay in this study.
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Should your disease become worse, should side effects become very severe, should new scientific developments occur that indicates the treatment is not in your best interest, or should your physician feel that participation in this study in no longer in your best interest, the treatment will be stopped. Further treatment will be discussed.


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CONFIDENTIALITY

Efforts will be made to keep your personal information confidential. However, your personal information may be disclosed if required by law.
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A Data Safety and Monitoring Board, an independent group of experts will be reviewing the data from this research throughout the study.
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Organizations that may inspect and/or copy your research records for quality assurance and data analysis include groups such as:

• The Eastern Cooperative Oncology Group (ECOG)
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• National Cancer Institute (NCI) (or its authorized representatives)
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• Food and Drug Administration (FDA) (or other regulatory agencies and/or their designated preresentatives)
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• Genentech (the manufacturer of rhuMab VEGF)
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• Cancer Trials Support Unit (CTSU)
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• Expanded Participation Project (Emmies Coproration)
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• The Kaiser Permanente Northern California Institutional Review Board (a grup of people who review research studies to protect the rights of participants)

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Because of the need to release information to these parties, absolute confidentiality cannot be guaranteed.
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By signing this consent form, you will also be giving consent for the medical research investogator or his/her assistants to review your medical records as may be necessary for this study.
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Your identity will not be revealed in any publication or release of study results.


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QUESTIONS

In case of study-related questions, problems or injureis, you can call the phyusician responsible fo rhte study within Kaiser Permanente in Northern California (the principle investigator), Louis Fehrenbacher, MD at telephone number: (707 651-2797, or you may clal the doctor(s) listed below:


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Dr. ____________________________________


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at (Physician Telephone Number)


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Dr. ____________________________________


at (Physician Telephone Number)
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Questions about your rights as a study participatn, comments or complaints about the study may be presented to the Institutional Reveiw Board fo rthe Protection of Human Subjects, Kaiser Foudnation Research Institute, 1800 Harrison Street, Oakland, CA 94612-3422, toll-free telephone (866 241 0690.
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You may call the NCI's Cancer Information Service at: 1-800-4-CANCER (1-800-422-6237) or TTY: 1-800-332-8615.


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I have read the above, asked questions and received answers concerning areas I did not understand. I hereby voluntarily consent to participate in the medical research study as described. I have ben given a copy of this ten-page consent form and the attached "Research Participants' Bill of Rights."



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Signature of Participant


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Date


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Name of Participant, printed



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I certify that I have explained to the above individual the nature and the purpose, the potential benefits and possible risks associated with participation in this clinical research study. I have answered any questions that have been raised, and have witnessed the above signature. These elements of informed consent conform to the assurance given by the IRB to the Department of Human Health Services to protect the rights of human subjects.


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Signature of Person Obtaining Consent


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Date


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I certify that the above study informatoin has bene explained to the above individual nad that any questions about this information have been answered.


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Investigator Name/Initials (print)



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Investigator Signature


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Date



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SCIENTIFIC STUDIES
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As part of this study, you are being asked to allow small samples of your serum, urine and biopsy tissue to be sent to CTSU central laboratories for additional testing. The serum sample will be collected using a needle to draw some blood out of a vein. The serum and urine will be collected just before your first and third cycle treatments after 18 cycles and at disease progression. the biopsy material will be from your original biopsy. No additional biopsies will be done to obtain this tissue.
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If you give your consent, a sample of your serum, tissue andurine will be sent to CTSU central laboratories where the tests will be performed. Researchers will be performing these tests in order to understand how your cnacer responded to the treatment. They hope this will help them better understand your type of cancer. The results from these tests will not be sent to you or yuour doctor, and willnot be used in planning your care. These tests are only for research purposes.


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Making Your Choice

Please read the sentence below and think about your choice. After reading the sentence, circle "Yes" or "No." No matter what you decide to do, it will not affect your care. You can participate in the treatment part of the study without participating in this additional research. If you hvae any questions, please talk to your doctor or nurse.

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I agree to participate in the scientific laboratory tests that are being done as a part of this study.

Yes
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No

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Please print and sign your name here after you circle your answer.


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Print Name:


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Your Signature


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Date:



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USE OF SAMPLES (BLOOD, TISSUE) FOR ADDITIONAL RESEARCH

We would like to keep some of yor blood, urine, and tissue that is left over for future research. If yo agree, this blood, urine, and tissue will be kept and may be used in research to learn more about cnacner and other diseases. This blood, urine, and tissue will only be given to researchers approved by the Cancer Trials Support Unit (CTSU).
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If you choose to participate in the correlative studies you will have some blood, urine and tissue samples sent to the central labs for analysis. Reports about research done with your blood, urine, and 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. The research that may be done with your blood,urine, and tissue will probably not help you. It might help people who have cnacer and other diseases in the future.
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The choice to let us keep the left over serum, urine, and tissue for future research is up to you. No matter what you decide to do, it will not affect your care and you may still take part in the study.
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If you decide now that your serum, urine and tissue can be kept for research, you can change your mind at any time. Just contact your study doctor and let him or her know that you do not want us to use your serum, urine and tissue. Then the serum, urine and tissue will no longer be used for research.
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In the future, people who do research may need to know more about your health. When the CTSU gives them reports about your health, it will not give them your name.
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Sometimes serum, urine and tissue are used for genetic research (about diseases that are passed on in families). Even if your serum, urine and tissue are used for this kind of research, the results will not be put in your health records.
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Your serum, urine and tissue will be used only for research and will not be sold. You will not be paid for allowing your leftover tissue, serum and urine to be used in research even though the research done with your tissue serum and urine may help to devleop new products in the future. Similarly there will be no cost to you for any tissue, serum and urine collected and stored by the CTSU.
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The benefits of research using serum, urine and tissue include learning more about what causes cancer and other diseases, how to prevent them, how to treat them, and how to cure them.
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There are vey few risks to you. The greatest risk is the release of information from your health records. The CTSU will protect your records so that your name will be kept private. The chance that this information will be given to someone else is very small.


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Making Your Choice
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Please read each sentence below and think about your choice. After reading each sentence, circle "Yes" or "No." No matter what you decide to do, it iwll not affect your care. You can participate in the treatmetn aprt of the study without participating in all or part of the blood research studies. If you have any questions, pelase talk to your doctor or nurse.

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My serum, urine and tissue may be kept for use in research to learn about, prevent and treat, or cure cancer.
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Yes
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No
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My serum, urine and tissue may be kept for research about other health problems (for example: causes of diabetes, Alzheimer's disease, and heart disease).
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Yes
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No
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My doctor (or someone from the CTSU) may contact me in the future to ask me to take part in more research.
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Yes
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No

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Please sign your name here after you circle your answers.


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Print Name:


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Your Signature


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Date:

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AUTHORIZATION (PERMISSION)
TO USE OR DISCLOSE IDENTIFIABLE HEALTH INFORMATION FOR RESEARCH


Participants Name: ___________________________________
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Birth Date: _______________________


What is the purpose of this form?

Kaiser Permanente researchesers would like to use your health information for research and to disclose your health informatoin to the Clinical Trial Support Unit (CTSU). the CTSU is an organization that does research to learn about the causese of cancer and how to prevent and treat cancer. Your health information may include data that identifies you. Please carefully review the information below. If you agree that Kaiser Permanente researchers can use and disclose your personal health informattion, you must sign and date this rorm to give them your permission.
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What personal health information do the researchers want to use?
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The researchers want to copy and use the portions of your medical record that they will need for their research. If you enter a CTSU research study, information that will be used and/or disclosed may include the following:

• The history and diagnosis of your disease;
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• Specific information about the treatments you received, including previous treatment(s) you may have had;
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• Information about other medical conditions that may affect your treatment;
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• Medical data, including laboratory test results, tumor measurements, CT scans, MRIs, x-rays, and pathology results;
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• Information on side effects (adverse events) you may experience, and how these were treated;
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• Long-term information about your general healthe status and the status of your disease;
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• Data that may be related to tissue and/or blood samples that may be collected fro you; and
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• Numbers of codes that will identify you, such as your social security number and medical record number.

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You may request a blank copyu of the CTSU data forms from the study doctor or his/her research staff to learn what information will be shared.
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Why do the researchers want my personal health information?
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If you enter this CTSU study, oncology researchers at Kaiser Permanente Northern California and the research team will collect your health information and share it with the CTSU Operations Center. The CTSU center will use your information in their cancer research study. Kaiser Permanente researchers will use your health information to conduct the study, monitor your health status, measuer effects of drugs, and determine research results.
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Who will be able to use my personal health information?

If you sign this authorization, Kaiser Permanente researchers and the research team may use your health information and may give your information to the follwoing groups taking part in the research. Kaiser Permanente may also permit these groups to come in to review your original records that are kept by Kaiser Permanente so that they can monitor their research study.

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• The CTSU Operations Center;
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• Public Health agencies and other government agencies (including non-U.S.) as authorized or required by law;
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• Other people or organizations assisting with CTSU research efforts;
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• Central laboratories, central review centers, and central reviewers. the central laboratories and review agencies may also give your health information to those groups listed in the five bullets above; and
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• If others, specify: ______________________________________
  
  

How will information about me be kept private?
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The CTSU will keep all patient information private to the extent possible, evne thought the CTSU is not required to follow the federal privacy laws. Only researchers working wtih the CTSU will have access to your information. the CTSU will not disclose personal health information about you to others except as authorized or required by law. However, once your information is given to other organizations that are not required to follow federal privayc laws, Kaiser Permanaente cannot assure that the information will remain protected.
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What happens if I do not sign this permission form?

If you do not sign this permission form, you will not be able to take art in the research study for which you are being considered.

If I sign this form, will I automatically be entered into the research study?
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No, you cannot be entered into any research study without further discussion and separate consent. After discussion, you may decide to take part in the research study. At that time, you will be asked to sign a specifid research consent form.
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What happens if I want to withdraw my persmission?

You can change your mind at any time and withdraw your permission to allow your personal health informaton to be used in the research. If this happens, you must withdraw your permission in writing. Beginning on the date you withdraw your permission, no new personal health information will be used for research. However, researchers may continue to use the health information that was provided before you withdrew your permission.
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If you sign this form and enter the research study, but late change your mind and withdraw your permission, you will be removed from the reseach study at that time.

To withdraw your permission, please contact the person below. He will make sure your written request to withdraw your permission is processed correctly.
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Louis Fehrenbacher, MD
Kaiser Permanente
Vallejo Medical Center
975 Sereno Drive
Vallejo, CA 94589

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Phone (707 651-2787
Fax (707 651-2798
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How long will this permission last?

If you agree by signing this form that researchers can use your personal health information, this permisson will expire at the end of this study. However, as stated, above, you can change your mind and withdraw your permission at any time.


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What are my rights regarding access to my personal health information?

You have the right to refuse to sign this permission form. You have the right to review and/or copy records of your personal health information kept by Kaiser Permanente. You do not have the right to review and/or copy records kept by the CTSU oro other researchers associated with the research study.


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Signatures

I agree that my personal health information may be used for the research purposes described in this form.


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Signature of Patient
or Patient's Legal Representative:_________________________


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Date: _______________________


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Printed Name of Legal Representative (if any:____________________________


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Representative's Authority to Act for Patient: _____________________________


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Signature of Person Obtaining Permission: __________________________________


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Date: ___________________________


Printed Name of Person Obtaining Permission: ______________________________





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CTSU Authorization

IRB Approval Date 07/01/03