Clinical trial: NCT00436215
Section: Alternatives
Subsections: Are There Benefits To Taking Part In The Study?

Taking part in this study may or may not make your health better. Bevacizumab by itself has been shown to be useful in the treatment of certain cancers such as colorectal cancer. Sorafenib by itself has been shown to be useful in the treatment of certain cancers such as kidney cancer. While doctors hope sorafenib and bevacizumab will be useful against your cancer, there is no proof of this yet. We do know that the information from this study will help doctors learn more about sorafenib and bevacizumab as a treatment for cancer. This information will help future cancer patients.  
  
STUDY NUMBER: 07-C-0058 CONTINUATION: page 15 of 21 pages What other choices do I have if I do not take part in this study? Your other choices may include:
- Getting standard treatment or care for your cancer in the community - Taking part in another study - Both drugs are commercially available, although not approved for your condition, and you can obtain them if your doctor agrees to prescribe them
- Getting no treatment
- Getting comfort care, also called palliative care. This type of care helps reduce pain, tiredness, appetite problems, and other problems caused by cancer. It does not treat the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible.  
Talk to your doctor about your choices before you decide if you will take part in this study.
Clinical trial: NCT00436215
Section: Confidentiality
Subsections: Will My Medical Information Be Kept Private?

We will do our best to make sure that the personal information in your medical record will be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used. Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include:
- The National Cancer Institute (NCI) and other government agencies, like the Food and Drug Administration (FDA), involved in keeping research safe for people.  
- Qualified representatives from Bayer Health Care Corporation and Onyx Pharmaceuticals who produce sorafenib and are the pharmaceutical sponsors of this trial. Genentech Pharmaceuticals who produce bevacizumab.  
A description of this clinical trial will be available on http://www.ClinicalTrials.gov. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.
Clinical trial: NCT00436215
Section: Duration of Study Involvement
Subsections: When I Am Finished Taking Sorafenib And Bevacizumab?

Your participation in this study will continue until either you or your study doctor decides that this medication is not beneficial to you or you wish you stop. Your participation is voluntary; so you may stop taking sorafenib and bevacizumab at any time. We ask that you speak to your study doctor if you are thinking about this and before you stop taking the medications. Your study doctor will be monitoring you and your cancer while you are taking sorafenib and bevacizumab. If your cancer is worsening, then the study doctor will suggest that you stop the experimental therapy and s/he will discuss other options with you. Also, if you are experiencing effects from the therapy which are dangerous to your health or too difficult for you to tolerate, you and the study team may decide that you should stop the study drugs. At the end of the study, no additional testing will be required unless you experience side effects from the study medications that we need to follow. We will ask you to consider an optional biopsy that would be performed the same way as the previous biopsies, again performed for only research purposes. This biopsy is not a required procedure and you are free to choose not to have it performed. If you are taken off of sorafenib for any reason including toxicity of the drug, you may continue on study with treatment with bevacizumab alone, if there is not evidence to suggest that your tumor is resistant to bevacizumab. You, your home physician, and your study doctor will discuss the option of continuing on bevacizumab alone versus other treatment options. You will be followed 4 weeks after stopping treatment with a phone call. If additional lab tests need to be done, you may be asked to return to the clinic for a follow-up visit.
Clinical trial: NCT00436215
Section: Participant's Rights
Subsections: What Are My Rights If I Take Part In This Study?

Taking part in this study is your choice. You may choose either to take part or not to take part in the study. If you decide to take part in this study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you and you will not lose any of your regular benefits. Leaving the study will not affect your medical care. You can still get your medical care from our institution 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. 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, Nicole Houston, RN (301) 443-6431, and/or Principal Investigator Dr. Christina Annunziata (301) 402-7189. For questions about your rights while taking part in this study, call the Clinical Center Patient Representative at (301) 496-2626.  
STUDY NUMBER: 07-C-0058 CONTINUATION: page 17 of 21 pages 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.
Clinical trial: NCT00436215
Section: Possible Risks, Discomforts, and Inconveniences
Subsections: What Side Effects Or Risks Can I Expect From Being In The Study?|Likely:|Occasional, Some May Be Serious|Rare, And Serious|Risks

If you choose to take part in this study, there is a risk that:
- You may lose time at work or home and spend more time in the hospital or doctor's office than usual
- You may be asked sensitive or private questions which you normally do not discuss The bevacizumab and sorafenib used in this study may affect how different parts of your body work such as your liver, kidneys, heart, and blood. The study doctor will be testing your blood and will let you know if changes occur that may affect your health.  
STUDY NUMBER: 07-C-0058 CONTINUATION: page 8 of 21 pages There is also a risk that you could have side effects from the study drugs/study approach. Here are important points about side effects:
- The study doctors do not know who will or will not have side effects.  
- Some side effects may go away soon, some may last a long time, or some may never go away.  
- Some side effects may interfere with your ability to have children.  
- Some side effects may be serious and may even result in death.  
Here are important points about how you and the study doctor can make side effects less of a problem:
- Tell the study doctor if you notice or feel anything different so they can see if you are having a side effect.  
- The study doctor may be able to treat some side effects.  
- The study doctor may adjust the study drugs to try to reduce side effects.  
The tables below show the most common and the most serious side effects that researchers know about. There might be other side effects that researchers do not yet know about. If important new side effects are found, the study doctor will discuss these with you. Risks and side effects related to sorafenib include those which are:

- Belly pain - Diarrhea - Nausea or the urge to vomit
- Fatigue or tiredness
- Increased blood level of a liver enzyme (ALT/SGPT)
- Increased blood level of a liver or bone enzyme (alkaline phosphatase) - Increased blood level of a liver enzyme (AST/SGOT) - Increased blood level of a liver pigment (bilirubin) often a sign of liver problems - Increased blood level of creatinine (a substance normally eliminated by the kidneys into the urine)
- Increased INR (measure of the ability of the blood to clot properly) which increases the risk of bleeding
- Increased blood level of fat-digesting enzyme (lipase)
- Decreased number of a type of white blood cell (lymphocyte)  
  
STUDY NUMBER: 07-C-0058 CONTINUATION: page 9 of 21 pages
- Decreased number of a type of blood cell that helps to clot blood (platelet)
- Increased blood level of a digestive enzyme (amylase)
- Weight loss - Decrease in the total number of white blood cells (leukocytes)
- Loss of appetite
- Increased blood sugar level - Decreased levels of a blood protein called albumin
- Decreased blood level of calcium
- Decreased blood level of sodium
- Decreased blood level of phosphate
- Hair loss
- Swelling and redness of the skin on the palms of the hands and soles of the feet
- Skin rash with the presence of macules (flat discolored area) and papules (raised bump)
Less Likely:  
  
- Lack of enough red blood cells (anemia)
- Fever associated with dangerously low levels of a type of white blood cell (neutrophils) - Irritation or sores in the lining of the anus - Fluid collection in the abdomen
- Constipation
- Bleeding in some organ(s) of the digestive tract
- Irritation or sores in the lining of the mouth
- Irritation or sores in the lining of the rectum
- Irritation or sores in the lining of the small bowel
- Vomiting - Swelling of the arms and/or legs
- Fever
- Chest pain not heart-related
- Infection
- Test that shows a problem in blood clotting
- Increased blood level of cholesterol
- Increased blood level of a liver enzyme (GGT)
- Decreased blood level of carbon dioxide - Decreased number of a type of white blood cell (neutrophil/granulocyte) - Increased blood level of calcium - Increased blood level of potassium
- Increased blood level of sodium  
  
  
  
STUDY NUMBER: 07-C-0058 CONTINUATION: page 10 of 21 pages
- Increased blood level of uric acid, a waste material from food digestion  
  
  
- Decreased blood sugar level
- Decreased blood level of potassium - Joint pain
- Back pain
- Bone pain - Muscle spasms
- Muscle pain
- Leg and/or arm pain
- Dizziness (or sensation of lightheadedness, unsteadiness, or giddiness)
- Headache or head pain
- Inflammation (swelling and redness) or degeneration of the peripheral nerves (those nerves outside of brain and spinal cord) causing numbness, tingling, burning
- Difficulty sleeping or falling asleep
- Sudden decrease of kidney function
- Blood in the urine
- Bleeding in the kidney - Presence of blood in a fallopian tube (tube between ovary to uterus [womb]) - Bleeding in the ovary
- Bleeding in the prostate
- Bleeding in the spermatic cord (a structure resembling a cord that suspends the testis within the scrotum and contains the vas deferens [the tube that carries sperm] and other vessels and nerves)
- Bleeding in the testis
- Bleeding in the uterus (womb)
- Bleeding in the vagina - Bleeding from the lungs
- Cough
- Shortness of breath - Nose bleed
- Irritation or sores in the lining of the voice box
- Irritation or sores in the lining of the throat - Irritation or sores in the lining of the windpipe
- Voice change
- Dry skin - Itching
- High blood pressure STUDY NUMBER: 07-C-0058 CONTINUATION: page 11 of 21 pages
- Formation of a blood clot that plugs the blood vessel; blood clots may break loose and travel to another place, such as the lung Rare but Serious:
- Collection of signs and symptoms that indicate sudden heart disease in which the heart does not get enough oxygen. Sudden symptoms such as chest pain, shortness of breath, or fainting could indicate heart disease and should be reported right away. Signs such as abnormal EKG and blood tests can confirm damage to the heart.  
- Decrease in heart's ability to pump blood during the "active" phase of the heartbeat
(systole)
- Heart attack caused by a blockage or decreased blood supply to the heart
- Gastrointestinal perforation : A tear or hole in the stomach or gut that can lead to serious complications and may require surgery to repair
- Serious, life-threatening allergic reaction requiring immediate medical treatment by your doctor. The reaction may include extremely low blood pressure, swelling of the throat, difficulty breathing, and loss of consciousness.  
- Bleeding in the brain - Abnormal changes in the brain that can cause a collection of symptoms including headache, confusion, seizures, and vision loss associated with MRI imaging findings (RPLS)
- Severe reaction of the skin and gut lining that may include rash and shedding or death of tissue
- Potentially life-threatening condition affecting less than 10% of the skin in which cell death causes the epidermis (outer layer) to separate from the dermis (middle layer)
Risks and side effects related to bevacizumab **include those which are:**

In 100 people receiving bevacizumab, from 4 to 20 may have:
- Anemia which may require blood transfusion
- Low white cell count that may increase the risk of infection
- Infection, including collection of pus in the belly or rectum
- Abnormal heartbeat which may cause palpitations or fainting - Pain in the belly, rectum, chest, joints, muscles, or tumor - Low appetite, constipation, diarrhea, heartburn, nausea, vomiting, or dehydration STUDY NUMBER: 07-C-0058 CONTINUATION: page 12 of 21 pages  
In 100 people receiving bevacizumab, from 4 to 20 may have:
- Internal bleeding which may cause black tarry stool, blood in vomit, coughing up of blood, or blood in urine
- Bleeding from other sites, including the vagina or nose
- Blockage of internal organs which may cause vomiting or inability to pass stool
- Sores in mouth
- Allergic reaction during or after infusion of bevacizumab which may cause fever, chills, rash, itching, hives, low blood pressure, wheezing, shortness of breath, swelling of the face or throat
- Delay in healing of wounds or spontaneous opening of wounds
- Weight loss, tiredness, or dizziness
- Damage to the jawbone which may cause loss of teeth
- Headache
- Numbness, tingling, or pain in the fingers or toes
- Hoarseness, stuffy nose, or cough
- Blood clot in limbs or lungs which may cause swelling, pain, or shortness of breath - Leakage of protein in the urine, which can rarely lead to damage to the kidney

In 100 people receiving bevacizumab, 3 or fewer may have:
- Clots in the arteries, causing stroke (which may cause paralysis or weakness) or heart attack (which may cause chest pain or shortness of breath). This risk is significantly increased in patients who are elderly or with history of diabetes
- Heart failure which may cause shortness of breath, swelling of ankles, or tiredness
- Bowel perforation (a tear in the bowel) that can cause pain or bleeding and require surgery to repair
- A tear or hole (fistula) in internal organs such as the nose, throat, lungs, esophagus, rectum, or vagina. These conditions may cause serious infections or bleeding and require surgery to repair
- Flesh-eating bacteria syndrome, an infection in the deep layers of skin - Bleeding in the tumor, brain, belly, or lungs which may cause confusion, blood in stool or coughing up blood
- Brain damage which may cause headache, seizure, blindness (also known as Reversible Posterior Leukoencephalopathy Syndrome)
- Kidney damage which may require dialysis Additional Notes on Possible Side Effects for Bevacizumab:
STUDY NUMBER: 07-C-0058 CONTINUATION: page 13 of 21 pages  
- Risk in children or adolescents: abnormal bone changes which may interfere with growth.  
- Risk in pre-menopausal women: more likely to develop menopause when taking bevacizumab.
Bevacizumab is the common name for the commercial drug Avastin. The bevacizumab used in this trial, however, is for use in research studies only and may be made at locations different from those where Avastin is made. Although some differences may exist, bevacizumab for research use and the commercial drug, Avastin, are manufactured by a similar process, meet similar standards for final product testing, and are expected to be very similar in safety and effectiveness. For more information about risks and side effects, ask your study team.  
 Other risks associated with this study include risks related to radiation exposure associated with the tests you will receive. This research study involves exposure to radiation from PET scans and potentially from CT scans used to guide biopsies for your safety. Please note that this radiation exposure is not necessary for your medical care and is for research purposes only. The total amount of radiation you will receive in this study is from 3 injections (scans or repetitions) of 15 mCi of F-18 FDG (a radioactively labeled form of sugar) in the PET scans and from CT directed biopsies (when needed). The NIH Radiation Safety Committee has reviewed the use of radiation in this research study and has approved this use as involving slightly more than minimal risk and necessary to obtain the research information desired. Using the standard way of describing radiation dose, from participating in this study, you will receive a total of 14.6 rem to your bladder wall, 10.1 rem to your heart wall, and 7.4 rem to your spleen. All other organs will receive smaller amounts of radiation.  
Although each organ will receive a different dose, the amount of radiation exposure you will receive from these procedures is equal to a uniform whole-body exposure of 3.7 rem. This calculated value is known as the "effective dose" and is used to relate the dose received by each organ to a single value. The amount of radiation received in this study is within the dose guideline established by the NIH Radiation Safety Committee for research subjects. The guideline is an effective dose of 5 rem (or 5,000 mrem) received per year2.  
For comparison, the average person in the United States receives a radiation exposure of 0.3 rem (or 300 mrem) per year from natural background sources, such as from the sun, outer space, and from radioactive materials that are found naturally in the earth's air and soil. The dose that you will receive from this research study is about the same amount you would normally receive in STUDY NUMBER: 07-C-0058 CONTINUATION: page 14 of 21 pages 12.3 years from these natural sources. If you would like more information about radiation and examples of exposure levels from other sources, please ask the investigator for a copy of the pamphlet called, *An Introduction to Radiation for NIH Research Subjects.* The effects of radiation exposure on humans have been studied for over 60 years. In fact, these studies are the most extensive ever done of any potentially harmful agent that could affect humans. In all these studies, no harmful effect to humans has been observed from the levels of radiation you will receive by taking part in this research study. However, scientists disagree on whether radiation doses at these levels are harmful. Even though no effects have been observed, some scientists believe that radiation can be harmful at any dose - even low doses such as those received during this research. One possible effect that could occur at these doses is a slight increase in the risk of cancer. Please be aware that the natural chance of a person getting a fatal cancer during his/her lifetime is about 1 out of 4 (or 25 percent). The increase in the chance of getting a fatal cancer, as a result of the radiation exposure received from this research study, is 0.15%. Therefore, the total risk of fatal cancer may be estimated to increase from 25 percent to 25.15%. This change in risk is small and cannot be measured directly. Compared with other everyday risks, such as flying in an airplane or driving a car, this increase is considered slight. Please tell your doctor if you have taken part in other research studies or received any medical care at the NIH or other places/hospitals that used radiation. This way we can make sure that you will not receive too much radiation. Consider x-rays taken in radiology departments, cardiac catheterization, and fluoroscopy as well as nuclear medicine scans in which radioactive materials were injected into your body. If you are pregnant or breast feeding, you may not participate in this research study. It is best to avoid radiation exposure to unborn or nursing children since they are more sensitive to radiation than adults.

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.
Clinical trial: NCT00436215
Section: Purpose of Research
Subsections: Why Is This Study Being Done?

The purpose of this study is to determine the effectiveness of the combination of two anti-cancer drugs, sorafenib and bevacizumab, and to find out what effects, good and/or bad, these drugs may have on you and your cancer. This study will also look at how the drugs may affect the cancer by measuring amounts of different proteins in small biopsy samples of your tumor taken before you start treatment and after different times of treatment. Optional biopsies will be performed 6 weeks after treatment begins and at the completion of therapy.  
Using these drugs together is experimental. These drugs work by targeting the blood vessels that allow tumors to grow. Our theory is that by combining two drugs that target blood vessels, we can more effectively block the formation of blood vessels that feed tumors. On the phase 1 trial of this combination that is also being performed by our group, 6 of 14 ovarian cancer patients have had documented tumor shrinkage. Both of these drugs have been approved by the FDA for use in other cancers but have not been approved for ovarian cancer. However, we have been studying the combination and believe it to be of potential value in ovarian cancer. How many people will take part in the study? Between 74-78 people will take part in this study. The study will be divided into 2 groups. One group will enroll patients who have received bevacizumab in the past and the other group will enroll patients who have not had treatment with bevacizumab. Patients in both groups will receive the same treatment. There will be no difference in dose or scheduling of the drugs between groups. What will happen if I take part in this research study?  
 Before you begin the study …
You will need to have the following exams, tests or procedures to find out if you can be in 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. If you have had some of them recently, they may not need to be repeated. This will be up to your study doctor. Blood tests: measurements of how your liver, kidneys and blood clotting work, measurement of your white blood cells, red blood cells and platelets, your blood sugar and blood electrolytes. Since ovarian, fallopian, and peritoneal cancer may make the protein CA-125, we ask that you have your CA-125 level checked as well. These will be done during your first visit to NIH as an outpatient.  
- Urinalysis. - CT Scan (or similar imaging test) to assess where your cancer may be
- Tissue block (pathology slides from biopsy or surgery) of the cancer to submit to the study doctor or a member of the research team STUDY NUMBER: 07-C-0058 CONTINUATION: page 3 of 21 pages If the initial exams, tests, and procedures show that you are eligible to be in the study, you will have the following tests and procedures performed during your participation. They are part of regular cancer care.  
- Clinic visit to ask how you are feeling and to evaluate you with a physical examination every 4 weeks while you remain on the study.  
- Blood tests: measurements of how your liver, kidneys and blood clotting work, measurement of your white blood cells, red blood cells and platelets, your blood sugar and blood electrolytes will be done every 2 weeks for one month then every 4 weeks. A CA-125 measurement will also be done every 4 weeks.  
- Urinalysis. This will be done every 2 weeks prior to receiving the bevacizumab infusion.  
You will need these tests and procedures that are part of regular cancer care. They may be done more often because you are in this study.  
- Computed tomography (CT) or other imaging test such as ultrasound or MRI that can detect your tumor will be done every 8 weeks while you are on the study. This is done so that any benefit of the study can be determined and if your cancer is not responding to the study drugs, the study team can advise you of this and help you to move to a different treatment program (discussed further below).  
- Twice weekly blood pressure measurements (for the first 8 weeks). You will be given a blood pressure cuff to use at home and we will ask you to record your blood pressure measurements and report them to us.
You will need these exams and procedures that are either being tested in this study or being done to see how the study is affecting your body.  
- Research blood samples (5 tubes or about 8 teaspoons) also will be taken at every 4 week clinic visit. Note: Research blood samples will no longer be collected each cycle after 04/11/14.  
- PET (Positron Emission Tomography). This will be done before you start study drugs, on the third day after you start taking the medications, and 6 weeks into treatment. A
PET scan is used by doctors to look at how different parts of the body utilize a sugarnutrient called glucose. The test works by injecting into your body a small amount of sugar labeled with a tiny amount of radioactivity that the PET imaging machine can detect. You are put in a chamber that looks like a tube while the machine performs the test. Cancer cells tend to consume sugar nutrients faster than normal cells and may pick up more signal than the normal cells. This test is being done to determine if there is any change in your tumor's activity level with the addition of these two drugs.  
STUDY NUMBER: 07-C-0058 CONTINUATION: page 4 of 21 pages
- Dynamic contrast-enhanced MRI or DCE-MRI. This will be done before you start study drugs, on the third day after you start taking the medications, and 6 weeks into treatment. This is a test that does not use any radiation. Instead, it uses magnetic energy to examining the inside of your body with a special non-radioactive dye, so that doctors can measure blood flow into the tumor. You are put in a chamber that looks like a tube while the machine performs the test. This test is being done to determine if there is any change in your tumor's blood flow with the addition of these two drugs.  
- Biopsy of your tumor: This will be done before you start a study drug. In addition, there are 2 optional tumor biopsies 1) at 6 weeks into treatment and 2) if you are taken off this study because your tumor progresses or because of side effects of the treatment, These biopsies are not required but may help us understand these drugs work on cancer cells. The biopsy will be performed by an experienced, highly skilled interventional radiologist. The procedure is performed with a small needle directed by either ultrasound or CT scan This biopsy will be used for research purposes, not for diagnostic purposes. You will not be allowed to undergo such a procedure if there is significant risk of harm from this procedure.  
- Quality of Life questionnaire: As part of this study, you will answer a questionnaire that asks you questions about your symptoms and how you are feeling about the study and your life. The questionnaire will be given to you just before you start the treatment and then every 8 weeks and when you come off study.  
The tumor biopsy, capture of a small piece of your cancer, is a necessary part of this trial and is done for research purposes. No formal pathology review of these biopsy specimens will be done routinely. Trained personnel will perform the biopsy keeping your safety in mind. All efforts will be made to minimize risks and discomfort involved with these biopsies. If any complication occurs, we will provide the medical care as appropriate. If, upon attempting the first biopsy, no tissue can be obtained or it has caused you harm, subsequent biopsies will not be done. If for any reason the biopsies cannot be done safely, you may still receive the study drugs. Biopsies will be done either using a small bore needle under CT guidance (looking at the needle location by CT scan). The CT scan helps the specialized radiologist know that the needle has been placed into the tumor mass. The needle biopsy is done by inserting a needle through the skin into the tumor mass. Typical risks of both procedures include, but are not limited to bleeding, infection, pain, and scarring. You will be counseled in more detail about the procedure and you will be asked to sign a separate consent that will describe the procedure and its associated risks at that time. Your safety is the most important thing at all times.  
STUDY NUMBER: 07-C-0058 CONTINUATION: page 5 of 21 pages
Clinical trial: NCT00436215
Section: Withdrawal from Study
Subsections: Can I Stop Being In The Study?

Yes. You can decide to stop at any time. Tell the study team if you are thinking about stopping or decide to stop. They will help you to stop safely and determine if a final follow-up visit is needed. If you decide at any time to withdraw your consent to participate in the trial, we will not collect any additional medical information about you. However, according to FDA guidelines, information collected on you up to that point may still be provided to Bayer Health Care Corporation and Onyx Pharmaceuticals or designated representatives. If you withdraw your consent and leave the trial, any samples of yours that have been obtained for the study and stored at the NCI can be destroyed upon request. However, any samples and data generated from the samples that have already been distributed to other researchers or placed in the research databases cannot be recalled and destroyed.  
The 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.