Clinical trial: NCT01688999
Section: Alternatives
Subsections: Alternative Approaches Or Treatments What Other Choices Do I Have If I Do Not Take Part In This Study?

Instead of being in this study, you have these options:
x Getting treatment or care for your cancer without being in a study x Taking part in another study  
PATIENT IDENTIFICATION CONTINUATION SHEET for **either:**  
NIH-2514-1 (07-09) NIH-2514-2 (10-84)  
P.A.: 09-25-0099 File in Section 4: Protocol Consent  
x Getting comfort care, also called palliative care. This type of care helps reduce pain, tiredness, appetite problems and other problems caused by the cancer. It does not treat the cancer directly. Instead, it tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible.
Please talk to your doctor about these and other options.
Clinical trial: NCT01688999
Section: Confidentiality
Subsections: Will My Medical Information Be Kept Private?|Certificate Of Confidentiality

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  
PATIENT IDENTIFICATION CONTINUATION SHEET for **either:**  
NIH-2514-1 (07-09) NIH-2514-2 (10-84)  
P.A.: 09-25-0099 File in Section 4: Protocol Consent  
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:
x The pharmaceutical collaborator that makes cabozantinib  
x The National Cancer Institute (NCI) and other government agencies, like the Food and Drug Administration (FDA), involved in keeping research safe for people
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of study results. You can search this Web site at any time.

To help us protect your privacy, we have obtained a Certificate of Confidentiality. The researchers can use this Certificate to legally refuse to disclose information that may identify you in any federal, state, or local civil, criminal, administrative, legislative, or other proceedings, for example, if there is a court subpoena. The researchers will use the Certificate to resist any demands for information that would identify you, except as explained below. You should also know that there are several circumstances in which the Certificate does not provide coverage. These include when information:  
x will be used for auditing or program evaluation internally by the NIH; or x must be disclosed to meet the legal requirements of the federal Food and Drug Administration (FDA).  
x is necessary for your medical treatment and you have consented to this disclosure; x is for other research.
In addition, identifiable, sensitive information protected by this Certificate cannot be admissible as evidence or used for any purpose in any action, suit, or proceeding without your consent. You should understand that a Certificate of Confidentiality does not prevent you or a member of your family from voluntarily releasing information about yourself or your involvement in this research. If an insurer, employer, or other person obtains your written consent to receive research information, then the researchers will not use the Certificate to withhold that information. The Certificate of Confidentiality will not protect against the required reporting by hospital staff of information on suspected child abuse, reportable communicable diseases, and/or possible threat of harm to self or others. We will also share information as described in item 1 on page 18.
Clinical trial: NCT01688999
Section: Duration of Study Involvement
Subsections: Before You Begin The Study:|During 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 the study team. These tests include:
x A complete physical examination including your medical history  
x A 12-lead ECG (electrocardiogram)
x Blood and urine tests  
x MRI or CT scan of your chest, abdomen and pelvis (This scan will be repeated if you have stopped taking the study drug and start again after more than 6 weeks)
x Sodium fluoride-18 PET CT scan in the event that you have bone disease. This is a special CT that uses a radioactive tracer (fluoride 18) to help us better see disease in your bones. (This scan will be repeated if you have stopped taking the study drug and start again after more than 6 weeks)
A pregnancy test if you are female. You will need to supply a complete list of your current medications to the study doctor. This includes over-the-counter medications and herbal supplements. Some medications may interact adversely with cabozantinib and it is important that your study doctor and prescribing physician be aware of any potential risks so that they can prescribe alternative medications as necessary. If you do not already do so, please consider carrying a list of your medications at all times.

If the exams, tests and procedures show that you can be in the study, and you choose to take part, then you will need the following tests and procedures:  
x Dental examination (if you have used or are using a type of medication called a bisphosphonate) - before you receive study drug You will need the following tests and procedures that are part of regular cancer care.  
x Blood tests x Pregnancy test if you are female - every 4 weeks
You will also need these tests and procedures that are part of regular cancer care. They are being done more often because you are in this study.  
x MRI or CT scan of the chest, abdomen, and pelvis - every 8 weeks x Sodium fluoride-18 PET CT scan in the event that you have or are suspected of having bone disease - every 8 weeks x Physical examination - every two weeks for the first 12 weeks, then every 4 weeks x Blood tests to evaluate toxicities- every two weeks for the first 12 weeks, then every 4 weeks x Urinalysis - every two weeks for the first 12 weeks, then every 4 weeks
You will need these tests and procedures that are either being tested in this study or being done to see how the study is affecting your body.  
x 12-lead ECG
x Research blood tests to study the effects of cabozantinib on markers in your blood. The research blood samples collected as part of this study are not expected to produce a significant decrease in the total amount of blood in your body. These tests will be done: - After you have enrolled but before you receive any study drug - Before you receive the study drug at each study visit and at the time of tumor biopsy. (May be collected up to 5 days before.)
- At the time your disease worsens - Some samples collected may be sent outside NIH for analysis x Research urine sample will be collected, at each clinic visit to study the effects of cabozantinib on markers in your urine.  
x Quality of life survey. We will ask you to complete a survey before you take any study drug and at the beginning of cycle 3 of your treatment to help us determine the severity of any symptoms you might be experiencing. The survey will take about 5 - 10 minutes to complete.  
x Biopsy (required for study participation)
- We will also require a sample of your tumor to study how cabozantinib might affect the immune cells within the tumor and the effects of this treatment on the blood vessels of your tumor. If you have any tissue from a previous surgery or biopsy, we will ask you to provide it to us. If adequate tumor tissue is not available, we will ask you to undergo a biopsy.  
x FDG PET/CT and optional FDG PET/MRI for research
- PET stands for Positron Emission Tomography. It is a technique that produces a 3-D image of functional processes in the body. PET/CT is an imaging technology that fuses PET images and CT images into one image. FDG or Fluorine-18 2-fluoro-2-deoxy-D-glucose is a radioactive tracer similar to sugar that is used to allow us to see images of how your cells take up the tracer. You will be asked to undergo PET/CT at the following times: before you have started taking the study drug, week 4 and week 8. We will not be using the results of the PET/CT to make clinical decisions. We will use these results only to determine how well they can track the progress of your disease.  
- On the day of your FDG-PET/CT scan, you will be first given an injection of a small amount of FDG into a vein in your arm or hand. The amount of radiation is very small, no more than what you would have during a normal xray. It only stays in your body for few hours. The FDG will travel to particular parts of your body. It travels to places where glucose is used for energy. It shows up cancer because the cancer cells use glucose in a different way from normal tissue.  
- The PET/CT scanner is a large machine with an opening of 27 to 30 inches in the middle. It looks like a donut with a table in the middle. Approximately 30-90 minutes after the injection of FDG, you will be asked to go to the bathroom (urinate) and then lie on a partially enclosed scanning table. The table will slide into the machine. You will be asked to remain still during the scan. You will hear buzzing or clicking sounds during the scan. You will need to lie still for about 20-60 minutes before coming off of the scanning table. If you feel any anxiety over being in enclosed spaces, let your study doctor know.  
- The entire FDG-PET/CT scan procedure is expected to take about 2 hours. - After the FDG-PET/CT scan is completed, you will be given the option of undergoing an additional scan called FDG-PET/MRI. You will not receive any additional injections of radioactivity and, because the MRI does not use ionizing radiation, there will be no additional radiation exposure. An additional hour of scanning will be required to complete this optional study.
You will be given the opportunity to undergo the optional FDG PET/MRI after your FDG-PET/CT.  
You will be provided with a wallet-sized information card ("Information on Possible Drug Interactions") that names your study agent and outlines the specific risk of adverse interactions with other drugs or substances. Should you require any new medications while on study, please consult with your study doctor if possible, and present the card to the prescriber (doctor, pharmacist, physician's assistant, or nurse practitioner). Please check with your doctor/prescriber or pharmacist before using any new over-the-counter medications or herbal supplements.
Clinical trial: NCT01688999
Section: Participant's Rights
Subsections: Resea**Rch Subject'S Rights** What Are The Costs Of Taking Part In This Study?

If you choose to take part in the study, the following will apply, in keeping with the NIH policy:  
x The study agent, cabozantinib, will be provided by the NCI. You will receive study treatment at no charge to you. This may include surgery, medicines, laboratory testing, x-rays or scans done at the Clinical Center, National Institutes of Health (NIH), or arranged for you by the research team to be done outside the Clinical Center, NIH if the study related treatment is not available at the NIH.  
x There are limited funds available to cover the cost of some tests and procedures performed outside the Clinical Center, NIH. You may have to pay for these costs if they are not covered by your insurance company.  
x Medicines that are not part of the study treatment will not be provided or paid for by the Clinical Center, NIH.  
x Once you have completed taking part in the study, medical care will no longer be provided by the Clinical Center, NIH.
Even though it probably won't happen, it is possible that the manufacturer may not continue to provide the cabozantinib to the NCI for some reason. If this would occur, other possible options are:  
x You might be able to get cabozantinib from the manufacturer or your pharmacy but you or your insurance company may have to pay for it.  
x If there is no cabozantinib available at all, no one will be able to get more and the study would close.
If a problem with getting cabozantinib occurs, your study doctor will talk to you about these options.
Clinical trial: NCT01688999
Section: Possible Risks, Discomforts, and Inconveniences
Subsections: Birth Control|Risks Or Discomforts Of Participation What Side Effects Or Risks Can I Expect From Being In This Study?|Risks And Side Effects Related To Cabozantinib: Common, Some May Be Serious|Occasional, Some May Be Serious|Rare, And Serious|Procedure Risks|Potential Benefits Of Participation Are There Benefits To Taking Part In This Study?

You should not become pregnant or father a baby while on this study because the drugs in this study can affect an unborn baby. It is important you understand that you need to use birth control before starting study treatment, during study treatment, and for 4 months after you finish study treatment. If you think that you or your partner is pregnant, you should tell your study doctor or nurse at once. Effective forms of birth control include:
- abstinence  
x intrauterine device (IUD) - hormonal [birth control pills, injections, or implants]
- tubal ligation
- vasectomy
You should recognize that no method of birth control besides abstinence provides 100% protection from pregnancy. Women should not breastfeed a baby while on this study.

If you choose to take part in this study, there is a risk that the XL184 (cabozantinib) may not be as good as the usual approach for your cancer or condition at shrinking or stabilizing your cancer. You also may have the following discomforts:
x Spend more time in the hospital or doctor's office.  
x Be asked sensitive or private questions about things you normally do not discuss.  
x May not be able to take part in future studies.  
The XL184 (cabozantinib) used in this study may affect how different parts of your body work such as your liver, kidneys, heart, and blood. The study doctor will test your blood and will let you know if changes occur that may affect your health.  
There is also a risk that you could have side effects from the study drug(s)/study approach.  
Here are important things to know about side effects:
x The study doctors do not know who will or will not have side effects.  
x Some side effects may go away soon, some may last a long time, and some may never go away.  
PATIENT IDENTIFICATION CONTINUATION SHEET for **either:**  
NIH-2514-1 (07-09) NIH-2514-2 (10-84)  
P.A.: 09-25-0099 File in Section 4: Protocol Consent  
x Some side effects may make it hard for you to have children.  
x Some side effects may be mild. Other side effects may be very serious and even result in death.  
You can ask your study doctor questions about side effects at any time. Here are important ways to make side effects less of a problem:  
x If you notice or feel anything different, tell your study doctor. He or she can check to see if it is a side effect.  
x Your study doctor will work with you to treat your side effects.  
x Your study doctor may adjust the study drugs to try to reduce side effects.
The tables below show the most common and the most serious side effects doctors know about. Keep in mind that there might be other side effects doctors do not yet know about. If important new side effects are found, the study doctor will discuss these with you."

In 100 people receiving XL184 (cabozantinib), more than 20 and up to 100 may have:
x Diarrhea, nausea, vomiting x Tiredness x Weight loss, loss of appetite x Changes in taste x Redness, pain or peeling of palms and soles x High blood pressure which may cause headaches, dizziness, blurred vision

In 100 people receiving XL184 (cabozantinib), from 4 to 20 may have:  
x Anemia which may require blood transfusion  
x Pain  
x Constipation, heartburn  
x Dry mouth, skin  
x Sores in the mouth which may cause difficulty swallowing  
x Swelling of arms, legs x Infection x Bruising, bleeding x Dehydration

In 100 people receiving XL184 (cabozantinib), 3 or fewer may have:  
x A tear or hole in internal organs that may require surgery x Non-healing surgical site x Damage to the jawbone which may cause loss of teeth x Bleeding in the brain which may cause confusion x Stroke which may cause paralysis, weakness x Brain damage which may cause headache, seizure, blindness (also known as Reversible Posterior Leukoencephalopathy Syndrome)
x Lung collapse

In addition to risks posed by the cabozantinib, you may be exposed to the following risks/discomforts: Blood drawing: Local pain, bruising, bleeding, blood clot formation, and, in rare instances, an infection might occur at the site where blood is drawn. There is also the possibility of dizziness or fainting while your blood is being drawn. ECG: The ECG (electrocardiogram) is a procedure that requires you to lie still for a few minutes while adhesive pads are attached to your chest to record the activity of your heart. The ECG leads may cause slight discomfort during their placement on and removal from your skin. Biopsy: Your tumor tissue will be analyzed for the presence of a protein called c-met. Tissue may be analyzed from a previous biopsy or a new tissue biopsy will be obtained prior to starting therapy. If we have enough tissue, we may also test this sample for white blood cells, blood vessels along other factors that affect tumor growth or factors that are expected to respond to the study drug. Furthermore, we may test any remaining sample for gene changes (see  
x Muscle weakness x Dizziness, headache x Cough, shortness of breath x Internal bleeding which may cause black tarry stool, blood in vomit, coughing up blood, or blood in urine x Bleeding from multiple sites including the nose x Changes in voice x Hair loss, rash x Change in hair color x Blood clot which may cause swelling, pain, shortness of breath
Optional Biopsy for a description). This procedure usually causes only brief discomfort at the site from which the biopsy is taken. Rarely, infection or bleeding may occur at the needle site. Radiation Risks: This research study involves exposure to radiation from 3 whole body PET/CT scans of 10mCi F-18 FDG. This radiation exposure is not required for your medical care and is for research purposes only. The amount of radiation you will receive in this study is 3.2 rem which is below the guideline of 5 rem per year allowed for adult research subjects by the NIH Radiation Safety Committee. The average person in the United States receives a radiation exposure of 0.3 rem per year from natural sources, such as the sun, outer space, and the earth's air and soil. If you would like more information about radiation, please ask the investigator for a copy of the pamphlet, An Introduction to Radiation for NIH Research Subjects. While there is no direct evidence that the amount of exposure received from participating in this study is harmful, there is indirect evidence it may not be completely safe. There may be a very slight increase in the risk of cancer. Please tell your doctor if you have had any radiation exposure in the past year, either from other research studies or from medical tests or care, so we can make sure that you will not receive too much radiation. Radiation exposure includes 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 you will not be permitted to participate in this research study. If you are breast feeding and the protocol involves injection of radioactive material you will not be permitted to participate. It is best to avoid radiation exposure to unborn or nursing infants since they are more sensitive to radiation than adults.

Taking part in this study may or may not make your health better. While doctors hope cabozantinib 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 drugs as a treatment for cancer. This information could help future cancer patients.
Clinical trial: NCT01688999
Section: Procedures
Subsections: Description Of Research Study What Will Happen If You Take Part In This Research Study?

This study will be conducted primarily on an outpatient basis. You will take 60 mg of cabozantinib by mouth once per day on each day of a 28 day cycle. Cabozantinib should be taken on an empty stomach (no food should be eaten 2 hours before and 1 hour after taking cabozantinib). If you miss a dose, do not make it up the next day. Avoid eating or drinking grapefruit/juice or Seville orange while on this study. You will be given a pill diary and a blood pressure monitoring form as part of the study. We ask that you record the times that you take cabozantinib each day in the pill diary. If you have a history of high blood pressure, you will also be asked to take your blood pressure at home once a week and record it on a blood pressure monitoring form. Please bring this (these) forms as well as all of your remaining study pills at each study visit. In addition, if you are taking a type of drug called a bisphosphonate (eg. alendronate, risedronate, pamidronate, etc.), we ask that you tell your doctor about any dental procedures that you have planned before you see the dentist.
Clinical trial: NCT01688999
Section: Purpose of Research
Subsections: Why Is This Study Being Done?|Why Are You Being Asked To Take Part In This Study?

Cabozantinib is an agent that slows down the growth of blood vessels that feed tumors. Although it has been approved by the Food and Drug Administration to treat medullary thyroid cancer, it has not been approved for urothelial cancer and its use in this study is experimental. Early studies have also shown that prostate and ovarian tumors respond to cabozantinib. This study is being done to determine whether and measure how much tumors in patients with progressive urothelial carcinoma that have received prior chemotherapy respond to cabozantinib. In addition, we will measure how long it takes for disease to progress and whether cabozantinib improves overall survival and what the side effects of cabozantinib are.  
PATIENT IDENTIFICATION CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH **STUDY**  
- Adult Patient or - Parent, for Minor Patient  
NIH-2514-1 (07-09) P.A.: 09-25-0099  
File in Section 4: Protocol Consent (1)

You are being asked to take part in this study because you have been diagnosed with metastatic urothelial carcinoma or another form of bladder cancer that has been treated with chemotherapy in the past but continues to worsen.
Clinical trial: NCT01688999
Section: Withdrawal from Study
Subsections: Stopping Therapy|When You Are Finished Taking Cabozantinib:

Your participation in this study will continue until either you or your study team decides that this medication is not beneficial to you. If your disease completely disappears, the medication will be stopped (drug holiday). You will be monitored by scans every 12 weeks. If your disease comes back, you will have the option to resume treatment. Your participation is voluntary; so you may stop receiving the study drugs at any time, but we ask that you speak to your study team before stopping. Your doctor may decide to permanently stop your therapy for the following reasons:  
x if he/she believes that it is in your best interest x if your disease progresses during treatment x if you have side effects from the treatment that your doctor thinks are too severe x if new information shows that another treatment would be better for you x if you are unable to comply with the protocol requirements x if you are unable to tolerate the lowest dose of cabozantinib (20 mg once per day)
x if your treatment has been delayed for more than 6 weeks and it is not clear that you have been benefiting from cabozantinib x if you are a woman and you become pregnant
In this case, you will be informed of the reason therapy is being stopped. You can stop taking part in the study at any time. However, if you decide to stop taking part in the study, we would like you to talk to the study doctor and your regular doctor first. If you decide at any time to withdraw your consent to participate in the trial, we will not collect any additional medical information about you. However, according to FDA guidelines, information collected on you up to that point may still be provided to Exelixis, the manufacturer of the study drug, or their 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.

30 - 37 days after you have stopped taking the study treatment (except when you stop treatment in order to take a drug holiday), we will telephone you to determine whether you have experienced any side effects. You will receive instructions on how to mail back any drug you have remaining at this time. If you have experienced any side effects that are still ongoing at the time of this call, the study team may request that you continue follow-up and/or testing for this until it has resolved. After this phone call, someone on the study team will try to contact you or a member of your family every 2 months, give or take a week to see how you are doing and to find out if you have started any other anti-cancer therapy.