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MEDICAL RECORD CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY • Adult Patient or • Parent, for Minor Patient

INSTITUTE: National Cancer Institute

STUDY NUMBER: 15-C-0160 PRINCIPAL INVESTIGATOR: Andrea Apolo, M.D.

STUDY TITLE: A Phase 1 Study of Cabozantinib plus Nivolumab (CaboNivo) Alone or in Combination with Ipilimumab (CaboNivoIpi) in Patients with Advanced/Metastatic Urothelial Carcinoma and other Genitourinary Tumors

Continuing Review Approved by the IRB on 10/17/17

Amendment Approved by the IRB on 09/19/17 (I)

Date posted to web: 11/25/17 Standard

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)

INTRODUCTION

We invite you to take part in a research study at the National Institutes of Health (NIH).

First, we want you to know that:

Taking part in NIH research is entirely voluntary.

You may choose not to take part, or you may withdraw from the study at any time. In either case, you will not lose any benefits to which you are otherwise entitled. However, to receive care at the NIH, you must be taking part in a study or be under evaluation for study participation.

You may receive no benefit from taking part. The research may give us knowledge that may help people in the future.

Second, some people have personal, religious or ethical beliefs that may limit the kinds of medical or research treatments they would want to receive (such as blood transfusions). If you have such beliefs, please discuss them with your NIH doctors or research team before you agree to the study.

Now we will describe this research study. Before you decide to take part, please take as much time as you need to ask any questions and discuss this study with anyone at NIH, or with family, friends or your personal physician or other health professional.

What is the usual approach to my advanced urothelial or other genitourinary cancer? You are being asked to take part in this study because you have been diagnosed with advanced urothelial or other genitourinary cancer. You have already been treated with platinum-based

MEDICAL RECORD CONTINUATION SHEET for either: NIH 2514-1, Consent to Participate in A Clinical Research Study NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study

STUDY NUMBER: 15-C-0160 CONTINUATION: page 2 of 23 pages

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

chemotherapy and your disease is now growing. People who are not in a study are usually treated with FDA approved systemic chemotherapeutic agents.

People who are not in a study also have their cancer monitored periodically using CT scans or MRI. A CT scan uses X-rays to create pictures of your cancer. An MRI is also used to take pictures of your cancer but this method uses magnets. In some people with this disease, the cancer sometimes spreads to the bone. If cancer spreads to the bone, it is usually monitored using a special type of CT scan called a PET CT. The PET CT combines X-rays and radiotracers to take pictures of your cancer. When radiotracers are injected into the body, they are taken up by cancer cells which allows them to be captured in the pictures taken by the PET scanner.

What are my other choices if I do not take part in this study?

If you decide not to take part in this study, you have other choices. For example:

• you may choose to have the usual approach described above

• you may choose to take part in a different study, if one is available

• or you may choose not to be treated for cancer

Why is this study being done?

The purpose of this study is to test whether cabozantinib given with nivolumab or cabozantinib given with nivolumab and ipilimumab is safe in people who have advanced genitourinary cancer. The combination of these drugs is not FDA approved. This study tested different doses of the drugs to see which dose was safer in people. As of January 2017, safe doses have been established for both combinations. We will now enroll up to 12 more people with genitourinary cancer to test the safety of a combination of cabozantinib, nivolumab and ipilimumab that was not assessed, referred to as dose level 8. In addition, we will test the activity (effect on your tumor) of one or both combinations in subjects with advanced adenocarcinoma of the bladder, squamous cell carcinoma of the bladder, clear cell renal cell carcinoma, urothelial carcinoma that has or has not previously been treated with a class of drug called immune checkpoint inhibitors (e.g. nivolumab) and squamous cell carcinoma of the penis. Moreover, additional data to evaluate the safety of both treatment combinations in patients with renal cell carcinoma will be obtained. There will be a total of 8 groups called expansion cohorts that will enroll patients based on the type of cancer, type of treatment received previously and type of treatment assigned on the study. The cohorts are summarized as follows:

1. Cabozantinib with nivolumab in subjects with urothelial carcinoma not previously treated with immune checkpoint inhibitors

2. Cabozantinib with nivolumab and ipilimumab in subjects with urothelial carcinoma not previously treated with immune checkpoint inhibitors

3. Cabozantinib with nivolumab in subjects with clear cell renal cell carcinoma




4. Cabozantinib with nivolumab and ipilimumab in subjects with clear cell renal cell carcinoma

5. Cabozantinib with nivolumab in subjects with adenocarcinoma of the bladder 6. Cabozantinib with nivolumab in subjects with squamous cell carcinoma of the bladder 7. Cabozantinib with nivolumab in subjects with urothelial carcinoma group that has been

previously treated with immune checkpoint inhibitors 8. Cabozantinib with nivolumab and ipilimumab in subjects with squamous cell carcinoma

of the penis

Cabozantinib is a drug that has been approved by the Food and Drug Administration (FDA) to treat medullary thyroid cancer and ipilimumab has been approved by the FDA to treat melanoma. Nivolumab has been approved by FDA to treat melanoma and to treat patient with locally advanced or metastatic urothelial carcinoma who have disease progression during or following platinum-containing chemotherapy or have disease progression within 12 months of neoadjuvant or adjuvant treatment with a platinum-containing chemotherapy. Researchers also want to see if using two radiotracers are better or the same as using one radiotracer alone to diagnose and monitor your type of cancer. There will be about 135 people taking part in this study.

What are the study groups?

Overview of Groups: This study will test 2 different combinations of the study drugs: 1) either cabozantinib with nivolumab, or 2) cabozantinib with nivolumab and ipilimumab.

Overview of Dosing in each Group: Different doses of the study drugs were given to several study participants. The first several participants received the lowest dose. As the study drugs did not cause serious side effects, they were given to other study participants at higher doses. The doses continued to be increased for every group of study participants. Though no dose was reached that required that the dose be lowered per the study plan, the investigators chose to stop raising the doses once levels were reached where several side effects, though not serious, occurred. You will be able to continue receiving study drugs as described in the section “How long will I be in the study?” below.

For all groups, cabozantinib should be taken on an empty stomach; i.e., you should not eat for at least two hours before and at least 1 hour after each dose of cabozantinib. Do not crush or chew. Do not take a missed dose within 12 hours of the next dose.

Group 1 You will take cabozantinib by mouth once a day and you will receive nivolumab in your vein over about 60 minutes once every 2 weeks.

Group 2 (includes dose level 8) You will take cabozantinib by mouth once a day and you will receive nivolumab in your vein over about 60 minutes, AND ipilimumab in your vein over about 90 minutes once every 3 weeks




for the first 12 weeks. After that, you will continue daily cabozantinib and receive nivolumab in your vein once every 2 weeks.

Group 3 (includes expansion cohorts 1, 3, 5, 6 and 7) You will receive the highest safe dose for cabozantinib given with nivolumab –based on the results in Group 1.

Group 4 (includes expansion cohorts 2,4 and 8) You will receive the highest safe dose for cabozantinib given with nivolumab and ipilimumab – based on the results in Group 2.

How long will I be in this study?

Group 1 and Group 3 You will receive nivolumab every 2 weeks for up to 84 weeks with daily cabozantinib. After 84 weeks of treatment, you will continue receiving nivolumab at a dose of 480 mg every 4 weeks. You may receive cabozantinib daily and Nivolumab continuously until your cancer worsens or there are serious side effects. If your disease worsens at any time, you may receive cabozantinib daily, nivolumab and ipilimumab every 3 weeks for no more than 12 weeks at the safe dose of the triple drug combination established earlier in the study. We refer to this as an ipilimumab challenge.

Group 2 and Group 4 If you are assigned to a group that includes ipilimumab, you will receive one dose every 3 weeks for no more than 12 weeks, and you will receive nivolumab every 3 weeks for 12 weeks then every two weeks for an additional 84 weeks (96 weeks in total). After 96 weeks of treatment, you will continue receiving nivolumab at a dose of 480 mg every 4 weeks. You may receive cabozantinib daily and Nivolumab continuously until your cancer worsens or there are serious side effects. If your disease worsens at any time, you may be allowed to repeat the course of ipilimumab one dose every 3 weeks for no more than 12 weeks in combination with cabozantinib and nivolumab every 3 weeks for 12 weeks at the safe doses of the triple drug combination established earlier in the study and then you will continue on cabozantinib and nivolumab until the disease worsens. We refer to this as an ipilimumab re-challenge.

All Groups As described above, based on the results of the scans that show worsening disease, some participants who are benefitting from the drug, study therapy with the cabozantinib/nivolumab combination at the established safe dose may continue even after you have completed the challenge or re-challenge with the triplet combination (ipilimumab, nivolumab, and cabozantinib). Nivolumab will continue at established safe dose and cabozantinib will continue at the dose that was given before challenge or re-challenge. The study therapy may continue until




you have intolerable side effects or your scans show worsening disease based on criteria that the investigator has established.

After you finish taking the study drugs, your doctor will continue to watch you for side effects and follow your condition for 100 days. We will also contact you every 2 months after the first 100 days to get information on your survival status.

What extra tests and procedures will I have if I take part in this study?

Most of the exams, tests, and procedures you will have are part of the usual approach for your cancer. However, there are some extra tests and procedures that you will need to have if you take part in this study.

Before you begin the study:

• A pregnancy test if you are female.

• A tumor biopsy if you do not have tissue left over from a previous surgery.

• 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.

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:

During the study:

• Dental examination (if you have used or are using a type of medication called a bisphosphonate) – before you receive study drug

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.

• MRI or CT scan of the chest, abdomen, and pelvis - every 6 or 8 weeks depending on study therapy

• PET CT scan in the event that you have or are suspected of having bone disease – every 6 or 8 weeks depending on study therapy

• Physical examination - every two to four weeks

• Blood tests to evaluate toxicities- every two to four weeks

• Urinalysis – every two to four 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.

• ECG to measure your heart function




• Blood draw to study the effects of markers 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 if you choose to have one. (May be collected up to 5 days before.)

- At the time your disease worsens

• Urine sample will be collected, at each clinic visit to study the effects of the study medication on markers in your body.

• Saliva sample will be collected at baseline to study the effects of the study medication on genetic markers in your body.

• Optional Combined FDG and 18F-NaF PET/CT

- FDG and 18F-NaF are two different types of radioactive tracer. You will be asked to undergo PET/CT at the following times: before you have started taking the study drug and at 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 and also to determine whether these two types of tracers can be used together.

- If you are having a combined FDG and 18F-NaF PET/CT scan, on the day of your PET/CT scan, you will be first given an injection of a small amount of 18F- FDG followed by an injection of a small amount of F18-NaF approximately 60 minutes later. The amount of radiation is very small, no more than what you would have during a normal x-ray. These radiotracers will be injected into a vein in your arm or hand. It only stays in your body for few hours. The tracers will travel to particular parts of your body. It travels to places where glucose is used for energy (FDG) or where bone is rebuilding (NaF). NaF PET scans show cancer because of the way cancer cells damage bone and the body’s normal response to repair those damaged areas of bone.

- 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 injection of the tracers, 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 PET/CT scan procedure is expected to take about 2 – 3 hours.

• 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.

Study Calendar:

Time Point Procedure

Prior to study enrollment

• Pregnancy test (for females of child bearing potential) • List of medications • Tumor biopsy (voluntary) • Blood tests

After enrollment but before starting study regimen

• Dental exam • Optional combined FDG and 18F-NaF PET/CT • Blood tests • Saliva Sample • Urine Sample

Day 1 of every cyclea

• Blood tests • Physical exam • Urinalysis • MRI or CTb • PET CTb, c • ECG • Urine Sample

Day 15d of every cycle (Group 1 and 3 patients only)

• Blood tests • Physical exam • Urinalysis • ECG • Urine Sample

aA cycle for Group 1 and 3 is 28 days. A cycle for Group 2 and 4 is 21 days for the first 12 weeks while on ipilimumab, then 28 days. b Performed every 6 or 8 weeks c Only performed if you are suspected of having bone disease d These tests will not be performed after 15 weeks of treatment

What possible risks can I expect from taking part in this study?

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 drugs 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.

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.

Possible Side Effects of Cabozantinib (XL184):

COMMON, SOME MAY BE SERIOUS In 100 people receiving cabozantinib (XL184), more than 20 and up to 100 may have:

• Diarrhea, nausea, vomiting • Tiredness • Weight loss, loss of appetite • Changes in taste • Changes in voice • Redness, pain or peeling of palms and soles




• High blood pressure which may cause blurred vision

OCCASIONAL, SOME MAY BE SERIOUS In 100 people receiving cabozantinib (XL184), from 4 to 20 may have:

• Anemia which may require blood transfusion • Pain • Constipation, heartburn • Dry mouth, skin • Sores in mouth which may cause difficulty swallowing • Swelling of arms, legs • Infection • Bruising, bleeding • Dehydration • Muscle spasms • Dizziness, headache • Kidney damage which may require dialysis • Cough, shortness of breath • Internal bleeding which may cause coughing up blood, black tarry stool or blood in vomit • Bleeding from multiple sites including the nose • Hair loss, rash • Change in hair color • Blood clot which may cause swelling, pain, shortness of breath

RARE, AND SERIOUS In 100 people receiving cabozantinib (XL184), 3 or fewer may have:

• A tear or hole in internal organs that may require surgery • Non-healing surgical site • Damage to the jawbone which may cause loss of teeth • Brain damage which may cause headache, seizure, blindness (also known as Reversible

Posterior Leukoencephalopathy Syndrome) • Lung collapse




Possible Side Effects of Nivolumab:

Special precautions

Side effects of BMS-936558 (nivolumab) may happen anytime during treatment or even after your treatment has ended. Some of these problems may happen more often when BMS-936558 is used in combination with ipilimumab. Call or see your healthcare provider right away if you develop any problems listed below or the symptoms get worse.

COMMON, SOME MAY BE SERIOUS In 100 people receiving BMS-936558, more than 20 and up to 100 may have:

• Tiredness

OCCASIONAL, SOME MAY BE SERIOUS In 100 people receiving BMS-936558, from 4 to 20 may have:

• Anemia which may require blood transfusion

• Swelling and redness of the eye

• Pain in belly

• Diarrhea, nausea, loss of appetite

• Dry mouth

• Fever

• Swelling and redness at the site of the medication injection

• Bruising, bleeding

• Pain or swelling of the joints

• Reaction during or following a drug infusion which may cause fever, chills, rash

BMS-936558 may cause your immune system to attack normal organs and cause side effects in many parts of the body. These problems may include but are not limited to:

• Lung problems (pneumonitis and pleural effusion). Symptoms may include: new or worsening cough, chest pain, shortness of breath.

• Intestinal problems (colitis) that can rarely lead to tears or holes in your intestine. Signs and symptoms of colitis may include: diarrhea or increase in bowel movements, blood in your stools or dark, tarry, sticky stools, severe belly pain or tenderness.




• Skin: itching; rash, blisters including inside the mouth; loss of skin pigment

• Liver problems (hepatitis) which can cause liver failure. Signs and symptoms of hepatitis may include: yellowing of your skin or the whites of your eyes, severe nausea or vomiting; drowsiness; pain in the right upper belly.

• Hormone gland problems (especially the thyroid, pituitary and adrenal glands, and pancreas). Signs and symptoms may include: headaches that will not go away or unusual headaches, extreme tiredness or changes in mood or behavior decreased sex drive; weight loss or weight gain; excessive thirst or urine; dizziness or fainting.

RARE, AND SERIOUS In 100 people receiving BMS-936558, 3 or fewer may have:

• Allergic reaction which may cause rash, low blood pressure, wheezing, shortness of breath, swelling of the face or throat

BMS-936558 may cause your immune system to attack normal organs and cause side effects in many parts of the body. These problems may include but are not limited to:

• Visual disturbances which may cause double vision, blurred vision, or loss of vision with a chance of blindness

• A condition with high blood sugar which leads to tiredness, frequent urination, excessive thirst, headache, nausea and vomiting, and can result in coma

• Kidney problems, including nephritis and kidney failure requiring dialysis. Signs of kidney problems may include: decrease in the amount of urine, blood in your urine, ankle swelling.

• Heart problems including inflammation and heart failure. Symptoms and signs of heart problem may include: Shortness of breath, swelling of the ankle and body.

• Problem of the muscle, including inflammation, which can cause muscle pain and severe muscle weakness sometimes with dark urine

• Inflammation of the brain (meningitis/encephalitis), which may cause: headache, confusion, sleepiness, seizures, and stiff neck

• Problem of the nerves that can cause paralysis. Signs and symptoms may include: numbness, tingling of hands and feet; weakness of the arms, legs and facial muscle movement.




• Complications associated with stem cell transplant using donor stem cells (allogeneic stem cell transplant). These complications are caused by attack of donor cells on the host organs (inducing liver, skin and gut), and can lead to death. If you are considering an allogeneic stem transplant after participating in this study, please tell your doctor that you have received BMS-936558 therapy, since the risk and severity of transplant-associated complications may be increased.

Possible Side Effects of Ipilimumab: Risk Profile for Ipilimumab (CAEPR Version 2.8, December 21, 2016)

Special precautions

Side effects of ipilimumab may happen anytime during treatment or even after your treatment has ended. Some of these problems may happen more often when ipilimumab is used in combination with BMS-936558 (nivolumab). Call or see your healthcare provider right away if you develop any problems listed below or the symptoms get worse.

COMMON, SOME MAY BE SERIOUS In 100 people receiving ipilimumab, more than 20 and up to 100 may have:

• Diarrhea, nausea

• Tiredness

Ipilimumab may cause your immune system to attack normal organs and cause side effects in many parts of the body. These problems may include but are not limited to:

• Skin: itching; rash, blisters including inside the mouth (can be severe); hives

OCCASIONAL, SOME MAY BE SERIOUS In 100 people receiving ipilimumab, from 4 to 20 may have:

• Abnormal heartbeat

• Hearing loss

• Swelling and redness of the eye

• Pain in belly

• Difficulty swallowing, vomiting, loss of appetite

• Fever




• Dehydration

• Pain or swelling of the joints

• Reaction during or following a drug infusion which may cause fever, chills, rash

• Low blood pressure which may cause feeling faint

Ipilimumab may cause your immune system to attack normal organs and cause side effects in many parts of the body. These problems may include but are not limited to:

• Lung problems (pneumonitis). Symptoms may include: new or worsening cough, chest pain, shortness of breath.

• Intestinal problems (colitis) that can rarely lead to tears or holes in your intestine. Signs and symptoms of colitis may include: diarrhea or increase in bowel movements, blood in your stools or dark, tarry, sticky stools, severe belly pain or tenderness.

• Kidney problems, including nephritis and kidney failure requiring dialysis. Signs of kidney problems may include: decrease in the amount of urine, blood in your urine, ankle swelling.

• Problem of the muscle, including inflammation, which can cause muscle pain and severe muscle weakness sometimes with dark urine.

• Problem of the nerves that can cause paralysis. Signs and symptoms may include: numbness, tingling of hands and feet; weakness of the arms, legs and facial muscle movement.

• Liver problems (hepatitis) which can cause liver failure. Signs and symptoms of hepatitis may include: yellowing of your skin or the whites of your eyes, severe nausea or vomiting; drowsiness; pain in the right upper belly.

• Hormone gland problems (especially the thyroid, pituitary and adrenal glands, and pancreas). Signs and symptoms may include: headaches that will not go away or unusual headaches, extreme tiredness or changes in mood or behavior decreased sex drive; weight loss or weight gain; excessive thirst or urine; dizziness or fainting.

RARE, AND SERIOUS In 100 people receiving ipilimumab, 3 or fewer may have:

• Bleeding

• Blockage of the bowels which may cause constipation

• Swelling of the brain which may cause headache, blurred vision, stiff neck, and/or confusion

Ipilimumab may cause your immune system to attack normal organs and cause side effects in




many parts of the body. These problems may include but are not limited to:

• A condition with high blood sugar which leads to tiredness, frequent urination, excessive thirst, headache, nausea and vomiting, and can result in coma

• Heart problems including inflammation and heart failure. Symptoms and signs of heart problem may include: Shortness of breath, swelling of the ankle and body.

• Complications associated with stem cell transplant using donor stem cells (allogeneic stem cell transplant). These complications are caused by attack of donor cells on the host organs (inducing liver, skin and gut), and can lead to death. If you are considering an allogeneic stem transplant after participating in this study, please tell your doctor that you have received ipilimumab therapy, since the risk and severity of transplant-associated complications may be increased.

Nivolumab and ipilimumab can cause severe and life threatening immune-mediated side effects because these medications can turn on certain types of immune cells. These immune-mediated side effects may involve any organ system; however, the most common are inflammation of the intestines, the liver and the skin, nerve damage and hormone problems. If you experience any of the side effects listed in the tables above, it is important to let your study doctor know right away. Additionally, let your study doctor know of any questions you have about possible side effects. You can ask the study doctor questions about side effects at any time.

Research Procedure Risks

Blood Draw Side effects of blood draws include pain and bruising in the area where the needle was placed, lightheadedness, and rarely, fainting. When large amounts of blood are collected, low red blood cell count (anemia) can develop.

Radiation Risks This research study involves 2 biopsies that may be performed with CT guidance as well as 2 investigational combined 3 mCi FDG and 10 mCi 18F-NaF PET/CT scans performed 8 weeks apart. In addition, we will perform other scans that are used to routinely diagnose and assess your cancer more frequently. 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 approximately 4.6 rem which is below the guideline of 5 rem per year allowed for 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

Reproductive risks You should not get pregnant, breastfeed, or father a baby while in this study. The drugs used in this study could be very damaging to an unborn baby. Check with the study doctor about what types of birth control, or pregnancy prevention, to use while in this study.

What possible benefits can I expect from taking part in this study?

This study is unlikely to help you. This study may help us learn things that may help people in the future.

Can I stop taking part in this study?

Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let the study doctor know as soon as possible so you can stop safely. If you stop, you can decide whether or not to let the study doctor continue to provide your medical information to the organization running the study.

The study doctor will tell you about new information or changes in the study that may affect your health or your willingness to continue in the study.

The study doctor may take you out of the study:

• If your health changes and the study is no longer in your best interest

• If new information becomes available

• If you do not follow the study rules

• If the study is stopped by the sponsor, IRB or FDA.




Research Subject’s Rights

What are my rights in this study? Taking part in this study is your choice. No matter what decision you make, and even if your decision changes, there will be no penalty to you. You will not lose medical care or any legal rights.

For questions about your rights while in this study, call the National Cancer Institute Central Institutional Review Board (NCI CIRB) at 888-657-3711.

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:

• 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.

• 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.

• Medicines that are not part of the study treatment will not be provided or paid for by the Clinical Center, NIH.

• Once you have completed taking part in the study, medical care will no longer be provided by the Clinical Center, NIH.

Who will see my medical information? Your privacy is very important to us and the researchers will make every effort to protect it. Your information may be given out if required by law. For example, certain states require doctors to report to health boards if they find a disease like tuberculosis. However, the researchers will do their best to make sure that any information that is released will not identify you. Some of your health information, and/or information about your specimen, from this study will be kept in a central database for research. Your name or contact information will not be put in the database.

There are organizations that may inspect your records. These organizations are required to make sure your information is kept private, unless required by law to provide information. Some of these organizations are:

• The study sponsor and any drug company supporting the study (Exelixis and Bristol Meyers Squibb are supporting this trial)




• The Institutional Review Board, IRB, is a group of people who review the research with the goal of protecting the people who take part in the study.

• The Food and Drug Administration and the National Cancer Institute in the U.S., and similar ones if other countries are involved in the study.

Where can I get more information? You may visit the NCI Web site at http://cancer.gov/ for more information about studies or general information about cancer. You may also call the NCI Cancer Information Service to get the same information at: 1-800-4-CANCER (1-800-422-6237).

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 the results. You can search this Web site at any time.

Conflict of Interest

The National Institutes of Health (NIH) reviews NIH staff researchers at least yearly for conflicts of interest. This process is detailed in a Protocol Review Guide. You may ask your research team for a copy of the Protocol Review Guide or for more information. Members of the research team who do not work for NIH are expected to follow these guidelines but they do not need to report their personal finances to the NIH.

Members of the research team working on this study may have up to $15,000 of stock in the companies that make products used in this study. This is allowed under federal rules and is not a conflict of interest.

The National Institutes of Health and the research team for this study are using drugs developed by Exelixis (cabozantinib) and Bristol Meyers Squibb (ipilimumab and nivolumab) through a joint study with your researchers and the companies. This means it is possible that the results of this study could lead to payments to NIH scientists and to the NIH. By law, government scientists are required to receive such payments for their inventions. You will not receive any money from the development of cabozantinib, ipilimumab and nivolumab.

ADDITIONAL STUDIES SECTION

This section is about optional studies you can choose to take part in This part of the consent form is about optional studies that you can choose to take part in. You will not get health benefits from any of these studies. The researchers leading this optional study hope the results will help other people with cancer in the future. The results will not be added to your medical records and you or your study doctor will not know the results.




You will not be billed for these optional studies. You can still take part in the main study even if you say “no” to any or all of these studies. If you sign up for but cannot complete any of the studies for any reason, you can still take part in the main study. Circle your choice of “yes” or “no” for each of the following studies.

Optional Tumor Biopsy

If you choose to take part in this study, we would like to collect a sample of your tumor before you begin treatment and any time after week 4 to see how the study medications might affect the immune cells within the tumor and the effects of this treatment on the blood vessels of your tumor.

If you agree to this tumor biopsy, it would involve collecting a small piece of tumor tissue from you. A hollow needle is used to withdraw small cylinders (or cores) of tissue from your tumor using a CT scan or ultrasound for guidance. The needle is put in 3 to 6 times to get the samples, or cores. This procedure usually causes only brief discomfort at the site from which the biopsy is taken and you will be offered medication to help numb the pain. Biopsy collection may cause bruising and bleeding, but usually does not leave scars. Rarely infection may occur at the needle site.

Please circle your answer: I choose to have a before treatment and after treatment tumor biopsy.

YES NO

Optional Sample Collections for Laboratory Studies and/or Biobanking for Possible Future Studies

Researchers are trying to learn more about cancer, diabetes, and other health problems. Much of this research is done using samples from your tissue, blood, urine, or other fluids. Through these studies, researchers hope to find new ways to prevent, detect, treat, or cure health problems. Some of these studies may be about genes. Genes carry information about features that are found in you and in people who are related to you. Researchers are interested in the way that genes affect how your body responds to treatment. If you choose to take part, some of your research specimens and data will also be saved for future research. The researchers ask your permission to store and use your samples and related health information (for example, your response to cancer treatment, results of study tests and medicines you are given) for medical research. The research that may be done is unknown at this time. Storing samples for future studies is called “biobanking”.




WHAT IS INVOLVED? If you agree to take part in biobanking, here is what will happen next:

1) Your left over samples and some related health information may be stored in the Biobank, along with samples and information from other people who take part. The samples will be kept until they are used up. Information from your medical record will be updated from time to time.

2) Qualified researchers can submit a request to use the materials stored in the Biobank. There will also be an ethics review to ensure that the request is necessary and proper. Researchers will not be given your name or any other information that could directly identify you.

3) You will not be notified when future studies will be conducted or given reports or other information about any research that is done using your samples.

4) Some of your genetic and health information may also be placed in central databases that may be public, along with information from many other people. Information that could directly identify you will not be included.

WHAT ARE THE POSSIBLE RISKS? 1) There is a risk that someone could get access to the personal information in your

medical records or other information researchers have stored about you. 2) There is a risk that someone could trace the information in a central database back to

you. Even without your name or other identifiers, your genetic information is unique to you. The researchers believe the chance that someone will identify you is very small, but the risk may change in the future as people come up with new ways of tracing information.

3) In some cases, this information could be used to make it harder for you to get or keep a job or insurance. There are laws against the misuse of genetic information, but they may not give full protection. There can also be a risk in knowing genetic information. New health information about inherited traits that might affect you or your blood relatives could be found during a study. The researchers believe the chance these things will happen is very small, but cannot promise that they will not occur.

HOW WILL INFORMATION ABOUT ME BE KEPT PRIVATE? Your privacy is very important to the researchers and they will make every effort to protect it. Here are just a few of the steps they will take:

1) When your samples are sent to the researchers, no information identifying you (such as your name) will be sent. Samples will be identified by a unique code only.

2) The list that links the unique code to your name will be kept separate from your sample and health information.




3) Researchers to whom the Biobank sends your sample and information will not know who you are.

4) Information that identifies you will not be given to anyone, unless required by law. 5) If research results are published, your name and other personal information will not

be used. WHAT ARE THE POSSIBLE BENEFITS? You will not benefit from taking part. Your samples may be helpful to research. The researchers, using the samples from you and others, might make discoveries that could help people in the future.

ARE THERE ANY COSTS OR PAYMENTS? There are no costs to you or your insurance. You will not be paid for taking part. If any of the research leads to new tests, drugs, or other commercial products, you will not share in any profits. WHAT IF I CHANGE MY MIND? If you decide you no longer want your samples to be used, you can call the study doctor, Andrea Apolo, MD, at 301-480-0536 who will let the researchers know. Then, any sample that remains in the bank will no longer be used and related health information will no longer be collected. Samples or related information that have already been given to or used by researchers will not be returned.

WHAT IF I HAVE MORE QUESTIONS? If you have questions about the use of your samples for research, contact the study doctor, Andrea Apolo, MD at 301-480-0536. Please circle your answer to show whether or not you would like to take part in each option:




SAMPLES FOR LABORATORY STUDIES I agree to have my specimen collected and I agree that my specimen sample(s) and related information may be used for the laboratory study(ies) described above.

YES NO

SAMPLES FOR FUTURE RESEARCH STUDIES

My samples and related information may be kept in a Biobank for use in future health research. YES NO

I agree that my study doctor, or their representative, may contact me or my physician to see if I wish to participate in other research in the future.

YES NO



PATIENT IDENTIFICATION CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY (Continuation Sheet)

• Adult Patient or • Parent, for Minor Patient NIH-2514-1 (07-09) P.A.: 09-25-0099 File in Section 4: Protocol Consent

OTHER PERTINENT INFORMATION

1. Confidentiality. When results of an NIH research study are reported in medical journals or at scientific meetings, the people who take part are not named and identified. In most cases, the NIH will not release any information about your research involvement without your written permission. However, if you sign a release of information form, for example, for an insurance company, the NIH will give the insurance company information from your medical record. This information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance.

The Federal Privacy Act protects the confidentiality of your NIH medical records. However, you should know that the Act allows release of some information from your medical record without your permission, for example, if it is required by the Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital accreditation organizations.

2. Policy Regarding Research-Related Injuries. The Clinical Center will provide short-term medical care for any injury resulting from your participation in research here. In general, no long-term medical care or financial compensation for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or the Federal Government. However, you have the right to pursue legal remedy if you believe that your injury justifies such action.

3. Payments. The amount of payment to research volunteers is guided by the National Institutes of Health policies. In general, patients are not paid for taking part in research studies at the National Institutes of Health. Reimbursement of travel and subsistence will be offered consistent with NIH guidelines.

4. Problems or Questions. If you have any problems or questions about this study, or about your rights as a research participant, or about any research-related injury, contact the Principal Investigator, Andrea Apolo, M.D., Building 10, Room 12N226, Telephone: 301- 480-0536. You may also call the Clinical Center Patient Representative at 301-496-2626. If you have any questions about the use of your specimens or data for future research studies, you may also contact the Office of the Clinical Director, Telephone: 240-760-6070.

5. Consent Document. Please keep a copy of this document in case you want to read it again.



PATIENT IDENTIFICATION CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY (Continuation Sheet)

• Adult Patient or • Parent, for Minor Patient NIH-2514-1 (07-09) P.A.: 09-25-0099 File in Section 4: Protocol Consent

COMPLETE APPROPRIATE ITEM(S) BELOW:

A. Adult Patient’s Consent B. Parent’s Permission for Minor Patient.

I have read the explanation about this study and have been given the opportunity to discuss it and to ask questions. I hereby consent to take part in this study.

I have read the explanation about this study and have been given the opportunity to discuss it and to ask questions. I hereby give permission for my child to take part in this study.

(Attach NIH 2514-2, Minor’s Assent, if applicable.)

Signature of Adult Patient/

Legal Representative

Date Signature of Parent(s)/ Guardian Date

Print Name

Print Name

C. Child’s Verbal Assent (If Applicable)

The information in the above consent was described to my child and my child agrees to participate in the study.

Signature of Parent(s)/Guardian Date Print Name

THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE FROM OCTOBER 17, 2017 THROUGH OCTOBER 16, 2018.

Signature of Investigator Date Signature of Witness Date

Print Name

Print Name

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