Clinical trial: NCT03452579
Section: Possible Risks, Discomforts, and Inconveniences
Subsections: What Possible Risks Can I Expect From Taking Part In This Study?|Risks Of Nivolumab|Please Inform Your Study Doctor Or Nurse At Once If You Experience Any Of The Following:|Risks Of Bevacizumab|What Possible Benefits 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
- The study drug(s)/study approach may not be better, and could possibly be worse, than the usual approach for your cancer.  
- Personal information in your medical records or other information researchers have kept about you. Someone might be able to trace this information back 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. In some cases, this
information could be used to make it harder for you to get or keep a job. There are laws against misuse of genetic information, but they may not give full protection. The researchers believe the chance these things will happen is very small, but cannot promise that they will not occur.  
Protocol Version Date 10/05/2017, 10/24/2017 Protocol Version Amendment 1 05/03/2018 Protocol Version Amendment 2 05/21/2018 Protocol Version Amendment 3 01/06/2020 Protocol Version Amendment 4 [03/20/2020]
ICF Version Date 01/24/2018, 01/29/2018, 05/03/2018, 05/21/2018, 12/18/2018, 09/30/2019, 01/06/2020, 03/20/2020, [01/05/2021]
9 There is also a risk that you could have side effects from the study drug(s)/study approach.  
Here are important points about side effects:
The study doctors do not know who will or will not have side effects.  
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Some side effects may go away soon, some may last a long time, or some may never go
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away.  
Some side effects may interfere with your ability to have children.  
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Some side effects may be serious and may even result in death.  
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Here are important points about how you and the study doctor can make side effects less of a poblem:
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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.
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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.  
In addition to side effects outlined above, you may also experience the possible side effects of bevacizumab listed below.

Very common side effects of nivolumab that may affect more than 1 in 10 people:
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Fatigue
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Rash Diarrhea
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Itching
Common side effects of nivolumab which may affect more than 1 in 100 but less than 1 in 10 people include:
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Alkaline phosphatase increased: lab test result associated with liver or bone abnormalities ALT increased: lab test result associated with abnormal liver function
Case 1317 Protocol Version Date 10/05/2017, 10/24/2017 Protocol Version Amendment 1 05/03/2018 Protocol Version Amendment 2 05/21/2018 Protocol Version Amendment 3 01/06/2020 Protocol Version Amendment 4 [03/20/2020]
ICF Version Date 01/24/2018, 01/29/2018, 05/03/2018, 05/21/2018, 12/18/2018, 09/30/2019, 01/06/2020, 03/20/2020, [01/05/2021]
10  
Abdominal pain Allergic reaction/hypersensitivity Decreased appetite Dizziness or vertigo (feeling off balance which can lead to dizziness)
Fever
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Bilirubin (liver function blood test) increased  
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Amylase increased: lab test result associated with pancreas inflammation AST increased: lab test result associated with abnormal liver functions  
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Chills
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Constipation
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function)
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Tingling, burning, numbness or weakness, possible in arms,legs,hands and feet Vomiting
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Bronchitis
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Cough Creatinine increased: lab test result associated with decreased kidney function Headache Lipase increased: lab test result associated with pancreas inflammation Increase blood sugar Inflammation of the colon Inflammation of the mouth Loss of color (pigment) from areas of skin Redness (of the skin) Shortness of breath Sodium levels in blood low Swelling including face, arms and legs Thyroid gland function decreased Thyroid stimulating hormone increased (lab test associated with abnormal thyroid Uncommon side effects of nivolumab which may affect more than 1 in 1,000 but less than 1 in 100 people Adrenal gland function decreased Case 1317 Protocol Version Date 10/05/2017, 10/24/2017 Protocol Version Amendment 1 05/03/2018 Protocol Version Amendment 2 05/21/2018 Protocol Version Amendment 3 01/06/2020 Protocol Version Amendment 4 [03/20/2020]
ICF Version Date 01/24/2018, 01/29/2018, 05/03/2018, 05/21/2018, 12/18/2018, 09/30/2019, 01/06/2020, 03/20/2020, [01/05/2021]
l l Dry mouth Dry skin Infusion related reaction Lung inflammation (pneumonitis-see details below)
Musculoskeletal pain Nausea Thyroid gland function increased
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Dehydration Diabetes Double vision Dry eye  
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Erythema  multiforme (allergic skin reaction)
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Hair loss
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Heart rate increased Heart rhythm abnormal High blood pressure
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Pemphigoid: blistering of the skin or mouth caused by immune system attacking health tissues Pituitary gland function decreased (you could experience fatigue, low blood pressure, weight loss, weakness, depression, nausea or vomiting)
Lung infiltrates associated with infection or inflammation Muscle inflammation
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Psoriasis: characterized by patches of abnormal, scaly skin Renal (kidney)failure or kidney injury Respiratory failure
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Upper respiratory tract infection Vision blurred Rare but potentially serious side effects of nivolumab which may affect up to 1 in 10,000 people but less than 1 in 1,000 people include:
Anaphylactic reaction (severe allergic reaction)
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Cranial nerve disorder, refers to an impairment of one of the twelve cranial nerves that
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emerge from the underside of the brain, pass through openings in the skull, and lead to parts of the head, neck, and trunk. These disorders can cause pain, tingling, numbness, weakness, or paralysis of the face including the eyes.  
Damage to the protective covering of the nerves in the brain and spinal cord
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Diabetes complications resulting in excess blood acids
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Drug induced liver injury
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Case 1317 Protocol Version Date 10/05/2017, 10/24/2017 Protocol Version Amendment 1 05/03/2018 Protocol Version Amendment 2 05/21/2018 Protocol Version Amendment 3 01/06/2020 Protocol Version Amendment 4 [03/20/2020]
ICF Version Date 01/24/2018, 01/29/2018, 05/03/2018, 05/21/2018, 12/18/2018, 09/30/2019, 01/06/2020, 03/20/2020, [01/05/2021]
12 Hives Inflammation of the eye Inflammation of the heart Inflammation of the kidney Inflammation of the pancreas Inflammation of the pituitary gland Inflammation of the stomach Inflammation of the thyroid gland Joint pain or stiffness Liver inflammation Low blood pressure  
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occurred as a result of their lung inflammation.  Signs and symptoms of lung inflammation may include difficulty breathing, pain or discomfort while breathing, chest pain, cough, shortness of breath, increased rate of breathing, fever, low blood oxygen levels, or fatigue.  
Your study doctor and nurse will watch you closely for changes in your ability to breathe and for other signs or symptoms that might show you are developing this type of lung inflammation and will perform regular tests including physical exams, measurement of oxygen levels through noninvasive testing (i.e., pulse oximeter), blood tests, chest x-rays and/or CT scans. Complications, including rejection, have also been reported in patients who have received an organ or tissue transplant. Treatment with nivolumab may increase the risk of rejection of the organ or tissue transplant

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Any new or increased shortness of breath; Any new or increased chest pain; Any new or increased pain/difficulty while breathing; Any new or increased cough or any significant change in your type of cough; for example any new or increased mucous or blood in your cough; Any change in the amount of oxygen you require; Any fever, fatigue, or other symptoms that occur at the same time as any changes to your breathing or other lung symptoms.

Likely (> than 10%, occurs in more than 10 people out of 100 people)  
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High blood pressure (including dangerously high blood pressure called hypertensive crisis that can have an effect on brain function and can be life threatening More protein leaking into the urine than usual (which may indicate kidney damage)
Shortness of breath Nose bleeds Sores in mouth and/or throat Changes in taste Watery eyes Skin and nail changes (including dryness itching, rash, discoloration, ulcers or peeling)
Protocol Version Date 10/05/2017, 10/24/2017 Protocol Version Amendment 1 05/03/2018 Protocol Version Amendment 2 05/21/2018 Protocol Version Amendment 3 01/06/2020 Protocol Version Amendment 4 [03/20/2020]
ICF Version Date 01/24/2018, 01/29/2018, 05/03/2018, 05/21/2018, 12/18/2018, 09/30/2019, 01/06/2020, 03/20/2020, [01/05/2021]
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Decrease in the number of red blood cell count (may cause anemia and make you fell weak and tired)
Weight loss
Decrease in the total number of platelets count that might interfere with clotting (may make you more likely to bruise or bleed)  
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Loss of appetite
Joint pain  
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Muscle pain Destruction or breakdown of jawbone Dizziness (or sensation of lightheadedness, unsteadiness, or giddiness) Headache or head pain  
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Inflammation (swelling and redness) or degeneration of the peripheral nerves (those nerves outside of brain and spinal cord) causing numbness, tingling, burning Fainting  
Blood in the urine Bleeding in the vagina
Stuffy or runny nose, sneezing  
Cough Hoarseness
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Skin rash with the presence of macules (flat discolored area) and papules (raised bump)
Hives  
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Formation of a blood clot that plugs the blood vessel; blood clots may break loose and  
travel to another place, such as the lung Loss of function of the ovaries, which can lead to menopause. The effect of this on fertility is not know
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Rare but serious (< 5%, occurs in less than 5 people out of 100 people)
Damage of or clots in small blood vessels in the kidney that can cause complications, some
.  
of which are serious including abnormal destruction of red blood cells (hemolysis) or platelets (that help to clot blood) and kidney failure 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.  
Heart failure: inability of the heart to adequately pump blood to supply oxygen to the body 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
Protocol Version Date 10/05/2017, 10/24/2017 Protocol Version Amendment 1 05/03/2018 Protocol Version Amendment 2 05/21/2018 Protocol Version Amendment 3 01/06/2020 Protocol Version Amendment 4 [03/20/2020]
ICF Version Date 01/24/2018, 01/29/2018, 05/03/2018, 05/21/2018, 12/18/2018, 09/30/2019, 01/06/2020, 03/20/2020, [01/05/2021]
16  
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Irregular heartbeat resulting from an abnormality in one of the lower chambers of the heart
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(ventricle) Ventricular fibrillation: irregular heartbeat that involves the lower chambers of the heart
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(ventricles) that results in uncoordinated contraction of the heart; life threatening and potentially fatal, needing immediate attention Gastrointestinal fistula: Abnormal hole between an organ of the digestive tract and another
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organ or tissue Gastrointestinal perforation: A tear or hole in the stomach or gut that can lead to serious
.  
complications and may require surgery to repair Sore (ulcer) somewhere in the digestive tract
.  
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.  
Leakage from stomach due to breakdown of an anastomosis (surgical connection of two
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separate body structures)
Bleeding in the brain
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Stroke caused by decreased blood flow to the brain
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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)
Sudden decrease of kidney function Abnormal hole between part of the urinary system and another organ or tissue Abnormal hole between the vagina and another organ or tissue Abnormal hole between the lower breathing tube and the body cavity that surrounds the lungs Bleeding from the lungs Hole in the wall that separates the nostrils of the nose Blockage or narrowing of a blood vessel (artery) that can cause damage or loss of function including a heart attack or stroke Abnormal hole between the breathing tube (windpipe) and the tube that goes from mouth to stomach through which food passes (esophagus). This is life-threatening and potentially fatal.  
Delay in wound healing or breakdown of a wound that had healed.  
Fertility issues for women. Bevacizumab could cause a women's ovaries to stop working and may impair her ability to have children  
Protocol Version Date 10/05/2017, 10/24/2017 Protocol Version Amendment 1 05/03/2018 Protocol Version Amendment 2 05/21/2018 Protocol Version Amendment 3 01/06/2020 Protocol Version Amendment 4 [03/20/2020]
ICF Version Date 01/24/2018, 01/29/2018, 05/03/2018, 05/21/2018, 12/18/2018, 09/30/2019, 01/06/2020, 03/20/2020, [01/05/2021]
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There is a very slight risk of an allergic reaction if contrast material is injected. Such reactions usually are mild and easily controlled by medication. If you experience allergic symptoms, a radiologist or other physician will be available for immediate assistance.  
Gadolinium-based contrast agents (dyes) may increase the risk of a rare but serious disease called nephrogenic systemic fibrosis in people with poor kidney function. Nephrogenic systemic fibrosis triggers thickening of the skin, organs and other tissues.  There is no effective treatment for this debilitating disease.  
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), effective May 21, 2010, generally makes it illegal for health insurance companies, group health plans, and most employers to discriminate against you based on your genetic information. This law generally will protect you in the following ways:
.  
.  
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Health insurance companies and group health plans may not request your genetic information that we get from this research.  
Health insurance companies and group health plans may not use your genetic information when making decisions regarding your eligibility or premiums.  
Employers with 15 or more employees may not use your genetic information that we get from this research when making a decision to hire, promote, or fire you or when setting the terms of your employment.
Be aware that this Federal law does not protect you against genetic discrimination by companies that sell life insurance, disability insurance, or long-term care insurance.  
There may be additional risks or side effects which are unknown at this time. Your condition may not get better or may become worse while you are in this study.  
Certain drugs may increase the severity of these side effects if taken during the study.  Ask your study doctor for a full list of prohibited medications 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. Case 1317 Protocol Version Date 10/05/2017, 10/24/2017 Protocol Version Amendment 1 05/03/2018 Protocol Version Amendment 2 05/21/2018 Protocol Version Amendment 3 01/06/2020 Protocol Version Amendment 4 [03/20/2020]
ICF Version Date 01/24/2018, 01/29/2018, 05/03/2018, 05/21/2018, 12/18/2018, 09/30/2019, 01/06/2020, 03/20/2020, [01/05/2021]
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you start to take any medication or non-prescription supplements (including over-the-
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If you become pregnant during this study, suspect pregnancy or if you missed your period or it is late, or if you have a change in your usual menstrual cycle (e.g., heavier bleeding during your period or bleeding between periods), you should immediately contact your study doctor.  
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), effective May 21, 2010, generally makes it illegal for health insurance companies, group health plans, and most employers to discriminate against you based on your genetic information. This law generally will protect you in the following ways:
. .  
.  
Health insurance companies and group health plans may not request your genetic information that we get from this research.  
Health insurance companies and group health plans may not use your genetic information when making decisions regarding your eligibility or premiums.  
Employers with 15 or more employees may not use your genetic information that we get from this research when making a decision to hire, promote, or fire you or when setting the terms of your employment.
Be aware that this Federal law does not protect you against genetic discrimination by companies that sell life insurance, disability insurance, or long-term care insurance.

We cannot know if you will have any benefit as a result of your participation in the study; it is possible the study treatment may improve your cancer, which may give you relief from some symptoms, improve your quality of life or prolong your survival. However, it is possible that your condition could worsen.  Your participation in this study will help to obtain information about treating subjects with recurrent glioblastoma (GBM).  
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. Case 1317 Protocol Version Date 10/05/2017, 10/24/2017 Protocol Version Amendment 1 05/03/2018 Protocol Version Amendment 2 05/21/2018 Protocol Version Amendment 3 01/06/2020 Protocol Version Amendment 4 [03/20/2020]
ICF Version Date 01/24/2018, 01/29/2018, 05/03/2018, 05/21/2018, 12/18/2018, 09/30/2019, 01/06/2020, 03/20/2020, [01/05/2021]
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Clinical trial: NCT03452579
Section: Procedures
Subsections: Screening|Treatment|Follow Up|Initial Follow-Up Phase (Follow Up Visits 1 And 2)

At the Screening visit you will be asked to read and sign this informed consent before any studyrelated procedures that are not standard of care are performed.  It is your right as a subject to have the study fully explained to you and you can ask that your study doctor explain or go over any parts of this informed consent that you do not understand.  
The following tests and procedures will be performed by the study staff to determine if you qualify to participate in this study:
Review of your medical history
•  
.  
. .  
.  
Review of medications you are currently taking and have taken in the past including herbal supplements, over the counter medications, and steroid medications A physical examination including measurement of your height, weight and vital signs
(temperature, blood pressure, respirations and heart rate) and your neurologic status.  
An electrocardiogram (ECG) to test the function of you heart You will be asked about the symptoms you are having from your disease (performance status)
Collection of your blood (approximately 4 teaspoons or 20 mLs) for laboratory tests which measure your blood chemistry, including kidney and liver function, count your red and white blood cells and platelets, measure your thyroid function, and check for hepatitis B or C infection.  You must not be HIV positive and your hepatitis B and C tests must be negative
.  
. .  
for you to participate in the study.  
A urine test (with dipstick) to check for any abnormalities If you have had brain cancer surgery in the past, either at Cleveland Clinic or elsewhere, your study doctor will request the original samples from the medical facility where it was done. In order to participate in this study, you must also provide your permission to obtain these original samples and allow your study doctor to send them to an additional laboratory for research testing.  
Your tumor samples will also be tested to determine whether your cancer tumors o have certain features which may help scientists better understand glioblastoma and also may help scientists understand why your specific type of glioblastoma either responded or did not respond to the study drug.  Scientists will look for certain types of genes and proteins which may be present on the surface of or within your tumor cells and may also look to see if certain types of white blood cells called lymphocytes are present within your tumor.  Genomic (DNA/RNA) testing will be used to identify specific genetic variants related to cancer risk, prognosis and treatments.  
Contrast enhanced magnetic resonance imaging (MRI) of your brain.  These images will
.  
allow your doctor to monitor your disease before, during and after you receive study drug and to see if the tumors change in size. Depending on your disease status at the time you Case 1317 Protocol Version Date 10/05/2017, 10/24/2017 Protocol Version Amendment 1 05/03/2018 Protocol Version Amendment 2 05/21/2018 Protocol Version Amendment 3 01/06/2020 Protocol Version Amendment 4 [03/20/2020]
ICF Version Date 01/24/2018, 01/29/2018, 05/03/2018, 05/21/2018, 12/18/2018, 09/30/2019, 01/06/2020, 03/20/2020, [01/05/2021]
s enroll into the study, the MRI images from your original GBM diagnosis may be used as  
part of this study.  
A urine or blood pregnancy test for women of childbearing potential will be performed¬
.  
Results of the pregnancy test must be negative for you to participate in this study.
If, based on the results of the screening visit tests and procedures, you qualify to participate in the study, you will return to the study doctor's office for the Baseline Visit.

If you qualify to participate in the study based on the results of the screening visit tests, and procedures, you will return to the study doctor's office/clinic. If you are assigned to treatment Arm A, nivolumab plus bevacizumab (standard dose) will be given to you as an intravenous infusion on Day 1 and then every 2 weeks.  You will then be given nivolumab and bevacizumab every 2 weeks for the remainder of the treatment period. If you are assigned to treatment Arm B, nivolumab plus bevacizumab (low dose) will be given to you as an intravenous infusion on Day 1 and every 2 weeks.  You will then be given nivolumab and bevacizumab every 2 weeks for the remainder of the treatment period. During the Treatment Period, you will be asked questions about your condition including:  
•
.  
.  
How your cancer is affecting your daily activities.  
What medications you took or are currently taking including herbal supplements and overthe-counter medicines. What side effects you experienced. During your clinic visits, you should report the development of any new or worsening medical problems (since your last visit) to the study doctor or other study personnel taking care of you.
The following procedures/samples will be performed and/or collected at Day 1 Week 1 and then every 2 weeks:  
A brief physical examination, including body weight and examination of performance status.  
.  
A neurological exam
.  
Vital sign measurements (blood pressure, heart rate, temperature and breathing rate) will be
.  
assessed. If you develop a reaction during the infusion, you will continue to have your vital signs measured until the study doctor determines it is no longer necessary.  
A urine test (with dipstick) to check for any abnormalities
.  
.  
An electrocardiogram (ECG) to test the function of your heart.  This test may be done if requested by your physician.
Protocol Version Date 10/05/2017, 10/24/2017 Protocol Version Amendment 1 05/03/2018 Protocol Version Amendment 2 05/21/2018 Protocol Version Amendment 3 01/06/2020 Protocol Version Amendment 4 [03/20/2020]
ICF Version Date 01/24/2018, 01/29/2018, 05/03/2018, 05/21/2018, 12/18/2018, 09/30/2019, 01/06/2020, 03/20/2020, [01/05/2021]
6  
.  
Pregnancy test will be done Day 1 Week 1 and then every 4 weeks
.  
Collection of your blood (approximately 4 teaspoons or 20 mLs) for laboratory tests which measure your blood chemistry, including kidney and liver function, count your red and white blood cells and platelets will be drawn prior to each study drug dose through Week 21 and then every 4 weeks Additional blood samples will be drawn for research purposes at week 4, week 8 and at every MRI visit thereafter A contrast enhanced MRI of your brain will be completed every 6-8 weeks (± 1 week)
.  
.  
thereafter, until your disease has worsened or you stop receiving study treatment (whichever occurs later). An MRI of your brain will show photographic images or pictures of your brain, which will allow your doctor to monitor the progress of your disease. Your doctor may decide to do an MRI more frequently if it is medically indicated.  
At about the same visit as the MRI, you doctor will assess your neurologic function by using a set of standard questions called the neurologic assessment in neuro-oncology (NANO)
You may be discontinued from receiving study treatment based on your disease assessments or if you are having side effects that make you unable to tolerate study therapy. Based on discussions between you and your study doctor, you may discontinue for other reasons including your decision to stop being treated.

When you stop or complete study treatments you will begin the last part of the study, the followup period. During this period your study doctor will continue to assess your health condition. It is important to know, for example, if you have recovered, developed an illness or suffered an important adverse event.

After stopping the study treatment, the first two follow up visits will be at your doctor's office.  
The first one will be about a month after you stop treatment and the second will be about 2 1/2 months after the first follow-up visit. It is important to know, for example, if you have recovered, developed an illness or suffered an important adverse event the procedures/samples performed and/or collected while you were taking study drug may be repeated at one or more of these follow up visits.  
A Physical exam, including body weight and examination of performance status Vital sign measurements (blood pressure, heart rate, temperature, and breathing rate
.  
.  
You will be asked about any medications you are taking and how you are feeling. Pregnancy test
.
Protocol Version Date 10/05/2017, 10/24/2017 Protocol Version Amendment 1 05/03/2018 Protocol Version Amendment 2 05/21/2018 Protocol Version Amendment 3 01/06/2020 Protocol Version Amendment 4 [03/20/2020]
ICF Version Date 01/24/2018, 01/29/2018, 05/03/2018, 05/21/2018, 12/18/2018, 09/30/2019, 01/06/2020, 03/20/2020, [01/05/2021]
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Your Responsibilities  
If you participate in this study, you will be expected to:
Keep all study appointments and follow all instructions given to you by your study doctor
.  
and study staff Describe how you feel and discuss possible side effects.  
.  
Tell the study doctor about all medications you are taking including prescriptions, herbal
.  
supplements and over-the-counter medications.  
Discuss any medication (prescription or over the counter) that you wish to start taking with
.  
your study doctor before you start taking it.  
Tell the study doctor about any changes in your health
.  
Certain medications cannot be taken while you are participating in this trial. Your study
.  
doctor will explain what these medications are. If you need treatment with any medications that are not allowed during your participation in this trial, you must inform the study doctor or the study staff. You will not be denied medications required to treat an illness you may have, but you may be required to stop taking the study medication. This is for your safety,
since some medications may not work well with the study treatment, and you might have physical problems.  
.  
.  
Tell your study doctor about any additional medical treatments that you plan to receive during the study (such as elective surgery or radiation).  
Tell your study doctor or study staff if you change your address, telephone number, or other contact information