Clinical trial: NCT03099486
Section: Alternatives
Subsections: Are There Benefits To Taking Part In The Study?|What Other Choices Do You Have If You Do Not Take Part In This Research Study?

Taking part in this study may or may not make your health better. While doctors hope that the regorafenib and 5FU combination therapy 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 Protocol version date: 12/14/2018 will help doctors learn more about the regorafenib and 5FU combination therapy as a treatment for cancer. This information could help future cancer patients.

Your other choices may include:
Getting treatment or care for your cancer without being in a study Taking part in another study Getting no treatment Getting comfort care, also called palliative care. This type of care helps reduce pain, tiredness, appetite problems and other problems caused by the cancer. It does not treat the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep you as active and comfortable as possible.
Talk to your doctor about your choices before you decide if you will take part in this study.
Clinical trial: NCT03099486
Section: Confidentiality
Subsections: Will Your Medical Information Be Kept Private?

We will do our best to make sure that the personal information in your medical record will be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used.  
Organizations that may look at and/or copy your medical records for research, quality assurance, and data analysis include:
Fox Chase Cancer Center and affiliated Joint Centers, The Institutional Review Boards of The Fox Chase Cancer Center and Temple University, Temple University, Temple University Health system, Inc., and its affiliates or subsidiaries and other authorized representatives of these organizations.  
The National Cancer Institute (NCI) and other government agencies, like the Food and Drug Administration (FDA), involved in keeping research safe for people Bayer Pharmaceuticals-supplier of the study drug Regorafenib
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.  
You will be given a separate form to review regarding the steps we will take to guard your privacy as part of your participation in the research study. By signing that additional authorization, you will be providing your consent to use and disclose information described in that form connected with your participation in this research study.
Clinical trial: NCT03099486
Section: Duration of Study Involvement
Subsections: After You Have Finished Study Treatment|How Long Will You Be In The Research Study?

We will perform a safety follow-up after 30 days of the discontinuation of the treatment. In this follow-up visit we will:  
Ask you about the medication that you are taking Perform a physical examination including vital signs, and weight We will ask you how cancer affects your daily activities Routine blood test (1 tablespoon) Urine test We will ask you about any side-effects that you may be experiencing due to the study treatment
We will continue to follow-up with you after the safety follow-up every 3 months for the next 2 years, every 6 months during 3 rd and 4 th year and then annually until death. During this follow-up your tumor may be monitored by MRI or a CT scan. Another way to find out what will happen to you during the research study is to read the chart below. Start reading at the top and read down the list, following the lines and arrows.  
Protocol version date: 12/14/2018  
  
You sign the informed consent document and test show that you can take part in the study Study treatment  
You begin the study treatment in clinic on Day 1 of cycle1. You will undergo study related tests and procedures You start taking Regorafenib, orally, daily, for the first 21 days of the 28 days cycle 5FU will be administered intravenously on Day 1 and Day 15 of each cycle After the end of cycle 1 (28 days), the next cycle begins. During the first 2 cycles you will visit clinic on day1, 8, 15 and 22. After 2 cycles you will visit clinic only on day 1 and 15.  
Your tumor will be measured every 2 cycles (8 weeks) to assess the treatment response
You continue to receive the treatment until  
  
Your disease gets worse You decide to withdraw from the study You experience severe side-effects In your Physician's opinion it is best for you to discontinue from the study

You will be asked to take Regorafenib and 5FU until your cancer gets worse or you have unacceptable toxicity or your doctor thinks it is best for you to stop being in the study. After you are finished taking the study treatment, the study doctor will ask you to visit the office for follow-up exams after 30 days of discontinuation and then every 3 months for the next 2 years and every 6 months for the 3 rd and 4 th year and then annually until death.
Clinical trial: NCT03099486
Section: Participant's Rights
Subsections: What Are Your Rights If You Take Part In This Research Study?

Taking part in this research study is your choice. You may choose either to take part or not to take part in the research study. If you decide to take part in this study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you and you will not
Clinical trial: NCT03099486
Section: Possible Risks, Discomforts, and Inconveniences
Subsections: What Side Effects Or Risks Can You Expect From Being In The Research Study?|Risks And Side Effects Related To The Regorafenib Include Those Which Are: Likely (>20%)|Less Likely (5-19%)|Less Likely (5-19%)|Rare But Serious (< 5%)|Rare But Serious (< 5%)|Rare But Serious (< 5%)|Risks And Side Effects Related To The 5-Fluorouracil (5-Fu) Includes Those Which Are: Likely (>20%)|Less Likely (5-19%)|Less Likely (5-19%)|Rare But Serious (< 5%)|Rare But Serious (< 5%)|Rare But Serious (< 5%)|Risks And Side Effects Related To The Leucovorin (Lv) Include Those Which Are: Likely (>20%)|Rare But Serious (< 5%)|Rare But Serious (< 5%)|Rare But Serious (< 5%)|Radiation Risk For Diagnostic Imaging|Blood Draw Risks|Reproductive Risks|What If You Are Injured While Taking Part In This Research Study?

You may have side effects while on the research study. Everyone taking part in the research study will be watched carefully for any side effects. However, doctors don't know all the side effects that may happen. Side effects may be mild or very serious. Your health care team may give you medicines to help lessen side effects. Many side effects go away soon after you stop taking regorafenib and 5FU. In some cases, side effects can be serious, long lasting, or may never go away. In rare but serious circumstances there is also a risk of death.  
You should talk to your study doctor about any side effects that you have while taking part in the research study.

Fatigue (feeling of being overly tired and lacking energy) Weakness Palmar-Plantar Erythrodyesthesia (Hand-Foot-Syndrome) Redness, tenderness, pain and possible peeling of the palms of the hands and soles of the feet. The redness looks like a sunburn. The affected area can become dry and peel with numbness or tingling developing Rash Diarrhea (increased frequency of bowel movements with loose, watery stools)
IRB Page 6 of 13

Headache Fever Infection Bleeding Hair loss Altered taste Dry mouth Pain Muscle stiffness Anemia (low hemoglobin, low hematocrit or low red blood cell count) - red blood cells carry oxygen and nutrients throughout the body. Symptoms that may be experienced as a result of low red blood cell counts may include feeling tired and weak, shortness of breath, increased heart rate, dizziness or lightheadedness, headache, chest pain and pale skin.  
Hypokalemia (low levels of potassium) Symptoms may include muscle weakness, cramping, leg discomfort, an irregular heart beat and confusion Elevated liver enzymes: Liver enzymes, proteins made by the liver, indicate how well your liver is functioning. High liver enzyme levels may cause you to feel overly tired or weak, you may bruise or bleed more easily, and you may experience abdominal pain or have a yellowing of the skin or eyes Hyperbilirubinemia (elevated bilirubin levels in the blood) Bilirubin is a chemical that is released when red blood cells are broken down. Bilirubin is used by the liver to make Mucositis/stomatitis- sores in the lining of your mouth and/or throat that can be painful and make it hard to swallow Loss of appetite Weight loss Hypertension (high blood pressure) Symptoms may include headache, dizziness, palpitations, blurred vision, ringing in the ears and nose bleeds Voice changes/hoarseness/difficulty forming sound Thrombocytopenia (low platelet count) - platelets are important in stopping bleeding. A
low platelet count can increase the time to form a blood clot Leukopenia/Neutropenia (low white blood cell count) - a low white blood cell count makes it hard for you to fight infections Hypocalcemia (low calcium levels in the blood) Symptoms of a low calcium level may include numbness and tingling in the hands and feet, muscle cramps, twitches and spasms, fatigue, confusion, disorientation and seizures.  
Hyponatremia (low sodium levels in the blood) Symptoms may include nausea and vomiting, loss of appetite, headache, confusion, fatigue, restlessness and irritability, muscle weakness, spasms or cramps, decreased consciousness, seizures or coma.  
Low blood levels of phosphorous (can affect your bones, muscles, heart, and central nervous system)
Increased blood levels of the pancreas enzyme called lipase Increased levels of protein in the urine- this may a sign of kidney damage IRB Page 7 of 13 bile. Symptoms of elevated bilirubin levels include a yellowing of the skin, eyes and mucous membranes.  
Low thyroid hormone production, which may cause symptoms including tiredness, depression, weight gain, cold intolerance, dry coarse hair, difficulty having bowel movements, dry skin, muscle cramps, high cholesterol, trouble with concentration and swelling of the legs.

Hair loss Dry itchy and cracked skin Darkening of nail beds and the vein where the drug was infused.  
Protocol version date: 12/14/2018 Nail loss Palmar-Plantar Erythrodyesthesia (Hand-Foot-Syndrome) - redness, tenderness, pain and possible peeling of the palms of the hands and soles of the feet. The redness looks like a sunburn. The affected area can become dry and peel with numbness or tingling developing.  
Headache Confusion Changes in vision Nose bleeds Chest pain Shortness of breath Irritation and/or tearing of the eyes Irritation of the veins

Delay in wound healing or breakdown of a wound that has healed Gastrointestinal (GI) perforation which is the development of an opening or hole in the wall of the bowel or stomach (gastrointestinal tract) that may require surgery to repair and can be life threatening Fistula- breakdown in the surgical connection between two pieces of bowel Reversible Posterior Leukoencephlopathy Syndrome (RPLS): a neurological disorder which can present with a headache, confusion, seizures, or vision changes Heart attack

Heart attack - symptoms may include chest pain/tightness, shortness of breath, nausea, sweating and dizziness Hypersensitivity Reaction (allergic Reaction) - an overactive immune response that results in local tissue injury or other changes throughout the body in response to a foreign substance or drug. Symptoms of an allergic reaction may include fever, fast heart rate, rash, hives, swelling, itching, flushing, changes in blood pressure, nausea, chest pain and shortness of breath.  
Anaphylaxis - a severe allergic reactions which can cause shock, low blood pressure and death Stomach ulcer/bleeding

Hypersensitivity Reaction (Allergic Reaction) - an overactive immune response that results in local tissue injury or other changes throughout the body in response to a foreign substance or drug. Symptoms of an allergic reaction may include rash, hives, swelling, itching, flushing, changes in blood pressure, nausea, chest pain and shortness of breadth

Diarrhea - increased frequency of bowel movements with loose watery stools Abdominal pain Anemia (low hemoglobin, low hematocrit or low red blood cell count) - red blood cells carry oxygen and nutrients throughout the body. Symptoms that may be experienced as a result of low red blood cell counts may include feeling tired and weak, shortness of breath, increased heart rate, dizziness or lightheadedness, headache, chest pain and pale skin Leukopenia/Neutropenia (low white blood cell count) - a low white blood cell count makes it hard for you to fight infections Thrombocytopenia (low platelet count) Platelets are important in stopping bleeding. A
low platelet count can increase the time to form a blood clot, causing you to bruise or bleed more easily Nausea - feeling sick to your stomach Vomiting - throwing up Mucositis/stomatitis - sores in the lining of the mouth and/or throat that can be painful and make it painful or hard to swallow Photosensitivity - skin sensitivity to the sun causing a painful rash and burn Loss of appetite

Headache Fever Infection Bleeding Hair loss Altered taste Dry mouth Pain Muscle stiffness Anemia (low hemoglobin, low hematocrit or low red blood cell count) - red blood cells carry oxygen and nutrients throughout the body. Symptoms that may be experienced as a result of low red blood cell counts may include feeling tired and weak, shortness of breath, increased heart rate, dizziness or lightheadedness, headache, chest pain and pale skin.  
Hypokalemia (low levels of potassium) Symptoms may include muscle weakness, cramping, leg discomfort, an irregular heart beat and confusion Elevated liver enzymes: Liver enzymes, proteins made by the liver, indicate how well your liver is functioning. High liver enzyme levels may cause you to feel overly tired or weak, you may bruise or bleed more easily, and you may experience abdominal pain or have a yellowing of the skin or eyes Hyperbilirubinemia (elevated bilirubin levels in the blood) Bilirubin is a chemical that is released when red blood cells are broken down. Bilirubin is used by the liver to make Mucositis/stomatitis- sores in the lining of your mouth and/or throat that can be painful and make it hard to swallow Loss of appetite Weight loss Hypertension (high blood pressure) Symptoms may include headache, dizziness, palpitations, blurred vision, ringing in the ears and nose bleeds Voice changes/hoarseness/difficulty forming sound Thrombocytopenia (low platelet count) - platelets are important in stopping bleeding. A
low platelet count can increase the time to form a blood clot Leukopenia/Neutropenia (low white blood cell count) - a low white blood cell count makes it hard for you to fight infections Hypocalcemia (low calcium levels in the blood) Symptoms of a low calcium level may include numbness and tingling in the hands and feet, muscle cramps, twitches and spasms, fatigue, confusion, disorientation and seizures.  
Hyponatremia (low sodium levels in the blood) Symptoms may include nausea and vomiting, loss of appetite, headache, confusion, fatigue, restlessness and irritability, muscle weakness, spasms or cramps, decreased consciousness, seizures or coma.  
Low blood levels of phosphorous (can affect your bones, muscles, heart, and central nervous system)
Increased blood levels of the pancreas enzyme called lipase Increased levels of protein in the urine- this may a sign of kidney damage IRB Page 7 of 13 bile. Symptoms of elevated bilirubin levels include a yellowing of the skin, eyes and mucous membranes.  
Low thyroid hormone production, which may cause symptoms including tiredness, depression, weight gain, cold intolerance, dry coarse hair, difficulty having bowel movements, dry skin, muscle cramps, high cholesterol, trouble with concentration and swelling of the legs.

Hair loss Dry itchy and cracked skin Darkening of nail beds and the vein where the drug was infused.  
Protocol version date: 12/14/2018 Nail loss Palmar-Plantar Erythrodyesthesia (Hand-Foot-Syndrome) - redness, tenderness, pain and possible peeling of the palms of the hands and soles of the feet. The redness looks like a sunburn. The affected area can become dry and peel with numbness or tingling developing.  
Headache Confusion Changes in vision Nose bleeds Chest pain Shortness of breath Irritation and/or tearing of the eyes Irritation of the veins

Delay in wound healing or breakdown of a wound that has healed Gastrointestinal (GI) perforation which is the development of an opening or hole in the wall of the bowel or stomach (gastrointestinal tract) that may require surgery to repair and can be life threatening Fistula- breakdown in the surgical connection between two pieces of bowel Reversible Posterior Leukoencephlopathy Syndrome (RPLS): a neurological disorder which can present with a headache, confusion, seizures, or vision changes Heart attack

Heart attack - symptoms may include chest pain/tightness, shortness of breath, nausea, sweating and dizziness Hypersensitivity Reaction (allergic Reaction) - an overactive immune response that results in local tissue injury or other changes throughout the body in response to a foreign substance or drug. Symptoms of an allergic reaction may include fever, fast heart rate, rash, hives, swelling, itching, flushing, changes in blood pressure, nausea, chest pain and shortness of breath.  
Anaphylaxis - a severe allergic reactions which can cause shock, low blood pressure and death Stomach ulcer/bleeding

Hypersensitivity Reaction (Allergic Reaction) - an overactive immune response that results in local tissue injury or other changes throughout the body in response to a foreign substance or drug. Symptoms of an allergic reaction may include rash, hives, swelling, itching, flushing, changes in blood pressure, nausea, chest pain and shortness of breadth

Fatigue - feeling of being overly tired and lacking energy Nausea - feeling sick to your stomach Vomiting - throwing up Diarrhea - increased frequency of bowel movements with loose, watery stools Rash Itching

Delay in wound healing or breakdown of a wound that has healed Gastrointestinal (GI) perforation which is the development of an opening or hole in the wall of the bowel or stomach (gastrointestinal tract) that may require surgery to repair and can be life threatening Fistula- breakdown in the surgical connection between two pieces of bowel Reversible Posterior Leukoencephlopathy Syndrome (RPLS): a neurological disorder which can present with a headache, confusion, seizures, or vision changes Heart attack

Heart attack - symptoms may include chest pain/tightness, shortness of breath, nausea, sweating and dizziness Hypersensitivity Reaction (allergic Reaction) - an overactive immune response that results in local tissue injury or other changes throughout the body in response to a foreign substance or drug. Symptoms of an allergic reaction may include fever, fast heart rate, rash, hives, swelling, itching, flushing, changes in blood pressure, nausea, chest pain and shortness of breath.  
Anaphylaxis - a severe allergic reactions which can cause shock, low blood pressure and death Stomach ulcer/bleeding

Hypersensitivity Reaction (Allergic Reaction) - an overactive immune response that results in local tissue injury or other changes throughout the body in response to a foreign substance or drug. Symptoms of an allergic reaction may include rash, hives, swelling, itching, flushing, changes in blood pressure, nausea, chest pain and shortness of breadth

It is unlikely that there will be any harmful effects from the radiation exposure you will receive from participating in this study.  
At high levels of exposure, scientists agree that radiation can cause cancer.  
At low exposure levels most scientists agree that the risk, if any, is very low. You will have low levels of radiation exposure with diagnostic imaging procedures.  
Risks from exposure to radiation may accumulate over a lifetime.

Fainting Bleeding Bruising at the place on your arm where the blood was drawn or needle inserted Pain at the needle insertion site Swelling Infection (rare)

Study treatments may make you sterile (unable to have children). The drugs in this study may affect a baby, before or after the baby is born. You should not become pregnant or father a baby while on this research study because the drugs you take could possibly hurt an unborn baby.  
If you are pregnant now or if you are breast-feeding now, you may not take part in this research study.  
If you become pregnant while you are on the research study, you may not continue to take part in the research study.  
For women who can become pregnant:
You should not become pregnant while you are in this study. You should not breast-feed your baby while taking drugs for this research study.
For men:
You should not make a woman pregnant while you are in this study.  
For women and men:
If you are having sex that could lead to pregnancy, you should use birth control while you are in this study.  
Check with the study doctor about birth control methods and how long to use them.  
Some methods might not be approved for use in this study.

If you are injured as a result of your participation in this research study, seek immediate medical care. Temple University Health System or its subsidiaries will treat the injury, though there is no commitment to provide monetary compensation or free medical care. Other financial compensation (such as lost wages or pain and suffering) for such injuries is not available.
Clinical trial: NCT03099486
Section: Procedures
Subsections: What Will Happen If You Take Part In This Research Study? Before You Begin The Research Study|During The Research Study Study Treatment|Tests And Procedures|Possible Use Of A Port

You will need to have the following exams, tests or procedures to find out if you can be in the research study. These exams, tests or procedures are part of regular cancer care and may be done even if you do not join the research study. If you have had some of them recently, they may not need to be repeated. This will be up to your study doctor.  
A review of your medical history and any medications you are currently taking or have taken in the past Physical examination including vital signs, weight and height You will be asked how cancer effects your daily activities Blood pregnancy test (2 teaspoons) within 3 days prior to registration, if you are a woman and are able to become pregnant.  
Routine blood test (1 tablespoon)
Urine test We will perform EKG to check how your heart is functioning We will ask you about any side-effects that you may be experiencing from previous treatments A CT scan or MRI scan of your tumor o A CT scan is a computerized X-ray that gives your study doctor pictures of the inside of your body o A MRI scan uses a magnetic field and radio waves to take pictures of the inside of your body

The drugs in this study will be administered in cycles. Each cycle is of 28 days and when one cycle ends the next cycle begins. During the study you will receive the following drugs to treat your cancer.  
Regorafenib to be taken orally, once daily for 21 days.  
5FU will be administered at the clinic intravenously on day 1 and day 15 of each cycle.
The treatment will go on as long as you continue to derive benefit from it, that is, your cancer is getting better or does not progress. The treatment will stop if your cancer gets worse or you have severe side-effects or if in your Physician's opinion it is best for you to discontinue from the

If the exams, tests and procedures show that you can be in the research study, and you choose to take part, then you will need the following tests and procedures. They are part of regular cancer care. They are being done more frequently because you are in this research study.  
We will ask you about all the medicines that you are taking We will perform physical examination including vital signs and weight We will ask you how cancer effects your daily activities Routine blood test (1 tablespoon) Urine test We will ask you if you are experiencing any side-effects due to the treatment An MRI or CT scan of your tumor

If the doctors or nurses cannot draw blood or give you medicine through your veins, you may be asked to have minor surgery to place an "indwelling catheter port" into a large vein in your chest. Medical staff will use the "port" to give you medicines and to draw blood. You will be asked to sign a separate consent form for this procedure, and the "port" will not be used unless you agree. If a port is necessary and you do not agree to its use, you may be unable to continue as part of the research study.
Clinical trial: NCT03099486
Section: Purpose of Research
Subsections: Why Is This Research Study Being Done?

The purpose of this research study is to determine whether a combination therapy of Regorafenib and 5-fluorouracil (5FU)/ Leucovorin (LV) will result in control of your metastatic colorectal cancer. Regorafenib and 5FU combination therapy is not yet approved for treatment of metastatic colorectal cancer in humans by FDA. There is some clinical evidence that suggests the combination therapy could be beneficial for treating metastatic colorectal cancer. We do not know if you will benefit from this research study. It is possible that your condition will get better, but it is also possible that there will be no effect on your condition or that your condition will get worse. We can use what we learn from this research study to help other people with the same disease.
Clinical trial: NCT03099486
Section: Withdrawal from Study
Subsections: After You Stop The Study Treatment|Can You Stop Being In The Research Study?|Can You Be Removed From This Research Study?

Safety follow-up after 30 days of discontinuation Long-term follow-up every 3 months for the next 2 years Lon-term follow-up every 6 months during 3 rd and 4 th year Long-term follow-up annually until death

Yes. You can decide to stop at any time. Your participation in this research is completely voluntary. If you agree to participate now and change your mind later, you may withdraw at any time. Tell the study doctor if you are thinking about stopping or decide to stop. He or she will tell you how to stop safely and will discuss with you options for withdrawal such as continuing to provide further data collection from routine medical care.

The study doctor may stop you from taking part in this research study at any time if he/she believes it is in your best interest; if you do not follow the research study rules; or if the research study is stopped.