Clinical trial: NCT04366713
Section: Alternatives
Subsections: Alternatives|What Happens If You Decide Not To Take Part In This Study?

In the event that you do not want to receive the treatment proposed for this study, your doctor will inform you of the therapeutic alternatives available for the treatment of your disease. There are other alternatives in addition to the treatment strategies that will be used in this clinical trial. You will be able to discuss the advantages and inconveniences of each of these alternative treatments with your doctor. Alternatives to participating in the study include:  
- Starting a different anticancer treatment and/or research study - No additional treatment for your breast cancer at this time

If you decide not to take part in the study you will not be in trouble or lose any rights you normally have. You will still have the same health care benefits and get your regular treatments from your regular doctor.  
You can decide after signing this informed consent document that you no longer want to take part in this study for any reason at any time. If you decide you want to stop taking part in the study, tell the study staff as soon as you can.  
- The study doctor will tell you how to stop safely. The study doctor will tell you if there are any dangers if you stop suddenly.  
- If you decide to stop, you can continue getting care from your regular doctor.  
- Your doctor will perform the following procedures within 5 days of your last dose of study drug if you decide to stop participating in the study: ask if you have any new symptoms or concerns about your health, perform a physical exam and collect vital signs including your weight.
Even if you want you to stay in the study, there may be reasons we will need to withdraw you from the study. You may be taken out of this study if the study doctor finds out it is not safe for you to stay in the study or if you are not coming for the study visits when scheduled. Your study doctor will let you know the reason for withdrawing you from this study.
Clinical trial: NCT04366713
Section: Confidentiality
Subsections: Privacy And Confidentiality

Your study doctor and the study staff will collect and use information about you for the study. This may include your identification number, location information, and health information, and data that is obtained from any biological samples taken from you such as your blood, tissue or saliva. This information is referred to as "Personal Data". Your Personal Data will be handled in accordance with the Regulation (EU) 679/2016, of 27 April 2016 (hereinafter, GDPR). In this study, the Personal Data the study doctor and study staff will collect, use share, and transfer out of the EU
as part of your coded Study Data, may include sensitive information about you such as your race, ethnic origins, genetic data and biometric data. If you want to consent to the collection, use and sharing of your sensitive Personal Data, then you should check the box next to the statement above your signature so we know you understand what your sensitive Personal Data may include, and specifically consent to the collection, use sharing, and transfer outside of the EU of that sensitive Personal Data as described in this Informed Consent Form. If you do not consent to the collection, use and sharing of your sensitive Personal Data as described in this Informed Consent Form, then you may not be in this study. If you consent to the use and sharing of your sensitive Personal Data as part of the coded Study Data by checking the box below, you have a right to withdraw that consent at any time and for whatever reason. If you do withdraw your consent, the Sponsor may continue to use your sensitive Personal Data that has already been collected as part of the coded Study Data. If you wish to withdraw your consent as to the collection, use and sharing of your sensitive Personal Data, please contact your study doctor.  
Your identity will be kept confidential as required by applicable law, but there is always a risk that some of your Personal Data may be disclosed. You will not be identified on any study form or study document by name, national identity number, address, telephone number, or by any other direct personal identifiers. Instead, you will be identified by an assigned subject identification number (code). The study doctor will keep the list that matches the subject identification numbers to subject names. That list will not be provided to the sponsor, and only the study doctor will have access to the list.  
The Personal Data together with other information collected about you during the study is referred to as the
"Study Data" and will be coded before it is transferred outside the study center. Study Data and the key reconnecting the Study Data to you will be kept by the study center for up to 25 years after the study is completed or for such longer time period that may be required under local law.  
The sponsor, parties working with or on behalf of the sponsor, the ethics committee responsible for approving the conduct of the study, local regulatory authorities and regulatory authorities in other countries where the sponsor may seek approval for the study drug, such as the United States Federal Food and Drug Administration, may access your medical records to make sure the study has been done properly, and may be able to identify you. Your medical records will be reviewed only at the study center. The Study Data will be used by the sponsor to carry out the study, to develop the study drug, to meet its legal obligations in connection with the conduct of the study and to make publications and presentations about the study. In addition, the sponsor and parties working with or on behalf of the sponsor may use your Study Data to perform additional unknown future research. Although the exact nature of the research that may be performed is not known at this time, such research will be in connection with patient care and public health, including the development of new drugs and treatments for diseases. The sponsor will limit and monitor access to your Study Data and put appropriate restrictions in place so that efforts are made to not identify you and to ensure that your Study Data are only used for the purposes described in this Patient Information Sheet. For certain reasons, you may have a right to oppose the use of your Study Data for additional future unknown research. If you wish to object to such use, please contact your study doctor. If you consent to the use and sharing of your Study Data by signing the attached Consent Form, you have a right to withdraw that consent at any time and for whatever reason. If you do withdraw your consent, the sponsor may continue to use the Study Data that has already been collected. If you wish to withdraw your consent, please contact your study doctor.  
THE SPONSOR AND SOME OF THE RECIPIENTS OF YOUR STUDY DATA MAY BE BASED IN COUNTRIES OUTSIDE
THE EUROPEAN UNION, SUCH AS THE UNITED STATES, THAT MAY NOT HAVE THE SAME LEVEL OF DATA PROTECTION AS IN PORTUGAL OR IN THE EUROPEAN UNION. HOWEVER, THE SPONSOR AND ITS
REPRESENTATIVES WILL TAKE REASONABLE MEASURES TO KEEP YOUR STUDY DATA CONFIDENTIAL IN
ACCORDANCE WITH APPLICABLE LAWS. BY PARTICIPATING IN THIS STUDY, YOU CONSENT TO THE TRANSFER OF YOUR STUDY DATA TO **THESE COUNTRIES.**
The results of this study may be published and presented to the public, and used for educational purposes.  
Information that could directly or indirectly identify you (like your name) will not be used in any publication or presentation.  
You have certain rights to your Study Data that is kept by the study center and the sponsor including the rights of access, rectification, restriction, and data portability. If you wish to exercise any of your rights, you should contact the study doctor. You also have a right to bring a complaint to the regulatory authority responsible for the protection of Personal Data in your country. In accordance with the applicable legislation, you are entitled to exercise the rights contained in the previous paragraph, and you can discuss them by contacting the doctor who is treating you in this study.  
Should you wish to know more about how your Personal Data is protected by the study sponsor, you may contact the sponsor at info@pumabiotechnology.com. A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by United States Law. This Web site will not include information that can directly or indirectly identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.
Clinical trial: NCT04366713
Section: Duration of Study Involvement
Subsections: Total Number Of Participants **And Study Duration**

- About 5 individuals will take part in this study. A total of 2 to 3 individuals will participate in the study at each site in the following countries: USA and Portugal.  
- The duration that each patient will participate in the study is approximately 1 year for patients with early stage breast cancer. For patients with metastatic breast cancer, treatment will continue until disease progression or until unacceptable side effects occur.  
- Overall study duration of the study is approximately 1.5 years.
Clinical trial: NCT04366713
Section: Possible Risks, Discomforts, and Inconveniences
Subsections: Risks Or Discomfort|Common (≥1/100 And <1/10) [May Occur Between 1 And 9 Subjects In 100]|Uncommon (≥1/1000 And <1/100) [May Occur In Less Than 1 Subject In 100]|Other Potential Side Effects Of Neratinib|Information On Other Risks: Risks Of Taking Neratinib With Acid-Reducing Medication|Risks Of Taking Capecitabine (Metastatic Breast Cancer Patients)|Risks Of Taking Loperamide|Risks Of Colonoscopy|Risks Of The Blood Collection|Risks Of The Muga Scan|Risks To Unborn Children|Unknown Risks|What If You Are Injured While You Are In The Study?

The following risks may occur: Based on safety information from previous subjects treated with neratinib, the following side effects have been observed:
Very common (≥ 1/10) [*may occur in 10 or more subjects in 100]*  
- Diarrhea
- Nausea - Vomiting
- Abdominal pain - Pain, redness, swelling or sores in the mouth, and/or throat - Fatigue
- Decreased appetite - Muscle spasms - Rash (includes red, flat, patchy rash or raised small bumps which may cause itchiness and may occur in more than one area of the body, and/or may contain fluid or pus)

- Increased blood levels of alanine aminotransferase (an increase in an enzyme that measures the function of the liver, also known as ALT)
- Increased blood levels of aspartate aminotransferase (an increase in an enzyme that measures the function of the liver, also known as AST)
- Increased blood levels of creatinine (an abnormally high level of creatinine in the bloodstream may indicate kidney disease)
- Dyspepsia (indigestion)
- Abdominal distension
- Urinary tract infection - Weight loss
- Dehydration
- Nose bleed - Nail disorder (inflammation/infection, breaking or discoloration) - Dry skin - Deep skin cracking - Dry mouth

- Increased blood levels of bilirubin (an increase in an enzyme that measures the function of the liver)
- Renal failure (damage to the kidney which may decrease its functioning)
Diarrhea and vomiting can quickly lead to a loss of too much water from your body (dehydration). If you get very dehydrated, this could make your blood pressure low and could make it hard for your kidneys to clean your blood. If the dehydration is not treated, this could lead to a subtype of kidney failure called pre-renal failure. This kidney failure gets better when fluids are given. Patients who suffered from pre-renal failure in neratinib trials have all fully recovered their renal function.  
Symptoms of mild dehydration include thirst, decreased urine volume, abnormally dark urine, unexplained tiredness or fatigue, irritability and negative mood, headache, dry mouth and dry skin, dizziness when standing, and in some cases can cause insomnia. Other possible symptoms include cloudy urine and stinging during urination. Make sure you drink enough liquids each day (8 to 10 large glasses or cups). If you have severe diarrhea and/or vomiting, even for a short period of time, call the study doctor immediately to prevent the signs of dehydration described above.

The side effects listed below have been reported with neratinib, however; the relationship of these events to treatment with neratinib is unknown at this time. They occurred uncommonly (≥0.1% - <1%) **between 1 and 9** subjects in 1000, but can be ultimately life-threatening if not treated rapidly. Call your study doctor immediately if you experience any of the symptoms described in the section below.  
Severe liver damage:
There have been reports of patients taking neratinib, who have had severe changes in liver function tests, which may indicate liver damage. Based on the reports observed so far, these changes appear to be reversible when neratinib is stopped. If you experience multiple loose bowel movements in a day or any worsening of fatigue, nausea, vomiting, abdominal pain or tenderness, fever or rash, notify your doctor immediately as these may be associated with changes in liver function tests.  
Interstitial lung disease:
One patient with non-small cell lung cancer who was treated with neratinib experienced interstitial lung disease (which is inflammation and scarring of the lungs). This lung problem could have been caused by neratinib. The patient's health improved when she stopped taking neratinib and began to take steroids and anti-infection medication to treat this side effect. If you feel shortness of breath along with fever or cough, please let your study doctor know immediately.  
You may experience some, all, or none of these side effects. However, life-threatening and even fatal side effects could occur. You will be monitored closely for all side effects including any that are unexpected. If symptoms develop, your study physician will start appropriate treatment. You must tell the study doctor about any new health problems that develop while you are participating in this study.

The absorption of neratinib in the stomach is dependent on stomach acidity. Medications that reduce the secretion of acid in the stomach such as antacids, proton pump inhibitors (such as Lansoprazole), and H2-receptor antagonists (such as ranitidine) may affect how neratinib dissolves in the stomach. It has been observed that a single 240-mg dose of neratinib combined with a proton pump inhibitor lowered the absorption of neratinib up to seven-fold. It is not known whether separating the time of taking a proton pump inhibitor and neratinib reduces the interaction. If you are required to take a H2-receptor antagonist (such as ranitidine) to reduce stomach acid, take neratinib 10 hours after taking the medication and at least 2 hours before the next dose of that medication. If antacids are necessary, the antacid dose and the neratinib dose should be separated by 2 to 4 hours. If you have any questions, you should consult with your doctor about what type of acid-reducing medication you are taking.

If you have metastatic breast cancer, you will need to take another anti-cancer drug, capecitabine, in combination with neratinib. Taking capecitabine may result in the following side effects: diarrhea, heart problems (heart attack, changes in electrical activity of your heart, problems with your heart muscle), dehydration, kidney failure, skin reactions (rash, blisters, peeling), mouth sores, changes in the sensation in your hands and feet, liver problems and decreases in the number of your white blood cells, red blood cells and platelets (a component of your blood involved in clotting). Life-threatening and even fatal side effects could occur. You will be monitored closely for all side effects including any that are unexpected. If symptoms develop, your study physician will start appropriate treatment.

You will need to take loperamide to treat diarrhea during the course of the study. Taking loperamide might be associated with, but not limited to, the following symptoms: constipation (decrease or absence of bowel movements), dry mouth, abdominal pain or discomfort, nausea and vomiting. Drowsiness, dizziness and fatigue may occur with loperamide as well. Difficulty or inability to completely void the bladder (difficulty to urinate) has been reported less frequently. Allergic reactions such as skin rash and itching including severe forms have also been reported; however, other medications may have caused or contributed to some of these cases. Please refer to the loperamide package insert for additional information.

As part of this study you will have two colonoscopies about 4 weeks apart. You doctor will follow the hospital procedure for preparing for the colonoscopy. A serious but uncommon (1 in 2000 procedures) risk during colonoscopy is rupture of your bowel. You would require immediate surgery if this were to happen. Another risk of the procedure is bleeding resulting from tissue sample collection. Delayed bleeding may occur during the first week following the procedure. A repeat colonoscopy may be necessary in the event that this bleeding is not selflimiting.  
Anesthesia is routinely given to patients undergoing colonoscopy. The risks involved with anesthesia include heart and lung problems such as a drop in blood pressure or a lowered concentration of oxygen in your blood. Other less common risks of anesthesia include an increased risk of blood clots, heart attack or stroke. Risks associated with anesthesia will be managed during the procedure by an anesthesiologist and the doctor performing the colonoscopy. Medications (laxatives) given to clear your colon prior to each colonoscopy can result in dehydration. Patients must drink sufficient amounts of fluid when preparing for the procedure to prevent dehydration. Severe dehydration can result in damage to your kidneys. Symptoms of dehydration include headache, tiredness, confusion, light headedness, and decrease in the volume of urine when emptying your bladder. You should inform your doctor if you experience any of these symptoms during the day you prepare for or the day of your colonoscopy.

You may have pain, swelling, or bruising around the vein where your blood is collected. There may be risk of infection. You may feel dizzy or you may faint. You may get an infection at the place on your body from which the blood is collected.

A **MUGA** scan measures how well your heart pumps blood. During a MUGA scan, a radioactive dye is injected into a vein, and special equipment is used to measure the pumping capacity of your heart. You will be exposed to radiation from the injection given for the MUGA scan. The needle puncture into the vein for the MUGA scan may cause bruising, inflammation, or infection at the site of the puncture.

It is not known whether neratinib may cause side effects to pregnant women, to an unborn child (an embryo or a fetus), or to children of nursing women. In a study with pregnant animals, administration of neratinib caused harm, including birth defects and death to the fetuses. Because of these unknown risks, if you are pregnant or trying to become pregnant you cannot enter the study. If you are nursing a child, you may not be entered in the study. If you are able to have children, you must have a negative pregnancy test before participating in the study. You are considered able to have children if you have not completed menopause or are not surgically sterile. If you are not surgically sterile or postmenopausal, you must agree and commit to the use of a reliable method of birth control (i.e., a highly effective non-hormonal method of contraception) while enrolled in the study. For women of childbearing potential, examples of reliable methods would be intrauterine device, bilateral tubal ligation, vasectomized partner, or abstinence (only when it is the preferred lifestyle). Male patients with a female partner of childbearing potential should agree and commit to use condom, and the female partner must agree and commit to use any of the above reliable methods, or hormonal contraception associated with inhibition of ovulation, while on treatment and for 3 months after last dose of investigational products.  
Your doctor can discuss acceptable birth control methods with you. After your last dose of the investigational drug you must continue to use medically acceptable birth control for 28 days. If you miss a period or think you might be pregnant during the study, you must tell your study doctor immediately. If you become pregnant during the study or within 28 days after your last dose of test article, your study doctor will ask to follow the outcome of your pregnancy and the condition of your newborn. The effects of the investigational drug on an unborn child (embryo or fetus) fathered by a man taking the test article are unknown. Men with partners of childbearing potential must use a medically acceptable method of birth control throughout the study and for 3 months after the last dose of investigational drug.

The investigational drug and procedures in this study may have risks that are not known at this time.  
You will be told in a timely manner of new information that may affect whether you will want to continue to participate in this study.

You will get medical treatment if you are injured as a result of taking part in this study. If you experience any injury or side effects, you should contact your study doctor at:
Clinical trial: NCT04366713
Section: Procedures
Subsections: What Will Happen During This Study?

If you have early stage breast cancer and decide to participate in this study and your doctor determines that you are eligible, you will receive the study drug, neratinib, taken by mouth, daily with food for approximately one year.  
You will not be required to make up missed doses of neratinib. If you have metastatic breast cancer and decide to participate in this study and your doctor determines that you are eligible, you will receive the study drug, neratinib, taken by mouth, daily with food for a period of 28 days. After your second colonoscopy is completed (following the initial 28 day dosing period), your treatment will continue in 21 day periods called cycles. During each of these cycles of treatment, you will receive the study drug on days 1 to 21 of each cycle in combination with another anti-cancer drug called capecitabine. Capecitabine is a tablet. Your study doctor will calculate your dose based on your most recent height and weight. You will take a total daily dose of 1500 mg/m2 (supplied as 150 mg and 500 mg tablets), divided in 2 doses to be taken once in the
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morning and once in the evening by mouth every day for **the first 14 days** of each 21 day cycle starting at Cycle 1/Day 1. The doses may be adjusted by your study doctor depending on how you are tolerating the treatment. There will be 7 days in each cycle that you do not take capecitabine, but you should continue taking the neratinib as directed by your study doctor. Capecitabine should be taken with water within 30 minutes after a meal.  
- The study drug, neratinib, is a medicine for women who have HER 2+ breast cancer. In patients with HER2+ breast cancer, neratinib works to block the growth pathways of cancer cells that have too many HER2 receptors.  
- Prior to starting treatment with and following the first 28 days taking the study drug, you will undergo a colonoscopy. A colonoscopy is a procedure where a doctor will use an instrument to examine the inside of your colon. During each colonoscopy, the doctor will perform approximately 8 biopsies (collection of small pieces of tissue) at various locations in your colon. Prior to the collection of each biopsy the doctor will take a photograph of the area. In addition, a blood sample (5 ml) and a stool sample will be collected at the time of each colonoscopy for laboratory analysis of markers of inflammation. Patients participating in the study will complete a total of 2 colonoscopies about 4 weeks part. This procedure is being performed to determine how the study drug affects your colon.  
- Your blood will be collected at screening and on the first day of taking the study drug just prior to dosing.  
Blood samples will be tested to determine the number of your red blood cells, white blood cells and parts of your blood which control bleeding. Additional tests will be made on your blood to determine the state of your liver function, kidney function and overall health. Approximately 15 ml of blood will be collected during the screening and first day of taking the study drug. Your doctor may perform additional blood tests during the study as he or she feels is necessary.  
- During screening, you will receive several tests to determine how well your heart functions. The first test, called an electrocardiogram, measures the electrical activity of your heart. The second test determines how well your heart works to pump your blood. This second test may be referred to as a MUGA or ECHO
test by your doctor. Your doctor may perform additional heart tests during the study as he or she feels is necessary.  
- Women who are capable of having children will be required to take a pregnancy test during screening. - Your doctor will perform a full physical examination during screening and a shorter physical exam on the first day of the first cycle of study drug. Your vital signs (heart rate, blood pressure and temperature) will be determined during these visits. These tests are used by your doctor in evaluating your overall health.  
- After you are determined to be eligible for study participation, you will begin taking six (6) 40 mg tablets
(240 mg) of neratinib daily.  
- A common side effect of neratinib is diarrhea. In order to prevent or lessen the severity of diarrhea, you will be taking loperamide (also known as Imodium). During the first two weeks of treatment, you will take 4 mg (2 tablets) of loperamide 3 times a day. The first dose of loperamide will be taken with the first dose of neratinib. During the second half of the first 28 days of treatment, you will take 4mg (2 tablets) 2 times a day. After the first 28 days of treatment with neratinib is completed, you will take further doses of loperamide on an as needed basis. During the first 28 days of taking neratinib, you will be asked to record your daily dose of neratinib and loperamide in a diary. If you take any other medications to control diarrhea, these will also be recorded in the diary.  
- For patients with early stage breast cancer, your doctor will perform a brief physical exam and collect a blood sample to measure your liver function approximately every 3 months. Five milliliters of blood will be collected at each of these study visits.
- For patients with metastatic breast cancer, your doctor will perform a brief physical exam including vital signs and collect blood samples to measure your kidney function, liver function, electrolytes, white and red blood cell counts and platelets (blood component involved in clotting) at the start of each 21 day cycle of treatment. Approximately fifteen milliliters of blood will be collected at each of these study visits. Tests to assess your heart function (electrocardiogram, ECHO or MUGA) will be performed on Day 1 of Cycle 3, Day 1 of Cycle 6 and on Day 1 of every sixth subsequent cycle of treatment.  
- An end of treatment visit with your doctor will take place on Day 28 of Cycle 13 for early breast cancer patients, followed by Safety Follow-up Visit 28 days after the last dose of neratinib. For patients with metastatic breast cancer, your end of treatment visit will be conducted by your doctor on Day 21 of your last cycle of treatment. A Safety Follow-up visit will take place 28 days after your last dose of neratinib.  
You will be required to complete an end of study visit in the event your disease reoccurs, progresses or if you are unable to tolerate neratinib.
Clinical trial: NCT04366713
Section: Purpose of Research
Subsections: Purpose Of The Study

The purpose of this study is to:  
- Increase our understanding of how your colon (the largest portion of the large intestine) is affected while taking the anticancer drug neratinib.
Clinical trial: NCT04366713
Section: Voluntary Participation
Subsections: Should You Take Part In This Study?|Voluntary Participation / Withdrawal

- This form tells you about this research study. After reading through this form and having the research explained to you by someone conducting this research, you can decide if you want to take part in it. Please note that you do not have to take part in this research to receive medical care.  
- You may have questions this form does not answer. If you do have questions, feel free to ask the study doctor or the person explaining the study, as you go along.  
- Take your time to think about the information that is being provided to you. - Feel free to talk it over with your regular doctor.

You should only take part in this study if you want to volunteer. You should not feel that there is any pressure to take part in the study. You are free to participate in this research or withdraw at any time. There will be no penalty or loss of benefits you are entitled to receive if you stop taking part in this study.  
You will be withdrawn from the study if:  
- Your study doctor believes it is in your best interest for any reason, including the need to start another anti-cancer treatment
- You have serious side effects that would make it unsafe to continue on the study - You do not follow the study rules
- The sponsor suspends or terminates the study or part of the study at any time for any reason