Clinical trial NCT04366713
Conditions: HER2 Amplified Breast Cancer
Keywords: HER2-Positive Breast Cancer Colon Pathology Colonoscopy
Sponsor: Puma Biotechnology, Inc.
Start date: 2020-06-30; Completion date: 2021-12-28
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This study will investigate colon pathology in patients with HER2-positive breast cancer treated with neratinib. Colonoscopy will be performed after eligibility has been confirmed, prior to administration of the first dose of neratinib, and after 28 days of neratinib treatment.

Detailed description:
This is an open-label, phase 2 study that will investigate colon pathology in patients with HER2-positive breast cancer treated with neratinib as monotherapy.

All patients will receive neratinib for the first 28 days as a single daily dose of 240 mg.

Colonoscopy will be performed after eligibility has been confirmed, but prior to administration of the first dose of neratinib and at Day 30 (± 3 days) the conclusion of Cycle 1 (28 days).

Following the second study colonoscopy procedure:

* For patients being treated for stage 1 to 3c breast cancer in the extended adjuvant setting, neratinib will continue to be administered at a single daily dose of 240 mg until completion of one year of therapy from start of treatment, or until disease recurrence (as determined by the Investigator), death, unacceptable toxicity, or other specified withdrawal criterion.
* For patients being treated for metastatic breast cancer (mBC), capecitabine will be introduced after the second study colonoscopy procedure at a dose of 750mg/m2 twice daily for 14 days of each 21 day treatment cycle, with neratinib administered continuously throughout at 240 mg daily, until disease progression, death, unacceptable toxicity, or other specified withdrawal criterion.

All patients will receive loperamide diarrhea prophylaxis daily for one 28-day cycle and then as needed.

Arms: arm 1: Neratinib with loperamide prophylaxis, and capecitabine for participants treated for metastatic breast cancer
Interventions: intervention 1: Neratinib intervention 2: Capecitabine intervention 3: Loperamide
Intervention descriptions: intervention 1: Administered orally once daily as a single daily dose of 240 mg intervention 2: Administered orally twice daily at 750 mg/m\^2 for 14 days of each 21 day treatment cycle intervention 3: Administered orally for prophylaxis for 28 days and then as needed

Protocol documents:
ICF_002.pdf: 
An Open-Label Phase 2 Study to Characterize Colon Pathology in Patients With HER2 Amplified Breast 
Cancer Treated With Neratinib 
NCT04366713 
Version: 1.0 
25-Sep-2019 


MASTER INFORMED CONSENT TO PARTICIPATE IN RESEARCH - PORTUGAL 
 
Protocol Nº PUMA-NER-6203 
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Information to Consider Before Taking Part in This Research Study and Informed Consent Form 
Study Title: An Open-Label Phase 2 Study to Characterize Colon Pathology in Patients with HER2 Amplified 
Breast Cancer Treated with Neratinib 
Protocol Number: PUMA-NER-6203 
EudraCT nº: 2019-001896-35 
Investigator Name: 
 
 
 
You are being asked to take part in a research study.  Research studies include only people who choose to take 
part.  This document is called an informed consent form and includes an information sheet and a consent form.  
Please read this information carefully and take your time making your decision.  Ask the researcher or study staff 
to discuss this consent form with you.  Please ask him/her to explain any words or information that you do not 
clearly understand.  We encourage you to talk with your family and friends before you decide to take part in this 
research study.  The nature of the study, risks, inconveniences, discomforts, potential benefits, and other 
important information about the study will be reviewed with you.  Once you understand the study and you agree 
to participate, you will be asked by the study staff to sign this form.  Additionally, the study staff will provide you 
with a copy of the signed form.  
Please tell the study doctor or study staff if you are taking part in another research study. Before reading, please 
check with your private health insurance or health subsystem if they agree with your participation in this study. 
We are asking you to take part in a research study called:  
An Open-Label Phase 2 Study to Characterize Colon Pathology in Patients with HER2 Amplified Breast Cancer 
Treated with Neratinib  
The person who is in charge of this research study is 
.  This person is called the Principal 
Investigator.  However, other research staff may be involved and can act on behalf of the Principal Investigator.   
The research will be conducted at Hospital CUF Descobertas, Lisbon (Portugal). 
This research study has been approved by the Ethics Committee for Clinical Research (CEIC) and the National 
Authority for Medicines and Health Products, I.P. (INFARMED), in accordance with the current legislation in force, 
namely Law No. 12/2005, of January 26th, and Decree-Law No. 131/2014, of August 29th, regulating personal 
genetic and health information, and Laws No. 21/2014, of April 16th, approving the law of clinical research, and No. 
73/2015, of July 27th, establishing the conditions under which monitors, auditors and inspectors may access the 
records of clinical trials’ participants. The study will also be carried out in accordance with the current revised 
version of the Declaration of Helsinki and Good Clinical Practice and any other legislation, where applicable. 
This research is being sponsored by Puma Biotechnology, Inc.   
 


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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.   
SHOULD YOU TAKE PART IN THIS STUDY? 
• 
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. 
This form explains: 
• 
Why this study is being done. 
• 
What will happen during this study and what you will need to do. 
• 
Whether there is any chance of benefit from being in this study.   
• 
The risks involved in this study. 
• 
How the information collected about you during this study will be used and with whom it may be shared. 
Providing informed consent to participate in this research study is up to you.  If you choose to be in the study, then 
you should sign the form.  If you do not want to take part in this study, you should not sign this form.  
WHY ARE YOU BEING ASKED TO TAKE PART? 
We are asking you to take part in this research study because you have been diagnosed with HER 2+ breast cancer.   
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.  


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• 
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. 
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.  
ALTERNATIVES 
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 
 
BENEFITS 
It cannot be guaranteed that your participation in this study will benefit you. The potential benefits of participating 
in this research study include: 
• 
Decreased risk of recurrence of your breast cancer (early breast cancer patients) 
• 
Improvement or stabilization of your metastatic breast cancer 
• 
Examination of your colon for any instances of a finding your doctor would consider abnormal 
 
It is also possible that you may not benefit personally from your participation in this study, but that the 
information obtained in the study may be useful in the treatment of other patients with the same disease in the 
future. 


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RISKS OR DISCOMFORT 
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) 
Common (≥1/100 and <1/10) [may occur between 1 and 9 subjects in 100] 
• 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 
Uncommon (≥1/1000 and <1/100) [may occur in less than 1 subject in 100] 
• 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. 


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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. 
Other Potential Side Effects of Neratinib 
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. 
 
Information on other risks: 
Risks of Taking Neratinib with Acid-Reducing Medication 
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. 


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Risks of Taking Capecitabine (metastatic breast cancer patients) 
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. 
Risks of Taking Loperamide 
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. 
Risks of Colonoscopy 
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 self-
limiting. 
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. 
Risks of the Blood Collection  
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. 
 
 


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Risks of the ECG/EKG and ECHO  
Placement of the leads may cause skin irritation, redness, or burning of the skin at the site where the leads were 
attached. 
Risks of the MUGA Scan 
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.  
RISKS TO UNBORN CHILDREN 
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. 
Unknown Risks 
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. 
 


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COMPENSATION 
You will not receive payment or other compensation for taking part in this study. You will not have to pay any 
expenses connected with the drugs or any examinations carried out in the course of the study. Expenses for 
travelling and meals that may be considered legitimate within the framework of this clinical trial will be reimbursed 
on presentation of confirmatory receipts. These amounts will be paid to you via the study team or the financial 
department of the hospital, after these receipts have been delivered and checked. 
Your health information and biological samples (such as blood, urine, or tissue) collected during this study may be 
used for the development of new or improved drugs or other products, tests, processes, or services that could 
have value and be sold for profit by the sponsor or by others for the sponsor’s benefit or the benefit of the study 
doctor or third parties.  The sponsor does not intend to provide you with financial compensation or to share with 
you any of the profits that may be earned as a result of any research conducted by the sponsor on these samples.  
Please be aware that the performance of this study entails specific research work and, therefore, both the hospital 
and the professionals participating in the study, including your doctor, will receive financial compensation from the 
sponsor.  
COSTS 
There will be no additional costs to you as a result of being in this study.  However, and if applicable, routine 
medical care for your condition (care you would have received whether or not you were in this study) will be 
charged to your insurance company.  You may wish to contact your insurance company to discuss this further. 
  
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.  


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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. 


MASTER INFORMED CONSENT TO PARTICIPATE IN RESEARCH - PORTUGAL 
 
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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. 
 
BIOLOGICAL SAMPLES 
WHAT WILL HAPPEN TO ANY SAMPLES I GIVE? 
Biological samples will be collected from you as described in this Patient Information Sheet. 
 Some biological samples collected during the study may be tested immediately at the local laboratory of the site 
where the research is being conducted in Portugal and then destroyed in accordance the site’s procedures.  Some 
samples will be sent for testing to the University of South Alabama College of Medicine (Division of 
Gastroenterology), Mobile, Alabama (United States). In addition, some of the samples will be retained by the 
sponsor until the samples have expired and are no longer usable.  These samples may be used by the sponsor and 
third parties working with the sponsor, in future research in connection with the development of the study drug, 
other drugs and diagnostics. The samples will not be marked with information that can identify you.  The data 
derived from the use of these samples in future research will be maintained as confidential in the same way as the 
rest of the data obtained during this study (see section on Privacy and Confidentiality).  
If you change your mind about taking part in the study, no further samples will be collected from you.    However, 
the sponsor needs to retain and use any samples that have already been collected and sent to the sponsor in order 
to maintain the quality of the study.  
You do not have to agree with this future use. If you decide to say no, you will be able to continue participating in 
the study. This decision will not affect the medical care that you are entitled to receive outside of the study.   
According to the Law No. 12/2005, of January 26th, and Decree-Law No. 131/2014, of August 29th, regulating 
personal genetic and health information, you have the right to know, if you so choose, about the genetic data 
obtained from the analysis of the samples taken. If you decide to request your genetic data, talk with your study 
doctor about what this may mean for you and your family.  
 
 VOLUNTARY PARTICIPATION / WITHDRAWAL 
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  


MASTER INFORMED CONSENT TO PARTICIPATE IN RESEARCH - PORTUGAL 
 
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FOLLOW UP  
It is very important for the success of the study that we are able to collect information on your response to the 
study drug throughout the duration of the study.  
If for some reason your study doctor loses contact with you (for example, there is no response after calling or 
mailing information to your home, after contacting the individuals that you provided as additional contact names 
at the start of the study or after contacting your private doctor) the study doctor will try to obtain your updated 
contact information by checking publicly available sources, such as information available on the computer.   
If updated contact information is not available and your study doctor is unable to contact you, your personal 
information/personal data (name, address, telephone and date of birth) may be given to the Sponsor’s 
representative (a patient finder company) in order to find more accurate contact information for you, through 
publicly available sources. The new information will be provided to your study doctor’s office so they may re-
establish contact with you and further assess your current health status. No personal information/personal data 
will be provided to the Sponsor from the patient locater service. 
If your personal information/personal data is given to the Sponsor’s representatives they will not share or 
distribute this information to any other party. They will keep this information in a protected location to help 
prevent unauthorized use, access, or disclosure. The information provided will be limited to information that is 
needed to try to re-establish contact with you. Your personal information will be kept confidential by the Sponsor’s 
representatives until the study is completed, and then the information will be destroyed.   
If you choose to no longer participate in the study and you withdrawal your consent completely, you will be asked 
to confirm this decision in writing. 
NEW INFORMATION ABOUT THE STUDY 
During the course of this study, we may find more information that could be important to you.  This includes 
information that, once learned, might cause you to change your mind about being in the study.  We will notify you 
through your study doctor as soon as possible if such information becomes available. 
In addition, when receiving new information, your doctor may consider that it is best for you to be withdrawn from 
the study. Your doctor will explain the reasons and will be responsible for ensuring that your medical care 
continues. 
WHAT IF YOU ARE INJURED WHILE YOU ARE IN THE 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: 
<site to insert contact name and telephone number> 
Your study doctor will explain the treatment options to you and tell you where you can get treatment.   
The sponsor has obtained an insurance policy which covers you as a study participant in accordance with the laws 
of Portugal. The insurance policy has been taken out with Lloyd’s Insurance Company S.A. with address at Bastion 
Tower, Marsveldplein 5, 1050 Brussels (Belgium), under Policy Number WIBCEQ19036. Your study doctor can 
provide more information about this insurance. 
Other compensation (including without limitation) for such things as lost wages, disability, or discomfort due to 
this type of injury is not available. Please note that your participation in this study may affect the general and 


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specific conditions (coverage) of your insurance policies (life, health, accident, etc.). Therefore, we recommend 
that you contact your insurer to determine whether your participation in this study will affect your current 
insurance policy. 
You will not lose any of your legal rights by signing the Consent Form.   
WHAT HAPPENS IF YOU DECIDE NOT TO TAKE PART IN THIS STUDY? 
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. 
YOU CAN GET THE ANSWERS TO YOUR QUESTIONS, CONCERNS, OR COMPLAINTS. 
If you have any questions, concerns or complaints about this study, call 
 at [telephone #]. 
The Comissão de Ética para a Investigação Clínica (CEIC) and the Autoridade Nacional do Medicamento e Produtos 
de Saúde I.P. (INFARMED) are the national regulatory authorities, which are directly involved in the process of 
evaluation and approval of this clinical trial. Therefore, they are equally available for any clarification, so do not 
hesitate to contact them. 
If you have questions about your rights as a patient in a clinical trial, or questions or complaints regarding this trial, 
please contact the Comissão de Ética para a Investigação Clínica: 
 
CEIC - Comissão de Ética para a Investigação Clínica 
Av. do Brasil, 53 – Pavilhão 17-A 
1749-004 Lisboa 
Tel.:21 7985340 
Fax: 21 7987209 
e-mail: ceic@ceic.pt 
 
 


MASTER INFORMED CONSENT TO PARTICIPATE IN RESEARCH - PORTUGAL 
 
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INFORMED CONSENT FORM 
STUDY TITLE: 
An Open-Label Phase 2 Study to Characterize Colon Pathology in 
Patients With HER2 Amplified Breast Cancer Treated With Neratinib 
PROTOCOL NUMBER: 
PUMA-NER-6203 
EUDRACT NUMBER: 
2019-001896-35 
I have received verbal (spoken) information on the above study and have read the attached written information. I 
have been given the chance to discuss the study and ask questions. 
I voluntarily consent to participate in this study, including all assessments, lifestyle restrictions, contraception 
requirements, and taking of biological samples. 
I understand that I am free to withdraw from this study at any time. I understand that if I choose to not participate 
or to withdraw, my current medical care will not be affected by this decision. 
I understand that I will receive and may keep a copy of this signed and dated Patient Information Sheet and 
Consent Form. 
By signing and dating this Consent Form, I have not waived any of the legal rights that I would have if I were not a 
participant in a medical research study. 
I CONSENT AND AUTHORIZE THAT MY STUDY DATA MAY BE TRANSFERRED WITHIN AND OUTSIDE THE 
EUROPEAN UNION, TO COUNTRIES, INCLUDING THE UNITED STATES, WHERE DATA MAY NOT HAVE THE SAME 
LEVEL OF DATA PROTECTION AS IN PORTUGAL OR IN THE EUROPEAN UNION. I AGREE THAT MY STUDY DATA 
MAY BE MADE AVAILABLE TO THE SPONSOR AND PARTIES WORKING WITH THE SPONSOR AS WELL AS TO 
OTHER PARTIES/ENTITIES IDENTIFIED IN THE PATIENT INFORMATION SHEET FOR THE PURPOSES STATED IN THE 
PATIENT INFORMATION SHEET. 
I AGREE THAT THE BIOLOGICAL SAMPLES COLLECTED FROM ME MAY BE USED AND DISCLOSED FOR THE 
PURPOSES STATED IN THE PATIENT INFORMATION SHEET. I ALSO AGREE THAT MY CODED BIOLOGICAL SAMPLES 
MAY BE TRANSFERRED OUTSIDE OF MY COUNTRY TO OTHER COUNTRIES, SUCH AS THE UNITED STATES, WHICH 
MAY NOT HAVE THE SAME LEVEL OF DATA PROTECTION AS IN PORTUGAL OR IN THE EUROPEAN UNION.  
BY SIGNING THIS FORM I CONSENT AND AUTHORIZE THE COLLECTION, USE AND SHARINGOF MY SENSITIVE 
PERSONAL DATA AS PART OF THE CODED STUDY DATA WITH THE SPONSOR AND OTHER PARTIES AS DESCRIBED 
IN THIS INFORMED CONSENT FORM. 
☐ BY CHECKING THIS BOX I CONSENT AND AUTHORIZE THE USE OF MY BIOLOGICAL SAMPLES AS PART OF THE 
CODED DATA BY THE SPONSOR AND OTHER PARTIES FOR POSSIBLE FUTURE STUDIES AS DESCRIBED IN THIS 
INFORMED CONSENT FORM. 
 
 
 
 
 
Signature of Person Taking Part in Study 
Date 
 
                                           
Printed Name of Person Taking Part in Study 


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STATEMENT OF PERSON OBTAINING INFORMED CONSENT AND RESEARCH AUTHORIZATION 
I have carefully explained to the person taking part in the study what he or she can expect from their participation. 
I hereby certify that when this person signs this form, to the best of my knowledge, he/she understands: 
• 
What the study is about; 
• 
What procedures/interventions/investigational drugs or devices will be used; 
• 
What the potential benefits might be; and  
• 
What the known risks might be.   
I can confirm that this research subject speaks the language that was used to explain this research and is receiving 
an informed consent form in the appropriate language.  Additionally, this subject reads well enough to understand 
this document or, if not, this person is able to hear and understand when the form is read to him or her.  This 
subject does not have a medical/psychological problem that would compromise comprehension and therefore 
makes it hard to understand what is being explained and can, therefore, give legally effective informed consent. 
This subject is not under any type of anesthesia or analgesic that may cloud their judgment or make it hard to 
understand what is being explained and, therefore, can be considered competent to give informed consent.   
 
_______________________________________________________________ 
____________ 
Signature of Investigator Obtaining Informed Consent / Research Authorization 
Date 
 
 
Printed Name of Investigator Obtaining Informed Consent / Research Authorization 
 
 


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IMPARTIAL WITNESSES’ INFORMED CONSENT FORM 
STUDY TITLE: 
An Open-Label Phase 2 Study to Characterize Colon Pathology in 
Patients With HER2 Amplified Breast Cancer Treated With Neratinib 
PROTOCOL NUMBER: 
PUMA-NER-6203 
EUDRACT NUMBER: 
2019-001896-35 
 
I, ……………………………………………………………………………………………….., declare under my responsibility that:  
(Full Witness's Name) 
 
………………………………………………………………………………………………….. 
(Full Patient's Name) 
The patient has received verbal (spoken) information on the above study and has read the attached written 
information. The patient has been given the chance to discuss the study and ask questions. 
He/she voluntarily consents to participate in this study, including all assessments, lifestyle restrictions, 
contraception requirements, and taking of biological samples. 
He/she understands that he/she is free to withdraw from this study at any time. He/she understands that if he/she 
chooses to not participate or to withdraw, his/her current medical care will not be affected by this decision. 
He/she understands that he/she will receive and may keep a copy of this signed and dated Patient Information 
Sheet and Consent Form. 
By signing and dating this Consent Form, he/she has not waived any of the legal rights that he/she would have if 
he/she was not a participant in a medical research study. 
THE PATIENT CONSENTS AND AUTHORIZES THAT HIS/HER STUDY DATA MAY BE TRANSFERRED WITHIN AND 
OUTSIDE THE EUROPEAN UNION, TO COUNTRIES, INCLUDING THE UNITED STATES, WHERE DATA MAY NOT 
HAVE THE SAME LEVEL OF DATA PROTECTION AS IN PORTUGAL OR IN THE EUROPEAN UNION. HE/SHE AGREES 
THAT HIS/HER STUDY DATA MAY BE MADE AVAILABLE TO THE SPONSOR AND PARTIES WORKING WITH THE 
SPONSOR AS WELL AS TO OTHER PARTIES/ENTITIES IDENTIFIED IN THE PATIENT INFORMATION SHEET FOR THE 
PURPOSES STATED IN THE PATIENT INFORMATION SHEET. 
HE/SHE AGREES THAT THE BIOLOGICAL SAMPLES COLLECTED FROM HIM/HER MAY BE USED AND DISCLOSED 
FOR THE PURPOSES STATED IN THE PATIENT INFORMATION SHEET. HE/SHE ALSO AGREES THAT HIS/HER CODED 
BIOLOGICAL SAMPLES MAY BE TRANSFERRED OUTSIDE OF HIS/HER COUNTRY TO OTHER COUNTRIES, SUCH AS 
THE UNITED STATES, WHICH MAY NOT HAVE THE SAME LEVEL OF DATA PROTECTION AS IN PORTUGAL OR IN 
THE EUROPEAN UNION.  
BY SIGNING THIS FORM HE/SHE CONSENTS AND AUTHORIZES THE COLLECTION, USE, PROCESSING AND 
SHARING OF HIS/HER SENSITIVE PERSONAL DATA AS PART OF THE CODED STUDY DATA WITH THE SPONSOR 
AND OTHER PARTIES AS DESCRIBED IN THIS INFORMED CONSENT FORM. 
☐ BY CHECKING THIS BOX HE/SHE CONSENTS AND AUTHORIZES THE USE OF HIS/HER BIOLOGICAL SAMPLES AS 
PART OF THE CODED DATA BY THE SPONSOR AND OTHER PARTIES FOR POSSIBLE FUTURE STUDIES AS 
DESCRIBED IN THIS INFORMED CONSENT FORM. 
 
 
                                                                           
SIGNATURE OF IMPARTIAL WITNESS                                
  DATE 
 


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STATEMENT OF PERSON OBTAINING INFORMED CONSENT AND RESEARCH AUTHORIZATION 
I have carefully explained to the person taking part in the study what he or she can expect from their participation. 
I hereby certify that when this person signs this form, to the best of my knowledge, he/she understands: 
• 
What the study is about; 
• 
What procedures/interventions/investigational drugs or devices will be used; 
• 
What the potential benefits might be; and  
• 
What the known risks might be.   
I can confirm that this research subject speaks the language that was used to explain this research and is receiving 
an informed consent form in the appropriate language.  Additionally, this subject reads well enough to understand 
this document or, if not, this person is able to hear and understand when the form is read to him or her.  This 
subject does not have a medical/psychological problem that would compromise comprehension and therefore 
makes it hard to understand what is being explained and can, therefore, give legally effective informed consent. 
This subject is not under any type of anesthesia or analgesic that may cloud their judgment or make it hard to 
understand what is being explained and, therefore, can be considered competent to give informed consent.   
 
___________________________________________________________________ 
____________ 
Signature of Investigator Obtaining Informed Consent / Research Authorization 
Date 
 
 
Printed Name of Investigator Obtaining Informed Consent / Research Authorization 
 
 
 
 
 
 
 
 

Prot_000.pdf: 
An Open-Label Phase 2 Study to Characterize Colon Pathology in Patients With HER2 Amplified Breast 
Cancer Treated With Neratinib 
NCT04366713 
Version: Original 
04-Sep-2019 


 
 
 
 
This document contains confidential information of Puma Biotechnology, Inc. This document must not be disclosed to 
anyone other than the study staff and members of the Independent Ethics Committee/Institutional Review Board. The 
information in this document cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Puma Biotechnology, Inc.  
 
An Open-Label Phase 2 Study to Characterize Colon Pathology in Patients With HER2 
Amplified Breast Cancer Treated With Neratinib 
Study Protocol Number: 
PUMA-NER-6203 
Disease Condition: 
HER2 Amplified (HER2+) Breast Cancer 
Sponsor’s Investigational Product 
Name/Formulation: 
Neratinib Tablets 
US IND Number 
066783 
EudraCT Number 
2019-001896-35 
Lead Investigator: 
  
Division of Gastroenterology  
University of South Alabama College of Medicine 
6000 University Commons 
74 University Boulevard, South 
Mobile, Alabama 36688 
Phone: +1 (251) 660-5555 
Email: 
@health.southalabama.edu 
 
Sponsor: 
Puma Biotechnology, Inc. 
10880 Wilshire Blvd, Suite 2150 
Los Angeles, CA 90024 
Phone: +1 (424) 248-6500  
Fax: +1 (424) 248-6501  
Sponsor’s Medical Contact: 
  
  
Phone: +1 (424) 248-6500 
Date of Protocol 
Original 
04 September 2019 


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CONFIDENTIAL 
DISCLOSURE STATEMENT  
This document contains information that is confidential and proprietary to the Sponsor. This 
information is being provided to you solely for the purpose of evaluating and/or conducting a 
clinical study for the Sponsor. You may disclose the contents of this document only to study 
personnel under your supervision, institutional review boards (IRBs)/independent ethics 
committees (IECs), or duly authorized representatives of regulatory agencies for this purpose 
under the condition that they maintain confidentiality. The contents of this document should not 
be used in any other clinical study, disclosed to any other person or entity, or published without 
the prior written permission of the Sponsor. The foregoing shall not apply to disclosure required 
by any regulations; however, you will give prompt notice to the Sponsor of any such disclosure. 
All other nonpublic information provided by the Sponsor, as well as any information that may be 
added to this document, also is confidential and proprietary to the Sponsor and must be kept in 
confidence in the same manner as the contents of this document.  
 
STUDY CONTACTS  
Refer to the study reference manuals.  
 


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PROTOCOL SYNOPSIS 
Name of Sponsor/Company: Puma Biotechnology, Inc.  
Name of Investigational Product: Neratinib tablets  
Name of Active Ingredient: Neratinib  
Title of Study: An Open-Label Phase 2 Study to Characterize Colon Pathology in Patients With HER2 Amplified 
Breast Cancer Treated With Neratinib  
Condition or Disease: HER2 Amplified (HER2+) breast cancer 
Approximate Values  
Number of Patients 
3-5 
Duration of Patient Participation 
1 year 
Number of Centers 
2 sites  
Duration of Study 
1.5 years  
Objectives:  
Primary: The primary objective of this study is to characterize and understand colon pathogenesis related to 
neratinib-induced diarrhea through biopsies and images obtained by colonoscopy study. 
Secondary: The secondary objectives are: 
 
To characterize the incidence and severity of diarrhea during the first 28-day cycle 
 
To analyze changes in serological and fecal inflammatory markers from baseline to second 
colonoscopy  
Study Design:  
This is an open-label, phase 2 study that will investigate colon pathology in patients with HER2-positive breast 
cancer treated with neratinib as monotherapy. 
All patients will receive neratinib for the first 28 days as a single daily dose of 240mg. 
Colonoscopy will be performed after eligibility has been confirmed, but prior to administration of the first dose of 
neratinib and at Day 30 (± 3 days) the conclusion of Cycle 1 (28 days).  
Following the second study colonoscopy procedure:  
 
For patients being treated for stage 1 to 3c breast cancer in the extended adjuvant setting, neratinib will 
continue to be administered at a single daily dose of 240 mg until completion of one year of therapy from 
start of treatment, or until disease recurrence (as determined by the Investigator), death, unacceptable toxicity, 
or other specified withdrawal criterion.  
 
For patients being treated for metastatic breast cancer (mBC), capecitabine will be introduced after the second 
study colonoscopy procedure at a dose of 750mg/m2 twice daily for 14 days of each 21 day treatment cycle, 
with neratinib administered continuously throughout at 240mg daily, until disease progression, death, 
unacceptable toxicity, or other specified withdrawal criterion. 
All patients will receive loperamide diarrhea prophylaxis daily for one (1) 28-day cycle and then as needed. 
Patients being treated for stage 1 to 3c breast cancer receiving extended adjuvant treatment will return to the clinic 
approximately every 3 months for safety assessments.  Patients with mBC will return to the clinic at scheduled 
cycles.  End of Treatment (EOT) visit is planned on upon completion of 1 year of treatment, followed by Safety 
Follow-up Visit 28 days after the last dose of neratinib. 
The primary analysis will be conducted after all patients have completed two consecutive colonoscopies with 
biopsies. The final analysis will be conducted when all patients have completed study treatment, discontinued 
treatment or met other specified withdrawal criterion.  
The study will end when all patients have been followed-up for 28 days after the last dose of neratinib. 
Clinical care beyond the scope of this protocol remains the responsibility of the treating physician..  


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Study Endpoints: 
 
The primary endpoint is change from baseline in pathological findings in colon biopsies after the first 
28 days of neratinib monotherapy.  
 
The secondary endpoint will be the incidence and severity of diarrhea during the first 28-day cycle of 
neratinib monotherapy.  
Neratinib and Loperamide Dose and Administration:  
 
Neratinib: Six (6) 40 mg tablets (total dose 240 mg) will be self-administered orally by patients once daily 
with food, preferably in the morning 
 
In patients with stage 1 to 3c breast cancer receiving extended adjuvant treatment with 
neratinib monotherapy, neratinib will be administered as a single 28-day cycle (Cycle 1) 
followed by continuous daily dosing for up to 1 year  or until disease recurrence (as determined 
by the Investigator), death, unacceptable toxicity, or other specified withdrawal criterion.  
 
In patients with mBC, neratinib will be administered as monotherapy for a single 28-day cycle 
(Cycle 1). Beginning in Cycle 2 following the completion of the second study colonoscopy 
procedure and in all subsequent cycles, neratinib will be administered continuously in 21-day 
cycles and capecitabine twice daily for 14 days of each 21 day treatment cycle  until disease 
recurrence (as determined by the Investigator), death, unacceptable toxicity, or other specified 
withdrawal criterion. 
 
Loperamide:  
 
Loperamide should be taken as instructed, titrating to 1-2 bowel movements per day. 
 
The initial dose of loperamide 4 mg will be self-administered orally with the first dose of neratinib. 
 
During weeks 1-2 (day 1 – 14) of Cycle 1 loperamide 4 mg will be self-administered administered three 
times daily (TID). 
 
During weeks 3-4 (days 15 – 28) of Cycle 1 loperamide 4 mg will be self-administered twice daily 
(BID). 
 
After the first 28 day Cycle, loperamide will be self-administered as needed (PRN) (not to exceed 16 mg 
per day).  
Additional instructions regarding loperamide dosing are provided in Section 6.2. 
During the first 28 days of treatment, patients must use a paper diary to record their intake of neratinib and 
loperamide, as well as the use of other antidiarrheals.  
Capecitabine Dose and Administration (mBC patients only) 
 
Capecitabine therapy will not begin until the second study colonoscopy procedure has been completed. 
 
Capecitabine (total daily dose of 1500 mg/m2 daily, administered as 750 mg/m2 orally twice daily as 
approximately evenly divided doses) will be self-administered on Day 1-14 of each cycle, beginning after 
completion of the second study colonoscopy procedure and biopsy on Day 30 ± 3 days.  
 
Capecitabine should be taken with water within 30 minutes after a meal.  
Diagnosis and Main Criteria for Inclusion:  
Study Population:  
Inclusion Criteria  
1. Aged ≥18 years at signing of informed consent.  
2. Histologically confirmed stage 1 through stage 4 primary adenocarcinoma of the breast 
(Edge  and  Compton, 2010).  
3. Documented HER2 overexpression or gene-amplified tumor by a validated approved method 
(Wolff  et  al, 2013).  
4. Patients with confirmed stage 1 to stage 3c breast cancer receiving extended adjuvant treatment with 
neratinib monotherapy must have completed a course of prior adjuvant trastuzumab or experienced side 
effects that resulted in early discontinuation of trastuzumab that have since resolved.  


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5. Patients with mBC must have had at least 2 prior HER2-directed regimens. 
6. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or 
echocardiogram (ECHO).  
7. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1.  
8. Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of 
reproductive capacity (those who are biologically capable of having children) and for women less than 
12 months after menopause. [Women are considered postmenopausal if they are ≥12 months without 
menses, in the absence of endocrine or anti-endocrine therapies.]  
9. Women of childbearing potential must agree and commit to the use of a highly effective non-hormonal 
method of contraception, i.e., intrauterine device, bilateral tubal ligation, vasectomized partner, or 
abstinence (only when it is the preferred lifestyle of the patient), from the time of informed consent until 
28 days after the last dose of the investigational products.  Men (male patient) with a female partner of 
childbearing potential must agree and commit to use condom and the female partner must agree and 
commit to use a highly effective method of contraception (i.e., any of the above methods, or for females, 
hormonal contraception associated with inhibition of ovulation) while on treatment and for 3 months 
after last dose of investigational products.  
10. Recovery (i.e., to Grade 1 or baseline) from all clinically significant AEs related to prior therapies 
(excluding alopecia, neuropathy, and nail changes).  
11. No major bleeding diathesis or use of anticoagulants that would pose a high risk for endoscopic 
procedure. 
12. Provide written, informed consent to participate in the study and follow the study procedures.  
Exclusion Criteria  
A patient will be excluded from this study if she/he meets any of the following criteria: 
1. Patients with confirmed stage 1 to stage 3c currently receiving chemotherapy, radiation therapy, 
immunotherapy, or biotherapy for breast cancer.  
2. Patients with mBC who have received prior capecitabine or HER2 directed TKI therapy. 
3. Currently using drugs that have been implicated as causing microscopic colitis/watery diarrhea, such as 
acarbose, aspirin, proton pump inhibitors, nonsteroidal anti-inflammatory drugs (NSAIDs), histamine 
H2-receptor antagonists, selective serotonin reuptake inhibitors, and ticlopidine (Pardi, 2017).  
4. Major surgery within <28 days of starting treatment or received chemotherapy, investigational agents, or 
other cancer therapy, except hormonal therapy (e.g., tamoxifen, aromatase inhibitors), <14 days prior to 
the initiation of investigational products.  
5. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York 
Heart Association functional classification of ≥2; including individuals who currently use digitalis, beta-
blockers, or calcium channel blockers specifically for congestive heart failure), unstable angina, 
myocardial infarction within 12 months of enrollment, or ventricular arrhythmia.  
6. QTc interval >0.450 seconds (males) or >0.470 (females), or known history of QTc prolongation or 
Torsade de Pointes (TdP).  
7. Diagnosis of inflammatory bowel disease 
8. Screening laboratory assessments outside the following limits:  
Laboratory Parameters 
Required Limit for Exclusion 
Absolute neutrophil count (ANC)  
<1,000/µl (<1.0 x 109/L) 
Platelet count  
<50,000/µl (<100 x 109/L) 
Hemoglobin  
<8 g/dL (transfusions allowed) 
Transfusions must be at least 14 days prior to initiation of 
treatment 
Total bilirubin  
>1.5 x institutional upper limit of normal (ULN) (in case 
of known Gilbert’s syndrome, <2 x ULN is allowed) 


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Aspartate aminotransferase (AST) and/or alanine 
aminotransferase (ALT)  
>2.5 x institutional ULN (>5 x ULN if liver metastases 
are present)  
Creatinine  
Creatinine clearance <30 mL/min (as calculated by 
Cockcroft-Gault formulaa or Modification of Diet in 
Renal Disease [MDRD] formulab) 
International Normalized Ratio (INR) 
>1.5 
a  Cockcroft and Gault, 1976  
b  Levey et al, 1999  
9. Active, unresolved infections.  
10. Patients with a second malignancy, other than adequately treated non-melanoma skin cancers, in situ 
melanoma or in situ cervical cancer. Patients with other non-mammary malignancies must have been 
disease-free for at least 5 years.  
11. Currently pregnant or breast-feeding.  
12. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, Crohn’s disease, 
malabsorption, or Grade ≥2 National Cancer Institute [NCI] Common Terminology Criteria for Adverse 
Events Version 4.0 [CTCAE v.4.0] diarrhea of any etiology at baseline).  
13. Clinically active infection with hepatitis B or hepatitis C virus.  
14. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social 
situations that could, in the Investigator’s judgment, make the patient inappropriate for this study.  
15. Known hypersensitivity to any component of the investigational products; known allergies to any of the 
medications or components of medications used in the trial. 
16. Unable or unwilling to swallow tablets 
Safety Assessments: 
The primary endpoint is descriptive assessment of colon pathology during the first 28 days of neratinib therapy.  
The secondary endpoint is the incidence and severity of diarrhea during the first 28-day cycle. The incidence of 
treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) for Cycle 1 through 28 days of 
neratinib monotherapy following the second study colonoscopy procedure in patients with stage 1 to 3c breast 
cancer treated in the extended adjuvant setting, and in Cycle 2 in patients with mBC will also be reported. AEs 
and SAEs will be graded according to the National Cancer Institute Common Terminology Criteria (NCI 
CTCAE), version 4.0 or higher.  
After28 days of neratinib monotherapy following the second study colonoscopy procedure in patients with stage 1 
to 3c breast cancer treated in the extended adjuvant setting, and in Cycle 2 in patients with mBC through 
28 calendar days after the last administration of neratinib, only SAE data will be collected and summarized. SAEs 
will be followed until resolution or until condition stabilizes. Should an Investigator be made aware of any SAEs 
occurring any time after the reporting period that may be causally related to administration of neratinib, it should 
be promptly reported. All SAEs must be reported within 24 hours of awareness of the event using the SAE Report 
Form.  
Safety will also be assessed based on medical history, vital sign measurements, physical examination findings, 
electrocardiogram results, MUGA or ECHO, and laboratory assessments.  
Colonoscopy:  
Microscopic colitis (MC) is a relatively common cause of chronic watery diarrhea. The diagnosis is based upon 
characteristic histological findings in the presence of diarrhea. The symptoms of MC are non-specific, and many 
patients meet the diagnostic criteria for irritable bowel syndrome; therefore, colon biopsies are required to 
definitively distinguish MC from the much more common irritable bowel syndrome (Pardi, 2017).  
MC has two main subtypes, lymphocytic colitis and collagenous colitis, with the main distinction being 
histological. The characteristic biopsy finding in lymphocytic colitis is intraepithelial lymphocytosis, defined as 
>20 intraepithelial lymphocytes per 100 surface epithelial cells. In addition, the lamina propria contains a mixed 
infiltrate of acute and chronic inflammatory cells. Collagenous colitis has similar inflammatory findings, although 
the intraepithelial lymphocyte infiltrate tends to be less prominent. The distinguishing histological feature of 


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collagenous colitis is a thickened subepithelial collagen band (>7 μm, compared with normal of ≤5 μm). Despite 
the normal appearance grossly, biopsies often show surface epithelial damage (Pardi, 2017).  
The ideal location in the colon to obtain biopsies is not clear. The inflammation and collagen thickening are not 
always uniform throughout the colon, and inflammation in lymphocytic colitis and collagen thickening in 
collagenous colitis may be worse in the right versus left colon. It is well established that distal colon biopsies are 
not sufficiently sensitive to make the diagnosis and that proximal and distal biopsies are standard of care. 
To characterize pathology of the colonic mucosa in HER2 amplified (HER2+) breast cancer treated with neratinib, 
colonoscopy in this study will be performed at before initiation of neratinib in Cycle 1 and on Day 30 (± 3 days) 
(Appendix 1). During colonoscopy, photographs of the colonic mucosa will be taken along with approximately 8 
biopsies from the terminal ileum, cecum, ascending colon, proximal transverse colon, splenic flexure, sigmoid 
colon, and rectum. If any abnormal appearing colon mucosa is identified endoscopically, it will be noted and 
biopsied in a separate jar. Biopsy material will be analyzed in a central laboratory. If polyps are identified, they 
will be removed during the examination; if cancer is identified, it will be sampled. Usual, standard clinical care 
will be provided for endoscopic findings unrelated to the study aims.  
At the time of colonoscopy, serological inflammatory markers (erythrocyte sedimentation rate [ESR], C-reactive 
protein [CRP]) will be sampled and stool markers for diarrhea (fecal calprotectin, fecal elastase) will be collected. 
Statistical Methods: 
Sample Size: Approximately 3-5 patients will be enrolled.  
Statistical Analysis: 
Given the limited number of patients in the study, listing of the data and narratives will be the primary means to 
present the data. Descriptive summary statistics may be used if warranted. Demographic data, medical history, 
concomitant disease, and concomitant medication will be included in the analyses.  
Safety: 
All patients who receive a dose of neratinib will be analyzed for safety. The incidence of TEAEs and SAEs for 
Cycle 1 through 28 days of neratinib monotherapy following the second study colonoscopy procedure in patients 
with stage 1 to 3c breast cancer treated in the extended adjuvant setting, and following the completion of Cycle 2 
in patients with mBC will be summarized after all biopsies have been completed.  Following 28 days of neratinib 
monotherapy after the completion of the second study colonoscopy procedure in patients with stage 1 to 3c breast 
cancer treated in the extended adjuvant setting, and Cycle 2 in patients with mBC through 28 calendar days after 
the last administration of neratinib, only SAE data will be collected and summarized. 
Final Analysis: 
The final analysis will be conducted when all extended adjuvant patients with stage 1 to3c disease have completed 
1 year of study treatment or discontinued the study, and have completed the Safety Follow-up Visit, and patients 
with mBC have completed study treatment or have discontinued the study, and have completed the Safety-Follow-
up Visit. 
Schedule of Procedures: 
A schedule of procedures is included in Appendix 1.  
 


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TABLE OF CONTENTS 
DISCLOSURE STATEMENT ........................................................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................3 
1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................13 
2. 
INTRODUCTION ......................................................................................................16 
2.1. 
Background .................................................................................................................16 
2.2. 
ERBB2 Gene and Cancer ...........................................................................................16 
2.2.1. 
The Epidermal Growth Factor Receptor Family ........................................................16 
2.2.2. 
ERBB2-positive Cancers ............................................................................................17 
2.3. 
Neratinib .....................................................................................................................17 
2.3.1. 
Clinical Activity of Neratinib .....................................................................................17 
2.3.1.1. 
Neratinib in Combination with Capecitabine .............................................................18 
2.3.2. 
Safety Profile of Neratinib in Monotherapy and Combination Therapy 
Studies.........................................................................................................................19 
2.3.3. 
Diarrhea Management Without Anti-diarrheal Prophylaxis .......................................19 
2.3.3.1. 
Incidence of Grade 3 Diarrhea in Study 3004 ............................................................20 
2.3.4. 
Diarrhea Management With Anti-diarrheal Prophylaxis ............................................21 
2.3.4.1. 
Incidence of Grade 3 Diarrhea in Study 6201 ............................................................22 
2.4. 
Study Rationale ...........................................................................................................23 
3. 
STUDY OBJECTIVES ..............................................................................................25 
3.1. 
Primary Objective .......................................................................................................25 
3.2. 
Secondary Objectives .................................................................................................25 
3.3. 
Exploratory Objectives ...............................................................................................25 
4. 
INVESTIGATIONAL PLAN .....................................................................................26 
4.1. 
Overall Study Design ..................................................................................................26 
4.2. 
Study Duration and Termination of Study ..................................................................27 
4.3. 
Randomization and Blinding ......................................................................................27 
5. 
STUDY POPULATION .............................................................................................28 
5.1. 
Inclusion Criteria ........................................................................................................28 
5.2. 
Exclusion Criteria .......................................................................................................28 
5.3. 
Patient Enrollment ......................................................................................................30 
6. 
ADMINISTRATION OF NERATINIB AND LOPERAMIDE 
TREATMENTS ..........................................................................................................31 


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6.1. 
Neratinib .....................................................................................................................31 
6.1.1. 
Neratinib Dose Adjustment ........................................................................................31 
6.2. 
Loperamide .................................................................................................................32 
6.3. 
Capecitabine ...............................................................................................................33 
6.3.1. 
Dose Adjustment ........................................................................................................34 
6.4. 
Packaging, Labeling, and Storage ..............................................................................34 
6.4.1. 
Neratinib .....................................................................................................................34 
6.4.2. 
Loperamide .................................................................................................................35 
6.4.3. 
Capecitabine ...............................................................................................................35 
6.5. 
Drug Accountability and Treatment Compliance .......................................................35 
7. 
CONCOMITANT MEDICATIONS ..........................................................................36 
7.1. 
Permitted Concomitant Treatment ..............................................................................36 
7.2. 
Required Loperamide Antidiarrheal Therapy .............................................................36 
7.3. 
Prohibited Concomitant Treatment .............................................................................39 
7.4. 
Potential for Drug-Drug Interactions ..........................................................................39 
7.5. 
Treatment Compliance ................................................................................................40 
8. 
STUDY ASSESSMENTS ..........................................................................................41 
8.1. 
Efficacy Assessment ...................................................................................................41 
8.2. 
Safety Assessments .....................................................................................................41 
8.2.1. 
Safety Endpoints .........................................................................................................41 
8.2.2. 
Colonoscopy ...............................................................................................................41 
8.2.3. 
Laboratory Assessments .............................................................................................42 
8.2.4. 
Vital Signs ..................................................................................................................43 
8.2.5. 
Physical Examination .................................................................................................43 
8.2.6. 
Electrocardiogram .......................................................................................................44 
8.2.7. 
Left Ventricular Ejection Fraction (LVEF) ................................................................44 
8.3. 
Other Study Assessments ...........................................................................................44 
8.3.1. 
Health Outcomes Assessments ...................................................................................44 
8.3.2. 
Disease Recurrence or Progression ............................................................................44 
8.4. 
Protocol Deviations ....................................................................................................44 
8.5. 
Study Drug Accountability/Patient Diary ...................................................................44 
8.5.1. 
Study Medication Accountability ...............................................................................44 
8.5.2. 
Patient Diary ...............................................................................................................44 


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9. 
STUDY CONDUCT ...................................................................................................45 
9.1. 
Screening/Baseline .....................................................................................................45 
9.2. 
Active Treatment Phase ..............................................................................................46 
9.3. 
Treatment Discontinuation or End-of-Treatment Assessments ..................................46 
9.4. 
Safety Follow-up Visit ................................................................................................46 
9.5. 
Long-term Follow-up ..................................................................................................46 
9.6. 
End of Study ...............................................................................................................47 
10. 
PATIENT WITHDRAWAL AND REPLACEMENT ...............................................48 
10.1. 
Investigational Product Discontinuation .....................................................................48 
10.2. 
Withdrawal from the Study ........................................................................................48 
10.3. 
Procedures for Investigational Product Discontinuation/Study Withdrawal ..............49 
10.4. 
Patient Replacement ...................................................................................................49 
11. 
PREMATURE TERMINATION OF STUDY ...........................................................50 
12. 
STATISTICAL METHODS .......................................................................................51 
12.1. 
Study Patients .............................................................................................................51 
12.2. 
Efficacy Analyses .......................................................................................................51 
12.3. 
Safety Analysis ...........................................................................................................51 
12.4. 
Primary Analysis ........................................................................................................52 
12.4.1. 
Secondary Objectives .................................................................................................52 
12.5. 
Final Analysis .............................................................................................................52 
12.6. 
Determination of Sample Size ....................................................................................52 
13. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING....................53 
13.1. 
Definitions ..................................................................................................................53 
13.1.1. 
Adverse Events ...........................................................................................................53 
13.1.2. 
Abnormal Laboratory Results .....................................................................................53 
13.1.3. 
Serious Adverse Events ..............................................................................................54 
13.1.4. 
Hospitalization ............................................................................................................54 
13.1.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................55 
13.1.6. 
Severity Assessment ...................................................................................................55 
13.1.7. 
Causality Assessment .................................................................................................56 
13.1.8. 
Special Reporting Situations .......................................................................................57 
13.2. 
Reporting Adverse Events ..........................................................................................57 
13.3. 
Reporting Serious Adverse Events .............................................................................57 


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13.4. 
Pregnancy ...................................................................................................................58 
13.5. 
Sponsor Reporting Requirements to Health Authorities and IRB/IEC ......................59 
14. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ....................................60 
14.1. 
Data Collection, Processing, and Monitoring .............................................................60 
14.1.1. 
Case Report Forms and Source Documentation .........................................................60 
14.1.2. 
Study Monitoring and Access to Source Documentation ...........................................60 
14.1.3. 
Data Quality Assurance ..............................................................................................61 
14.1.4. 
Data Processing ..........................................................................................................61 
14.1.5. 
Retention of Data and Study Records .........................................................................61 
14.2. 
Ethical Aspects ...........................................................................................................62 
14.2.1. 
Good Clinical Practice and Ethical Conduct of the Study ..........................................62 
14.2.2. 
Informed Consent Responsibilities .............................................................................62 
14.2.3. 
Confidentiality of Data ...............................................................................................63 
14.3. 
Other Study Administrative Aspects ..........................................................................63 
14.3.1. 
Protocol Approval and Protocol Amendment.............................................................63 
14.3.2. 
Investigator Responsibilities .......................................................................................64 
14.3.3. 
Patient Responsibilities ...............................................................................................65 
14.3.4. 
Financial Disclosure ...................................................................................................65 
14.3.5. 
Publication Policy .......................................................................................................65 
15. 
REFERENCES ...........................................................................................................67 
16. 
SIGNATURE PAGES ................................................................................................70 
17. 
APPENDICES ............................................................................................................72 
 
LIST OF TABLES 
Table 1: 
Characteristics of Diarrhea in Study 3004 (No Anti-diarrheal Prophylaxis) .............20 
Table 2: 
Characteristics of Diarrhea in Study 6201 (Prophylaxis Months 1 and 2) .................22 
Table 3: 
Dose Reduction Levels for Neratinib-Related Toxicity .............................................31 
Table 4: 
Loperamide Dosing ....................................................................................................32 
Table 5: 
Loperamide Dose Reduction Levels for Constipation ................................................33 
Table 6: 
Dose Reduction Levels for Capecitabine-Related Toxicity (When 
Administered in Combination with Neratinib) ...........................................................34 
Table 7: 
Laboratory Parameters ................................................................................................42 
 
 


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LIST OF FIGURES 
Figure 1: 
Incidence of Treatment-emergent Grade 2 or Grade 3 Diarrhea Over Time in 
Study 3004 Neratinib Arm (No Prophylaxis) .............................................................21 
Figure 2: 
Incidence of Treatment-emergent Grade 2 or Grade 3 Diarrhea Over Time in 
Study 6201 With Loperamide Prophylaxis.................................................................23 
 


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1. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Term/Definition 
ADL 
activities of daily living 
AE 
adverse event 
AESI 
adverse events of special interest 
ALT  
ALP 
alanine aminotransferase 
alkaline phosphatase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical [Classification System] 
BID  
twice daily 
BUN 
blood urea nitrogen 
C 
cycle 
CBC  
complete blood count 
CFR 
Code of Federal Regulations 
CRA 
clinical research associate 
CRF 
case report form 
CRP 
C-reactive protein 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 enzyme 
D 
day 
DCIS 
ductal carcinoma in situ  
DFS 
disease-free survival  
ECG 
electrocardiogram 
ECHO  
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EGFR  
epidermal growth factor receptor (also known as HER) 
EIU  
exposure-in-utero 
EMA 
European Medicines Agency  
EOS 
end of study 
EOT 
end of treatment 
ERBB  
epidermal growth factor family of trans-membrane receptors (also known as HER) 
ERBB2  
avian erythroblastic leukemia viral oncogene homolog 2, HER2 
ESR 
erythrocyte sedimentation rate 
ExteNET 
Extended Adjuvant Treatment with Neratinib, study 3144A2-3004-WW  
FDA 
Food and Drug Administration (United States) 
FISH 
fluorescence in situ hybridization 
GCP  
Good Clinical Practice 
GDPR 
General Data Protection Regulation 
GI 
gastrointestinal 
GLP 
Good Laboratory Practice 


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Abbreviation 
Term/Definition 
Hb 
hemoglobin 
hCG  
β-human chorionic gonadotropin 
Hct 
hematocrit 
HER 
human epidermal growth factor receptor 
HER2 
human epidermal growth factor receptor 2; also known as c-erB2, ERBB2, or p185 
HIPAA  
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 
IC50 
concentration at which there is 50% inhibition 
ICF  
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IM 
intramuscular(ly) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
LDH  
lactate dehydrogenase 
LFT 
liver function test 
LVEF  
left ventricular ejection fraction 
MC 
microscopic colitis  
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
MTD 
maximum tolerated dose 
mTOR 
mammalian target of rapamycin  
MUGA 
multiple-gated accession scan 
NCI 
National Cancer Institute 
NERLYNX 
neratinib 
NP 
nurse practioner 
NSAID 
nonsteroidal anti-inflammatory drug 
ORR 
objective response rate 
OS 
overall survival 
PA 
physician’s assistant 
PB-272 
neratinib 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PI3K  
phosphoinositide 3-kinase 
PPE 
palmar-plantar erythrodysesthesia 
PPI 
proton pump inhibitor 
PRN 
pro re nata (as needed) 
PT  
preferred term 
QTc  
QT interval, corrected for heart rate 
RBC  
red blood cell 
SAE 
serious adverse event 


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Abbreviation 
Term/Definition 
SC  
subcutaneous(ly) 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment-emergent adverse event 
TdP  
Torsade de Pointes 
TID  
three times daily 
TKI 
tyrosine kinase inhibitor 
ULN  
upper limit of normal 
US 
United States (of America) 
WBC 
white blood cell 


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2. 
INTRODUCTION 
2.1. 
Background 
Breast cancer is the most frequently diagnosed malignancy in women and still the second leading 
cause of death in developed countries despite the advances made in the field over the past years 
(Ginsburg et al, 2017). In fact, more than 250,000 new cases of breast cancer were diagnosed in 
the United States in 2017 (Waks and Weiner, 2019). Globally, there were over 2 million new 
cases accounted for in 2018 (Bray et al, 2018). 
2.2. 
ERBB2 Gene and Cancer  
2.2.1. 
The Epidermal Growth Factor Receptor Family  
Members of the epidermal growth factor family of trans-membrane receptors (ERBB family) are 
potent mediators of normal cell growth and development and are expressed in various tissues of 
epithelial, mesenchymal and neuronal origin (Baselga et al, 2009). The ERBB family consists of 
4 closely related type 1 trans-membrane tyrosine kinase receptors: epidermal growth factor 
receptor (EGFR; also known as HER1), ERBB2 (HER2), ERBB3 (HER3), and ERBB4 (HER4).  
Aberrant expression of HER1, HER2, and HER3 are linked to development of many epithelial 
cancers including colorectal, gastric, breast, and head and neck cancers. These membrane-
spanning proteins receive extracellular signals from small peptide-ligand molecules, including 
epidermal growth factor-like molecules, transforming growth factor-α and neuregulins. Under 
normal physiological conditions, activation of the ERBB receptors is controlled by the spatial 
and temporal expression of their ligands (Yarden and Sliwkowski, 2001). Ligand binding 
triggers intracellular signaling through a complex and tightly controlled array of signaling 
pathways that together drive and regulate many cellular functions, including cell proliferation 
and organ development and repair. Binding of ligands to extracellular parts of HER1, HER3 and 
HER4 will result in dimerization and initiates a series of signaling cascades that includes 
mitogen-activated protein kinase, phosphoinositide 3-kinase (PI3K), Akt, and mammalian target 
of rapamycin (mTOR) (Garrett and Arteaga, 2011).  
Each receptor comprises an extracellular domain at which ligand binding occurs, an alpha-helical 
trans-membrane segment and an intracellular protein tyrosine kinase domain (Olayioye et al, 
2000). Receptor dimerization is an essential requirement for signaling activity of these receptors 
and can occur between two different ERBB receptors (hetero-dimerization) or between two 
molecules of the same receptor (homo-dimerization) (Olayioye et al, 2000; Ferguson et al, 2003). 
ERBB homodimers weakly perpetuate signals compared with heterodimers 
(Yarden  and  Sliwkowski, 2001). As the natural ligand for HER2 has not been identified, the 
receptor is presumed to exert its effects via formation of heterodimers with other HER family 
members and it is thought to be the preferred dimerization partner for the other receptors 
(Rosen  et al, 2010). In fact, heterodimer formation with HER2 has been shown to increase the 
affinity of ligand binding to the dimerization partner (Graus-Porta et al, 1997). Dimerization of 
HER3, which lacks intrinsic kinase activity, with HER2 induces phosphorylation of HER3, 
which then activates the PI3K and Akt pathways (Graus-Porta et al, 1997).  


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2.2.2. 
ERBB2-positive Cancers  
ERBB2 amplification and over-expression have been reported in 18 to 25% of human breast 
cancers and subsets of patients with ovarian and salivary gland tumors (Slamon et al, 1987; 
Vermeij et al, 2008; Cornolti et al, 2007). Approximately 15 to 20% (Ahn et al, 2012; 
Saini  et  al,  2011) of women with breast cancer are ERBB2-positive, which is associated with 
aggressive disease and poor prognosis (Slamon et al, 1987), including enhanced cell 
proliferation, reduced progression-free survival (PFS), and reduced overall survival (OS) 
(Slamon et al, 1987; Zhang et al, 2007; Badache and Goncalves 2006; Slamon et al, 1987). 
Compared with female breast cancer, male breast cancer cases are more often hormonal receptor 
(estrogen receptor/progesterone receptor) positive and HER2 negative, but treatment of male 
breast cancer patients follows the same indications as female postmenopausal breast cancer with 
surgery, systemic therapy and radiotherapy (Ottini et al, 2010). These observations have 
motivated the development of therapies targeting HER2.  
2.3. 
Neratinib  
Neratinib (HKI-272) is a potent irreversible pan ERBB inhibitor. Neratinib is an orally available 
small molecule that inhibits ERBB1, ERBB2, and ERBB4 at the intracellular tyrosine kinase 
domains, a mechanism of action that is different from trastuzumab. Neratinib reduces ERBB1 
and ERBB2 autophosphorylation, downstream signaling, and the growth of ERBB1 and ERBB2 
dependent cell lines. Preclinical data suggest that neratinib has antitumor activity in ERBB1- 
and/or ERBB2-expressing carcinoma cell lines, with cellular IC50 <100 nM 
(Rabindran  et  al,  2004).  
Neratinib have advantages over other HER2 inhibitors due to its ability to irreversibly inhibit 
both HER1 and HER2. Breast cancer cells become resistant to trastuzumab over-time on the 
basis of extracellular domain truncation of HER2 receptor, which can no longer be recognized by 
the antibody (Xia et al, 2004), or because of coactivation of HER1 signaling (Rampaul et al, 
2005; Zaczek et al, 2005). However, since neratinib acts on the intracellular tyrosine kinase 
domain, such cells are likely to maintain sensitivity to neratinib (Mosesson and Yarden, 2004).  
A summary of preclinical studies, human pharmacokinetic studies, and previous clinical studies 
of neratinib for treatment of HER2 positive breast cancer are provided in the neratinib 
Investigator’s Brochure (IB).  
2.3.1. 
Clinical Activity of Neratinib  
In Phase 1 and 2 clinical studies as a single agent or in combination with other anti-cancer 
agents, neratinib has shown anti-tumor activity in patients with HER2-positive/amplified breast 
cancer (Awada et al, 2013; Burstein et al, 2010; Chow et al, 2013; Saura et al, 2014). Analyses 
of the primary efficacy endpoint (disease-free survival, DFS) data from a pivotal, randomized 
Phase 3 ExteNET trial (Extended Adjuvant Treatment with Neratinib [3144A2-3004-WW, 
‘Study 3004’], (Chan et al, 2016; Martin et al, 2017); showed that neratinib reduced the risk of 
DFS events by 33% compared with placebo in women with HER2-positive locally advanced 
breast cancer who were treated with neratinib for 1 year after adjuvant trastuzumab. The one-
sided p-value from the stratified log rank test was 0.005 indicating that DFS was significantly 
prolonged for patients randomized to the neratinib arm compared with the placebo arm. 
Furthermore, neratinib resulted in a statistically significant improvement in the secondary 


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efficacy endpoint, DFS including ductal carcinoma in situ (DFS DCIS). Neratinib reduced the 
risk of DFS DCIS events by 37% compared with placebo. The one-sided-p value from the 
stratified log rank test was <0.001 indicating that DFS DCIS was significantly prolonged for 
patients randomized to the neratinib arm compared with the placebo arm.  
On 17-JUL-2017, the United States (US) Food and Drug Administration (FDA) approved 
neratinib (NERLYNX®) for the extended adjuvant treatment of adult patients with early-stage 
HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy 
(Singh et al, 2018).  
On 31-AUG-2018, the European Commission (EC) granted marketing authorization for neratinib 
(NERLYNX®) for the extended adjuvant treatment of adult patients with early stage hormone 
receptor-positive HER2-overexpressed/amplified breast cancer and who are less than one year 
from the completion of prior adjuvant trastuzumab based therapy.  
2.3.1.1. 
Neratinib in Combination with Capecitabine 
In a Phase 1/2 clinical study investigating the combination of neratinib plus capecitabine, the 
maximum tolerated dose (MTD) of neratinib 240 mg was established in combination with 
capecitabine 1500 mg/m2 in patients with solid tumors. Subsequent investigation of this dose 
regimen in patients with HER2+ advanced breast cancer demonstrated that this combination 
treatment was clinically active and has a manageable toxicity profile. 
In the study, clinical responses at the MTD were observed in 63% of patients (64% of those with 
no prior lapatinib exposure and 57% of those with prior lapatinib), while median durations of 
response were 46 and 48 weeks, respectively. This is a slightly higher response rate and similar 
duration of response to that observed in previous neratinib monotherapy studies, but in a full 
study population previously treated with trastuzumab (Burstein et al, 2010; Wong et al, 2009); an 
objective response rate (ORR) of 29% with neratinib monotherapy has also been reported 
(Martin et al, 2011). In this study, all patients progressed to previous trastuzumab-based therapy, 
and median PFS with neratinib plus capecitabine was 40 weeks in the lapatinib-naive cohort and 
36 weeks in the lapatinib-treated cohort. These results compare favorably with those previously 
observed in the monotherapy study for patients who received prior trastuzumab (22 weeks) 
(Geyer et al, 2006). The results of this study suggest that the combination of neratinib plus 
capecitabine may have superior efficacy in patients with prior therapy with anti HER2-targeted 
therapies. 
The results of this Phase 1/2 study also compare favorably with results obtained from the 
combination of lapatinib plus capecitabine in an indirect comparison. In a Phase 3 study, ORR 
(44.2%), clinical benefit rate (57.7%), and PFS (6.34 months) with lapatinib plus capecitabine 
were lower than was observed with neratinib plus capecitabine in the Phase 1/2 study (Xu et al, 
2011). 
The combination of neratinib plus capecitabine was associated with an acceptable safety and 
tolerability profile in the Phase 1/2 study. Diarrhea was the most common Grade 3/4 AE in the 
study (reported by 23% of patients), although only 4 patients discontinued treatment due to the 
event (6%), which is similar to previous experience in neratinib monotherapy studies (Burstein et 
al, 2010; Wong et al, 2009). Diarrhea typically occurred within a few days of neratinib initiation 
(median, 2 days) and was most often managed by a dose delay or reduction. Across previous 


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neratinib studies, diarrhea typically occurred within 2 to 8.5 days of neratinib initiation and was 
generally managed with dose adjustments or antidiarrheal medications (Burstein et al, 2010; 
Wong et al., 2009). 
The most frequent toxicities reported with capecitabine monotherapy are palmar-plantar 
erythrodysesthesia syndrome (PPE) and gastrointestinal events. While the incidence of PPE (all 
grades, 47%) in this study was similar to the range reported in capecitabine monotherapy studies 
(37% to 60%), the incidence of diarrhea was higher (all grades, 88% compared with 5% to 58% 
reported in monotherapy studies) (Burstein et al, 2010; Wong et al, 2009), as may be expected 
from the combination of two drugs that are associated with gastrointestinal effects. Overall, no 
unexpected toxicity was observed in patients receiving neratinib plus capecitabine, and few 
patients discontinued treatment due to toxicity. 
2.3.2. 
Safety Profile of Neratinib in Monotherapy and Combination Therapy Studies  
Safety results from completed and ongoing clinical studies conducted in patients with breast 
cancer or other solid tumors show that neratinib is generally well tolerated with a consistent 
safety profile. Gastrointestinal (GI) disorders, such as diarrhea, nausea, and vomiting, account 
for the most-frequently reported treatment-emergent adverse events. Fatigue, decreased appetite, 
abdominal pain, headache, rash, and hepatotoxicity (abnormal liver function test) have also been 
reported in patients treated with neratinib. Refer to the neratinib Investigator Brochure (IB) for 
more detailed information regarding benefits and identified and potential risks for patients, as 
well as for a summary of findings from neratinib nonclinical studies that potentially have clinical 
significance.  
Refer to Appendix 2 (Dose Adjustment Guidelines) for further information regarding the 
management of neratinib-related toxicities.  
2.3.3. 
Diarrhea Management Without Anti-diarrheal Prophylaxis  
As the mechanism of action of neratinib targets EGFRs, which are present in high numbers in the 
GI tract, diarrhea is a predicted on-target effect. Consistent with neratinib binding to the target 
receptors in the GI tract, diarrhea was the most common treatment-emergent adverse event 
(TEAE) leading to discontinuation in the Phase 3 ExteNET trial (Study 3004), in which 2,840 
women with early-stage HER2 positive breast cancer who had completed adjuvant treatment 
with trastuzumab were randomized 1:1 to receive either neratinib or placebo daily for one year. 
Anti-diarrheal prophylaxis to prevent the neratinib related diarrhea was not mandated in 
Study 3004; however, patients were allowed the use of anti-diarrheal agents after experiencing 
diarrhea at any time during the study. Thus, Study 3004 patients initiated neratinib dosing 
without concomitant anti-diarrheals and only took anti-diarrheal agents after diarrhea had 
occurred.  
In Study 3004, 95.4% of patients experienced diarrhea of any grade and 39.8% of patients 
experienced Grade 3 diarrhea. The majority of patients reporting Grade 3 diarrhea experienced 
the event in the first month of treatment. Although diarrhea was a frequent adverse event (AE), 
diarrhea episodes were predominately short in duration and rarely associated with severe or 
serious complications. Diarrhea due to neratinib was managed with anti-diarrheals and/or with 
dose adjustments. These diarrhea management techniques resulted in 95.0% of the diarrhea in 
the neratinib arm being resolved, similar to the 96.8% in the placebo arm. Only 1.6% of patients 


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treated with neratinib had diarrhea that was categorized as a serious adverse event (SAE). All 
AEs related to diarrhea were reversible with supportive care, treatment interruption, and/or 
discontinuation. The median cumulative duration of Grade 2 or higher diarrhea was 10 days and 
the discontinuation rate due to diarrhea was 16.8% in patients receiving neratinib in Study 3004 
(Table 1).  
Table 1: 
Characteristics of Diarrhea in Study 3004 (No Anti-diarrheal Prophylaxis) 
 
Neratinib Arm 
(N=1408) 
Placebo Arm 
(N=1408) 
Duration of treatment (months) 
Median (Min, Max) 
11.6 (0.03, 13.3) 
11.8 (0.1, 13.2) 
Incidence of diarrhea by worst grade – n (%) 
Any Grade  
1343 (95.4) 
499 (35.4) 
Grade 1 
323 (22.9) 
382 (27.1) 
Grade 2 
458 (32.5) 
94 (6.7) 
Grade 3 
561 (39.8) 
23 (1.6) 
Grade 4 
1 (0.1) 
0 (0.0) 
Cumulative duration of grade 2 or higher per patient (days) 
Median  
10  
3  
Cumulative duration of grade 3 or higher per patient (days)* 
Median  
5 
2  
Action taken 
Dose hold due to diarrhea-n (%) 
477 (33.9) 
26 (1.8) 
Dose reduction due to diarrhea -n (%) 
372 (26.4) 
8 (0.6) 
Discontinuation due to diarrhea – n (%) 
237 (16.8) 
3 (0.2) 
Diarrhea leading to hospitalization - n (%) 
20 (1.4) 
1 (0.1) 
* Includes one episode of Grade 4 diarrhea  
2.3.3.1. 
Incidence of Grade 3 Diarrhea in Study 3004  
In Study 3004 neratinib arm, 95.4% of patients experienced diarrhea of any grade and 39.8% of 
patients experienced Grade 3 diarrhea (Table 1). The majority of patients reporting Grade 3 
diarrhea experienced the event in the first month of treatment. The incidence of Grade 3 diarrhea 
decreased in subsequent months (Figure 1).  


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Figure 1: 
Incidence of Treatment-emergent Grade 2 or Grade 3 Diarrhea Over Time 
in Study 3004 Neratinib Arm (No Prophylaxis)  
 
The severity grade for diarrhea is the worst grade during the treatment month. 
One month is defined as 30 days. 
2.3.4. 
Diarrhea Management With Anti-diarrheal Prophylaxis  
While Study 3004 was ongoing, trials in metastatic breast cancer showed that administering 
anti-diarrheal agents on the same day as initiating neratinib therapy helped to reduce neratinib-
related diarrhea (Ustaris et al, 2015). In these studies, neratinib and loperamide were given 
together on Day 1 and then continued to be given together for the first month of treatment. After 
the first month, the prophylactic loperamide was stopped and neratinib continued to be given 
daily with loperamide given as needed (PRN) after diarrhea occurred.  
Based on the results obtained in the metastatic setting demonstrating a reduction in the incidence 
of diarrhea with the prophylactic use of loperamide, study PUMA-NER-6201 (Study 6201) was 
initiated in the extended adjuvant breast cancer setting to assess the effectiveness of multiple 
prophylaxis regimens on reducing the incidence of neratinib-related diarrhea. Study 6201 
enrolled the same patient population and had the same dose, frequency of administration, and 
duration of neratinib treatment as in the pivotal efficacy Study 3004. The first cohort in 
Study 6201 was designed to confirm the previous results by using loperamide anti-diarrheal 
prophylaxis.  
In Study 6201 loperamide cohort, 79.6% of patients experienced diarrhea of any grade and 
30.7% of patients experienced Grade 3 diarrhea. The median cumulative duration of Grade 2 or 
higher diarrhea was 5 days and the discontinuation rate due to diarrhea was 20.4% (Table 2).  
 


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Table 2: 
Characteristics of Diarrhea in Study 6201 (Prophylaxis Months 1 and 2)  
 
Loperamide Cohort* 
(N=137) 
Duration of treatment (months) 
Median (Min, Max) 
11.63 (0.1, 13.1) 
Incidence of diarrhea by worst grade – n (%) 
Any Grade 
109 (79.6) 
Grade 1 
33 (24.1) 
Grade 2 
34 (24.8) 
Grade 3 
42 (30.7) 
Grade 4 
0 (0.0) 
Cumulative duration of grade 2 or higher per patient (days) 
Median  
5.0 
Cumulative duration of grade 3 or higher per patient (days) 
Median  
3.0 
Action taken 
Dose hold due to diarrhea-n (%) 
20 (14.6) 
Dose reduction due to diarrhea -n (%) 
11 (8.0)  
Discontinuation due to diarrhea – n (%) 
28 (20.4) 
Diarrhea leading to hospitalization - n (%) 
2 (1.5) 
* In the loperamide cohort of Study 6201, 2 different prophylaxis regimens were evaluated; values presented in the 
table combine the data from the 2 regimens.  
2.3.4.1. 
Incidence of Grade 3 Diarrhea in Study 6201  
The data from Study 6201 suggest that the use of antidiarrheal prophylaxis with loperamide 
reduces the diarrhea experienced by the patients taking neratinib compared to that seen in 
Study 3004. The data from Study 6201 also confirm the previous observation made in 
Study 3004 that the highest incidence of Grade 3 diarrhea with neratinib therapy is observed in 
the first month of treatment and that the incidence is reduced in subsequent months (Figure 2).  


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Figure 2: 
Incidence of Treatment-emergent Grade 2 or Grade 3 Diarrhea Over Time 
in Study 6201 With Loperamide Prophylaxis  
 
1 month = 30 days  
2.4. 
Study Rationale  
A rat model for neratinib-associated diarrhea has identified inflammation of the terminal ileum 
and proximal colon as a potential cause of the neratinib-related diarrhea. Studies conducted in 
this model demonstrated that budesonide, a locally acting corticosteroid used for inflammatory 
GI conditions, and colesevelam, a bile acid sequestrant, each reduced the amount of days with 
moderate diarrhea compared with neratinib alone. In the proximal colon, rats treated with 
neratinib had higher levels of apoptosis compared with controls; budesonide significantly 
reduced histopathological injury in the proximal and distal colon in rats (Secombe et al, 2017; 
Secombe et al, 2019).  
Microscopic colitis (MC) is a relatively common cause of chronic watery diarrhea. The diagnosis 
is based upon characteristic histological findings in the presence of diarrhea. The symptoms of 
MC are non-specific, and many patients meet the diagnostic criteria for irritable bowel 
syndrome; therefore, colon biopsies are required to definitively distinguish MC from the much 
more common irritable bowel syndrome.  
MC has two main subtypes, lymphocytic colitis and collagenous colitis, with the main distinction 
being histological. The characteristic biopsy finding in lymphocytic colitis is intraepithelial 
lymphocytosis, defined as >20 intraepithelial lymphocytes per 100 surface epithelial cells. In 
addition, the lamina propria contains a mixed infiltrate of acute and chronic inflammatory cells. 
Collagenous colitis has similar inflammatory findings, although the intraepithelial lymphocyte 
infiltrate tends to be less prominent. The distinguishing histological feature of collagenous colitis 
is a thickened subepithelial collagen band (>7 μm, compared with normal of ≤5 μm). Despite the 
normal appearance grossly, biopsies often show surface epithelial damage.  
The ideal location in the colon to obtain biopsies is not clear. The inflammation and collagen 
thickening are not always uniform throughout the colon, and inflammation in lymphocytic colitis 
and collagen thickening in collagenous colitis may be worse in the right versus left colon. It is 


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well established that distal colon biopsies are not sufficiently sensitive to make the diagnosis and 
that proximal and distal biopsies are standard of care. 
This study aims to characterize the pathology of colonic mucosa in patients with HER2 positive 
breast cancer treated with neratinib by performing a colonoscopy at before the initiation of 
neratinib in Cycle 1 and on Day 30 (± 3 days) (Appendix 1). During colonoscopy, photographs 
of the colonic mucosa will be taken along with approximately 8 biopsies from the terminal 
ileum, cecum, ascending colon, proximal transverse colon, splenic flexure, sigmoid colon, and 
rectum. If any abnormal appearing colon mucosa is identified endoscopically, it will be noted 
and biopsied in a separate jar. Biopsy material will be analyzed in a central laboratory. If polyps 
are identified, they will be removed during the examination; if cancer is identified, it will be 
sampled. Usual, standard clinical care will be provided for endoscopic findings unrelated to the 
study aims.  
At the time of colonoscopy, serological inflammatory markers (erythrocyte sedimentation rate 
[ESR], C-reactive protein [CRP]) will be sampled and stool markers for diarrhea (fecal 
calprotectin, fecal elastase) will be collected. 


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3. 
STUDY OBJECTIVES  
3.1. 
Primary Objective  
The primary objective of this study is to characterize and understand colon pathogenesis related 
to neratinib-induced diarrhea through biopsies and images obtained by colonoscopy study 
3.2. 
Secondary Objectives  
The secondary objectives of this study are:  
 To characterize the incidence and severity of diarrhea during the first 28-day cycle. 
 To analyze changes in serological and fecal inflammatory markers from baseline to 
second colonoscopy. 
3.3. 
Exploratory Objectives  
None.  


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4. 
INVESTIGATIONAL PLAN  
4.1. 
Overall Study Design  
This is an open-label, phase 2 study that will investigate colon pathology in patients with HER2-
positive breast cancer treated with neratinib as monotherapy. 
All patients will receive neratinib for the first 28 days as a single daily dose of 240mg.  
Following the second study colonoscopy procedure:  
 For patients being treated for stage 1 to 3c breast cancer in the extended adjuvant 
setting, neratinib will continue to be administered at a single daily dose of 240mg 
until completion of one year of therapy from start of treatment , or until disease 
recurrence (as determined by the Investigator), death, unacceptable toxicity, or other 
specified withdrawal criterion.  
 For patients being treated for metastatic breast cancer (mBC), capecitabine will be 
introduced after the second study colonoscopy procedure at a dose of 750mg/m2 twice 
daily for 14 days of each 21 day treatment cycle, with neratinib administered 
continuously throughout at 240mg daily, until disease progression, death, 
unacceptable toxicity, or other specified withdrawal criterion. 
All patients will receive loperamide diarrhea prophylaxis daily for one (1) 28-day cycle and then 
as needed. 
Following a 28-day screening period (Section 9.1), eligible patients will be enrolled. Baseline 
assessments will be performed prior to Cycle 1/Day 1 dosing. Patients will then participate in the 
active treatment phase, consisting of, in both groups, a single 28-day cycle of neratinib 
monotherapy (Section 9.2). Neratinib and loperamide will be administered orally by patients as 
described in Section 6. The morning dose of neratinib will be held on the day of the second study 
colonoscopy procedure (Section 6.1).  
Colonoscopy will be performed after eligibility has been confirmed, but prior to administration 
of the first dose of neratinib on Day 1 of Cycle 1, and at Day 30 (± 3 days). Thereafter, extended 
adjuvant patients with stage 1 to 3c breast cancer will continue to receive neratinib monotherapy 
for 1 year or until progression of disease, death, or intolerance to study prescribed therapy. 
Patients with mBC will continue to receive neratinib in 21-day cycles, beginning in Cycle 2, 
after completion of the second study colonoscopy procedure, in combination with capecitabine 
administered on Day 1-14 of each cycle, until progression of disease, death, or intolerance to 
study prescribed therapy. 
NOTE; patients with mBC cannot be exposed to capecitabine until after completion of the 
second study colonoscopy procedure. 
In extended adjuvant patients with stage 1 to 3c breast cancer, patients will return to the clinic 
approximately every 3 months for safety assessments. End of Treatment (EOT) visit is planned 
on upon completion of 1 year of treatment, followed by Safety Follow-up Visit 28 days after the 
last dose of neratinib.  


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In patients with mBC, clinic visits during the active treatment phase are planned on Day 1 of 
Cycle 1, Cycle 2, and each subsequent cycle. Treatment discontinuation visit is planned 0-3 days 
after the last dose, followed by a Safety Follow-up Visit 28 days after the last dose of neratinib.  
Assessments required throughout the study are summarized in the Schedule of Study Procedures 
(Appendix 1).  
Patients may be discontinued from investigational product or from the study, as described in 
Section 10 and Section 11.  
The primary endpoint of the study is change from baseline in pathological findings in colon 
biopsies after the first 28 days of neratinib. The secondary endpoint is the incidence and severity 
of diarrhea during the first 28-day cycle.  
The study will end when all patients have been followed-up for 28 days after the last dose of 
neratinib.  
Approximately 3-5 patients will be enrolled at approximately 2 centers.  
4.2. 
Study Duration and Termination of Study 
The approximate duration of the study is 1.5 years.  
Patients with stage 1 to 3c disease receiving extended adjuvant therapy are anticipated to 
participate in the study for approximately 1 year. This includes 1 month for screening, 
approximately 12 months for the active treatment phase until progression of disease or 
intolerance to study prescribed therapy, and safety follow-up visit 28 days after the last dose of 
neratinib.  
Patients with mBC are anticipated to participate in the study for an average of 12 months. This 
includes approximately 1 month for screening, an estimated average of 9.5 months for the active 
treatment phase, and an estimated average of 1 month for initial Safety Follow-up.  Patients who 
permanently discontinue treatment due to unacceptable toxicity will be followed-up for 28 days 
after the last dose of neratinib to collect any adverse events (AEs) (Section 9.4).  
The primary analysis will be conducted after all patients have completed two sets of colon 
biopsies. The final analysis will be conducted when all patients with stage 1 to 3c breast cancer 
have completed 1 year of study treatment or have met other specified withdrawal criteria and 
patients with mBC have discontinued therapy or have met other specified withdrawal criteria 
(see Section 10).  
The study will end when all patients have been followed up for 28 days after the last dose of 
neratinib.  
In the event that end of treatment (EOT) is declared earlier by the Sponsor, patients will be 
offered the opportunity to complete treatment through a treatment extension study. 
4.3. 
Randomization and Blinding  
This is a non-randomized, open-label study.  


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5. 
STUDY POPULATION  
5.1. 
Inclusion Criteria  
Each patient will be entered into this study only if she/he meets all of the following criteria:  
1. Aged ≥18 years at signing of informed consent.  
2. Histologically confirmed stage 1 through stage 4 primary adenocarcinoma of the breast 
(Edge and Compton, 2010).  
3. Documented HER2 overexpression or gene-amplified tumor by a validated approved 
method (Wolff et al, 2013).  
4. Patients with confirmed stage 1 to 3c breast cancer receiving neratinib monotherapy must 
have completed a course of prior adjuvant trastuzumab or experienced side effects that 
resulted in early discontinuation of trastuzumab that have since resolved.  
5. Patients with mBC must have had at least 2 prior HER2-directed regimens.  
6. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition 
scan (MUGA) or echocardiogram (ECHO).  
7. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1.  
8. Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal 
women of reproductive capacity (those who are biologically capable of having children) 
and for women less than 12 months after menopause. Women are considered 
postmenopausal if they are ≥12 months without menses, in the absence of endocrine or 
anti-endocrine therapies.  
9. Women of childbearing potential must agree and commit to the use of a highly effective 
non-hormonal method of contraception, i.e., intrauterine device, bilateral tubal ligation, 
vasectomized partner, or abstinence (only when it is the preferred lifestyle of the patient), 
from the time of informed consent until 28 days after the last dose of the investigational 
products.  Men (male patient) with a female partner of childbearing potential must agree 
and commit to use condom and the female partner must agree and commit to use a highly 
effective method of contraception (i.e., any of the above methods, or for females, 
hormonal contraception associated with inhibition of ovulation) while on treatment and 
for 3 months after last dose of investigational products.  
10. Recovery (i.e., to Grade 1 or baseline) from all clinically significant AEs related to prior 
therapies (excluding alopecia, neuropathy, and nail changes). 
11. No major bleeding diathesis or use of anticoagulants that would pose a high risk for 
endoscopic procedure. 
12. Provide written, informed consent to participate in the study and follow the study 
procedures.  
5.2. 
Exclusion Criteria  
A patient will be excluded from this study if she/he meets any of the following criteria.  


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1. Patients with confirmed stage 1 through stage 3c breast cancer currently receiving 
chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer.  
2. Patients with mBC that have received prior capecitabine or HER2 directed TKI therapy. 
3. Currently using drugs that have been implicated as causing microscopic colitis/watery 
diarrhea, such as acarbose, aspirin, proton pump inhibitors, nonsteroidal anti-
inflammatory drugs (NSAIDs), histamine H2-receptor antagonists, selective serotonin 
reuptake inhibitors, and ticlopidine (Pardi, 2017).  
4. Major surgery within <28 days of starting treatment or received chemotherapy, 
investigational agents, or other cancer therapy, except hormonal therapy (eg, tamoxifen, 
aromatase inhibitors), <14 days prior to the initiation of investigational products.  
5. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure 
(New York Heart Association functional classification of ≥2; including individuals who 
currently use digitalis, beta-blockers, or calcium channel blockers specifically for 
congestive heart failure), unstable angina, myocardial infarction within 12 months of 
enrollment, or ventricular arrhythmia.  
6. QTc interval >0.450 seconds (males) or >0.470 (females), or known history of QTc 
prolongation or Torsade de Pointes (TdP).  
7. Diagnosis of inflammatory bowel disease. 
8. Screening laboratory assessments outside the following limits:  
Laboratory Parameters 
Required Limit for Exclusion 
Absolute neutrophil count (ANC) 
<1,000/µl (<1.0 x 109/L) 
Platelet count 
<50,000/µl (<100 x 109/L) 
Hemoglobin 
<8 g/dL (transfusions allowed) 
Transfusions must be at least 14 days prior to initiation 
of treatment 
Total bilirubin 
>1.5 x institutional upper limit of normal (ULN) (in case of 
known Gilbert’s syndrome, <2 x ULN is allowed) 
Aspartate aminotransferase (AST) and/or 
alanine aminotransferase (ALT) 
>2.5 x institutional ULN (>5 x ULN if liver metastases 
are present in mBC patients) 
Creatinine  
Creatinine clearance <30 mL/min (as calculated by 
Cockcroft-Gault formulaa or Modification of Diet in Renal 
Disease [MDRD] formulab) 
International Normalized Ratio (INR) 
≥1.5 
a Cockcroft and Gault, 1976  
b Levey et al, 1999  
9. Active, unresolved infections.  
10. Patients with a second malignancy, other than adequately treated non-melanoma skin 
cancers, in situ melanoma or in situ cervical cancer. Patients with other non-mammary 
malignancies must have been disease-free for at least 5 years.  


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11. Currently pregnant or breast-feeding.  
12. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, 
Crohn’s disease, malabsorption, or Grade ≥2 National Cancer Institute [NCI] Common 
Terminology Criteria for Adverse Events Version 4.0 [CTCAE v.4.0] diarrhea of any 
etiology at baseline).  
13. Clinically active infection with hepatitis B or hepatitis C virus.  
14. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric 
illness/social situations that could, in the Investigator’s judgment, make the patient 
inappropriate for this study.  
15. Known hypersensitivity to any component of the investigational products; known 
allergies to any of the medications or components of medications used in the trial.  
16. Unable or unwilling to swallow tablets.  
5.3. 
Patient Enrollment  
Enrollment will occur only after the patient has given written informed consent, all screening 
assessments have been completed, and the patient meets all eligibility criteria.  


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6. 
ADMINISTRATION OF NERATINIB AND LOPERAMIDE 
TREATMENTS  
6.1. 
Neratinib  
Neratinib will be supplied as 40-mg, film-coated tablets packaged in bottles with desiccant.  
Neratinib (240 mg; provided as six 40-mg tablets) will be self-administered orally by patients on 
a daily basis, starting with Cycle 1/Day 1. Neratinib must be taken with food, preferably in the 
morning.  
In patients with stage 1 to 3c disease, extended adjuvant treatment with neratinib will be given 
continuously as a single 28-day cycle followed by continuous daily dosing for up to 1 year  
In patients with mBC, following completion of a 28-day cycle of neratinib monotherapy and 
completion of the second study colonoscopy procedure, neratinib will be given continuously in 
21-day cycles in combination with capecitabine. On the day of the second study colonoscopy 
procedure in both groups, the morning dose of neratinib will be held. Neratinib will be resumed 
the day following the second study colonoscopy procedure. In both groups, daily dosing should 
continue until disease recurrence or progression (as determined by the Investigator), death, 
unacceptable toxicity, or other specified withdrawal criterion is met (see Section 10).   
During the first 28 days, patients must use a diary to record their intake of neratinib (see 
Section 8.5.2).  
6.1.1. 
Neratinib Dose Adjustment 
Neratinib dose adjustment and/or discontinuation and/or management of toxicity should be 
performed according to Appendix 2 and Section 10.1.  
Recommended dose reductions for the -1 and -2 dose levels of neratinib are listed in Table 3.  
Table 3: 
Dose Reduction Levels for Neratinib-Related Toxicity 
Dose Level 
Neratinib 
Recommended Starting Dose 
240 mg 
First dose reduction 
200 mg 
Second dose reduction 
160 mg 
Third dose reduction 
120 mg 
mg = milligrams 
If doses of neratinib are held, study procedures for that cycle will proceed on schedule as 
planned, without any delay. Missed dose(s) of neratinib (i.e., any dose that is not administered 
within the protocol-defined administration window) will not be made up. Note: Patients should 
take one dose per calendar day. The dose adjustment guidelines represent the minimum set of 
measures the Investigator must follow. However, additional measures may be taken, as 
necessary, for certain patients per the Investigator’s medical judgment. All dose 
modifications/adjustments should be documented in the patient’s source file. 


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Once the neratinib dose has been reduced for a patient, all subsequent cycles must be 
administered at that dose, unless further dose reduction is required. Dose re-escalation will only 
be permitted if explicitly approved in advance by the Sponsor. Evidence of this approval must be 
contained within the patient’s source file.  
Patients must discontinue the investigational product if a criterion for withdrawal is met (see 
Section 10.1).  
Reintroduction of the discontinued investigational product at a later time during the active 
treatment phase is not permitted. 
Detailed rules for dose adjustments of neratinib in case of toxicity, including the dose levels to 
which the investigational product should be adjusted, are provided in Appendix 2.  
6.2. 
Loperamide  
Detailed dosing instructions and recommendations for management of diarrhea are provided in 
Section 7.2. Prior to initiation of study drug in Cycle 1. 
 Inform patients that they will experience diarrhea while taking neratinib. 
 Loperamide should be taken as instructed 
 The initial dose of loperamide 4 mg will be self-administered orally with the first dose of 
neratinib. 
 During weeks 1-2 (day 1 – 14) of Cycle 1 loperamide 4 mg will be self-administered 
administered three time daily. 
 During weeks 3-4 (days 15 – 28) of Cycle 1 loperamide 4 mg will be self-administered 
twice daily  
 After the first 28 days, loperamide will be self-administered as needed (PRN) (not to 
exceed 16 mg per day).  
Recommended loperamide dosing is listed below in Table 4.  
Table 4: 
Loperamide Dosing  
Day 
Loperamide Dose 
1-14 
Daily dose of 12 mg in 3 divided doses of 4 mg 
15-28 
Daily dose of 8 mg in 2 divided doses of 4 mg 
29+ 
Daily dose as needed (not to exceed 16 mg per day) 
During the first 28 days, patients must use a diary to record their intake of loperamide as well as 
the use of other antidiarrheals. Loperamide pill counts will be conducted only during the first 
cycle (28 days) of therapy.  
Documentation of the number of stools at baseline should be captured in the patient’s record. 
Any occurrences of loose stools, diarrhea or constipation must be documented by the patient and 
captured in the Patient Diary (see Section 8.5.2) during Cycle 1. The entries in the Patient Diary 
should be reviewed by the study staff together with the patient.  


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The Patient Diary will contain details of the daily number of unformed stools the patient has 
experienced since the last visit. Documenting the toxicity grade of the diarrhea or constipation by 
the study staff needs to be reported accurately on the Case Report Form (CRF) using the NCI 
CTCAE version 4.0 criteria.  
Loperamide Dose Adjustment 
Patients are expected to take loperamide prophylaxis as directed. However, patients may require 
individualization of loperamide prophylaxis dose (up to a maximum dose of 16 mg per day). 
 For patients who develop diarrhea during Cycles 1, loperamide should be increased up to 
a maximum of 16 mg a day.  
 If a patient is unable to tolerate loperamide due to symptomatic constipation, loperamide 
should be held until after the first bowel movement and then resumed at a dose reduced 
by one level.  
 For recurrent symptomatic constipation events, hold loperamide until after the first bowel 
movement and then resume at a dose reduced to the next lower dose level.  
 If a patient is unable to tolerate once-daily loperamide due to constipation, hold 
loperamide and discuss subsequent loperamide dosing with the Medical Monitor.  
 Neratinib dosing should continue if loperamide is held.  
Recommended dose reductions for loperamide are listed in Table 5.  
Table 5: 
Loperamide Dose Reduction Levels for Constipation 
Dose Level 
Loperamide Dose 
Tablets/Capsules per Day 
 0 
4 mg TID 
6 tablets/capsules a day 
-1 
4 mg BID 
4 tablets/capsules a day 
-2 
2 mg TID 
3 tablets/capsules a day 
-3 
2 mg BID 
2 tablets/capsules a day 
-4 
2 mg once a day 
1 tablet/capsule a day 
Abbreviations: BID = twice daily; mg = milligrams; TID = three times daily 
If a patient experiences an AE leading to dose interruption of neratinib for reasons other than 
diarrhea, consider holding loperamide until neratinib treatment is resumed.  
6.3. 
Capecitabine 
Patients with mBC will receive capecitabine, beginning in Cycle 2 of treatment (i.e., following 
completion of the second study colonoscopy procedure and biopsy). 
Capecitabine is available at 150 mg and 500 mg film-coated tablets. 
Capecitabine (total dose of 1500 mg/m2 daily, administered as 750 mg/m2 in approximately 
evenly divided doses) will be self-administered orally by patients starting with Cycle 2/Day 1 
(i.e. following completion of the second study colonoscopy procedure and biopsy). Doses are to 


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be taken daily on Days 1 to 14 of each 21-day cycle. Capecitabine should be taken with water 
within 30 minutes after a meal.  
During treatment with neratinib plus capecitabine, patients should be monitored for conditions 
that may require dose to be held or discontinued as described in Appendix 2.  Careful attention 
should be paid to the onset of diarrhea or hand-foot syndrome in particular, and early dose 
adjustment or prophylactic therapy should be implemented as described in Appendix 2.  
Daily dose of neratinib plus capecitabine should continue until a criterion for treatment 
withdrawal or study withdrawal is met (see Section 10.1 and Section 10.2, respectively). 
Refer to the capecitabine (Xeloda®) US Package Insert and/or the SPC for further information 
on dosing, safety assessments and toxicity management.  
6.3.1. 
Dose Adjustment 
Investigational product dose adjustment and/or discontinuation should be performed according to 
Appendix 2 and Section 10.1. 
Recommended dose reductions for the -1 and -2 dose levels of capecitabine in combination with 
neratinib are listed in Table 6. 
Table 6: 
Dose Reduction Levels for Capecitabine-Related Toxicity (When 
Administered in Combination with Neratinib) 
Dose Level 
Capecitabine (administered in combination with neratinib) 
Starting Dose 
1500 mg/m2, 750 mg/m2 BID 
-1aa 
1100 mg/m2, 550 mg/m2 BID 
-2a 
750 mg/m2, 375 mg/m2 BID 
Abbreviation: BID: twice daily 
a Since capecitabine is provided as 150 mg or 500 mg tablets, it is recommended that the capecitabine dose 
reduction(s) (to 75% [level -1] or 50% [level -2] of the starting dose) is rounded down to the nearest 500 mg or 
multiple of 150 mg for the BID dose. If the patient’s body surface area is >2.0, the standard of care for the study 
center can be utilized for capecitabine mg/m2 dosing.  
6.4. 
Packaging, Labeling, and Storage 
6.4.1. 
Neratinib 
Neratinib will be supplied as 40-mg, film-coated tablets packaged in bottles with desiccant.  
Neratinib should be stored at 25°C (77°F) or below; do not freeze. Neratinib should be stored 
with desiccant. Excursions are permitted from 15°C (59°F) to 30°C (86°F). Neratinib should be 
stored in a secure location with limited access. Patients should be instructed to store neratinib in 
a safe place at room temperature.  
Detailed packaging information is available in the study reference manuals. Neratinib will be 
labeled according to local regulations and include the study number.  


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6.4.2. 
Loperamide 
Commercially available loperamide will be provided to the subjects by the study sites.  
6.4.3. 
Capecitabine 
Commercially available capecitabine will be provided to the subjects with mBC by the study 
sites. 
6.5. 
Drug Accountability and Treatment Compliance 
The study site must maintain accurate records documenting dates and quantities of 
investigational product, capecitabine and loperamide supplied/ reimbursed by the Sponsor. 
Records must also be maintained documenting dates and quantities (i.e., pill counts) of neratinib, 
capecitabine and loperamide received, dispensed (per-patient), and returned (per-patient). Such 
documentation should permit a running log of the receipt and per-patient disposition of all 
investigational products on site. Any investigational product, capecitabine or loperamide 
accidentally or deliberately destroyed must also be documented.  
Throughout the study, reconciliation will be made between the amounts of neratinib, 
capecitabine and loperamide supplied, dispensed, returned, and subsequently destroyed or 
returned to the Sponsor. All investigational products, capecitabine and loperamide will be 
returned to Sponsor or its representative, or destroyed at the site in accordance with local 
standard operating procedures, as specified in writing by the Sponsor.  
Individual patient dosing compliance should be reviewed and documented at each study visit by 
study site staff. If patient non-compliance is noted, the patient should be re-instructed regarding 
proper dosing procedures in order to continue in the study. If repeated non-compliance is noted, 
additional steps may be taken, including withdrawal of the patient from the study (see 
Section 10.2).  


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7. 
CONCOMITANT MEDICATIONS  
All concomitant medications and concomitant nonpharmacological treatments/therapies will be 
recorded at screening from 28 days prior to the signing of the informed consent form (ICF), on 
Day 1 of Cycle 1 through completion of the second study colonoscopy procedure.  This will 
include the start date, stop date, generic name, route of administration, dose and indication for 
treatment. At screening, patients will be asked what medications they have taken during the 
previous 28 days and which medications are ongoing at the time of screening. 
7.1. 
Permitted Concomitant Treatment  
Any palliative and/or supportive care for cancer-related symptoms, which are not otherwise 
specified in the list of prohibited medications (Section 7.3), or drugs with potential for drug-drug 
interactions (Section 7.4), or in the associated Appendices (Appendix 4, Appendix 5, 
Appendix 6), including hormonal therapy (eg, tamoxifen, aromatase inhibitors) is permitted at 
the Investigator’s discretion.  
Specifically, the following treatments are permitted during the study:  
 Standard therapies for preexisting medical conditions and for medical and/or surgical 
complications. All medication(s) as well as dose and length of therapy should be recorded 
in the case report form (CRF).  
 Adjuvant endocrine therapy is allowed for hormone receptor-positive disease.  
 Bisphosphonates and receptor activator of nuclear factor kappa-B ligand inhibitors (eg, 
denosumab), are allowed regardless of indication.  
 Secondary prophylactic use of growth factors (e.g., granulocyte colony stimulating factor 
or granulocyte macrophage colony stimulating factor) may be implemented per the 
American Society of Clinical Oncology guidelines at the Investigator’s discretion, if 
significant neutropenia or febrile neutropenia/infection is observed. 
7.2. 
Required Loperamide Antidiarrheal Therapy  
Diarrhea is the major dose-limiting toxicity of neratinib with onset typically occurring early in 
the course of treatment (during the first few weeks of treatment). Primary prophylactic use of 
antidiarrheal medication is mandatory for all enrolled patients taking neratinib.  
As noted in Section 6.2, loperamide is the recommended standard therapy to treat diarrhea in this 
study. If alternative antidiarrheal medication is proposed, this should be discussed with the 
Medical Monitor and the reason documented in the source documents. Second-line antidiarrheal 
treatments (diphenoxylate hydrochloride and atropine sulfate) may be used in Cycle 1. 
Adjunctive therapies (eg, octreotide [SANDOSTATIN®] (or equivalent as approved by the 
Sponsor) are also recommended for use when appropriate; however, the use of octreotide should 
be avoided in Cycle 1.  
The Investigator must review with the patient the Patient Instructions for the management of 
diarrhea and the Patient Diary used by the patient to record daily the number of stools, use of 
loperamide and/or other anti-diarrheals, and the use of investigational product for the first cycle 
(28 days) of the study (see Section 8.5.2). Both the patient and the Investigator must sign the 


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patient instructions for the management of diarrhea. The Patient Instructions and Patient Diary 
are to be handed to the patient before leaving the site with investigational product on or before 
Cycle 1/Day 1, with clear instructions to contact the Investigator in the event of de novo onset or 
persistent Grade ≥2 diarrhea to discuss the appropriate course of treatment. The Investigator 
must also complete and sign the Investigator Checklist on or before Cycle 1/Day 1.  
Documentation of any occurrences of loose stools or diarrhea must be as precise as possible and 
captured in the Patient Diary. For AE recording, documentation of “Intermittent” events of 
diarrhea is limited to Grade 1. If events of Grade 1 diarrhea are separated by 3 days without any 
diarrhea, then each event must be documented as separate AEs with corresponding start and stop 
dates.  
The entries on the Patient Diary should be reviewed together with the patient. If the patient has 
experienced diarrhea since the last visit, details of the daily number of unformed stools provided 
on the diary help to grade the diarrhea as precisely as possible (per NCI CTCAE v.4.0). Also, the 
daily dose of loperamide (or other antidiarrheals, if applicable) noted on the diary will be 
reviewed and recorded on the CRF.  
Loperamide (along with neratinib) will be dispensed directly by the site on or before 
Cycle 1/Day 1 and during subsequent visits as needed. It is very important to initiate treatment 
with loperamide concomitantly with the first dose of neratinib to minimize occurrence and 
severity of diarrhea.  
Loperamide Prophylactic Dosing Instructions (Cycle 1)  
 Inform patients that they will experience diarrhea while taking neratinib.  
 Administer loperamide:  
 The initial dose of loperamide 4 mg will be self-administered orally with the first 
dose of neratinib.  
 For the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered 
orally by patients TID (total 12 mg a day).  
 During weeks 3-4 (days 15-28) loperamide 4 mg will be self-administered BID 
 After the first 28 days, loperamide will be self-administered as needed (PRN) (not to 
exceed 16 mg/day) 
 For patients who develop diarrhea during Cycle 1, loperamide should be increased up to a 
maximum of 16 mg a day.  
 At any time during the study, for patients with persistent Grade 1 diarrhea (<4 stools per 
day above baseline) on a maximum dose of loperamide (16 mg a day), Lomotil® 
(diphenoxylate hydrochloride and atropine sulfate) 1 tablet (2.5 mg) every 6 to 8 hours 
may be added (or equivalent as approved by Sponsor).  
 For Grade 2 diarrhea during the 28 days of neratinib monotherapy following the second 
study colonoscopy procedure in patients with stage 1 to 3c breast cancer treated in the 
extended adjuvant setting, or during Cycle 2 in patients with mBC and beyond (4 to 6 
stools per day above baseline, despite intensive anti-diarrheal therapy), consider adding 
octreotide (short-acting) 150 µg subcutaneous [SC] injection TID, or after initial dose of 


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short-acting octreotide, if well tolerated, a single dose of octreotide LAR 20 mg by 
intramuscular (IM) injection (equivalent medication may be used with approval of the 
Sponsor).  
 After resolution of diarrhea, loperamide prophylaxis can be increased in 2 mg increments 
with the goal of titrating to 1-2 bowel movements a day.  
 Instruct patients to promptly report diarrhea symptoms.  
 Instruct patient to record the number of stools per day and the dose of any anti-diarrheal 
medication taken each day (see Section 8.5).  
For new onset uncomplicated Grade 1 or Grade 2 diarrhea  
Dietetic measures  
 Stop all lactose-containing products.  
 Drink 8 to 10 large glasses of clear liquids per day (~2000 mL).  
 Eat frequent small meals.  
 Recommend low fat regimen enriched with bananas, rice, applesauce and toast until 
resolution of diarrhea.  
Pharmacological treatment  
 Administer loperamide: initial dose of 4 mg (2 tablets/capsules) with the first bout of 
diarrhea followed by 2 mg (1 tablet/capsule) every 4 hours or after every unformed stool 
(maximum 16 mg a day) and continue loperamide at this frequency until diarrhea-free for 
12 hours.  
 At any time during the study, for patients with persistent Grade 1 diarrhea on loperamide, 
Lomotil® (diphenoxylate hydrochloride and atropine sulfate) 1 tablet (2.5 mg) every 6 
hours to 8 hours may be added (or equivalent as approved by the Sponsor).  
 For 28 days of neratinib monotherapy following the second study colonoscopy procedure 
in patients with stage 1 to 3c breast cancer treated in the extended adjuvant setting, or 
during Cycle 2 in patients with mBC and beyond, for Grade 2 diarrhea (4 to 6 stools per 
day above baseline, despite intensive antidiarrheal therapy), consider adding octreotide 
(short-acting) 150 µg subcutaneously (SC) TID; or after initial dose of short-acting 
octreotide, if well tolerated, a single dose of octreotide LAR 20 mg intramuscularly (IM) 
(equivalent medication may be used with approval of the Sponsor).  
For Grade 3 or Grade 4 diarrhea with complicating features (dehydration, fever, and/or 
Grade 3-4 neutropenia  
Dietetic measures (same as above)  
Pharmacologic treatment  
 Administer loperamide: initial dose of 4 mg (2 tablets/capsules) with the first bout of 
diarrhea followed by 2 mg (1 tablet/capsule) every 4 hours or after every unformed stool 
(maximum 16 mg a day) and continue loperamide at this frequency until diarrhea-free for 


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12 hours. Then titrate the amount of loperamide used to keep diarrhea controlled 
(<4 stools/day).  
 Administer octreotide [100-150 µg SC BID or intravenously (IV) (25-50 µg/h) if 
dehydration is severe, with dose escalation up to 500 µg SC TID].  
 Use IV fluids as appropriate.  
 Consider prophylactic antibiotics as needed (eg, fluoroquinolones) especially if diarrhea 
is persistent beyond 24 hours or there is fever or Grade 3-4 neutropenia.  
The Investigator or designee should contact the Sponsor or the Medical Monitor for advice if at 
any time there is a concern for the appropriate course of action for the management of diarrhea.  
Stool cultures should be done to exclude infectious causes of Grade 3 or Grade 4 diarrhea or 
diarrhea of any grade with complicating features (dehydration, fever, and/or Grade 3 or Grade 4 
neutropenia) per the Investigator’s discretion. Results from occult blood, fecal leukocyte stain, 
Clostridium difficile, Campylobacter, Salmonella, and Shigella testing, when performed, should 
be reported using the appropriate CRF.  
Patients with significant diarrhea who are unresponsive to medical treatment may require 
treatment interruption or dose reduction.  
7.3. 
Prohibited Concomitant Treatment  
The following treatments are prohibited throughout the duration of the active (treatment) 
stage/phase of the study:  
 Any concurrent chemotherapy, radiotherapy (including palliative radiotherapy), surgery 
related to cancer, anticancer immunotherapy, or other anticancer treatments, except 
hormonal therapy (eg, tamoxifen, aromatase inhibitors), including other investigational 
agents.  
 Acarbose, aspirin, proton pump inhibitors, NSAIDs, histamine H2-receptor antagonists, 
selective serotonin inhibitors, and ticlopidine (See Section 5.2 Exclusion Criterion 2) are 
excluded in Cycle 1 and until after the completion of the second study colonoscopy 
procedure. 
 Systemic steroid use, by oral or parenteral route, including budesonide in Cycle 1 until 
after the completion of the second study colonoscopy procedure.  
7.4. 
Potential for Drug-Drug Interactions  
Patients should avoid agents known to be strong cytochrome P450 (CYP) 3A4 inducers or 
inhibitors (eg, ketoconazole) for the duration of the active stage/phase of the study. Patients 
should also avoid grapefruit/grapefruit juice and herbal remedies, including St John's Wort. 
Refer to Appendix 4 for a list of inhibitors and inducers of CYP isoenzymes. If unavoidable, 
patients taking such agents should be monitored closely.  
Patients using drugs known to cause QT/QTc prolongation should be monitored closely with 
serial electrocardiograms (ECG) at the Investigator’s discretion. Refer to Appendix 6 for a 


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summary of drugs known to have a risk of causing QT/QTc prolongation, potentially causing 
Torsade’s de Pointes (TdP).  
Patients taking digoxin, a P-glycoprotein (P-gp) substrate with a narrow therapeutic window, 
should be monitored closely. The digoxin dose should be adjusted as needed, since neratinib is 
an inhibitor of P-gp. Co-administration of neratinib with digoxin could result in increased 
digoxin levels and associated digoxin toxicity. Refer to Appendix 5 for a list of substrates and 
inhibitors of P-gp.  
Patients taking oral coumadin-derivative anticoagulants (i.e., warfarin and phenprocoumon) 
should be monitored closely and their anticoagulant dose adjusted as needed.  
The solubility of neratinib is pH dependent and treatments that alter gastrointestinal pH such as 
proton pump inhibitors (PPIs), histamine H2-receptor antagonists, and antacids may lower the 
solubility of neratinib. It has been observed that a single 240-mg dose of neratinib combined with 
lansoprazole may decrease neratinib AUC by up to 70%. It is unknown whether separating PPI 
and neratinib doses reduce the interaction. If an H2-receptor antagonist such as ranitidine is 
required, neratinib should be taken at least 2 hours before the next dose of the H2-receptor 
antagonist and 10 hours after the H2-receptor antagonist dosing. If antacids are necessary, the 
antacid dose and the neratinib dose should be separated by 3 hours.  
7.5. 
Treatment Compliance  
Refer to Section 6.5.  


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8. 
STUDY ASSESSMENTS  
8.1. 
Efficacy Assessment  
There are no study mandated imaging requirements. Clinical care is within the purview of the 
investigator and patient.  
8.2. 
Safety Assessments  
8.2.1. 
Safety Endpoints  
 The primary endpoint is descriptive assessment of colon pathology during the first 
28 days of neratinib therapy.  
 The secondary endpoint is the incidence and severity of diarrhea during the first 28-day 
cycle.  
The incidence of TEAEs and SAEs for Cycle 1 through 28 days of neratinib monotherapy 
following the second study colonoscopy procedure in patients with stage 1 to 3c breast cancer 
treated in the extended adjuvant setting, and in and Cycle 2 in patients with mBC will also be 
reported. AEs and SAEs will be graded according to the National Cancer Institute Common 
Terminology Criteria (NCI CTCAE), version 4.0 or higher.  
After the completion of 28 days following the second study colonoscopy procedure in patients 
with stage 1 to 3c breast cancer treated in the extended adjuvant setting and in Cycle 2 in patients 
with mBC through 28 calendar days after the last administration of neratinib, only SAE data will 
be collected and summarized. SAEs will be followed until resolution or until condition stabilizes. 
Should an Investigator be made aware of any SAEs occurring any time after the reporting period 
that may be causally related to administration of neratinib, it should be promptly reported. All 
SAEs must be reported within 24 hours of awareness of the event using the SAE Report Form. 
More details on AEs can be found in Section 13. 
SAEs will be followed until resolution or until condition stabilizes. Should an Investigator be 
made aware of any SAEs occurring any time after the reporting period that may be causally 
related to administration of neratinib, it should be promptly reported. All SAEs must be reported 
within 24 hours of awareness of the event using the SAE Report Form. More details on AEs can 
be found in Section 13.  
Safety will also be assessed based on medical history, vital sign measurements, physical 
examination findings, and laboratory assessments. Refer to the Schedule of Procedures 
(Appendix 1) for time points.  
The diary used for recording of investigational product intake will also be used by patients to 
document any other study treatment. In case of diarrhea, it also serves to document the number 
of loose stools per day, and use of loperamide/other antidiarrheal treatments taken.  
8.2.2. 
Colonoscopy  
Microscopic colitis (MC) is a relatively common cause of chronic watery diarrhea. The diagnosis 
is based upon characteristic histological findings in the presence of diarrhea. The symptoms of 


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MC are non-specific; therefore, colon biopsies are required to definitively distinguish MC from 
the much more common irritable bowel syndrome.  
To characterize pathology of the colonic mucosa in patients with HER2 positive breast cancer 
treated with neratinib, colonoscopy in this study will be performed prior to the first dose of 
neratinib (Cycle 1 Day 1) and on Day 30 (± 3 days) (Appendix 1).  
During colonoscopy, photographs of the colonic mucosa will be taken along with approximately 
8 biopsies from the terminal ileum, cecum, ascending colon, proximal transverse colon, splenic 
flexure, sigmoid colon, and rectum. If any abnormal appearing colon mucosa is identified 
endoscopically, it will be noted and biopsied in a separate jar. If polyps are identified, they will 
be removed during the examination; if cancer is identified, it will be sampled. Usual, standard 
clinical care will be provided for endoscopic findings unrelated to the study aims. Biopsy 
material will be analyzed in a central laboratory. At the time of colonoscopy, serological 
inflammatory markers (ESR, CRP) will be sampled and stool markers for diarrhea (fecal 
calprotectin, fecal elastase) will be collected. 
Results for appearance, histology, and pathology should be reported using the appropriate CRF.  
Descriptions of photography, biopsy and tissue collection, and histology procedures are provided 
in the Biopsy Collection and Processing Manual.  
8.2.3. 
Laboratory Assessments  
Laboratory testing will be performed in accordance with the Schedule of Procedures 
(Appendix 1).  
The institutional laboratory will analyze all laboratory endpoints from samples collected.  
Screening laboratory results may be accepted as the baseline assessment if they are performed 
within 72 hours of initiation of enrollment. 
The following laboratory endpoints will be determined, as summarized in Table 7. 
Table 7: 
Laboratory Parameters 
Hematology 
Hematocrit (Hct) 
Hemoglobin (Hb) 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count, with differential 
Clinical chemistry 
Albumin  
Alkaline phosphatase  
ALT 
AST 
Blood urea nitrogen 
(BUN) 
Calcium 
Chloride  
Creatinine 
Glucose (non-fasting) 
Lactate dehydrogenase (LDH) 
Magnesium 
Phosphorus 
Potassium  
Sodium  
Total bilirubin 
Serum lipase 
Serum amylase  


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Table 7: 
Laboratory Parameters (Continued) 
Hematology 
Hematocrit (Hct) 
Hemoglobin (Hb) 
Platelet count 
Red blood cell (RBC) count 
White blood cell (WBC) count, with differential 
Serum or urine pregnancy 
test 
In women of child-bearing capacity (at screening and second test within 72 
hours prior to C1D1). 
Coagulation 
International Normalized Ratio (INR) 
Inflammatory markers 
ESR, CRP, fecal calprotein, fecal elastase 
All clinically important abnormal laboratory tests occurring during the study will be repeated at 
appropriate intervals until they return either to baseline or to a nonclinically significant level 
deemed acceptable by the Investigator and the Sponsor Medical Monitor (or his/her designated 
representative), or until a diagnosis that explains them is made.  
Criteria for reporting abnormal laboratory values as AEs are summarized in Section 13.1.2.  
The total volume of blood collected from each patient during the course of the study will be 
dependent upon the number of treatment cycles the patient completes. For patients receiving 
neratinib as monotherapy in the adjuvant setting who complete 1 year of treatment, 
approximately 50 mL of blood, corresponding to approximately 15 mL blood during screening, 
15 mL on Day 1/Cycle 1 and 5 mL blood approximately every 3 months up to 1 year will be 
sampled. For patients with mBC, 15 mL of blood will be sampled at screening and on Day 1 of 
each treatment 21-day treatment cycle. 
8.2.4. 
Vital Signs  
The following vital signs will be assessed in accordance with the Schedule of Procedures 
(Appendix 1): 
 Blood pressure (systolic and diastolic; mmHg)  
 Resting heart rate (beats per minute)  
 Body temperature (°C), [oral]  
 Respiration rate  
 Weight (kg)  
 Height (screening only)  
Vital signs will be measured after resting in a seated position for 5 minutes, prior to dosing.  
8.2.5. 
Physical Examination  
Physical examinations will be performed in accordance with the Schedule of Procedures 
(Appendix 1).  


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8.2.6. 
Electrocardiogram  
Single standard 12-lead digital ECGs will be performed in accordance with the Schedule of 
Procedures (Appendix 1).  
The ECG (measured after resting in a supine position for 5 minutes) will include heart rate, 
rhythm and RR, PR, QRS, and QTc intervals. The ECG will be read and interpreted at the 
investigational site for patient safety monitoring, and documentation stored with the source 
documents.  
8.2.7. 
Left Ventricular Ejection Fraction (LVEF)  
MUGA scan or ECHO scans to determine LVEF will be performed in accordance with the 
Schedule of Procedures (Appendix 1). It is strongly recommended to use the same method of 
measurement for the same patient throughout the duration of the study.  
8.3. 
Other Study Assessments  
8.3.1. 
Health Outcomes Assessments  
None.  
8.3.2. 
Disease Recurrence or Progression 
Clinical documentation of recurrence or progression, including date and site of recurrence or 
progression, will be collected at the EOT visit.  
8.4. 
Protocol Deviations 
Protocol deviations should be reported to the Sponsor (or designee) as they occur or are 
discovered and should be captured in CRFs at the time of monitoring and medical review of data 
line listings. 
8.5. 
Study Drug Accountability/Patient Diary  
8.5.1. 
Study Medication Accountability  
The study site must maintain accurate records documenting dates and quantities of medicinal 
product received from the Sponsor. On a per patient basis, records must be maintained 
documenting dates and quantities of medicinal product dispensed and returned at each study 
visit. Any medicinal product accidentally or deliberately destroyed must be documented. 
Throughout the study, reconciliation will be made between the amount of medicinal product 
supplied, dispensed, returned, and subsequently destroyed or returned to Sponsor. All medicinal 
products will be returned to Sponsor or its representative, or destroyed at the site in accordance 
with local standard operating procedures (SOPs), as specified in writing by the Sponsor.  
8.5.2. 
Patient Diary  
A paper patient diary will be provided by the Investigator for the patient to record daily study 
medication intake for the first cycle. The number of stools per day and the use of antidiarrheal 
treatment will be recorded in the patient diary during the first 28-day treatment cycle.  


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9. 
STUDY CONDUCT  
A Schedule of Procedures is provided in Appendix 1.  
In addition to the procedures listed below, unscheduled clinic visits and procedures should be 
performed at the Investigator’s discretion to assess symptoms and concerns newly reported by 
the patient to rule out or confirm potential recurrence, or for the purpose of assessing the 
patient’s safety.  
9.1. 
Screening/Baseline  
Screening activities are to be conducted within 28 days prior to Cycle 1/Day 1, except for serum 
or urine pregnancy test for women of child-bearing potential (see Inclusion Criterion 7 in 
Section 5.1), which should be performed, both, at screening and repeated within 72 hours prior to 
Cycle 1/Day 1.  
Documentation of locally assessed ERBB2-amplified status by fluorescence in situ hybridization 
(FISH) (>2.2) or ERBB2 overexpression by immunohistochemistry (IHC) (3+) by a validated 
approved method (Wolff et al, 2013) must be confirmed.  
The following information/assessments will be collected/recorded at Screening:  
 Medical history:  
 Presence of chronic conditions and/or medical history of significance (include review 
of history of cardiac, pulmonary, and gastrointestinal disease) including relevant 
surgical procedures.  
 Assessment of bowel movements experienced during the previous 28 days as well as 
those ongoing at the time of screening 
 Cancer history, including but not limited to, date of first diagnosis, histology, tumor 
stage, and previous chemotherapy/biotherapy/immunotherapy exposure.  
 Other previous and concomitant medication will be documented, as described in 
Section 7.  
 Demography: sex, ethnicity, and race (Asian, Black or African American, White, Other).  
 Physical examination; refer to Section 8.2.5.  
 Vital signs, including height and weight; refer to Section 8.2.4.  
 ECG; refer to Section 8.2.6.  
 LVEF; refer to Section 8.2.7.  
 Laboratory tests; refer to Section 8.2.3.  
 Colonoscopy; refer to Section 8.2.2.  
 ECOG status will be assessed in accordance with the Schedule of Procedures 
(Appendix 1). The ECOG categories are summarized in 0.  


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The Cycle 1/Day 1 physical examination and blood sample may be omitted if the screening 
values were obtained within 72 hours prior to initiation of treatment.  
9.2. 
Active Treatment Phase  
Neratinib will be self-administered by patients daily during each 28-day cycle.  
The following will be performed in accordance with the Schedule of Procedures (Appendix 1):  
 Serum or urine pregnancy testing; refer to Inclusion Criterion 7 in Section 5.1 and 
Section 8.2.3.  
 Brief, symptom-guided physical examination; refer to Section 8.2.5.  
 Vital signs, including height and weight; refer to Section 8.2.4.  
 Laboratory tests; refer to Section 8.2.3.  
 Concomitant medication assessment. Refer to Section 7.  
 AE assessment. Refer to Section 13.  
 Colonoscopy; refer to Section 8.2.2.  
 Treatment compliance assessment; refer to Section 6.5.  
 Collect Patient Diary at C2D1 visit.  
9.3. 
Treatment Discontinuation or End-of-Treatment Assessments  
The EOT visit will occur within 5 business days of the last dose of neratinib monotherapy in 
patients with Stage 1 to 3c disease receiving extended adjuvant therapy and within 0-3 days after 
the last dose neratinib in patients with mBC. When a patient discontinues study treatment for 
reasons of toxicity, disease progression, or other reasons, an EOT visit will occur within 
5 business days of last dose of neratinib.  
The following will be performed in accordance with the Schedule of Procedures (Appendix 1):  
 AE assessment; refer to Section 13.  
 Physical examination; refer to Section 8.2.5.  
 Vital signs, including weight. Refer to Section 8.2.4.  
 Disease recurrence as applicable. Refer to Section 8.3.2. 
9.4. 
Safety Follow-up Visit 
Patients who complete the active treatment phase or who discontinue due to unacceptable 
toxicity will be followed-up for 28 days after the last dose of neratinib to collect SAEs.  
9.5. 
Long-term Follow-up  
Not applicable for this study.  


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9.6. 
End of Study  
The study will end when all patients have been followed-up for 28 days after the last dose of 
neratinib. The end of study (EOS) is defined as the last safety follow-up visit of the last patient 
or the completion of any/all follow-up monitoring and data collection described in the protocol.  
In the event that EOS is declared earlier other than safety, patients with stage 1 to 3c disease will 
be offered the opportunity to complete the 1-year course of treatment while patients with mBC 
will be offered the opportunity to complete therapy until disease progression or unacceptable 
toxicity.  


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10. 
PATIENT WITHDRAWAL AND REPLACEMENT  
10.1. 
Investigational Product Discontinuation  
Patients must be discontinued from investigational product under the following circumstances 
listed below and in Appendix 2, unless otherwise agreed with the Medical Monitor:  
 If the patient requires more than 2 dose reductions of neratinib (see Appendix 2) 
 If neratinib is withheld due to an SAEs for >28 days. Patients who are clinically 
benefiting from therapy with neratinib may be resumed on therapy after 28 days if 
approved in advance by the Sponsor  
 Disease recurrence  
 Initiation of alternative anti-cancer therapy. Any concurrent chemotherapy, radiotherapy 
(including palliative radiotherapy), surgery related to cancer, anticancer immunotherapy, 
or other anticancer treatments including other investigational agents (see Section 7.3).  
 Pregnancy (see Section 13.4)  
 Investigator request  
 Patient request (i.e., withdrawal of consent for treatment)  
 AEs/toxicity  
Withdrawal due to AE should be distinguished from withdrawal due to other causes, and 
recorded on the appropriate AE page of CRF. If a patient withdraws due to toxicity, even if 
discontinuation is not otherwise required per protocol guidelines, the withdrawal should be 
classified as withdrawal due to AE.  
10.2. 
Withdrawal from the Study  
Patients may withdraw from the entire study including follow up at any time without penalty and 
for any reason without prejudice to his or her future medical care.  
Patients may be required to withdraw from the study after discussion with the Sponsor and/or 
Investigator (whenever possible) for the following reasons:  
 At the discretion of the Investigator  
 At patient’s request (withdrawal of consent for the study) (see Section 10.3)  
 Lost to follow-up (defined as after three attempts at contact by phone followed by one 
attempt by sending a certified letter)  
 If the entire study is terminated prematurely as described in Section 11 
 Inability to complete a second study colonoscopy procedure 
A patient may also be withdrawn from investigational product/study by the Sponsor, Regulatory 
Authorities, or IRBs/IECs.  


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10.3. 
Procedures for Investigational Product Discontinuation/Study 
Withdrawal  
When a patient is withdrawn from the study, the Investigator will notify the Sponsor. In all cases, 
the reason(s) for premature discontinuation/withdrawal, and the primary reason, must be 
recorded on the CRF. If a patient is prematurely withdrawn from the investigational product or 
the study for any reason, the Investigator must make every effort to perform the evaluations 
described for the EOT visit (performed within 5 days of the last dose of investigational product 
as appropriate). If a patient discontinues due to an AE, he/she should be strongly encouraged to 
undergo the EOT assessments and continue to be under medical supervision until symptoms 
cease or the condition becomes stable.  
If a patient is lost to follow-up, or voluntarily withdraws from study participation, every effort 
should be made to determine why a patient is lost to follow-up or withdraws consent. This 
information, including the date, should also be recorded on the patient's conclusion of patient 
participation CRF.  
All patients will remain on active study treatment until a cause of early treatment discontinuation 
occurs; these include disease progression, unacceptable toxicity, and withdrawal of consent 
(Section 10), or until study closure.  
10.4. 
Patient Replacement  
Patients who do not complete 2 consecutive colonoscopies with successful biopsy collection will 
be replaced.  


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11. 
PREMATURE TERMINATION OF STUDY 
The Sponsor may suspend or terminate the study or part of the study at any time for any reason. 
Investigational product will be available to patients to complete treatment as described in 
Section 4.2. 
If the Investigator suspends or terminates the study, the Investigator will promptly inform the 
Sponsor and the IRB/IEC and provide them with a detailed written explanation. The Investigator 
will also return all investigational products, investigational product containers, and other study 
materials to the Sponsor or have them destroyed locally according to Sponsor guidelines. Upon 
study completion, the Investigator will provide the Sponsor, IRB/IEC, and regulatory agency 
with final reports and summaries as required by regulations. For investigational new drug 
application studies, the Investigator must submit a written report to the Sponsor and the IRB/IEC 
within 3 months after the completion or termination of the study.  


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12. 
STATISTICAL METHODS  
The statistical considerations summarized in this section outline the plan for data analysis of this 
study.  
12.1. 
Study Patients  
Descriptive statistics will be used to characterize the patient cohort. Demographic data, medical 
history, concomitant disease, and concomitant medication will be summarized by means of 
descriptive statistics for continuous variables (n, mean, standard deviation, median, minimum 
and maximum) and frequency tables for categorical variables.  
Duration of treatment will be summarized. The number of patients with dose holds, dose 
reductions, a summary of diarrhea and other GI events will be tabulated. Treatment 
discontinuation and the reasons for discontinuation will be summarized.  
12.2. 
Efficacy Analyses  
Not applicable for this study.  
12.3. 
Safety Analyses  
All patients who receive a dose of neratinib will be analyzed for safety. The incidence of TEAEs 
and SAEs for Cycle 1 through 28 days of neratinib monotherapy following the second study 
colonoscopy procedure in patients with stage 1 to 3c breast cancer treated in the extended 
adjuvant setting, and following the completion of Cycle 2 in patients with mBC will be 
summarized after all biopsies have been completed.  Following 28 days of neratinib 
monotherapy after the completion of the second study colonoscopy procedure in patients with 
stage 1 to 3c breast cancer treated in the extended adjuvant setting, and Cycle 2 in patients with 
mBC through 28 calendar days after the last administration of neratinib, only SAE data will be 
collected and summarized. 
AEs will be coded using the Medical Dictionary for Regulatory Activities MedDRA coding 
system and all AEs will be graded by the Investigator according to the NCI-CTCAE version 4.0.  
Incidence of AEs will be summarized by system organ class (SOC) and preferred term (PT), and 
will be summarized by grade. A patient who experiences the same AE more than once within a 
SOC or preferred term category will be counted only once, using the worst toxicity grade for that 
event. SAEs will be summarized.  
Serious AE and deaths will be provided in a listing. All AEs resulting in discontinuation of 
neratinib in Cycle 1 through 28 days of neratinib monotherapy following the second study 
colonoscopy procedure in patients with stage 1 to 3c breast cancer treated in the extended 
adjuvant setting, and following the completion of Cycle 2 in patients with mBC, dose 
modification, dosing interruption, and/or treatment delay of investigational product will also be 
listed and tabulated by PT.  
Laboratory test results will be collected at screening and on Day 1/Cycle 1 and Cycle 2. 
On-study laboratory test abnormalities reported during screening, Cycle 1 and Cycle 2 will be 
summarized. In subsequent visits only liver function tests will be collected.  


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12.3.1. 
Primary Endpoint 
The primary endpoint is change from baseline in pathological findings in colon biopsies after the 
first 28 days of neratinib monotherapy. The primary analysis of pathology findings will be 
conducted after all patients have completed 2 colonoscopies with associated biopsies.  
12.3.2. 
Secondary Endpoints 
The secondary endpoints are the incidence and severity of diarrhea summarized according to the 
NCI-CTCAE version 4.0 in the first 28-day cycle of neratinib treatment and change from 
baseline at the time of the first colonoscopy (prior to initiation of therapy with neratinib) to the 
second study colonoscopy procedure in serological and fecal inflammatory markers. The primary 
analysis of the incidence and severity of diarrhea and inflammatory markers will be conducted 
after all patients have completed 2 colonoscopies and all samples have been collected and 
analyzed. 
12.4. 
Final Analysis  
The final analysis will be conducted when all patients with stage 1 to 3c disease have completed 
1 year of study treatment or have met other specified withdrawal criteria and patients with mBC 
have completed study treatment, discontinued treatment or met other specified withdrawal 
criterion. 
12.5. 
Determination of Sample Size 
Based on feasibility, 3-5 patients are to be enrolled in this study.  


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13. 
SAFETY DATA COLLECTION, RECORDING, AND 
REPORTING  
All observed or volunteered AEs regardless of treatment group or causal relationship to 
investigational product will be recorded on the AE page(s) of the CRF.  
13.1. 
Definitions  
13.1.1. 
Adverse Events  
An AE is any untoward medical occurrence in a patient or clinical investigation patient 
administered a pharmaceutical product, and which does not necessarily have a causal 
relationship with the treatment. An AE can therefore be any unfavorable and unintended sign 
(including abnormal laboratory finding), symptom, or disease temporally associated with the use 
of an investigational product, whether or not considered related to the medicinal product 
(definition per International Conference on Harmonisation [ICH] E2A and E6 R1).  
All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, must be 
recorded using medical terminology on the AE CRF page. Whenever possible, diagnoses should 
be given when signs and symptoms are due to a common etiology (eg, cough, runny nose, 
sneezing, sore throat, and head congestion should be reported as “upper respiratory infection”). 
All measures required for AE management must be recorded in the source document and 
reported according to Sponsor instructions.  
For all AEs, the Investigator must pursue and obtain information adequate to both determine the 
outcome of the AE and to assess whether it meets the criteria for classification as a SAE 
(see Section 13.3 on SAEs) requiring immediate notification to the Sponsor or its designated 
representative. For all AEs, sufficient information should be obtained by the Investigator to 
determine the causality of the AE.  
Interventions for pretreatment conditions (eg, elective cosmetic surgery) or medical procedures 
that were planned before study enrollment are not considered AE.  
13.1.2. 
Abnormal Laboratory Results  
The criteria for determining whether an abnormal laboratory test result should be reported as an 
AE are as follows:  
 Test result is associated with accompanying symptoms, and/or,  
 Test result requires additional diagnostic testing or medical/surgical intervention (merely 
repeating an abnormal test, in the absence of any of the above conditions, does not meet 
criteria for reporting an AE), and/or  
 Test result leads to a change in study dosing or discontinuation from the study, significant 
additional concomitant drug treatment or other therapy, and/or  
 Test result leads to any of the outcomes included in the definition of a SAE, and/or  
 Test result is considered to be an AE by the Investigator or by the Sponsor  


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Any abnormal test result that is determined to be an error does not require reporting as an AE, 
even if it did meet one of the above criteria except for when the test result leads to any of the 
outcomes included in the definition of a SAE. Clinically significant laboratory results must be 
recorded in the patient’s CRF.  
13.1.3. 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose (ICH E2A and E6 R2): 
 Results in death  
 Is life-threatening  
This means that the patient is at risk of death at the time of the event; it does not mean 
that the event hypothetically might have caused death if it were more severe. 
 Requires inpatient hospitalization or prolongation of existing hospitalization  
 Results in persistent or significant disability or incapacity  
 Is a congenital anomaly or birth defect 
Medical and scientific judgment should be exercised in deciding whether expedited reporting is 
appropriate in other situations, such as important medical event(s) that may not be immediately 
life-threatening or result in death or hospitalization but that may jeopardize the patient or require 
intervention to prevent one of the other outcomes listed in the definition above. These should 
also usually be considered serious. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization; or development of drug dependency or drug abuse.  
Disease progression should not be recorded as an AE or SAE term; instead, signs and symptoms 
of clinical sequelae resulting from disease progression will be reported if they fulfill the SAE 
definition.  
13.1.4. 
Hospitalization  
Any inpatient hospital admission that includes a minimum of an overnight stay to a healthcare 
facility meets the criteria for ‘hospitalization’. Admission also includes transfer within the 
hospital to an acute/intensive care unit (eg, from the psychiatric wing to a medical floor, medical 
floor to a coronary care unit, neurological floor to a tuberculosis unit).  
The following are not considered to be hospitalization:  
 Rehabilitation facilities  
 Hospice facilities  
 Respite care (eg, caregiver relief)  
 Skilled nursing facilities  
 Nursing homes  
 Routine emergency room admissions  
 Same day surgeries (as outpatient /same day/ambulatory procedures)  


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Hospitalization or prolongation of hospitalization in the absence of a precipitating, clinical AE is 
not in itself a SAE. Examples include:  
 Admission for treatment of a preexisting condition not associated with the development 
of a new AE or with a worsening of the preexisting condition (eg, for work-up of 
persistent pre-treatment lab abnormality)   
 Social admission (eg, patient has no place to sleep)  
 Administrative admission (eg, for yearly physical examination)  
 Protocol-specified admission during a study (eg, for a procedure required by the study 
protocol)  
 Optional admission not associated with a precipitating clinical AE (eg, for elective 
cosmetic surgery)  
 Hospitalization for observation without a medical AE  
 Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation and/or for the individual patient  
 Admission exclusively for the administration of blood products  
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as the AE, and the resulting appendectomy 
should be recorded as treatment of the AE.  
13.1.5. 
Suspected Unexpected Serious Adverse Reaction  
Suspected unexpected serious adverse reactions (SUSAR) are events which are serious as per the 
above criteria, the nature or severity of which is not consistent with the applicable product 
information (eg, IB) and are judged by the Investigator or by the Sponsor to be related to 
investigational product. For a non-Sponsored investigational product (eg, a comparator product) 
with a marketing authorization, the expectedness of an AE will be determined by whether or not 
it is listed in the package insert/SmPC.  
13.1.6. 
Severity Assessment  
Adverse events will be graded by the Investigator according to the NCI CTCAE v.4.0 (Publish 
Date: May 28, 2009, http://ctep.cancer.gov/reporting/ctc.html), according to the following 
general categories:  
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental activities of daily living.  


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Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting 
self-care activities of daily living. 
Grade 4: 
Life-threatening consequences; urgent intervention indicated.  
Grade 5: 
Death related to AE. 
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily a serious adverse event. For example, a headache may be severe (interferes 
significantly with patient's usual function) but would not be classified as serious unless it meets 
one of the criteria for SAEs, listed above.  
13.1.7. 
Causality Assessment  
The Investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the Investigator must record the causal relationship in the CRF and report such an 
assessment in accordance with the serious adverse reporting requirements, if applicable. 
A suspected adverse reaction means any AE for which there is a reasonable possibility that the 
investigational product caused the AE. An Investigator’s causality assessment is the 
determination of whether there exists a reasonable possibility that the investigational product 
caused or contributed to an AE; generally the facts (evidence) or arguments to suggest a causal 
relationship should be provided. If the Investigator does not know whether or not the 
investigational product caused the event, then the event will be handled as “related to 
investigational product” for reporting purposes, as defined by the Sponsor (see Section 13.2). If 
the Investigator's causality assessment is “unknown but not related to investigational product”, 
this should be clearly documented on study records.  
For all AEs, sufficient information should be obtained by the Investigator to determine the 
causality of the AE (eg, investigational product or other illness). The relationship of the AE to 
the study treatment (investigational product, comparator or placebo [as applicable]) will be 
assessed following the definitions below:  
 ‘No’ (unrelated): Any event that does not follow a reasonable temporal sequence from 
administration of investigational product AND is likely to have been produced by the 
patient’s clinical state or other modes of therapy administered to the patient.  
 ‘Yes’ (related): Any reaction that follows a reasonable temporal sequence from 
administration of investigational product AND follows a known response pattern to the 
suspected investigational product AND recurs with re-challenge, AND/OR is improved 
by stopping the investigational product or reducing the dose.  
In addition, if the Investigator determines an AE is associated with study procedures, the 
Investigator must record this causal relationship on the AE CRF page and report such an 
assessment in accordance with the SAE reporting requirements, if applicable.  


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13.1.8. 
Special Reporting Situations  
Safety events of interest on the Sponsor’s investigational product that may require expedited 
reporting and/or safety evaluation include, but are not limited to:  
 Overdose of an investigational product  
 Suspected abuse/misuse of an investigational product  
 Inadvertent or accidental exposure to an investigational product  
 Medication error that may result from the administration or consumption of the wrong 
drug, by the wrong patient, at the wrong time, or at the wrong dosage strength  
 Suspected transmission via an investigational product of an infectious agent  
Special reporting situations should be recorded on the AE CRF page. Any special reporting 
situation that meets the criteria of a SAE should be recorded on the SAE form and reported as 
required (see Section 13.3).  
13.2. 
Reporting Adverse Events  
For serious and non-serious AEs, the reporting period to the Sponsor (or its designated 
representative) begins from the time that the patient provides informed consent, which is 
obtained prior to the patient’s participation in the study, i.e., prior to undergoing any 
study-related procedure and/or receiving investigational product, through 28 calendar days after 
the last administration of the investigational product.  
For all AEs with causal relationship to the investigational product, follow-up by the Investigator 
may be required until the event or its sequelae resolve or stabilize at the level acceptable to the 
Investigator, and the Sponsor concurs with that assessment.  
If a patient begins a new anticancer therapy, the AE reporting period for non-serious AEs ends at 
the time the new treatment is started. Death must be reported if it occurs during the SAE 
reporting period after the last dose of investigational product, irrespective of any intervening 
treatment.  
The Sponsor will evaluate any safety information that is spontaneously reported by an 
Investigator beyond the time frame specified in the protocol.  
13.3. 
Reporting Serious Adverse Events  
All SAEs, irrespective of relationship to investigational product, must be reported within 
24 hours of discovery or notification of the event to the Sponsor or designated representative 
using the SAE form. The SAE form must be signed by the Investigator. In particular, if the SAE 
is fatal or life-threatening, notification to the Sponsor must be made immediately, irrespective of 
the extent of available AE information. This timeframe also applies to follow-up information on 
previously forwarded SAE reports as well as to the initial and follow-up reporting of exposure 
during pregnancy and exposure via breast feeding cases. For SAE reporting information, please 
refer to the Study Contact List which is provided as a separate document.  
Relevant medical records should be provided to the Sponsor or its designated representative as 
soon as they become available; autopsy reports should be provided for deaths if available.  


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Should an Investigator be made aware of any SAEs occurring any time after the reporting period 
that may be causally related to neratinib administration, it should be promptly reported.  
All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the patient's participation in the study, must be followed until any of the 
following occurs:  
 The event resolves  
 The event stabilizes  
 The event returns to baseline, if a baseline value/status is available  
 The event can be attributed to agents other than the investigational product or to factors 
unrelated to study conduct  
 It becomes unlikely that any additional information can be obtained (patient or health 
care practitioner refusal to provide additional information, lost to follow-up after 
demonstration of due diligence with follow-up efforts)  
13.4. 
Pregnancy  
All initial reports of pregnancy must be reported to the Sponsor by the investigational staff 
within 24 hours of their knowledge of the event using the appropriate Exposure In Utero (EIU) 
form.  
For investigational products and for marketed products used as investigational product in 
neratinib studies, an exposure during pregnancy occurs if:  
 A female becomes, or is found to be, pregnant either while receiving or having been 
directly exposed (eg, environmental exposure) to the investigational product, or the 
female becomes or is found to be, pregnant after discontinuing and/or being directly 
exposed to the investigational product (maternal exposure) for 28 days after last dose of 
or exposure to neratinib.  
 A male partner of a pregnant female has been exposed to the investigational product, 
either due to treatment or environmental exposure, within 3 months prior to the time of 
conception and/or is exposed during his partner’s pregnancy (paternal exposure).  
If any study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product or exposure as defined above, the 
Investigator must submit this information on an EIU form to the Sponsor (or its designated 
representative). In addition, the Investigator must submit information regarding environmental 
exposure to an investigational product in a pregnant woman (eg, a patient reports that she is 
pregnant and has been exposed to a cytotoxic product by inhalation or spillage) using the EIU 
form. This must be done irrespective of whether an AE has occurred and within 24 hours of 
awareness of the pregnancy. The information submitted should include the anticipated date of 
delivery (see following information related to induce termination of pregnancy).  
Follow-up is conducted to obtain pregnancy outcome information on all exposure during 
pregnancy reports with an unknown outcome. The Investigator will follow the pregnancy until 
completion or until pregnancy termination (eg, induced abortion) and then notify the Sponsor or 


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its designated representative of the outcome as a follow-up to the initial EIU form. In the case of 
a live birth, the structural integrity of the neonate can be assessed at the time of birth. In the 
event of a termination, the reason(s) for termination should be specified and, if clinically 
possible, the structural integrity of the terminated fetus should be assessed by gross visual 
inspection (unless pre-procedure test findings are conclusive for a congenital anomaly and the 
findings are reported).  
If the outcome of the pregnancy meets the criteria for immediate classification as an SAE (eg, 
ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or congenital 
anomaly [including that in a live born, a terminated fetus, an intrauterine fetal demise, or a 
neonatal death]), the Investigator should follow the procedures for reporting SAEs.  
Additional information about pregnancy outcomes that are classified as SAEs follows:  
 “Spontaneous abortion” includes miscarriage and missed abortion  
 All neonatal deaths that occur within 1 month of birth should be reported, without regard 
to causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs 
when the Investigator assesses the infant’s death as related to exposure to investigational 
product.  
Additional information regarding the exposure during pregnancy may be requested by the 
Investigator. Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required.  
13.5. 
Sponsor Reporting Requirements to Health Authorities and 
IRB/IEC  
The Sponsor assumes responsibility for reporting of AEs including SUSARs according to local 
and international regulations, as appropriate. The Investigator (or the Sponsor where required) 
must report these events to the appropriate IRB/IEC that approved the protocol unless otherwise 
required and documented by the IRB/IEC.  


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14. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS  
The Sponsor of this study may delegate some administrative aspects of this study to a duly 
authorized representative including, but not limited to, study initiation, monitoring, and 
management of SAE reports.  
14.1. 
Data Collection, Processing, and Monitoring  
14.1.1. 
Case Report Forms and Source Documentation  
All data captured for the study is planned to be electronic using the Electronic Data Capture 
system. 
eCRFs will be provided by the Sponsor or its representative and should be handled in accordance 
with the instructions provided by the Sponsor or designated representative.  
The Investigator is responsible for maintaining adequate and accurate eCRFs which have been 
designed to record all observations and other data pertinent to the clinical investigation. Visit 
data should be entered into the eCRFs within 5 business days. Each eCRF should be completed 
by the Investigator or delegate as stated in the Site Delegation List.  
The site will perform data entry of all eCRFs as per source documents. Completion Instructions 
for eCRFs will be provided for the Study Coordinator’s use. Once the site monitor has verified 
the contents of the completed eCRF pages against the source data, queries may be raised if the 
data are unclear or contradictory. These queries must be addressed by the Investigator and 
verified by the clinical research associate (CRA). After all the data issues are resolved, these 
eCRFs may be locked to prevent any further data changes. At the end of the study or prior to the 
site closeout visit, the Investigator will review and approve the data for completeness and 
accuracy. 
14.1.2. 
Study Monitoring and Access to Source Documentation 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of the US Food and Drug Administration (FDA), 
the European Medicines Agency (EMA), other national authorities (eg, the United Kingdom 
Medicines and Healthcare products Regulatory Agency, the German Federal Institute for Drugs 
and Medical Devices, and local health authorities as applicable, the Sponsor and representatives, 
and the IRB/IEC for each study site. The Investigator will permit authorized representatives of 
the Sponsor, the respective national or local health authorities, and auditors to inspect facilities 
and records relevant to this study.  
The Sponsor or representative’s monitor is responsible for verifying the CRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy, and 
consistency of the data; and adherence to local regulations on the conduct of clinical research. 
Source data to be reviewed during this study will include, but is not restricted to: patient’s 
medical file, patient’s diary cards (if applicable), and original laboratory test, histology, and 
pathology reports. All key data must be recorded in the patient’s hospital notes.  
Auditors, IRB/IEC and/or regulatory inspectors will also have access to the CRFs and source 
documents. The ICF will include a statement by which the patient allows the 


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monitor/auditor/inspector from the IRB/IEC or regulatory authority access to source data (eg, 
patient’s medical file, appointment books, original laboratory test reports, X-rays, etc.) that 
substantiate information in the CRFs. These personnel, bound by professional secrecy, will not 
disclose any personal information or personal drug information.  
14.1.3. 
Data Quality Assurance  
During and/or after completion of the study, quality assurance auditor(s) named by the Sponsor 
or the regulatory authorities may wish to perform on-site audits. The Investigators will be 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested.  
The Sponsor’s representatives are responsible for contacting and visiting the Investigator for the 
purpose of inspecting the facilities and, upon request, inspecting the various records of the 
clinical study (eg, CRFs and other pertinent data) provided that patient confidentiality is 
respected.  
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved.  
In accordance with ICH E6 Good Clinical Practice (GCP) and the Sponsor’s audit plans, this 
study may be selected for audit by representatives from the Sponsor’s (or designee’s) Quality 
Assurance Department. Inspection of site facilities (eg, pharmacy, drug storage areas, 
laboratories) and review of study-related records will occur to evaluate the study conduct and 
compliance with the protocol, ICH GCP (ICH E6), US Investigational Drugs (21 CFR§50, §54, 
§56, and §312), EU Clinical Studies Directive (Directive 2001/20/EC), and applicable regional 
regulatory requirements.  
14.1.4. 
Data Processing  
All data will be entered by site personnel into the electronic data capture system/CRF (as 
detailed in Section 14.1.1).  
The data-review and data-handling document will include specifications for consistency and 
plausibility checks on data and will also include data-handling rules for obvious data errors.  
The data management plan will include specifications for data review and data consistency. 
Outstanding query reports will be sent to the study monitors for resolution by site personnel. 
Previous and concomitant medications will be coded using the World Health Organization Drug 
Reference List, which employs the Anatomical Therapeutic Chemical (ATC) classification 
system. Medical history and AEs will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA) terminology. The versions of the coding dictionaries will be provided in 
the Clinical Study Report (CSR).  
14.1.5. 
Retention of Data and Study Records 
As described in the ICH GCP Guidelines, ‘essential documents’, including CRFs, source 
documents, ICFs, laboratory test results, and drug inventory records, should be retained by the 
Investigator until at least 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH region or 


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at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period; however, if 
required by the applicable regulatory requirements or by agreement with the Sponsor. The 
Investigator should obtain written permission from the Sponsor prior to the destruction of any 
study document.  
These records should be made available at reasonable times for inspection and duplication, if 
required, by a properly authorized representative of the US FDA in accordance with 
21 CFR §312.68 or other National Regulatory Authorities.  
14.2. 
Ethical Aspects  
14.2.1. 
Good Clinical Practice and Ethical Conduct of the Study  
This protocol accords with the principles of the World Medical Association Declaration of 
Helsinki as set forth at the 18th General Assembly (World Medical Association Declaration of 
Helsinki, Helsinki, Finland, 1964) and amendments thereto. The most current amended version 
will be in effect.  
The procedures set out in this study protocol are also designed to ensure that the Sponsor and 
Investigator abide by the principles of the GCP guidelines of the ICH, the Directives of the 
European Union, and in keeping with local legal requirements.  
The study will not commence without the prior written approval of a properly constituted 
IRB/IEC. No changes will be made to the study protocol without the prior written approval of 
the Sponsor and the IRB or IEC, except where necessary to eliminate an immediate hazard to the 
patients. 
14.2.2. 
Informed Consent Responsibilities  
It is the responsibility of the Investigator to obtain written informed consent from the patient or 
patient’s legal representative. If informed consent has not been obtained, then no protocol 
required procedures are to be performed on the patient and no patient data are to be transferred to 
the Sponsor. Documentation of informed consent must be recorded in the source documents for 
each patient.  
The study will be discussed with the patient, and the patient will receive written information and 
an explanation of what the study involves, i.e., the objectives, potential benefits and risk, 
inconveniences and the patient’s rights and responsibilities. If applicable, the information will be 
provided in a certified translation of the local language.  
A signed, IRB/IEC approved ICF must be obtained from patient before any study specific 
procedures can occur. Confirmation of the patient’s informed consent and the informed consent 
process must also be documented in the patient’s medical record. Signed ICFs must remain in 
each patient’s study file and must be available for verification by study monitors at any time. A 
copy of the fully signed ICFs will be given to the patient.  
If the IRB/IEC requires modification of this form, the documentation supporting this requirement 
must be provided to the Sponsor, along with the new version. The Sponsor reserves the right to 
reject these modifications, should they not cover the minimum information required by ICH 
GCP. 


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A patient wishing to participate must also provide Authorization for Use and Release of Health 
and Research Study Information prior to any study-related procedures or change in treatment. 
If a patient is not physically or mentally competent to understand and to give their informed 
consent to participate in the study (eg, is blind or illiterate), a legally acceptable representative or 
impartial witness as applicable, may sign the ICF on behalf of the patient. It remains the 
responsibility of the principal Investigator to assure that the patient is suitable for inclusion in 
this study and will be able to adhere to all study procedures throughout the course of the study. 
The explicit wish of a minor, or mentally incapacitated adult, who is capable of forming an 
opinion and assessing the study information, to refuse participation in or to be withdrawn from 
the study at any time will be respected by the Investigator. 
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to the 
protocol. If the consent form is revised, it must be reviewed and approved by the appropriate 
IRB/IEC, and signed by all patients subsequently enrolled in the study as well as those currently 
enrolled in the study.  
14.2.3. 
Confidentiality of Data  
Any personal data of the sponsor, principal investigator, site, subject and / or any other 
individual collected and/or used in connection with the clinical trial, especially including  the 
informed consent forms, will comply with the General Data Protection Regulation (EU) 
2016/679 and other applicable data privacy laws and regulations with regard to the processing 
and transfer of such personal data. 
All data used in the study will be anonymized and analysis will be performed on a deidentified 
patient-level dataset. The data system will be maintained and secured as requested by the local 
patient privacy regulations of each country participating in the study. Processes assuring data 
security will be employed during data extraction, storage and back-up. The data and all study 
documents will be kept until written notification that records may be destroyed. 
Computer files will be password protected on computers which are stored in offices locked and 
accessible to study staff.  Only the members of the study staff will have access to the passwords.  
All parties will ensure protection of subject’s personal data and will not include subject names 
on any Sponsor forms, reports, publications, or in any other disclosures, except where required 
by laws. All local privacy laws will be followed to ensure confidentiality of data is maintained. 
14.3. 
Other Study Administrative Aspects  
14.3.1. 
Protocol Approval and Protocol Amendment  
The protocol (approved by the Sponsor or its representative) will be submitted to the IRB/IEC 
for review and it must be approved before the study is initiated. Prior to implementing changes in 
the study, the Sponsor will produce a protocol amendment and the IRB/IEC must also approve 
any amendments to the protocol.  
Any change in the study plan requires a protocol amendment. An Investigator must not make any 
changes to the study without IRB/IEC and Sponsor approval except when necessary to eliminate 
apparent immediate hazards to the patients. A protocol change intended to eliminate an apparent 
immediate hazard to patients may be implemented immediately, but the change must then be 


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documented in an amendment, reported to the IRB/IEC within 5 working days, and submitted to 
the appropriate regulatory agency in the required time frame. All protocol amendments must be 
reviewed and approved, by the Sponsor and the Investigator.  
14.3.2. 
Investigator Responsibilities  
The Investigator undertakes to perform the study in compliance with the protocol, ICH 
Guidelines per GCP and the applicable regulatory requirements. A copy of the guidelines will be 
available in the Investigator Site File.  
It is the Investigator’s responsibility to ensure that adequate time and appropriate resources are 
available at the investigational site prior to commitment to participate in this study. The 
Investigator should also be able to demonstrate a potential for recruiting the required number of 
suitable patient within the agreed recruitment period.  
The Investigator will maintain a list of appropriately qualified persons to whom the Investigator 
has delegated significant study-related tasks. An up-to-date copy of the curriculum vitae for the 
Investigator and sub-Investigator(s) will be provided to the Sponsor (or its representative) before 
starting the study.  
If the patient has a primary physician, the Investigator should, with the patient’s consent, inform 
the primary physician of the patient’s participation in the study.  
Agreement with the final CSR will be documented by the signed and dated signature of the 
principal or coordinating Investigator (Lead Investigator of the study) in compliance with 
ICH E3. 
The Investigator must adhere to the protocol as detailed in this document. The Investigator will 
be responsible for enrolling only those patients who have met protocol eligibility criteria. The 
Investigators will be required to sign an Investigator agreement to confirm acceptance and 
willingness to comply with the study protocol. 
It is the Investigator’s responsibility to communicate with their local IRB/IEC to ensure accurate 
and timely information is provided at all phases during the study. In particular, the appropriate 
approvals must be in place prior to recruitment, notification of any SAEs during the study must 
take place and the IRB/IEC must be informed of study completion. 
It is the responsibility of the Investigator to submit this protocol, the final approved informed 
consent document (approved by the Sponsor or its representative), relevant supporting 
information, all types of patient recruitment or advertisement information (approved by the 
Sponsor or its representative), and any other written information to be provided to the patient to 
the IRB/IEC for review and these must be approved before the study is initiated. Prior to 
implementing changes in the study, the Sponsor will produce a protocol amendment and the 
IRB/IEC must also approve any amendments to the protocol. 
On the approval letter, the study (title, protocol number and version), the documents reviewed 
(protocol, informed consent material, amendments) and the date of review should be clearly 
stated. 
Investigational product supplies will not be released and the patient recruitment will not begin 
until this written approval has been received by the Sponsor or its designee. 


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The Investigator is responsible for keeping the IRB/IEC apprised of the progress of the study and 
of any changes made to the protocol as deemed appropriate, and at least once a year. The 
Investigator must also keep the IRB/IEC informed of any serious and significant AEs. 
14.3.3. 
Patient Responsibilities  
Data collected during this study may be used to support the development, registration or 
marketing of neratinib. All data collected during the study will be controlled by the Sponsor (or 
designee) and the Sponsor will abide by all relevant data protection laws. 
After a patient has consented to take part in the study, their medical records and the data 
collected during the study will be reviewed by representatives of the Sponsor and/or the 
company organizing the research on the Sponsor’s behalf to confirm that the data collected are 
accurate and for the purpose of analyzing the results. These records and data may additionally be 
reviewed by auditors or by regulatory authorities. The patient’s name, however, will not be 
disclosed outside the hospital. They will be known by a unique patient number. The results of 
this study may be used in other countries throughout the world that have ensured an adequate 
level of protection for personal data. 
Written authorization (United States [US] sites only) or written informed consent in accordance 
with current data protection regulations (EU sites only) is to be obtained from each patient prior 
to enrollment into the study, and/or from the patient's legally authorized representative in 
accordance with the applicable privacy requirements (eg, the Health Insurance Portability and 
Accountability Act of 1996 Standards for Privacy of Individually Identifiable Health Information 
(“HIPAA”), General Data Protection Regulation (EU) 2016/679(“GDPR”) and any other state 
privacy requirements). If the patient is under the legal age of consent, the Authorization must be 
signed by the legally authorized representative in accordance with the applicable privacy 
requirements and other state privacy requirements. 
14.3.4. 
Financial Disclosure  
The Investigator will be required to disclose any financial arrangement whereby the value of the 
compensation for conducting the study could be influenced by the outcome of the study; any 
significant payments of other sorts from the Sponsor, such as a grant to fund ongoing research, 
compensation in the form of equipment, retainer for ongoing consultation, or honoraria; any 
proprietary interest in neratinib; any significant equity interest in the Sponsor, as defined in the 
US Code of Federal Regulations (21 CFR §54.2(b)). 
In consideration of participation in the study, the Sponsor will pay the Investigator, study site or 
nominated payee the sums set out in the payment schedule attached to the Investigator 
Agreement. 
14.3.5. 
Publication Policy  
The Sponsor encourages publication of results derived from the clinical research it sponsors. 
Publications include a paper in a peer reviewed medical journal, abstract submission with a 
poster or oral presentation at a scientific meeting, or making results public by some other means. 
The Sponsor will retain the right to review all material prior to presentation or submission for 
publication and neither institution(s) nor Study Co-chairs/Principal Investigator(s) are permitted 
to publish/present the results of the study, in part or in their entirety, without the written 


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authorization of the Sponsor. The review is aimed at protecting the Sponsor’s pre-existing 
propriety information and commercial interests.  
First Publication  
The results of the entire multicenter study shall be presented in a first publication upon 
completion of the entire multicenter study (data lock), with authorship being determined by the 
Sponsor and Study Investigators using the criteria defined by the International Committee of 
Medical Journal Editors. At least two Sponsor representatives will also be included as coauthors 
on the first publication of the results of the entire multicenter study to allow recognition of the 
Sponsor’s involvement in the design and execution of the study.  
Subsequent Publications  
Results from data subsets should not be published in advance of the first publication, and must 
make reference to it. Publications must include at least 2 Sponsor authors to allow recognition of 
the Sponsor’s involvement.  
In all publications, the study is to be identified as PUMA-NER-6203. The Study Principal 
Investigator(s) shall be free to publish or present, subject to the timing described in the Clinical 
Study Agreement.  


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Rabindran SK, Discafani CM, Rosfjord EC, et al. Antitumor activity of HKI-272, an orally 
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Rampaul RS, Pinder SE, Nicholson RI, Gullick WJ, Robertson JF and Ellis IO. Clinical value of 
epidermal growth factor receptor expression in primary breast cancer. Adv Anat Pathol 
2005;12:271-273.  
Rosen LS, Ashurst HL, Chap L. Targeting signal transduction pathways in metastatic breast 
cancer: a comprehensive review. Oncologist. 2010;15:216-235.  
Saini KS, Azim HA, Metzger-Filho O, et al. Beyond trastuzumab: New treatment options for 
HER2-positive breast cancer. The Breast 2011;20:S20-S27.  
Saura C, Garcia-Saenz JA, Xu B, et al. Safety and Efficacy of Neratinib in Combination With 
Capecitabine in Patients With Metastatic Human Epidermal Growth Factor Receptor 2-Positive 
Breast Cancer. J Clin Oncol 2014;32:3626-3633.  
Secombe KR, Ball IA, Shirren J, et al. Budesonide Reduces Neratinib-Induced Gastrointestinal 
Injury and Diarrhea in Rats. Presented at: 44th Clinical Oncology Society of Australia Annual 
Scientific Meeting (2017 COSA ASM); November 13-15, 2017; Sydney, Australia, Asia-Pac J 
Clin Oncol 13:60-105, abstr 40.  
Secombe KR, Ball IA, Shirren J, et al. Targeting neratinib-induced diarrhea with budesonide and 
colesevelam in a rat model. Cancer Chemother Pharmacol 2019;83:531-543.  


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Singh H, Walker AJ, Amiri-Kordestani L, et al. U.S. Food and Drug Administration Approval: 
Neratinib for the Extended Adjuvant Treatment of Early Stage HER2-Positive Breast Cancer. 
Clin Cancer Res 2018;24:3486-3491.  
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: 
correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 
1987;235:177-182.  
Tatro, DS. Drug Interaction Facts: The Authority on Drug Interactions. St. Louis, MI: Wolters 
Kluwer Health; 2012.  
Ustaris F, Saura C, Di Palma J, et al. Effective Management and Prevention of Neratinib-Induced 
Diarrhea. Am J Hematol Oncol 2015;11:13-22.  
Vermeij J, Teugels E, Bourgain C, et al. Genomic activation of the EGFR and HER2-neu genes 
in a significant proportion of invasive epithelial ovarian cancers. BMC Cancer. 2008;8:3.  
Waks AG and Winer EP; Breast cancer Treatment: A review. J Am Med Assoc. 2019; 321: 288-
300. 
Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth 
factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of 
American Pathologists clinical practice guideline update. J Clin Oncol 2013;31:3997-4013. 
Wong KK, Fracasso PM, Bukowski RM et al. A phase I study with neratinib (HKI-272), an 
irreversible pan ErbB receptor tyrosine kinase inhibitor, in patients with solid tumors. Clin 
Cancer Res 2009; 15: 2552-8. 
Xia W, Liu LH, Ho P and Spector NL. Truncated ErbB2 receptor (p95ErbB2) is regulated by 
heregulin through heterodimer formation with ErbB3 yet remains sensitive to the dual 
EGFR/ErbB2 kinase inhibitor GW572016. Oncogene 2004;23:646-653.  
Xu BH, Jiang ZF, Chua D, et al. Lapatinib plus capecitabine in treating HER2-positive advanced 
breast cancer: efficacy, safety and biomarker results from Chinese patients. Chin J Cancer 
2011;30(5):327-35. 
Yarden Y, Sliwkowski MX. Untangling the ErbB signaling network. Nat Rev Mol Cell Biol. 
2001;2:127-137.  
Zaczek A, Brandt B, Bielawski KP. The diverse signaling network of EGFR, HER2, HER3 and 
HER4 tyrosine kinase receptors and the consequences for therapeutic approaches. Histol 
Histopathol. 2005;20(3):1005-1015. 
Zhang H, Berezov A, Wang Q, et al. ErbB receptors: from oncogenes to targeted cancer 
therapies. J Clin Invest 2007;117:2051-2058.  


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16. 
SIGNATURE PAGES  
Declaration of Sponsor or Responsible Medical Officer  
Title of Study:  An Open-Label Phase 2 Study to Characterize Colon Pathology in Patients With 
HER2 Amplified Breast Cancer Treated With Neratinib  
Study Number: PUMA-NER-6203  
I have read and approve this protocol. My signature, in conjunction with the signature of the 
Investigator, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws, regulations, and guidelines, including, but 
not limited to, the International Conference on Harmonisation (ICH) Guideline for Good Clinical 
Practice (GCP), the United States Code of Federal Regulations (CFR), the Directives of the 
European Union, the ethical principles that have their origins in the Declaration of Helsinki, and 
applicable privacy laws.  
 
 
_____________________________________ 
Signature  
 
_ 
_____________________ 
Name (Printed) 
 
 
 
 
Date 
 
__
_______ 
Title  
 


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Declaration of Principal Investigator  
Title of Study: An Open-Label Phase 2 Study to Characterize Colon Pathology in Patients With 
HER2 Amplified Breast Cancer Treated With Neratinib 
Study Number: PUMA-NER-6203  
I have read and approve this protocol. My signature, in conjunction with the signature of the 
Sponsor, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws, regulations, and guidelines, including, but 
not limited to, the International Conference on Harmonisation (ICH) Guideline for Good Clinical 
Practice (GCP), the United States Code of Federal Regulations (CFR), the Directives of the 
European Union, the ethical principles that have their origins in the Declaration of Helsinki, and 
applicable privacy laws.  
The study will not be commenced without the prior written approval of a properly constituted 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC). No changes will be 
made to the study protocol without the prior written approval of the Sponsor and the IRB or IEC, 
except where necessary to eliminate an immediate hazard to the patients.  
Nothing in this document is intended to limit the authority of a physician to provide emergency 
medical care under applicable regulations.  
 
 
_____________________________________ 
Signature  
 
__
____________________ 
______________________________ 
Name (Printed) 
 
 
 
 
Date 
 
_____________________________________ 
Univ South Alabama College of Medicine 
Title 
 
 
 
 
 
 
Institution (block letters) and site number  
 
6000 University Commons 
74 University Boulevard South 
Mobile, Alabama 36688______________ 
 
+1 (251) 660-5555__________________ 
Address 
 
 
 
 
 
Phone number  


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17. 
APPENDICES  
 


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APPENDIX 1. SCHEDULE OF PROCEDURES 
Table A1.1. 
Schedule of Study Procedures – Neratinib Monotherapy in the Extended Adjuvant Setting 
Study Procedures 
Screeninga 
Active Treatmentb 
Safety Follow-up 
Visit 
Cycle / Day (C/D) 
Days 
-28 to -1 
C1/D1 
(28-day cycle) 
Colonoscopy 2 
Post-second colonoscopy  
Visit 1-2-3 
EOT Visit 
28 Days After Last 
Dose 
Study visit window in Days 
0 
-3b 
+/-3 
Every 3 months ±10 
±5 
+5 
Informed consentc 
X 
 
 
 
 
 
Medical/Cancer history/Demographyd 
X 
 
 
 
 
 
ERBB2 status documentatione 
X 
 
 
 
 
 
ECOG performance status 
X 
 
 
 
 
 
Serum or urine β-hCGf 
X 
X 
 
 
 
 
Physical examinationg 
X 
X 
X 
X 
X 
 
Vital signsh 
X 
X 
 
 
X 
 
CBC plus differentiali 
X 
X 
 
 
 
 
Serum chemistryj 
X 
X 
 
 
 
 
Liver function testsk 
X 
X 
 
X 
 
 
INR 
X 
 
 
 
 
 
ESR and CRPl 
 
X 
X 
 
 
 
MUGA or ECHOm  
X 
 
 
 
 
 
ECG (12-lead) 
X 
 
 
 
 
 
Colonoscopyn 
 
X 
X 
 
 
 
Fecal calprotein and fecal elastase 
 
X 
X 
 
 
 
Concomitant medications or treatmentso 
X 
X 
X 
X 
 
 
Neratinib administrationp 
 
Continuous once-daily dosing (pill count at each visit) 
 
Loperamide administrationq 
 
Loperamide 
dosing 
during C1 
As needed 
 
Adverse eventsr 
 
X 
X-----------------------------------------------------------------------X 
X 
Abbreviations: β-hCG=beta-human chorionic gonadotropin; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; C=cycle; CBC=complete blood count; CRP = C-reactive protein; D=day; ECG= electrocardiogram; ECHO=echocardiogram; 
ECOG=Eastern Collaborative Oncology Group; eCRF=electronic case report form; EOT = end of treatment; ESR = erythrocyte sedimentation rate; FISH = 


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fluorescence in situ hybridization ; Hb=hemoglobin; Hct=hematocrit; IHC=immunohistochemistry; INR = International Normalized Ratio; LFT=liver function 
test; LDH=lactate dehydrogenase; MUGA=multiple-gated acquisition scan; NP=nurse practioner; PA=physician’s assistant; RBC=red blood cell; SAE=serious 
adverse event; TEAE=treatment-emergent adverse event; WBC=white blood cell.  
a Screening procedures and enrollment may occur on one day, however, enrollment must not be done before all screening procedures have been completed and 
results confirming eligibility have been reviewed.  
b Cycle 1 is defined as 28 days.  The EOT Visit will be performed as soon as possible, but no later than 5 business days after the last dose and before start of new 
anticancer regimen.  If patient discontinues neratinib for reasons of toxicity or disease progression, all activities indicated for the EOT Visit should be 
conducted within 5 business days of  last dose of neratinib.  All visit dates are calculated from the date of first dose.  If a visit occurs before or after a 
scheduled visit date, the next visit is still expected to occur on the date initially calculated for this visit, and is not shifted due to an earlier or later prior visit.  
c Informed consent must be obtained before any protocol required assessments are performed.  Certain procedures done prior to informed consent as part of the 
standard work-up are acceptable, as long as they have been performed within 28 days from the date of enrollment.  Acceptable procedures are: CBC (with 
differential), serum chemistry, MUGA/ECHO, and ECGs. When obtaining the patient’s informed consent, the Investigator must review with the patient the 
Patient Instructions for the management of diarrhea and the Patient Diary for the patient’s daily recording of neratinib dose, any adverse reactions, number of 
loose stools and use of loperamide and/or other antidiarrheals (adverse reactions, stools, and antidiarrheals are to be documented only for the first cycle [28 
days]). Both the patient and the Investigator must sign the patient instructions for the management of diarrhea. Copies of both documents are handed to the 
patient before she leaves the site with neratinib and loperamide on Cycle 1/Day 1. The Investigator must also complete and sign the Investigator Checklist by 
Cycle 1/Day 1.  
d Collect presence of chronic conditions and/or medical history of significance; include review of history of cardiac, pulmonary, and gastrointestinal disease 
including assessment of bowel movements experienced during the previous 28 days as well as those ongoing at the time of screening, any medical conditions 
that require medication, and therapies such as chemotherapy/biotherapy/immunotherapy. 
e Documentation of locally assessed ERBB2-amplified status by FISH (>2.2) or ERBB2 overexpression by IHC (3+) by a validated approved method must be 
confirmed.  
f For women of childbearing potential, serum or urine β-hCG test to be performed both at screening and repeated within 72 hours prior to Cycle 1/Day 1. 
bleeding.  
g Physical examination may be delegated and performed by a properly trained NP, PA or equivalent.  During treatment, brief symptom-guided physical 
examinations including worsening of medical history conditions will be done approximately every 3 months.  As per Section 12.3 beginning with Cycle 3 
through the end of the study and during visits scheduled per standard of care, only SAEs will be reported. 
h Vital signs will be measured after resting in a seated position for 5 minutes, prior to dosing, and will include: blood pressure (systolic and diastolic; mmHg), 
resting heart rate (beats per minute), body temperature (°C), respiration rate, weight (kg), height (screening only).  
i CBC to include Hct, Hb, platelet count, RBC and WBC count plus differential.  CBCs must be tested at screening and on Day 1 of Cycle 1 (-3 days), and as 
clinically indicated.  The Cycle 1/Day 1 tests do not need to be performed, if the screening tests were done within 72 hours of enrollment.  
j Serum chemistry tests include sodium, potassium, chloride, calcium, magnesium, BUN or urea, serum creatinine, albumin, LDH, phosphorus, and glucose 
(non-fasting).  The Cycle 1/Day 1 tests do not need to be performed, if the screening tests were done within 72 hours of enrollment. 
k LFTs must include total bilirubin, ALT, ALP, and AST.  LFTs must be tested at screening, on Day 1 of Cycle 1,and approximately every 3 months, and as 
clinically indicated.  Visits for LFT testing should be aligned with CBC testing and other routine study visits when possible.  LFTs should also be tested in 
patients experiencing Grade 3 or higher diarrhea or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash or eosinophilia.  During the evaluation of potential hepatotoxicity, bilirubin should be fractionated and prothrombin 
time should be measured.  Also, liver imaging should be obtained for patients with any signs or symptoms of hepatotoxicity and/or Grade 3 or higher LFT 
elevations, or as clinically indicated.  Refer to the guidelines for the management of LFT changes in the main section of the protocol.  


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l ESR and CRP must be collected at the time of the Baseline colonoscopy or prior to initiation of neratinib in Cycle 1 and at the time of the second study 
colonoscopy procedure after the first 28-day cycle, i.e., Day 1 of Cycle 2 (+ 5 days).  If Screening is to be performed within 72 hours of enrollment and the 
first colonoscopy, ESR and CRP testing may be performed at the time of screening. 
m During trial participation, ECHO or MUGA will be performed at Screening, and as clinically indicated. It is strongly recommended to use the same method of 
measurement for the same patient throughout the duration of the study.  
n Colonoscopy will be performed after eligibility has been confirmed, but prior to administration of the first dose of neratinib on Day 1 of Cycle 1, Andon Day 
30 (± 3 days). Oral medications, including the morning dose of neratinib, will be withheld on the day of the colonoscopy as per local standard of care. In 
addition, biopsies will be collected as described in Section 8.2.2.  
o Concomitant medications and concomitant nonpharmacological treatments/therapies are recorded at screening from 28 days before signing of the informed 
consent form, on Day 1 of Cycle 1, on the day before and day of the second study colonoscopy procedure, and on Day 1 of Cycle 3.  
p Neratinib is to be self-administered as per instructions in Section 6.1. 
q Loperamide is to be self-administered as per instructions in Section Section 6.4.2. Patients are asked to document administration of neratinib and loperamide in 
a diary on a daily basis during the first cycle (28 days) of the study, and to return this diary to the site at appropriate visit. Individual patient dosing compliance 
should be reviewed by study site staff. Investigators must ensure that patients have loperamide on hand when starting to take neratinib. Neratinib will be 
dispensed directly by the study sites on or before Cycle 1/Day 1 and during subsequent visits as needed. Loperamide is the recommended standard therapy to 
treat diarrhea in this study. If alternative antidiarrheal medication is used, the reason must be documented in the source documents.  Acceptable reasons are 
non-tolerance of loperamide or lack of efficacy.  
r From the signing of the informed consent form through 28 days of neratinib monotherapy following the second study colonoscopy procedure in patients with 
stage 1 to 3c breast cancer treated in the extended adjuvant setting, and in and Cycle 2 in patients with mBC, TEAEs and SAEs will be monitored continuously 
and recorded in the eCRF.  Patients must use the diary to document any episodes of diarrhea for the first cycle (28 days) of the study.  
r After the completion of Cycle 2 through 28 calendar days after the last administration of neratinib, only SAE data will be collected. Should an Investigator be 
made aware of any SAEs occurring any time after the reporting period that may be causally related to administration of neratinib, it should be promptly 
reported. All SAEs must be reported within 24 hours of awareness of the event using the SAE Report Form.  
 
 


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Table A1.2. 
Schedule of Study Procedures – Neratinib In Combination with Capecitabine in Metastatic Breast Cancer  
Study Procedures 
Screeningb 
Active Treatmenta 
Treatment 
Discontinuation 
Safety Follow-up 
Contact 
Cycle / Day (C/D)  
Days 
-28 to -1 
C1/D1 (28-
day) 
C2/D1 
(21-day) 
Colonoscopy 2 
C3+  
(21-day)q,r 
0-3 Days  
After Last Dose 
28 Days After Last 
Dose  
Study visit window in Days 
0 
-3b 
±5 
 
±5 
 
±5 
Informed consentc 
X 
 
 
 
 
 
 
Medical/Cancer history/Demographyd 
X 
 
 
 
 
 
 
ERBB2 status documentatione 
X 
 
 
 
 
 
 
ECOG performance status 
X 
 
 
 
 
 
 
Serum or urine β-hCGf 
X 
X 
 
 
 
 
 
Physical examination 
X 
Xg 
Xg 
 
Xg 
Xg 
 
Vital signsh 
X 
X 
X 
 
X 
X 
 
CBC plus differentiali 
X 
X 
 
 
X 
X 
 
Serum chemistryj 
X 
X 
 
 
X 
X 
 
Liver function testsk 
X 
X 
X 
 
X 
X 
 
INR 
X 
 
 
 
 
 
 
ESR and CRPl 
 
X 
 
X 
 
 
 
MUGA or ECHOm  
X 
 
 
 
X 
 
 
ECG (12-lead)n 
X 
 
 
 
X 
X 
 
Colonoscopyo 
 
X 
 
X 
 
 
 
Fecal calprotein and fecal elastase 
 
X 
 
X 
 
 
 
Concomitant medications or treatmentsp 
X 
X 
X 
X 
X 
 
 
Neratinib administrationq 
 
Continuous once-daily dosing (pill count at each visit) 
 
Capecitabiner 
 
 
X 
 
X 
 
 


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Study Procedures 
Screeningb 
Active Treatmenta 
Treatment 
Discontinuation 
Safety Follow-up 
Contact 
Cycle / Day (C/D)  
Days 
-28 to -1 
C1/D1 (28-
day) 
C2/D1 
(21-day) 
Colonoscopy 2 
C3+  
(21-day)q,r 
0-3 Days  
After Last Dose 
28 Days After Last 
Dose  
Study visit window in Days 
0 
-3b 
±5 
 
±5 
 
±5 
Loperamide administrationq 
 
Loperamide 
dosing 
during C1 
As needed 
 
 
Adverse eventss,t 
 
Xs 
Xt-----------------------------------------------------------------------X 
Abbreviations: β-hCG=beta-human chorionic gonadotropin; ALP=alkaline phosphatase; ALT=alanine aminotransferase; AST=aspartate aminotransferase; 
BUN=blood urea nitrogen; C=cycle; CBC=complete blood count; CRP = C-reactive protein; D=day; ECG= electrocardiogram; ECHO=echocardiogram; 
ECOG=Eastern Collaborative Oncology Group; eCRF=electronic case report form; EOT = end of treatment; ESR = erythrocyte sedimentation rate; FISH= 
fluorescence in situ hybridization; Hb=hemoglobin; Hct=hematocrit; IHC=immunohistochemistry; INR = International Normalized Ratio; LFT=liver function 
test; LDH=lactate dehydrogenase; MUGA=multiple-gated acquisition scan; NP=nurse practioner; PA=physician’s assistant; RBC=red blood cell; SAE=serious 
adverse event; TEAE=treatment-emergent adverse event; WBC=white blood cell.  
a Cycle 1, neratinib monotherapy, is defined as 28 days. Cycle 2 and all subsequent cycles are defined as 21 days.  Cycle 2 will begin after the completion of the 
second study colonoscopy procedure. The Treatment Discontinuation Visit will be performed as soon as possible, but no later than 3 business days after the 
last dose and before start of new anticancer regimen.  All visit dates are calculated from the date of first dose of neratinib.  If a visit occurs before or after a 
scheduled visit date, the next visit is still expected to occur on the date initially calculated for this visit, and is not shifted due to an earlier or later prior visit.  
b Screening procedures and enrollment may occur on one day, however, enrollment must not be done before all screening procedures have been completed and 
results confirming eligibility have been reviewed.  
c Informed consent must be obtained before any protocol required assessments are performed.  Certain procedures done prior to informed consent as part of the 
standard work-up are acceptable, as long as they have been performed within 28 days from the date of enrollment.  Acceptable procedures are: CBC (with 
differential), serum chemistry, MUGA/ECHO, and ECGs. When obtaining the patient’s informed consent, the Investigator must review with the patient the 
Patient Instructions for the management of diarrhea and the Patient Diary for the patient’s daily recording of neratinib dose, any adverse reactions, number of 
loose stools and use of loperamide and/or other antidiarrheals (adverse reactions, stools, and antidiarrheals are to be documented only for the first cycle [21 
days]). Both the patient and the Investigator must sign the patient instructions for the management of diarrhea. Copies of both documents are handed to the 
patient before she leaves the site with neratinib and loperamide on Cycle 1/Day 1. The Investigator must also complete and sign the Investigator Checklist by 
Cycle 1/Day 1.  


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d Collect presence of chronic conditions and/or medical history of significance (include review of history of cardiac, pulmonary, and gastrointestinal disease 
experienced during the previous 28 days as well as those ongoing at the time of screening, any medical conditions that require medication, and therapies such 
as chemotherapy/biotherapy/immunotherapy. 
e Documentation of locally assessed ERBB2-amplified status by FISH (>2.2) or ERBB2 overexpression by IHC (3+) by a validated approved method must be 
confirmed.  
f For women of childbearing potential, serum or urine β-hCG test to be performed both at screening and repeated within 72 hours prior to Cycle 1/Day 1. 
bleeding.  
g Physical examination may be delegated and performed by a properly trained NP, PA or equivalent.  During treatment, brief symptom-guided physical 
examinations including worsening of medical history conditions will be done on Day 1 of each cycle. As per Section 12.3 beginning with Cycle 3 through the 
end of the study and during visits scheduled per standard of care, only SAEs will be reported. 
h Vital signs will be measured after resting in a seated position for 5 minutes, prior to dosing, and will include: blood pressure (systolic and diastolic; mmHg), 
resting heart rate (beats per minute), body temperature (°C), respiration rate, weight (kg), and height (screening only).  
i CBC to include Hct, Hb, platelet count, RBC and WBC count plus differential.  CBCs must be tested at screening and on Day 1 of Cycle 1 (-3 days), and as 
clinically indicated.  Visits for CBC testing should be aligned with LFT testing and other routine study visits when possible.  The Cycle 1/Day 1 tests do not 
need to be performed, if the screening tests were done within 72 hours of enrollment.  
j Serum chemistry tests include sodium, potassium, chloride, calcium, magnesium, BUN or urea, serum creatinine, albumin, LDH, phosphorus, and glucose 
(non-fasting).  The Cycle 1/Day 1 tests do not need to be performed, if the screening tests were done within 72 hours of enrollment. 
k LFTs must include total bilirubin, ALT, ALP, and AST, as well as serum lipase and serum amylase.  LFTs must be tested at screening, on Day 1 of each 
treatment cycle, and as clinically indicated.  Visits for LFT testing should be aligned with CBC testing and other routine study visits when possible.  LFTs 
should also be tested in patients experiencing Grade 3 or higher diarrhea or any signs or symptoms of hepatotoxicity, such as worsening of fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, fever, rash or eosinophilia.  During the evaluation of potential hepatotoxicity, bilirubin should be 
fractionated and prothrombin time should be measured.  Also, liver imaging should be obtained for patients with any signs or symptoms of hepatotoxicity 
and/or Grade 3 or higher LFT elevations, or as clinically indicated.  Refer to the guidelines for the management of LFT changes in the main section of the 
protocol.  Patients receiving neratinib and capecitabine on study should be monitored for signs or symptoms related to pancreatitis, including abdominal pain, 
especially epigastric pain radiating to the back and elevations in serum lipase and serum amylase. Severe pancreatitis can also be accompanied by ecchymotic 
discoloration of the periumbilical or flank regions, fever, hypotension, and hypoxemia. Serum lipase and (pancreatic) amylase should be measured at baseline 
and subsequently at any time if pancreatitis is suspected. If pancreatic enzymes are elevated, imaging should be performed in accordance with standard 
institutional protocols for investigation of acute pancreatitis. 
l ESR and CRP must be collected at the time of the Baseline colonoscopy or prior to initiation of neratinib in Cycle 1 and at the time of the second  study 
colonoscopy procedure after the first 28-day cycle, ie, Day 1 of Cycle 2 (+ 5 days).  If Screening is to be performed within 72 hours of enrollment and the first 
colonoscopy, ESR and CRP testing may be performed at the time of screening. 
m During trial participation, ECHO or MUGA will be performed at Screening, and should be repeated at Cycle 3/Day 1, Cycle 6/Day 1, Day 1 of every 6th 
subsequent cycle, as clinically indicated. It is strongly recommended to use the same method of measurement for the same patient throughout the duration of 
the study.  
n ECGs should be performed at Screening, and should be repeated at Cycle 3/Day 1, Cycle 6/Day 1, every 6th subsequent cycle during the active treatment 
phase, and as clinically indicated. ECG should also be performed at Treatment Discontinuation if not done during the previous 12 weeks.  Patients using drugs 
known to cause QT/QTc prolongation should be monitored closed with serial ECGs at the Investigator’s discretion.  Refer to Appendix 6 for a summary of 
drugs known to have a risk of causing QT/QTc prolongation, potentially causing Torsade’s de Pointes. 


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o Colonoscopy will be performed after eligibility has been confirmed, but prior to administration of the first dose of neratinib on Day 1 of Cycle 1, and after the 
first 28-day cycle, i.e., Day 1 of Cycle 2 (+ 5 days).  Oral medications, including the morning dose of neratinib on the day of the Day 1/Cycle 2 colonoscopy, 
will be withheld on the day of the colonoscopy as per local standard of care. In addition, biopsies will be collected as described in Section 8.2.2.  
p Concomitant medications and concomitant nonpharmacological treatments/therapies are recorded at screening from 28 days before signing of the informed 
consent form, on Day 1 of Cycle 1, on Day 1 of Cycle 2, on the day before and day of the second study colonoscopy procedure, and on Day 1 of Cycle 3. 
q Loperamide is to be administered as per instructions in Section 6.2. Patients are asked to document administration of neratinib and loperamide in a diary on a 
daily basis during the first cycle (28 days) of the study, and to return this diary to the site at appropriate visit. Individual patient dosing compliance should be 
reviewed by study site staff. Investigators must ensure that patients have loperamide on hand when starting to take neratinib. Neratinib will be dispensed 
directly by the study sites on or before Cycle 1/Day 1 and during subsequent visits as needed. Loperamide is the recommended standard therapy to treat 
diarrhea in this study. If alternative antidiarrheal medication is used, the reason must be documented in the source documents.  Acceptable reasons are 
non-tolerance of loperamide or lack of efficacy.  
r Capecitabine therapy will begin following the completion of the second study colonoscopy procedure and will be administered on Day 1-14 of each cycle. Note: 
capecitabine cannot be administered until after the second study colonoscopy procedure is completed. 
s From the signing of the informed consent form through the end of Cycle 2 TEAEs and SAEs will be monitored continuously and recorded in the eCRF.  
Patients must use the diary to document any episodes of diarrhea for the first cycle (28 days) of the study.  
t After the completion of Cycle 2 through 28 calendar days after the last administration of neratinib, only SAE data will be collected. Should an Investigator be 
made aware of any SAEs occurring any time after the reporting period that may be causally related to administration of neratinib, it should be promptly 
reported. All SAEs must be reported within 24 hours of awareness of the event using the SAE Report Form.  
 


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APPENDIX 2. INVESTIGATIONAL PRODUCT DOSE ADJUSTMENT 
FOR TOXICITY  
1. Dose adjustment levels  
Recommended dose reductions for the -1 and -2 dose levels of neratinib and capecitabine are 
listed in Table 3 in Section 6.1.1 and in Table 6 in Section 6.3.1.  
2. Toxicities Requiring Investigational Product Dose Adjustments  
General Toxicities:  
The guidelines for dose adjustments of neratinib and capecitabine for general toxicities due to 
the combination of neratinib plus capecitabine are shown in Table A2.1.  
Table A2.1. 
General Toxicities Requiring Dose Adjustment of Neratinib  
NCI CTCAE v.4.0 
Action 
Grade 2 adverse reaction  
 1st appearance  
 Hold neratinib and capecitabine until event resolves to Grade ≤1; then resume 
neratinib at the starting dose level. 
 2nd appearance  
 Hold neratinib and capecitabine until event resolves to Grade ≤1; then resume 
neratinib at 160 mg and capecitabine at 1100 mg/m2 (550 mg/m2 BID). 
 3rd appearance  
 Hold neratinib and capecitabine until event resolves to Grade ≤1; then resume 
neratinib at 120 mg and capecitabine at 750 mg/m2 (375 mg/m2 BID). 
 4th appearance  
 Discontinue neratinib and capecitabine permanently. 
Grade 3 adverse reaction 
 1st appearance  
 Hold neratinib and capecitabine until event resolves to Grade ≤1; then resume 
neratinib at 160 mg and capecitabine at 1100 mg/m2 (550 mg/m2 BID). 
 2nd appearance  
 Hold neratinib and capecitabine until event resolves to Grade ≤1; then resume 
neratinib at 120 mg and capecitabine at 750 mg/m2 (375 mg/m2 BID). 
 3rd appearance  
 Discontinue neratinib and capecitabine permanently. 
Grade 4 adverse reaction 
 1st appearance  
 Discontinue neratinib and capecitabine permanently OR if Investigator deems 
it to be in the patient’s best interest to continue, hold neratinib and 
capecitabine until resolved to Grade ≤1; then resume neratinib at 120 mg and 
capecitabine at 750 mg/m2 (375 mg/m2 BID). 
 If the event occurs again despite one dose reduction, permanently discontinued 
neratinib. 
Abbreviations: BID: twice daily; NCI CTCAE v4.0, National Cancer Institute Common Terminology for Adverse 
Events Version 4.0. 
 
Gastrointestinal Toxicity:  
Guidelines for adjusting doses of neratinib and capecitabine in the event of gastrointestinal 
toxicity diarrhea are shown in Table A2.2.  


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Table A2.2. 
Gastrointestinal Toxicities Requiring Dose Adjustment of Neratinib and 
Capecitabine 
NCI CTCAE V4.0 
Action 
 Grade 1 Diarrhea [Increase of <4 stools per 
day over baseline; mild increase in ostomy 
output compared to baseline.]  
OR  
 Grade 2 Diarrhea [Increase of 4-6 stools 
per day over baseline; moderate increase in 
ostomy output compared to baseline;] lasting 
<5 days  
OR  
 Grade 3 Diarrhea [Increase of ≥7 stools per 
day over baseline; incontinence; hospitalization 
indicated; severe increase in ostomy output 
compared to baseline limiting self-care 
activities of daily living (ADL)] lasting ≤2 days 
 Adjust anti-diarrheal treatment, as per the guidelines for 
management of diarrhea at the first onset of diarrhea (refer 
to Section 6.2 and Section 7.2). 
 Continue neratinib and capecitabine at full dose.  
 Instruct patient to follow dietetic recommendations in the 
guidelines for management of diarrhea (refer to 
Section 7.2).  
 Fluid intake of ~2L should be maintained to avoid 
dehydration.  
 Once the event resolved to ≤ Grade 1 or baseline, start 
loperamide 4 mg with each subsequent neratinib 
administration.  
 Persisting and intolerable Grade 2 Diarrhea 
lasting ≥5 days despite being treated with 
optimal medical therapy,  or associated with 
fever, dehydration, or Grade 3-4 neutropenia  
OR  
 Grade 3 Diarrhea lasting > 2 days despite 
being treated with optimal medical therapy, or 
associated with fever, dehydration, or 
Grade 3-4 neutropenia  
OR  
 Any Grade 4 diarrhea [Life-threatening 
consequences; urgent intervention indicated]  
 Adjust anti-diarrheal treatment, as per the guidelines for 
management of diarrhea at the first onset of diarrhea (refer 
to Section 6.2 and Section 7.2).  
 Hold neratinib and capecitabine until recovery to ≤ Grade 
1 or baseline.  
 Instruct patient to follow dietetic recommendations of the 
guidelines for management of diarrhea.  
 Fluid intake of ~2L should be maintained, intravenously if 
needed.  
 If recovery occurs:  
o ≤1 week after withholding treatment, resume same dose 
of neratinib and capecitabine.  
o Within 1-4 weeks after withholding treatment, reduce 
neratinib dose to the next lower dose level and maintain 
the same dose of capecitabine.  
 If event occurs a 2nd time and the neratinib dose has not 
already been decreased, reduce neratinib dose to the next 
lower dose level and maintain the same dose of 
capecitabine. If neratinib dose has already been reduced, 
the reduce the dose of capecitabine to 1100 mg/m2a 
(550  mg/m2 BID) (maintain same dose of neratinib) 
 If subsequent events occur, reduce the dose of neratinib or 
capecitabine to the next lower dose level in an alternate 
fashion (i.e., reduce capecitabine to 750 mg /m2 (375 
mg/m2 BID) if neratinib was previously reduced, or reduce 
neratinib to 120 mg if capecitabine was previously 
reduced..  
 Once the event resolved to ≤ Grade 1 or baseline, start 
loperamide 4 mg with each subsequent neratinib 
administration.  
Abbreviations: BID: twice daily; IV: intravenous; L: liter; NCI CTCAE v4.0: National Cancer Institute Common 
Terminology Criteria for Adverse Events version 4.0. 
a Since capecitabine is provided as 150 mg or 500 mg tablets, it is recommended that the capecitabine dose 
reduction(s) is rounded down to the nearest 500 mg or multiple of 150 mg for the BID dose. If the patient's body 
surface are is >2.0, the standard of care for the study center can be utilized for capecitabine mg/m2 dosing.  
 


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Pulmonary Toxicity:  
Guidelines for adjusting doses of neratinib in the event of pulmonary toxicities are shown in 
Table A2.3. Interstitial lung disease, which can sometimes be fatal, has been reported with other 
oral tyrosine kinase inhibitors that target EGFR ±HER2 (ERBB2), including lapatinib, gefitinib, 
and erlotinib. Rare cases of pneumonitis (0.6%) and lung infiltration (0.4%) have been reported 
in patients treated with neratinib monotherapy, and considered drug-related. Patients receiving 
neratinib should be monitored for acute onset or worsening of pulmonary symptoms such as 
dyspnea, cough, and fever and treated appropriately.  
Table A2.3. 
Pulmonary Toxicities Requiring Dose Adjustment of Neratinib  
NCI CTCAE V4.0 
Action 
 Grade 2 Pneumonitis/Interstitial Lung Disease 
[Symptomatic; medical intervention indicated; 
limiting instrumental ADL] 
 Hold neratinib until recovery to ≤ Grade 1 or baseline.  
 Reduce neratinib to 160 mg or discontinue neratinib 
as per Investigator’s best medical judgment.  
 Grade 3 Pneumonitis/Interstitial Lung Disease 
[Severe symptoms; limiting self-care ADL; oxygen 
indicated] 
 Discontinue neratinib permanently.  
Abbreviations: NCI CTCAE v4.0: National Cancer Institute Common Terminology Criteria for Adverse Events 
version 4.0. 
Liver Toxicity:  
Guidelines for adjustment of neratinib and capecitabine in the event of liver toxicity are shown 
in Table A2.4.  
Abnormal values in ALT concurrent with abnormal elevations in total bilirubin that meet the 
criteria outlined below in the absence of other causes of liver injury are considered potential 
cases of drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events.  
Patients who experience ≥Grade 3 diarrhea requiring IV fluid treatment or any signs or 
symptoms of hepatotoxicity such as worsening of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash or eosinophilia should be evaluated for changes in liver function 
tests. Fractionated bilirubin and prothrombin time must also be collected during hepatotoxicity 
evaluation.  


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Table A2.4. 
Liver Function Test Abnormalities Requiring Dose Adjustment of Neratinib  
NCI CTCAE V4.0 
Action 
Grade 3 ALT (>5 – 20x ULN)  
OR  
Grade 3 bilirubin (>3-10x ULN) 
 Hold neratinib and capecitabine until recovery to ≤ 
Grade 1 for patients with ALT ≤ Grade 1 at baseline OR ≤ 
Grade 2 for patients with Grade 2 ALT at baseline.  
 Evaluate alternative causes.  
 For patients with ALT ≤ Grade 1 at baseline: Resume 
neratinib at the next lower dose level (160 mg) and 
capecitabine at the next lower dose level (1100 mg/m2 
[550 mg/m2 BID])a if recovery to ≤Grade 1 occurs within 
4 weeks. If Grade 3 ALT or bilirubin occurs again despite 
one dose reduction, permanently discontinue neratinib 
and capecitabine.  
Grade 4 ALT (>20x ULN) 
OR 
Grade 4 Bilirubin (>10x ULN) 
 Permanently discontinue neratinib and capecitabine.  
 Evaluate alternative causes.  
ALT >3x ULN  
AND  
Total bilirubin >2x ULN  
AND  
Alkaline phospatase <2x ULN  
(potential Hy’s law indicators of drug-induced liver 
damage) 
 Hold neratinib and capecitabine.  
The patient should return to the investigational site and be 
evaluated as soon as possible, preferably within 48 hours 
from awareness of the abnormal results. This evaluation 
should include laboratory tests, detailed history and 
physical assessment and for oncology studies, the 
possibility of hepatic neoplasm (primary or secondary) 
should be considered. In addition to repeating AST and 
ALT, laboratory tests should include albumin, total 
bilirubin, direct bilirubin, PT and alkaline phosphatase. A 
detailed history, including relevant information, such as 
review of ethanol, concomitant medications, recreational 
drug and supplement consumption, family history, sexual 
history, travel history, history of contact with a jaundiced 
patient, surgery, blood transfusion, history of liver or 
allergic disease, and work exposure, should be collected. 
Further testing for acute hepatitis A, B, or C infection and 
liver imaging (eg, biliary tract) may be warranted. All cases 
confirmed on repeat testing as meeting the criteria 
mentioned above (i.e., ALT > 3 x ULN associated with 
bilirubin >2 x ULN and alkaline phosphatase <2 x ULN), 
with no other cause for liver function test abnormalities 
identified at the time should be considered potential Hy’s 
Law cases, irrespective of availability of all the results of 
the investigations performed to determine etiology of the 
abnormal liver function tests. 
 Contact the Sponsor immediately to discuss next steps, 
including evaluation of alternative causes, and 
management of investigational product.  
 These events must be reported as SAEs.  
Abbreviations; ALT=alanine aminotransferase; AST: aspartate aminotransferase; BID: twice daily; PT: prothrombin 
time; SAE: serious adverse event; ULN: upper limit of normal. 
NOTE: During evaluation of hepatotoxicity, bilirubin must be fractionated, prothrombin time must be measured, and 
liver imaging should be considered. 


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a Since capecitabine is provided as 150 mg or 500 mg tablets, it is recommended that the capecitabine dose 
reduction(s) is rounded down to the nearest 500 mg or multiple of 150 mg for the BID dose. If the patient's body 
surface are is >2.0, the standard of care for the study center can be utilized for capecitabine mg/m2 dosing.  
 
Left Ventricular Ejection Fraction Toxicity 
Guidelines for dose adjustments of neratinib in the event of abnormalities in LVEF are shown in 
Table A2.5. LVEF assessments will be performed according to the Schedule of Procedures 
(Appendix 1 ). It is strongly recommended to use the same method of cardiac evaluation (ECHO 
or MUGA) at each time point for each patient. 
Table A2.5: Left Ventricular Ejection Fraction (LVEF) Results Requiring Dose 
Adjustments of Neratinib 
EVENT ON DAY OF SCHEDULED 
TREATMENT 
Action 
Asymptomatic absolute decline of LVEF ≥15% 
from baseline OR absolute decline of LVEF ≥10% 
ad below the lower limit of normal of 50%  
A) If LVEF is below 40%: hold neratinib and seek 
cardiology input OR continue neratinib with great 
caution. 
Initiate monthly monitoring of LVEF 
 
If while monitoring monthly, LVEF remains <40%: 
reconsider neratinib only if appropriate and after 
cardiology consult. 
 
If while monitoring monthly, LVEF increases to ≥40%: 
continue neratinib, monitor LVEF every 12 weeks and 
consider cardiac support with input from cardiologist  
B) If LVEF is between 40% to 50%: continue neratinib 
with caution and surveillance. 
Initiate monthly monitoring of LVEF. 
 
If while monitoring, LVEF falls to <40%: Follow bullet 
point A instructions described above. 
 
If while monitoring, LVEF remains ≥40%: continue 
neratinib, monitor LVEF every 12 weeks and consider 
cardiac support with input from cardiology. 
Symptomatic cardiac failure 
  Neratinib should be discontinued. 
Abbreviations: LVEF: left ventricular ejection fraction. 
If a patient has a second episode of asymptomatic decline in LVEF that meets either of the above 
criteria, permanently discontinue neratinib, repeat LVEF in 3-4 weeks and consider cardiology 
consult. 
Note that, for AEs other than symptomatic LVEF decline, if neratinib is held for >28 days, the 
patient should be withdrawn from the active treatment phase of the study (see Section 10.1 ). In 
case of asymptomatic LVEF decline, patients may resume neratinib within 1 week after LVEF 
recovery is documented as above, even if the timeframe exceeds 3 weeks. If a site does not 
provide normal ranges for ECHO or MUGA, a lower limit of normal of 50% should be used.  
Hematologic Toxicity 
Patients with baseline neutrophil counts of <1.5 x 109/L and/or thrombocyte counts of 
<100 x 109/L should not be treated with capecitabine. If unscheduled laboratory assessments 


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during a treatment cycle show Grade 3 or 4 hematologic toxicity, treatment with capecitabine 
should be held.  
Guidelines for dose adjustments of capecitabine for hematologic toxicity due to combination of 
neratinib plus capecitabine are shown in Table A2.6. 
Table A2.6: Hematologic Abnormalities Requiring Dose Adjustment of Capecitabine 
(When Administered in Combination with Neratinib) 
NCI CTCAE v 4.0 
Action 
Grade 3 
Neutrophil: <1000-500/mm3; <1-0.5 x 109/L 
Platelet: <50,000-25,000/mm3; <50-25 x 109/L 
Hemoglobin decreased: <8 g/dL; <4.9 mmol/L; <80 g/L; 
transfusion indicated  
 
Neratinib should be continued at the same dose 
 
Hold capecitabine until event resolves or decreases 
to Grade 1 or Grade 2 
 
Reduce next capecitabine dose to 1100 mg/m2 
(550  mg/m2 BID) 
 
If the event recurs a 2nd time, hold capecitabine 
until event resolves or decreases to Grade 1 or 
Grade 2 
 
Reduce next capecitabine dose of 750 mg/m2 
(375 mg/m2 BID) 
 
If the event recurs/persists, discontinue 
capecitabine permanently. 
Grade 4 
Neutrophil: <500/mm3; <0.5 x 109/L 
Platelet: <25,000/mm3; <25 x 109/L 
Hemoglobin decreased: life-threatening consequences; 
urgent intervention indicated 
 
Neratinib should be continued at the same dose. 
 
Capecitabine should be discontinued permanently 
OR if the Investigator deems it to be in the patient’s 
best interest to continue, hold capecitabine until 
resolved to Grade ≤1 
 
If the Investigator decides to resume capecitabine, 
reduce the dose to 750 mg/m2 (375 mg/m2 BID) 
 
If the event recurs/persists, discontinue 
capecitabine permanently 
Abbreviations: BID: twice daily; L=liter; NCI CTCAE v 4.0: National Cancer Institute Common Terminology 
Criteria for Adverse Events Version 4.0. 
 
Hand and Foot Syndrome 
Guidelines for dose adjustments of neratinib and capecitabine for toxicity of Hand and Foot 
Syndrome (Palmar-Plantar Erythrodysesthesia syndrome) due to combination of neratinib plus 
capecitabine are show in Table A2.7. 
Table  A2.7: Hand and Foot Syndrome (Palmar-Plantar Erythrodysesthesia Syndrome) 
Requiring Dose Adjustment of Neratinib and Capecitabine 
NCI CTCAE v4.0 
Action 
Grade 1: Minimal skin changes or dermatitis (e.g., 
erythema, edema, or hyperkeratosis) without pain 
 
Continue neratinib and capecitabine at starting 
dose  


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NCI CTCAE v4.0 
Action 
Grade 2: Skin changes, e.g., peeling, blisters, edema, or 
hyperkeratosis, with pain, limiting instrumental ADL.  
PI: painful erythema and swelling of the hands and/or 
feet and/or discomfort affecting ADL. 
 
Continue neratinib at starting dose level and hold 
capecitabine until recovery or to ≤grade 1, then 
resume at starting dose. 
 
If the event recurs/persists, continue neratinib at 
starting dose level and reduce capecitabine dose to 
1100 mg/m2 (550 mg/m2 BID) 
Table  A2.7: Hand and Foot Syndrome (Palmar-Plantar Erythrodysesthesia Syndrome) 
Requiring Dose Adjustment of Neratinib and Capecitabine (Continued) 
NCI CTCAE v4.0 
Action 
Grade 3: Severe skin changes, e.g., peeling, blisters, 
edema, or hyperkeratosis, with pain, limiting self-case 
ADL.  
PI: moist desquamation, ulceration, blistering or severe 
pain of the hands and/or feet and/or sever discomfort 
limiting self-care ADL 
 
Continue neratinib at starting dose level and hold 
capecitabine until recovery or to grade ≤1, then 
reduce dose to 1100 mg/m2 (550 mg/m2 BID) 
 
If the event recurs/persists, continue neratinib at 
starting dose level and capecitabine dose of 750 
mg/m2 (375 mg/m2 BID) 
Abbreviations: ADL: activities of daily living; BID: twice daily; NCI CTCAE v 4.0 National Cancer Institute 
Common Terminology Criteria for Adverse Events Version 4.0. 
 
Pancreatitis  
Guidelines for dose adjustments of neratinib and capecitabine for pancreatitis due to combination 
of neratinib plus capecitabine are show in Table A2.8. 
Table A2.8: Recommendations for Dose Adjustment of Neratinib and Capecitabine and 
Management of Patients with Pancreatitis 
NCI CTCAE v.4.0 
Action 
Grade 2 Pancreatitis: 
Enzyme elevation or radiologic 
findings 
OR 
Grade 3 Pancreatitis: 
Severe pain; vomiting; medical 
intervention indicated (e.g., 
analgesia, nutritional support) 
 
Temporarily suspend (i.e., hold) neratinib and capecitabine 
 
Evaluate for any possible alternative causes 
 
If no alternative cause for pancreatitis is identified, discontinue neratinib 
and capecitabine permanently. 
 
If an alternative cause is identified (e.g., gallstones) or enzyme levels return 
to baseline within 3 weeks with clinical recovery, re-start treatment with 
reduced doses of neratinib 160 mg and capecitabine 1100 mg/m2 (550 
mg/m2 BID). 
 
If the event occurs a second time, discontinue neratinib and capecitabine 
permanently. 
Grade 4 Pancreatitis: 
Life-threatening consequences; 
urgent intervention indicated 
 
Discontinue neratinib and capecitabine permanently. 
Abbreviations: BID: twice daily; NCI CTCAE v 4.0 National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 4.0 


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APPENDIX 3. EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS 
Description 
Grade 
Fully active, able to carry on all pre-disease performance without restriction. 
0 
Restricted in physically strenuous activity, but ambulatory and able to carry out 
work of a light or sedentary nature, i.e., light house work, office work. 
1 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours. 
2 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours. 
3 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair. 
4 
Dead 
5 
 


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APPENDIX 4. INHIBITORS AND INDUCERS OF THE CYTOCHROME 
P450 ISOENZYMES  
CYP3A4 Inducers 
Carbamazepine 
Macrolide antibiotics 
Rifabutin 
Efavirenz 
Phenobarbital 
Rifampin 
Glucocorticoids: 
Phenylbutazone 
Rifapentine 
Dexamethasone 
Phenytoin 
St. John’s Wort 
Prednisone 
Primidone 
Sulfinpyrazone 
CYP3A4 Inhibitors 
Amprenavir 
Grapefruit juice 
Paroxetine 
Anastrozole 
Indinavir 
Propranolol 
Cimetidine 
Itraconazole 
Quinidine 
Clarithromycin 
Ketoconazole 
Quinine 
Clotrimazole 
Mibefradil 
Ranitidine 
Danazol 
Miconazole 
Ritonavir 
Delavirdine 
Mirtazapine (weak) 
Saquinavir 
Diethyldithiocarbamate 
Nefazodone 
Sertraline 
Diltiazem 
Nelfinavir 
Sildenafil (weak) 
Erythromycin 
Nevirapine 
Troglitazone 
Fluconazole 
Norfloxacin 
Troleandomycin 
Fluoxetine 
Norfluoxetine 
Zafirlukast 
Fluvoxamine 
 
 
CYP3A5-7 Inducers 
Phenobarbital 
Primidone 
Rifampin 
Phenytoin 
 
 
Source: Tatro,2012.  


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APPENDIX 5. SUBSTRATES AND INHIBITORS OF P-GLYCOPROTEIN 
(P-GP)  
P-glycoprotein Substrates 
Amiodarone (eg, Cordarone) 
Fluphenazine (eg, Prolixin) 
Progesterone (eg, Prometrium) 
Chlorpromazine (eg, Thorazine) 
Hydrocortisone (eg, Cortef) 
Promethazine (eg, Phenergan) 
Clarithromycin (eg, Biaxin) 
Indinavir (Crixivan) 
Quinidine 
Cyclosporine (eg, Neoral) 
Itraconazole (eg, Sporanox) 
Reserpine 
Dactinomycin (Cosmegen) 
Ketoconazole (eg, Nizoral) 
Ritonavir (Norvir) 
Daunorubicin (eg, Cerubidine) 
Lidocaine (eg, Xylocaine) 
Saquinavir (eg, Fortovase) 
Dexamethasone (eg, Decadron) 
Loperamide (eg, Imodium) 
Sirolimus (Rapamune) 
Digoxin (eg, Lanoxin) 
Lovastatin (eg, Mevacor) 
Tacrolimus (Prograf) 
Diltiazem (eg, Cardizem) 
Mifepristone (Mifeprex) 
Tamoxifen (eg, Nolvadex) 
Doxorubicin (eg, Adriamycin) 
Mitoxantrone (Novantrone) 
Teniposide (Vumon) 
Erythromycin (eg, Ery-Tab) 
Nelfinavir (Viracept) 
Testosterone Delatestryl) 
Estradiol (eg, Estrace) 
Nicardapine (eg, Cardene) 
Trifluoperazine 
Etoposide (eg, Vepesid) 
Nifedipine (eg, Procardia) 
Verapamil (eg, Calan) 
Felodipine (Plendil) 
Ondansetron (Zofran) 
Vinblastine (eg, Velban) 
Fexofenadine (Allegra) 
Paclitaxel (eg, Taxol) 
Vincristine (eg, Vincasar PFS) 
P-glycoprotein Inhibitors 
Amiodarone (eg, Cordarone) 
Indinavir (Crixivan) 
Quinidine 
Atorvastatin (Lipitor) 
Itraconazole (eg, Sporanox) 
Reserpine 
Chlorpromazine (eg, Thorazine) 
Ketoconazole (eg, Nizoral) 
Ritonavir (Norvir) 
Clarithromycin (eg, Biaxin) 
Lidocaine (eg, Xylocaine) 
Saquinavir (eg, Fortovase) 
Cyclosporine (eg, Neoral) 
Mifepristone (Mifeprex) 
Tacrolimus (Prograf) 
Diltiazem (eg, Cardizem) 
Nelfinavir (Viracept) 
Tamoxifen (eg, Nolvadex) 
Erythromycin (eg, Ery-Tab) 
Nicardipine (eg, Cardene) 
Testosterone (Delatestryl) 
Felodipine (Plendil) 
Nifedipine (eg, Procardia) 
Trifluoperazine 
Fluphenazine (eg, Prolixin) 
Progesterone (eg, Prometrium) 
Verapamil (eg, Calan 
Hydrocortisone (eg, Cortef) 
Propranolol (eg, Inderal) 
 
Source: Tatro, 2012. 


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APPENDIX 6. DRUGS ASSOCIATED WITH RISK OF QT/QTC 
PROLONGATION LEADING TO TORSADE DE POINTES 
Drugs Reported to Prolong QT Interval 
Analgesics 
Celecoxib (Celebrex) 
Methadone (eg, Dolophine, Methadose) 
Anesthetic agents 
Enflurane (eg, Ethrane) 
Halothane 
Isoflurane (eg, Forane) 
 
Antiarrhythmic agents 
Class IA 
Class III 
Disopyramide (eg, Norpace)* 
Amiodarone (eg, Cordarone)*b 
Procainamide (eg, Procanbid)* 
Bretylium* 
Quinidine* 
Dofetilide (Tikosyn)*b 
Class IC 
Ibutilide (Corvert)*b 
Flecainide (eg, Tambocor)*a 
Sotalol (eg, Betapace)*b 
Propafenone (eg, Rythmol)*b 
 
Anticonvulsants 
Felbamate (Felbatol)* 
Fosphenytoin (Cerebyx) 
Antiemetics 
Dolasetron (Anzemet)b 
Droperidol (eg, Inapsine)*b 
Ondansetron (Zofran) 
Antihistamines 
Desloratadine (Clarinex)b (overdose) 
Fexofenadine (Allegra) 
Diphenhydramine (eg, Benadryl) 
Hydroxyzine (Atarax) 
Anti-infectives 
Amantadine (eg, Symmetrel)* 
Macrolides and related antibiotics 
Antimalarials 
Azithromycin (eg, Zithromax) 
Mefloquine (eg, Lariam)b 
Clarithromycin (eg, Biaxin)*b 
Quinine* 
Erythromycin (eg, Ery-Tab, EES)*b 
Antivirals 
Telithromycin (Ketek)b 
Efavirenz (Sustiva)* 
Troleandomycin 
Azole antifungal agents 
Pentamidine (eg, Pentam 300, Nebupent)* 
Fluconazole (eg, Diflucan)*b 
Quinolones 
Itraconazole (eg, Sporanox) 
Gatifloxacin (eg, Tequin)*b 


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Drugs Reported to Prolong QT Interval 
Ketoconazole (eg, Nizoral) 
Levofloxacin (eg, Levaquin)*a, b 
Voriconazole (Vfend)b 
Moxifloxacin (eg, Avelox)b 
Chloroquine (eg, Aralen)* 
Ofloxacin (eg, Floxin)*b 
Clindamycin (eg, Cleocin) 
Sparfloxacin (Zagam)b 
Foscarnet (Foscavir) 
Trimethoprim/sulfamethoxazole (eg, Bactrim)* 
Antineoplastics 
Arsenic trioxide (Trixenox)*b 
Doxorubicin (eg, Adriamycin) 
Tamoxifen (eg, Nolvadex) 
Bronchodilators 
Albuterol (eg, Proventil)b 
Salmeterol (Serevent)b 
Formoterol (Foradil)b 
Terbutaline (eg, Brethine)b 
Isoproterenol (eg, Isuprel) 
 
Calcium channel blockers 
Isradipine (DynaCirc) 
Nicardipine (eg, Cardene) 
Contrast media 
Ionic contrast media* 
Non-ionic contrast media: Iohexol (Omnipaque) 
Corticosteroids 
Prednisolone (eg, Prelone) 
Prednisone (eg, Deltasone)* 
Diuretics 
Furosemide (eg, Lasix) 
Indapamide (eg, Lozol) 
Gastrointestinal agents 
Cisapride (Propulsid)*b,  
Famotidine (eg, Pepcid)* 
Immunosuppressants 
Tacrolimus (Protopic)*b (postmarketing) 
Miscellaneous 
Levomethadyl 
Papaverine (eg, Pavaden three times daily [TID])* 
Moexipril/Hydrochlorothiazide (Uniretic) 
Probucol (Lorelco)* 
Octreotide (Sandostatin)b 
Vasopressin (eg, Pitressin)* 
Oxytocin (eg, Pitocin; intravenous bolus) 
 
Psychotropics 
Droperidol (eg, Inapsine)* 
Primozide (Orap)*b,  
Trazodone (eg, Desyrel) 
Haloperidol (eg, Haldol)* 
Quetiapine (Seroquel)b 
Tricyclic antidepressants 
Lithium (eg, Eskalith)* 
Risperidone (Risperdal)b 
(overdose) 
Amitriptyline* 


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Drugs Reported to Prolong QT Interval 
Maprotiline* 
Serotonin Reuptake Inhibitors 
(SRIs) 
Clomipramine (eg, 
Anafranil) 
Phenothiazines 
Citalopram (eg, Celexa)* 
Desipramine (eg, 
Norpramin)* 
Chrlorpromazine (eg, 
Thorazine)* 
Fluoxetine (eg, Prozac)*a 
Doxepin (eg, Sinequan)* 
Fluphenazine (eg, 
Prolixin)* 
Paroxetine  
(eg, Paxil)* 
Imipramine (eg, Tofranil)* 
Perphenazine 
Sertraline (Zoloft)*a, b 
(postmarketing) 
Nortriptyline (eg, Pamelor) 
Thioridazine (Mellaril)*b 
Venlafaxine (Effexor)b 
(postmarketing) 
 
Trifluopherazine 
 
Serotonin 5-HT1 agonists 
Naratriptan (Amerge) 
Sumatriptan (Imitrex)b 
Zolmitriptan (Zomig)b 
Skeletal muscle relaxants 
Tizanidine (eg, Zanaflex)b (animals) 
*  Drugs for which Torsades de Pointes has also been reported.  
a  Association unclear  
b  QT, QTc, and/or Torsades de Pointes association listed in FDA-approved product labeling  
Source: Tatro, 2012.  


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SAP_001.pdf: 
An Open-Label Phase 2 Study to Characterize Colon Pathology in Patients With HER2 Amplified Breast 
Cancer Treated With Neratinib 
NCT04366713 
Version: Original 1.0 
11-Feb-2020 


Document ID: 093d860c813eea22
 
This document contains confidential information of Puma Biotechnology, Inc. This document must not be 
disclosed to anyone other than the study staff and members of the Independent Ethics Committee/ Institutional 
Review Board. The information in this document cannot be used for any purpose other than the evaluation or 
conduct of the clinical investigation without the prior written consent of Puma Biotechnology Inc.  
 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
An Open-Label Phase 2 Study to Characterize Colon Pathology 
in Patients With HER2 Amplified Breast Cancer Treated With 
Neratinib  
 
Study Protocol No. 
PUMA-NER-6203 
Disease Condition 
HER2 Amplified (HER2+) Breast Cancer 
Sponsor 
Puma Biotechnology, Inc. 
10880 Wilshire Blvd, Suite 2150 
Los Angeles, CA 90024 USA 
Phone: +1 424.248.6500 
Fax: +1 424.248.6501 
 
 
Date of SAP 
Original v 1.0 
11-February-2020 
 
 
 
     
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ............................................................................................ 4 
1. 
PURPOSE OF ANALYSIS ........................................................................................ 5 
2. 
PROTOCOL SUMMARY ......................................................................................... 6 
2.1 Study Objectives .................................................................................................... 6 
2.1.1 
Primary Objective .................................................................................. 6 
2.1.2 
Secondary Objectives ............................................................................. 6 
2.2 Study Endpoints ..................................................................................................... 6 
2.2.1 
Primary Endpoint ................................................................................... 6 
2.2.2 
Secondary Endpoints .............................................................................. 6 
2.3 Overall Study Design and Plan ................................................................................. 6 
2.3.1 
Study Design ......................................................................................... 6 
2.3.2 
Neratinib Adjustments ............................................................................ 8 
2.3.3 
Loperamide ........................................................................................... 9 
2.3.4 
Loperamide Dose Adjustments ................................................................ 9 
2.3.5 
Capecitabine .......................................................................................... 9 
2.3.6 
Capecitabine Dose Adjustment .............................................................. 10 
2.4 Study Population .................................................................................................. 10 
3. 
DEFINITIONS ........................................................................................................ 11 
4. 
DATA SCREENING, ACCEPTANCE AND PROGRAMMING ............................... 13 
4.1 General Principles ................................................................................................ 13 
4.2 Handling of Missing and Incomplete Data ............................................................... 13 
4.3 Testing/Validation Plan ......................................................................................... 13 
5. 
ANALYSIS POPULATIONS ................................................................................... 14 
5.1 Safety Population ................................................................................................. 14 
6. 
ANALYSIS METHODS .......................................................................................... 15 
6.1 Disposition of Patients .......................................................................................... 15 
6.2 Deviations ........................................................................................................... 15 
6.3 Demographic and Baseline Characteristics .............................................................. 15 
6.4 Medical History ................................................................................................... 15 
6.5 Cancer History ..................................................................................................... 15 
6.5.1 
Summary of Cancer History .................................................................. 15 
6.5.2 
Prior Anti-cancer Medications ............................................................... 15 
6.6 Serological and Stool Parameters ........................................................................... 16 
6.7 Study Medications ................................................................................................ 16 
6.7.1 
Study Medication (Neratinib)................................................................. 16 
6.7.2 
Study Medication (Capecitabine) ........................................................... 16 
6.8 Concomitant Medications and Therapy ................................................................... 16 
6.8.1 
Loperamide During the First Cycle ......................................................... 16 
6.8.2 
Anti-diarrheal Medication During the First Cycle ..................................... 17 
6.8.3 
Concomitant Therapy ........................................................................... 17 
6.9 Adverse Events (AEs) ........................................................................................... 17 
6.9.1 
Treatment-emergent Diarrhea ................................................................ 17 
6.9.2 
Treatment-Emergent Adverse Events (TEAEs) ........................................ 18 
6.9.3 
Adverse Events of Special Interest (AESI) .............................................. 18 
6.9.4 
Death .................................................................................................. 19 


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6.10 
Clinical Laboratory Parameters ....................................................................... 19 
6.11 
Vital Signs .................................................................................................... 19 
6.12 
ECG Abnormality ......................................................................................... 19 
6.13 
Left Ventricular Ejection Fraction (LVEF) ....................................................... 19 
6.14 
Disease Recurrence ........................................................................................ 19 
7. 
INTERIM ANALYSES ........................................................................................... 20 
8. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL ....................... 21 
9. 
LIST OF PLANNED TABLES, FIGURES, AND LISTINGS .................................... 22 
9.1 TABLES ............................................................................................................. 22 
9.2 LISTINGS ........................................................................................................... 22 
10. REFERENCES ....................................................................................................... 24 
 


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LIST OF ABBREVIATIONS 
 
Abbreviation 
Term/Definition 
AE 
adverse event 
AESI 
adverse events of special interest 
ATC 
Anatomical Therapeutic Chemical 
BMI 
body mass index 
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
ECHO  
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EOS 
end of study 
EOT 
end of treatment 
HER 
human epidermal growth factor receptor 
HER2 
human epidermal growth factor receptor 2 (neu [N ethyl nitrosourea stimulated] gene 
product); also known as c erB2, ERBB2, or p185 
IP 
Investigational Product 
LVEF  
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mBC 
metastatic breast cancer 
mg 
Milligrams 
MUGA 
multiple-gated accession scan 
NCI 
National Cancer Institute 
PT  
preferred term 
QTc  
QT interval, corrected for heart rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
 


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1. PURPOSE OF ANALYSIS 
The statistical analysis plan (SAP) outlines details of the statistical methods and analyses 
of the protocol “An Open-Label Phase 2 Study to Characterize Colon Pathology in 
Patients With HER2 Amplified Breast Cancer Treated With Neratinib” (PUMA-
NER-6203), dated 04 September 2019.   
The purpose of the SAP is to pre-specify analyses that are consistent with the protocol 
objectives to ensure appropriate interpretation of the data. It supplements the statistical 
section specified in the protocol with additional details and clarity related to the statistical 
analyses. The SAP must be finalized prior to database lock according to standard 
operating procedures. Deviations from this plan will be documented and described in the 
CSR.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. PROTOCOL SUMMARY 
2.1 
Study Objectives 
2.1.1 Primary Objective  
The primary objective of this study is to characterize and understand colon pathogenesis 
related to neratinib-induced diarrhea through biopsies and images obtained by 
colonoscopy study 
This objective will not be addressed by PUMA in this SAP. 
 
2.1.2 Secondary Objectives 
The secondary objectives of this study are: 
 To characterize the incidence and severity of diarrhea during the first 28-day 
cycle.  
 To analyze changes in serological and fecal inflammatory markers from baseline 
to second colonoscopy. 
 
2.2 
Study Endpoints 
2.2.1 Primary Endpoint 
The primary endpoint is change from baseline in pathological findings in colon biopsies 
after the first 28 days of neratinib monotherapy.  
 
2.2.2 Secondary Endpoints 
The secondary endpoint will be the incidence and severity of diarrhea during the first 28-
day cycle of neratinib monotherapy. 
 
 
2.3 
Overall Study Design and Plan 
2.3.1 Study Design 
This is an open-label, phase 2 study that will investigate colon pathology in patients with 
HER2-positive breast cancer treated with neratinib as monotherapy. 
All patients will receive neratinib for the first 28 days as a single daily dose of 240mg.  
Following the second study colonoscopy procedure:  
 For patients being treated for stage 1 to 3c breast cancer in the extended adjuvant 
setting, neratinib will continue to be administered at a single daily dose of 240mg 
until completion of one year of therapy from start of treatment , or until disease 


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recurrence (as determined by the Investigator), death, unacceptable toxicity, or 
other specified withdrawal criterion.  
 For patients being treated for metastatic breast cancer (mBC), capecitabine will be 
introduced after the second study colonoscopy procedure at a dose of 750mg/m2 
twice daily for 14 days of each 21 day treatment cycle, with neratinib 
administered continuously throughout at 240mg daily, until disease progression, 
death, unacceptable toxicity, or other specified withdrawal criterion. 
All patients will receive loperamide diarrhea prophylaxis daily for one (1) 28-day cycle 
and then as needed. 
Following a 28-day screening period, eligible patients will be enrolled. Baseline 
assessments will be performed prior to Cycle 1/Day 1 dosing. Patients will then 
participate in the active treatment phase, consisting of, in both groups, a single 28-day 
cycle of neratinib monotherapy. Neratinib and loperamide will be administered orally by 
patients. The morning dose of neratinib will be held on the day of the second study 
colonoscopy procedure.  
Colonoscopy will be performed after eligibility has been confirmed, but prior to 
administration of the first dose of neratinib on Day 1 of Cycle 1, and at Day 30 (± 3 
days). Thereafter, extended adjuvant patients with stage 1 to 3c breast cancer will 
continue to receive neratinib monotherapy for 1 year or until progression of disease, 
death, or intolerance to study prescribed therapy. Patients with mBC will continue to 
receive neratinib in 21-day cycles, beginning in Cycle 2, after completion of the second 
study colonoscopy procedure, in combination with capecitabine administered on Day 1-
14 of each cycle, until progression of disease, death, or intolerance to study prescribed 
therapy. 
NOTE; patients with mBC cannot be exposed to capecitabine until after completion 
of the second study colonoscopy procedure. 
In extended adjuvant patients with stage 1 to 3c breast cancer, patients will return to the 
clinic approximately every 3 months for safety assessments. End of Treatment (EOT) 
visit is planned on upon completion of 1 year of treatment, followed by Safety Follow-up 
Visit 28 days after the last dose of neratinib.  
In patients with mBC, clinic visits during the active treatment phase are planned on Day 1 
of Cycle 1, Cycle 2, and each subsequent cycle. Treatment discontinuation visit is 
planned 0-3 days after the last dose, followed by a Safety Follow-up Visit 28 days after 
the last dose of neratinib.  
The study will end when all patients have been followed-up for 28 days after the last dose 
of neratinib.  
Approximately 3-5 patients will be enrolled at approximately 2 centers.  
The approximate duration of the study is 1.5 years.  


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Patients with stage 1 to 3c disease receiving extended adjuvant therapy are anticipated to 
participate in the study for approximately 1 year. This includes 1 month for screening, 
approximately 12 months for the active treatment phase until progression of disease or 
intolerance to study prescribed therapy, and safety follow-up visit 28 days after the last 
dose of neratinib.  
Patients with mBC are anticipated to participate in the study for an average of 12 months. 
This includes approximately 1 month for screening, an estimated average of 9.5 months 
for the active treatment phase, and an estimated average of 1 month for initial Safety 
Follow-up.  Patients who permanently discontinue treatment due to unacceptable toxicity 
will be followed-up for 28 days after the last dose of neratinib to collect any adverse 
events (AEs) (Section 9.4).  
The primary analysis will be conducted after all patients have completed two sets of 
colon biopsies. The final analysis will be conducted when all patients with stage 1 to 3c 
breast cancer have completed 1 year of study treatment or have met other specified 
withdrawal criteria and patients with mBC have discontinued therapy or have met other 
specified withdrawal criteria.  
The study will end when all patients have been followed up for 28 days after the last dose 
of neratinib.  
In the event that end of treatment (EOT) is declared earlier by the Sponsor, patients will 
be offered the opportunity to complete treatment through a treatment extension study. 
 
2.3.2 Neratinib Adjustments 
Neratinib may be dose-adjusted/reduced due to neratinib-related toxicity. The prescribed 
dose levels can be 240mg, 200mg, 160mg, 120mg, with the latter three doses 
representing the reduction levels. If doses of neratinib are held, study procedures for that 
cycle will proceed on schedule as planned, without any delay. Missed dose(s) of neratinib 
(i.e., any dose that is not administered within the protocol-defined administration 
window) will not be made up. Note: Patients should take one dose per calendar day. 
The dose adjustment guidelines represent the minimum set of measures the Investigator 
must follow. However, additional measures may be taken, as necessary, for certain 
patients per the Investigator’s medical judgment. All dose modifications/adjustments 
should be documented in the patient’s source file. 
Once the neratinib dose has been reduced for a patient, all subsequent cycles must be 
administered at that dose, unless further dose reduction is required. Dose re-escalation 
will only be permitted if explicitly approved in advance by the Sponsor. Evidence of this 
approval must be contained within the patient’s source file.  
Patients must discontinue the investigational product if a criterion for withdrawal is met. 
Reintroduction of the discontinued investigational product at a later time during the 
active treatment phase is not permitted. 


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2.3.3 Loperamide 
 The initial dose of loperamide 4 mg will be self-administered orally with the first 
dose of neratinib. 
 During weeks 1-2 (day 1 – 14) of Cycle 1 loperamide 4 mg will be self-
administered administered three time daily. 
 During weeks 3-4 (days 15 – 28) of Cycle 1 loperamide 4 mg will be self-
administered twice daily  
 After the first 28 days, loperamide will be self-administered as needed (PRN) (not 
to exceed 16 mg per day).  
 
 
2.3.4 Loperamide Dose Adjustments 
Patients are expected to take loperamide prophylaxis as directed. However, patients may 
require individualization of loperamide prophylaxis dose (up to a maximum dose of 
16 mg per day). 
 For patients who develop diarrhea during Cycles 1, loperamide should be 
increased up to a maximum of 16 mg a day.  
 If a patient is unable to tolerate loperamide due to symptomatic constipation, 
loperamide should be held until after the first bowel movement and then resumed 
at a dose reduced by one level.  
 For recurrent symptomatic constipation events, hold loperamide until after the 
first bowel movement and then resume at a dose reduced to the next lower dose 
level.  
 If a patient is unable to tolerate once-daily loperamide due to constipation, hold 
loperamide and discuss subsequent loperamide dosing with the Medical Monitor. 
 Neratinib dosing should continue if loperamide is held.  
 
Loperamide dose reduction levels for constipation are:  
 Dose Level 0 (4mg TID or 6 tablets/capsules a day) 
 Dose Level -1 (4 mg BID or 4 tablets/capsules a day) 
 Dose Level -2 (2mg TID or 3 tablets/capsules a day) 
 Dose Level -3 (2 mg BID or 2 tablets/capsules a day) 
 Dose Level -4 (2 mg once a day or 1 tablet/capsule a day) 
 
If a patient experiences an AE leading to dose interruption of neratinib for reasons other 
than diarrhea, consider holding loperamide until neratinib treatment is resumed. 
 
2.3.5 Capecitabine 
Patients with mBC will receive capecitabine, beginning in Cycle 2 of treatment (i.e., 
following completion of the second study colonoscopy procedure and biopsy). 
Capecitabine is available at 150 mg and 500 mg film-coated tablets. 


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Capecitabine (total dose of 1500 mg/m2 daily, administered as 750 mg/m2 in 
approximately evenly divided doses) will be self-administered orally by patients starting 
with Cycle 2/Day 1 (i.e. following completion of the second study colonoscopy 
procedure and biopsy). Doses are to be taken daily on Days 1 to 14 of each 21-day cycle. 
Capecitabine should be taken with water within 30 minutes after a meal.  
During treatment with neratinib plus capecitabine, patients should be monitored for 
conditions that may require dose to be held or discontinued.  Careful attention should be 
paid to the onset of diarrhea or hand-foot syndrome in particular, and early dose 
adjustment or prophylactic therapy should be implemented.  
Daily dose of neratinib plus capecitabine should continue until a criterion for treatment 
withdrawal or study withdrawal is met. 
2.3.6 Capecitabine Dose Adjustment 
Recommended dose reductions for capecitabine-related toxicity in combination with 
neratinib are listed below: 
Dose Level 
Capecitabine (administered in combination with neratinib) 
Starting Dose 
1500 mg/m2, 750 mg/m2 BID 
-1aa 
1100 mg/m2, 550 mg/m2 BID 
-2a 
750 mg/m2, 375 mg/m2 BID 
 
 
 
2.4 
Study Population 
Approximately 3-5 patients will be enrolled.  


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3. DEFINITIONS 
Baseline 
The baseline value for a parameter of interest is the last measurement obtained prior to or 
on the date of the first dose of neratinib. 
 
Cycle 
The first cycle is 28 days for all subjects, all of whom receive neratinib and loperamide 
prophylaxis. After the first 28-day cycle, stage 1 to 3c breast cancer patients receiving 
extended adjuvant treatment return to clinic every 3 months. Metastatic breast cancer 
patients return to clinic at scheduled 21-day cycles, during with time they receive both 
neratinib and capecitabine. 
 
Study Day 1 
Study Day 1 is the date the first dose of neratinib is taken.  
 
Treatment duration 
 
Treatment duration in days = last dose date - first dose date + 1  
 
 
Actual Dose Intensity  
The actual dose intensity is defined as the cumulative actual dose divided by treatment 
duration.  
 
Relative Actual Dose Intensity  
The relative actual dose intensity is defined as the actual dose intensity divided by the 
planned dose intensity.  
 
Prescribed Dose Intensity  
The prescribed dose intensity is defined as the cumulative prescribed dose divided by 
treatment duration. 
 
Treatment-Emergent Adverse Event (TEAE) 


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A TEAE is defined as an AE that occurs or worsens on or after the first administration of 
neratinib and up to 28 days after the second colonoscopy in patients with stage 1 to 3c 
breast cancer, and following completion of Cycle 2 in mBC patients. 
 
 
Investigational Product (IP) 
Investigational product (IP) is used to reference neratinib and capecitabine. 
 
 
 


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4. DATA SCREENING, ACCEPTANCE AND PROGRAMMING 
4.1 
General Principles 
Clinical data are entered into the Medrio database. Data cleaning and query resolution are 
performed according to the study specific data management plan. Prior to any formal 
analysis, a data cut-off date will be established by the clinical study team to ensure 
appropriate cleaning and query resolution of data up to the data cut-off date. Data extracts 
in SAS formats will be taken from a snapshot of the live database or a locked database 
will be used for the analyses.  
The clinical study team will identify the criteria for important protocol deviations.  
Important protocol deviations will be summarized and listed in the clinical study report. 
 
4.2 
Handling of Missing and Incomplete Data 
Missing and incomplete data will be identified for investigation, and possible resolution, 
as part of the data cleaning.  At the analysis time, missing data will be treated as missing, 
unless otherwise specified. Missing and incomplete dates for adverse events, concomitant 
medications, and historical data may be imputed for certain analyses. 
 
Partial dates will be defined as dates that are missing certain elements of the date field. 
This may include missing information for the month, day or year, or two of these 
elements, but not all three. If either month or year is missing or the date is completely 
missing then no data imputation will be implemented.  
 
AEs with completely missing start dates will be considered as treatment-emergent 
adverse events unless there is clear evidence that the AEs start prior to the first dose.  
 
 
4.3 
Testing/Validation Plan 
Statistical programming will be performed using SAS software, version 9.4 or higher, on 
a Windows Server OS.  All SAS programs will be documented, QC’ed, written in 
accordance with department SOPs. 
Analyses performed by statistical software other than SAS are permitted if the analyses 
cannot be readily performed in SAS. All statistical programming must follow commonly 
accepted practice including adequate comments within the program, code review, logic 
review, and check of program log. Key analysis results may require additional validation 
including but not limited to independent programming.   
 


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5. ANALYSIS POPULATIONS  
5.1 
Safety Population 
The safety population is defined as all enrolled patients who have received at least one 
dose of  neratinib.   
 
 
 
 
 


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6. ANALYSIS METHODS 
A minimum of 2 analyses will be conducted: primary and final. The primary analysis will 
occur after all patients have completed the second study colonoscopy. The final analysis 
will occur after all patients have either discontinued or completed study treatment. Unless 
otherwise indicated, all data will be presented at both analyses and only in the form of 
listings. 
 
In the case of data summaries, for continuous endpoints, the sample size (n), mean, 
standard deviation, median, 25th percentile (Q1), 75th percentile (Q3) , minimum, and 
maximum will be provided. For discrete data, the frequency and percent distributions will 
be provided.  
 
6.1 
Disposition of Patients 
Reasons for treatment discontinuation and study discontinuation will be listed.  
 
 
6.2 
Deviations 
A listing will be provided for protocol deviations. 
 
6.3 
Demographic and Baseline Characteristics 
A listing will be provided for demographics, which will include age at study enrollment, 
sex, ethnicity, race, menopausal status, height (cm), weight (kg), and BMI (kg/m2).  
 
 
6.4 
Medical History 
Medical history will be listed by system organ class and preferred terms. 
 
6.5 
Cancer History 
6.5.1 Summary of Cancer History 
A listing will be provided. The listing will include ECOG performance status and disease 
setting.  
6.5.2 Prior Anti-cancer Medications 
A listing will be provided for prior anti-cancer medications. The listing will include status 
(yes/no) of prior anti-cancer medication, indication (neoadjuvant, adjuvant, 
metastatic/locally advanced). 


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6.6 
Serological and Stool Parameters 
Listings will be provided for the following parameters: serological inflammatory markers 
and stool inflammatory markers, along with applicable data elements from each form. 
 
6.7 
Study Medications 
6.7.1 Study Medication (Neratinib) 
Exposure to neratinib during the study will be listed. Variables will include treatment 
duration in months, cumulative actual dose (mg), actual dose intensity (mg/day), relative 
actual dose intensity, cumulative prescribed dose, prescribed dose intensity, and 
compliance. The compliance for neratinib is calculated by using actual dose intensity 
divided by the prescribed dose intensity.  
 
Indicator for dose reduction (yes/no), dose reduction due to AE (yes/no), and the lowest 
dose reduction level, will be included in the listing. In addition, indicator for the dose 
withheld due to AE (yes/no) will be included. 
 
6.7.2 Study Medication (Capecitabine) 
A listing will be provided for capecitabine exposure, which will include treatment 
duration (months), cumulative actual dose (mg/m2), actual dose intensity (mg/m2/day), 
relative actual dose intensity (%).  
Indicator for dose reduction (yes/no) and dose reduction due to AE (yes/no) and the 
lowest dose reduction level will be included in the listing. In addition, indicator for dose 
withheld due to AE (yes/no) will be included. 
 
6.8 
Concomitant Medications and Therapy 
Concomitant medications will be listed by Anatomical Therapeutic Chemical (ATC) 
category and preferred term.  
 
6.8.1 Loperamide During the First Cycle 
Exposure to loperamide during the first cycle (28 days) will be listed by treatment 
duration (days), cumulative actual dose (mg), actual dose intensity (mg/day) and relative 
actual dose intensity. In addition, the initial loading dose will also be provided. 
The highest daily dose, lowest daily dose, dose reduction due to AE (yes/no), dose 
increase due to AE (yes/no), and dose hold due to AE (yes/no). 


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For loperamide, for the first 14 days, the planned dose intensity is 12mg/day; for days 15 
through 28, the planned dose intensity is 8 mg/day. The planned dose intensity for 
loperamide for the first cycle is (12mgx14days + 8mgx14days)/28 = 10mg/day. 
 
6.8.2 Anti-diarrheal Medication During the First Cycle 
All anti-diarrhea medication (including loperamide and any other concomitant 
medication for diarrhea) during the first cycle, will be listed to include the anti-diarrhea 
medication name and anti-diarrheal medication use duration. 
6.8.3 Concomitant Therapy 
Concomitant therapy will be listed.  
 
 
6.9 
 
Adverse Events (AEs) 
AEs are graded by the investigators according to the NCI CTCAE v.4.0. AEs will be 
coded using MedDRA. Summaries will focus on treatment-emergent adverse events 
(TEAEs). 
 
 
6.9.1 Treatment-emergent Diarrhea 
Additional summaries will be provided for incidence of diarrhea by worst grade, and 
incidences of serious, treatment-related, and serious treatment related diarrhea, as well as 
the incidences of the action taken categories as a result of the diarrhea event, and the 
outcome of the last episode of diarrhea. The time to onset of first treatment emergent 
diarrhea, duration of treatment emergent diarrhea per episode and per patient and will be 
summarized. Same summaries will be repeated for grade 2 or higher diarrhea and grade 
3 or higher diarrhea. The incidence of dose interruption due to diarrhea, dose reduction 
due to diarrhea and the number of dose interruptions and time to the first dose reduction 
and interruption will also be summarized. 


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6.9.2 Treatment-Emergent Adverse Events (TEAEs) 
A high-level summary of TEAE will be provided and select summaries of TEAE 
subgroups (indicated in parentheses).   
TEAEs will also be presented in incidence tables by system organ class (SOC), preferred 
term (PT), and grade for the following: 
 Any TEAE (summary) 
 
 Treatment-related TEAE 
 
 Serious TEAE 
 
 Serious treatment-related TEAE 
 
 Grade 3 or 4 TEAE (summary) 
 
 Fatal TEAE (summary) 
 
 TEAE leading to dose reduction 
 
 TEAE leading to dose interruption 
 
 TEAE leading to treatment discontinuation 
 
Incidence tables of TEAEs in descending order of frequency by PT will be presented for 
any TEAE, Grade 3 or 4 TEAE, and fatal TEAE. 
Listings will be provided for SAEs, TEAEs, and TEAEs leading to study drug 
discontinuation. 
 
 
6.9.3 Adverse Events of Special Interest (AESI) 
The AESI for neratinib will be based on SMQ or the complete list of the Sponsor-defined 
group of PTs. Tables will be provided with a summary of the incidence of all AESI by PT 
and Grade.  
 


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6.9.4 Death 
If applicable, deaths will be listed with the following variables: indicator of death 
(yes/no), on-study deaths (within 28 days after last dose of neratinib) (yes/no), and cause 
of death. 
 
6.10 Clinical Laboratory Parameters 
Laboratory data will be listed by visit/collection timepoint. 
Listings of laboratory values for blood chemistry parameters and hematology parameters 
will be provided. 
In addition, abnormalities in liver function tests will be listed.  
 
6.11 Vital Signs  
Vital sign measures (systolic and diastolic blood pressure, pulse,  respiratory rate, oral 
temperature and weight) will be listed.  
 
6.12 ECG Abnormality 
Electrocardiograms (ECGs) are measured after resting in a supine position for 5 minutes 
and include Heart rate, Rhythm pattern, RR interval PR interval, QRS interval, QT 
interval, QTc interval-Bazett’s, QTc interval-Fridericia’s, QTc interval-Other. Overall 
evaluation is also indicated. 
 
A listing of ECGs will be provided. 
 
 
6.13 Left Ventricular Ejection Fraction (LVEF) 
LVEF data will be listed.  
 
6.14 Disease Recurrence 
Disease recurrence data will be listed. 
 
 


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7. INTERIM ANALYSES 
Not applicable 


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8. CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
Not applicable 
 


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9. LIST OF PLANNED TABLES, FIGURES, AND LISTINGS 
9.1 
 TABLES 
 
Tables 
Summary of treatment-emergent diarrhea characteristics 
TEAE (high-level summary) 
TEAE by SOC, PT, and Grade 
Grade 3 or 4 TEAE by SOC, PT, and Grade 
Fatal TEAE by SOC, PT, and Grade 
TEAE in descending order of incidence by PT 
Grade 3 or 4 TEAE in descending order of incidence by PT 
Fatal TEAE in descending order of incidence by PT 
AESI by event category, PT, and Grade 
Incidence of liver function test abnormality 
 
 
9.2 
LISTINGS 
 
Listings 
Listing of disposition 
Listing of deviations 


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Listing of demographics 
Listing of cancer history 
Listing of prior anti-cancer medications 
Listing of serological parameters 
Listing of stool parameters 
Listing of neratinib exposure 
Listing of capecitabine exposure 
Listing of loperamide exposure 
Listing of concomitant therapy 
Listing of SAEs 
Listing of TEAEs 
Listing of TEAEs leading to IP discontinuation 
Listing of deaths 
Listing of laboratory values, blood chemistry 
Listing of laboratory values, hematology 
Listing of liver function test values 
Listing of ECGs 
Listing of Vital Signs 
Listing of LVEF 
Listing of disease recurrence 
 


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10. REFERENCES 
Study Protocol Number PUMA-NER-6203: An Open-Label Phase 2 Study to 
Characterize Colon Pathology in Patients With HER2 Amplified Breast Cancer Treated 
With Neratinib. PUMA Biotechnology, 04 September 2019. 
 


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