Clinical trial NCT02400476
Conditions: Early Stage HER2+ Breast Cancer
Keywords: HER2 + Breast Cancer Neratinib Nerlynx Loperamide Colestipol Budesonide
Sponsor: Puma Biotechnology, Inc.
Start date: 2015-02-01; Completion date: 2021-04-22
Enrollment: 563 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients with Early-Stage HER2+ Breast Cancer Treated with Neratinib and Loperamide or other prophylactic measures.

Detailed description:
This is an open-label, Phase 2 study that will investigate the incidence and severity of diarrhea in early-stage HER2+ breast cancer patients receiving neratinib with loperamide, alone and in combination with an anti-inflammatory treatment or a bile acid sequestrant treatment, or neratinib dose escalation, who have previously undergone a course of trastuzumab therapy in the adjuvant setting.

Patients will receive:

* Neratinib 240 mg orally once daily with food for thirteen 28-day cycles.
* Loperamide daily for two 28-day cycles and then as needed.
* Amendment 3, an anti-inflammatory treatment for one cycle and loperamide to be administered daily for two 28-day cycles and then as needed. Closed to enrollment.
* Amendment 4, colestipol for one cycle and loperamide to be administered one cycle and then as needed. Closed to enrollment.
* Amendment 5, colestipol for one cycle and loperamide as needed. Closed to enrollment.
* Amendment 6/6.1, 120 mg neratinib for Week 1 (C1D1-C1D7), followed by 160 mg neratinib for Week 2 (C1D8-C1D14), followed by 240 mg neratinib for Week 3 and thereafter (C1D15 to end of treatment). Loperamide as needed. Closed to enrollment.
* Amendment 7/7.1, 160 mg neratinib for the first 2 weeks (C1D1 - C1D14), followed by 200 mg neratinib for the next 2 weeks (C1D15 - C1D28), followed by 240 mg neratinib thereafter (C2D1 to end of treatment). Loperamide as needed.

Arms: arm 1: 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Loperamide daily for two 28-day cycles and then as needed. arm 2: 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Anti-inflammatory treatment for 1 cycle and Loperamide to be administered daily for two 28-day cycles and then as needed, thereafter. arm 3: 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered 1 cycle and then as needed, thereafter. arm 4: 240 mg Neratinib orally once daily with food for thirteen 28-day cycles. Colestipol for 1 cycle and loperamide to be administered as needed. arm 5: 120 mg Neratinib for Week 1, followed by 160 mg Neratinib starting for Week 2, followed by 240 mg Neratinib starting at Week 3 and thereafter (C1D15 to End of Treatment). Loperamide administered as needed. arm 6: 160 mg neratinib for the first 2 weeks, followed by 200 mg neratinib for the next 2 weeks, followed by 240 mg neratinib thereafter (C2D1 to End of treatment. Loperamide will be administered on an as-needed basis only.
Interventions: intervention 1: Neratinib intervention 2: Loperamide intervention 3: Colestipol intervention 4: Budesonide
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: 2 g twice daily with or without food for one 28 day cycle intervention 4: 9 mg extended release tablets once daily with or without food for 28 days

Protocol documents:
ICF_002.pdf: 
An Open-Label Study to Characterize the Incidence and 
Severity of Diarrhea in Patients 
with Early-Stage HER2+ Breast Cancer Treated with 
Neratinib and Loperamide 
 
NCT02400476 
 
Informed Consent Form – Amendment 7.1 
 
15-Aug-2019 


Document ID: 093d860c811c45e7
MASTER INFORMED CONSENT TO PARTICIPATE IN RESEARCH 
 
 
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Protocol Version: Amendment 7.1 (25-JUL-2019)  
ICF Version: 15-AUG-2019 
 
ONLY FOR PATIENTS ENROLLED UNDER AMENDMENT 7.1 
(North America & Asia Pacific) 
 
Information to Consider Before Taking Part in This Research Study 
 
Puma-NER-6201: An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients 
with Early Stage HER2+ Breast Cancer Treated with Neratinib and Loperamide 
 
Investigator Name: [name of principal investigator] 
 
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. Please read this information carefully and take your time 
making your decision. Ask the study doctor 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 kind of study, risks, inconveniences, 
discomforts, potential benefits, and other important information about the study will be reviewed with you. If you 
understand the study and you agree to participate, the study staff will ask you to sign this form.  Additionally, the 
study staff will provide you with a copy of this signed form. 
 
Please tell the study doctor or study staff if you are taking part in another research study.  
 
We are asking you to take part in a research study called: 
 
An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in Patients with Early Stage 
HER2+ Breast Cancer Treated with Neratinib and Loperamide 
 
The person who is in charge of this research study is [Insert PI name]. This person is called the Principal 
Investigator. However, other qualified study staff may be involved and can act on behalf of the Principal 
Investigator. 
 
This research study will be conducted at [List the site(s) where the participant will be expected to take part in 
the research]. 
 
This research study is being sponsored by Puma Biotechnology, Inc. 
 
 
PURPOSE OF THE STUDY 
Neratinib is a drug being studied as a potential new treatment for patients with breast cancer that show an 
increased amount of a gene or protein called HER2 or otherwise known as HER2+. A previous study showed that 
one year of neratinib decreased the rate of breast cancer returning in patients with early stage HER2+ breast 
cancer who had undergone prior therapy with chemotherapy and trastuzumab (Herceptin®). Neratinib (Nerlynx®) 
is a FDA (Food and Drug Administration) approved drug in the United States of America. 
 
The purpose of this study is to evaluate the occurrence and severity of diarrhea in patients being treated with 
neratinib for early stage HER2+ breast cancer and who take loperamide when needed to help prevent or 
decrease diarrhea. These patients would have received prior chemotherapy and trastuzumab (Herceptin®) 
treatment before joining the study. 


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SHOULD YOU TAKE PART IN THIS STUDY? 
 
 
This informed consent form explains this research study. After reading through this form and having the 
study explained to you by someone conducting this research, you can decide if you want to take part.  You do 
not have to take part in this study 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, at any time. 
 
Take your time to think about the information that is being provided to you. 
 
Feel Free to talk it over with your regular doctor if you wish. 
 
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, 
please sign this 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 received prior chemotherapy and trastuzumab 
(Herceptin®) treatment for early stage HER2+ breast cancer. 
 
WHAT WILL HAPPEN DURING THIS STUDY? 
 
Prior to participating in this study you will be given the opportunity to read this consent form and have all your 
questions answered. If you agree to participate you will be asked to sign this document and a copy will be provided 
to you for your files. You will participate in a screening period to determine if you are eligible to participate in the 
study. 
 
A procedure to collect your blood for research will be performed at Screening, Cycle 7 Day 1, Cycle 13 Day 28 
and/or at time of treatment discontinuation, or disease recurrence. 
 
The cell-free DNA (cfDNA) that is collected will undergo testing to identify whether there is breast 
cancer genetic material that may be a marker for breast cancer recurrence. 
 
This cfDNA testing will be done during and/or after you have participated in this study. In order to do 
this, genetic material from your blood will be tested. The information resulting from the analysis will be 
used anonymously meaning that your identity will not be revealed. You will not receive the results of this 
testing. Your sample will be used only for research and will not be sold. The research done with your 
sample may help to develop new breast cancer treatments in the future. 
 
You will complete questionnaires called the EuroQol 5D-5L (EQ-5D-5L), Functional Assessment of Cancer Therapy 
Breast (FACT-B), and the Rotterdam Symptom Checklist (RSCL) at Day 1 of Cycles 1, 2, 4, 7, 10 and at Day 28 of 


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Cycle 13 (End of Treatment). These questionnaires will evaluate your own understanding about your symptoms and 
health-related quality of life. You will need to complete these questionnaires yourself (i.e. a caregiver or study 
personnel should not complete the questionnaires for you) and before any other study procedures are given at your 
study visit. 
1. The EQ-5D-5L is a questionnaire that measures your health status based on mobility, self-care, usual 
activities, pain/discomfort, and anxiety. General health is also measured by a vertical visual analog scale. 
2. The FACT-B is a questionnaire assessing physical, social, emotional, and functional well-being and 
additional concerns that are more specific to women with breast cancer. 
3. The RSCL is a self-report measure to assess the quality of life of cancer patients. 
 
At some sites, a stool sample will be collected during the study to look at the effect that the study drug may have on 
the gut bacteria. 
 
Before You Begin the Study (Screening Period) 
 
A schedule of procedures is provided in the table below (Study Calendar). In addition to the procedures listed 
below, unscheduled clinic visits and additional procedures may be performed. An unscheduled visit and/or 
additional procedures may be required if your study doctor believes it is necessary to assess symptoms and 
concerns that you may have reported; to confirm or rule out potential return of your cancer, and/or for your safety. 
 
You will need to have the following exams, tests or procedures to find out if you can participate in the study.  These 
exams, tests or procedures are part of your regular cancer care and may be done even if you do not take part the 
study. If you have had any of them completed recently, they may not need to be repeated, depending on when you 
last completed the tests. Your study doctor will decide what exams, tests and/or procedures may need to be done. 
 
 
Research blood sample for cfDNA testing (about 4 teaspoons) 
 
Medical history - a discussion of your past and present health issues, including a discussion of your cancer, 
treatments and past cancer related surgeries 
 
Demographics – date of birth, sex and race 
 
Medication history – a review of all other medications you have taken in the last 30 days 
 
Vital signs (blood pressure, breathing rate, heart rate and temperature) 
 
Height and weight 
 
Performance status - an evaluation of how well you perform normal daily activities 
 
Physical exam 
 
Routine blood tests (about 4 teaspoons) 
o 
Measure your blood counts (make sure you are not anemic) 
o 
See how well your liver, kidneys and other organs are working 
 
Electrocardiogram (ECG) will be obtained to make sure your heart is functioning normally 
 
Echocardiogram (an ultrasound of the heart) or MUGA (a special x-ray) to make sure your heart is 
pumping normally 
 
Pregnancy test- If you are a woman who can have children 
o 
This can be done with a blood draw or using a urine sample 
 
Stool sample- at select study centers 
 
Possibly a bone scan or positron emission tomography (PET) scan (imaging test to rule out the spread of 
cancer to bone) if you have a specific abnormal laboratory test before starting the study that shows 
possible indicated bone involvement, called alkaline phosphatase 


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 
Possibly a computed tomography (CT) scan, magnetic resonance imaging (MRI) or ultrasound of the 
abdomen and chest (special imaging tests) if the liver blood tests before starting the study shows possible 
liver involvement 
 
Other imaging may be performed if your physician thinks it necessary 
 
The Cycle 1 Day 1 physical examination and routine blood tests may be omitted if the screening values and a physical 
examination were obtained within 72 hours prior to initiation of treatment. 
 
During the Active Treatment Stage 
 
This is an open-label study which means that you and your study doctor will know exactly what treatment you will 
receive. You will take neratinib by mouth with the following schedule: 
 
 
Week 1- Week 2 (C1D1-C1D14): 160 mg (four 40mg tablets) 
 
Week 3- Week 4 (C1D15-C1D28): 200 mg (five 40mg tablets) 
 
Week 5 through the End of Treatment (C2D1-EOT): 240 mg (six 40mg tablets) 
 
This 28-day period of time is called a cycle (C). Missed dose(s) of neratinib (i.e., any dose that is not administered 
per your doctor’s instructions) will not be made up. Please take neratinib with food, preferably in the morning; 
however, neratinib may be taken in the evening. It is important that you take neratinib at the same time every day. 
Neratinib must be stored at room temperature and out of direct sunlight. 
 
For female patients of child-bearing potential, for months that you do not have a scheduled visit (Cycles 5, 6, 8, 9, 
11, 12, 13 and/or the Safety follow-up): You will be asked to take a monthly urine pregnancy test at home. The 
Investigator or research staff will contact you during each cycle to confirm that you have performed the pregnancy 
test and to collect the results of the pregnancy test. 
 
Your study doctor will assign you to the group listed below for the first 28 days (Cycle 1). This group will enroll 
approximately 100 patients. 
 
Group: Neratinib dose escalation (Amendment 7): neratinib + loperamide (as needed) 
 
Along with neratinib 160 mg (four 40mg tablets) for week 1 through the end of week 2, 200 mg (five 
40mg tablets) for week 3 through the end of week 4, and then 240 mg (six 40mg tablets) for week 5 
through the end of treatment date. You can take loperamide on an as needed basis. 
 
If you experience loose stools after you take your first dose of neratinib, please note the following loperamide 
dosing instructions: 
 
 
The first dose of loperamide 4mg (2 tablets/capsules) right after the first loose stool 
 
Then take 2 mg (1 tablet/capsule) every 4 hours or after every loose stool until you have not had any 
loose stools for at least 12 hours 
 
You are allowed to up dose to keep your loose stools controlled (1-2 a day) 
 
The maximum dose of loperamide is 8 tablets (16 mg) in any 24-hour period 


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If your diarrhea continues after taking 8 tablets (16 mg loperamide) in one day, or if you are constipated, call your 
doctor or nurse immediately. Do not stop taking loperamide or your study medications unless instructed by your 
doctor. 
 
Your doctor or nurse will contact you by phone each of the first three days after you start taking neratinib to ask 
how much diarrhea you have and make any treatment adjustments. In addition, your doctor or nurse will also 
contact you by phone the end of the second and fourth weeks of treatment to make sure you have taken your 
neratinib correctly. NOTE: Your study doctor will provide you with a separate instruction sheet which will provide 
direction on how to manage your diarrhea. 
 
You are required to use a patient electronic diary (eDiary) or access an eDiary web link to record the number of 
neratinib and loperamide tablets (if taken) each day for the first two cycles of the study. After the first two cycles, the 
eDiary web link or use of a patient electronic diary (eDiary) will continue to be available or you may switch to a paper 
diary to be completed on a daily basis throughout the remainder of the study. Additionally, your study doctor will 
instruct you to record the number of stools you have each day. You will be required to record all doses of neratinib in 
the eDiary for only the first two cycles of the study. 
 
If you are given an eDiary device, you will need to bring your eDiary to your doctor’s office before each cycle visit. You 
should also bring any unused study medications and pill bottles (even if empty) to your doctor’s office at every visit. 
 
The cycle (28 days) will be repeated for 13 cycles. Each cycle is numbered in order. You will receive treatment unless 
your disease worsens or you have a side effect from neratinib that requires you to stop treatment. 
 
If the exams, tests and procedures show that you can be in the study, and you choose to take part, then you will need 
the following tests and procedures. Most are part of regular cancer care. In addition to the procedures listed below, 
unscheduled clinic visits and procedures may be performed if your study doctor believes that it is medically necessary 
to assess symptoms and concerns that you may have reported and to confirm or rule out potential return of your 
cancer or for your safety. If recommended by your study doctor, patients that experience significant diarrhea can 
choose to have an optional colonoscopy with biopsy completed. The sponsor will pay for the costs of the colonoscopy 
and the biopsy. 
 
The following tests and procedures will be performed at Day 1 of Cycles 1, 2, 3, and 4 (every 4 weeks): 
 
 
Patient-reported health outcomes questionnaires (EQ-5D-5L, FACT-B, and RSCL) 
o 
Collected on Day 1 of Cycles 1, 2, and 4 
 
Vital signs, weight, and targeted physical exam 
 
Routine blood tests (about 4 teaspoons) 
 
Phone calls on day 1, day 2, and day 3 after starting neratinib to see how you are feeling 
 
Phone calls at the on the following days during cycle 1: 
o 
Day 14 or Day 15 to remind you to increase your dose from 160mg to 200 mg 
o 
Cycle 1 Day 28 or Cycle 2 Day 1 to remind you to increase your dose from 200mg to 240 mg 
 
Review of symptoms and side effects 
 
Medication review – a review of all medications you are currently taking 
 
Pregnancy test – If you are a woman who can have children 
o 
This can be done with a blood draw or using a urine sample 
o 
Collected within 72hrs of the first dose of Cycle 1, and on Day 1 of Cycles 2-4 


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 
Stool kit will be provided to collect a small amount of stool - at select study centers 
o 
Collected on Day 1 of Cycles 2 and 4 
 
Electrocardiogram (ECG) 
o 
Collected on Day 1 of Cycles 2 and 4 
 
 
The following tests and procedures will be performed at Day 1 of Cycles 7 and 10 (every 12 weeks): 
 
 
Patient-reported health outcomes questionnaires (EQ-5D-5L, FACT-B, and RSCL) 
 
Research blood sample for cfDNA testing (about 4 teaspoons) 
o 
Collected on Day 1 of Cycle 7 
 
Vital signs, weight, and targeted physical exam 
 
Routine blood tests (about 4 teaspoons) 
 
Review of symptoms and side effects 
 
Medication review – a review of all medications you are currently taking 
 
Pregnancy test – If you are a woman who can have children 
o 
This can be done with a blood draw or using a urine sample 
 
Electrocardiogram (ECG) 
 
When you finish taking Neratinib (Cycle 13, Day 28 / End of Treatment Visit) 
 
You will need the following tests and procedures within 5 days after stopping treatment. They are part of your regular 
cancer care. These tests and procedures are detailed below: 
 
 
Patient-reported health outcomes questionnaires (EQ-5D-5L, FACT-B, and RSCL) 
 
Research blood sample for cfDNA testing (about 4 teaspoons) 
 
Vital signs, weight, and physical exam 
Medication review – a review of all medications you are currently taking 
 
Pregnancy test – If you are a woman who can have children 
o 
This can be done with a blood draw or using a urine sample 
 
Review of symptoms and side effects 
 
Routine blood tests (about 4 teaspoons) 
 
Electrocardiogram (ECG) will be obtained to make sure your heart is functioning normally 
 
Echocardiogram (an ultrasound of the heart) or MUGA (a special x-ray) to make sure your heart is 
pumping normally 
 
Stool kit will be provided to collect a small amount of stool – at select study centers, will be collected if 
your End of Treatment is earlier than Cycle 4. 
 
Safety Follow-up 
 
Twenty Eight days after you stop taking neratinib the following tests and procedures will be performed: 
 
Medication review – a review of all medications you are currently taking 
 
Pregnancy test- If you are a woman who can have children 
o 
This can be done with a blood draw or using a urine sample 
 
Review of symptoms and side effects 






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Talk to your study doctor about your choices before you decide if you will take part in this study. Alternatives to 
participating in the study include: 
 
Receiving treatment or care for your cancer without being in a study 
 
Taking part in another study 
 
Receiving no treatment 
 
Receiving comfort care, also called palliative care. This type of care helps reduce pain, tiredness, appetite 
problems and other problems caused by your cancer. It does not treat the cancer directly, but instead tries 
to improve how you feel. Comfort care tries to keep you as active and comfortable as possible. 
 
BENEFITS 
We are unsure if you will receive any benefits by taking part in this research study, however, the information gained 
from this study will help study doctors learn more about neratinib as a treatment for cancer. This information may 
help future cancer patients. 
 
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 (abnormally high level of creatinine in the bloodstream which may 
indicate kidney disease) 
 
Dyspepsia (indigestion) 
 
Abdominal distension 
 
Urinary tract infection 
 
Weight loss 
 
Dehydration 
 
 


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 
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 your dehydration is not treated, this could lead to a subtype of kidney failure called pre-renal failure. This type of 
kidney failure gets better when fluids are given. Patients who suffered from pre-renal failure in neratinib trials have 
all fully recovered their renal function. 
 
Symptoms of mild dehydration include thirst, decreased urine volume, abnormally dark urine, unexplained 
tiredness or fatigue, irritability and negative mood, headache, dry mouth and dry skin, dizziness when standing, and 
in some cases can cause insomnia. Other possible symptoms include cloudy urine, and burning sensation 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 your study doctor immediately to prevent the signs of dehydration 
described above. 
 
Other Potential Side Effect 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 important 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 your liver function. 
 
 
Interstitial lung disease: 
One patient with non-small cell lung cancer who was treated with neratinib experienced interstitial lung 
disease (inflammation and scarring of the lungs that is similar to pneumonia). 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 


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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. 
 
Risk of Loperamide 
Loperamide may be taken to treat diarrhea during the course of the study. Taking loperamide might be associated 
with, but is not limited to the following symptoms: constipation (decreased 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 
often. 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 the Blood Collection 
You may have pain, swelling, or bruising around the vein where your blood is collected. You may feel dizzy or you may 
faint. An infection may develop on your body where your blood is collected. 
 
Risks of the ECG (EKG) 
During an electrocardiogram, leads (wires) connected to small metal disks will be attached to certain points on your 
body to measure the electrical activity of your heart. Placement of the leads may cause skin irritation, redness, or 
burning of the skin at the site where the leads are attached. 
Risks of an ECHO 
An echocardiogram is a type of ultrasound test that uses sound waves to create pictures of the heart. The technician 
will put gel on your chest to help the sound waves pass through your chest. A probe is passed over your chest which 
picks up echoes of sound waves as they bounce off different parts of the heart. There are no known risks associated 
with this test. 
 
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 of the Bone Scan 
A bone scan is done to detect or rule out malignant bone lesions. It is not necessary to fast before the bone scan, but 
it is best to avoid eating a meal or drinking large amounts of fluids before the test. A tourniquet will be applied to 
your arm, and a radioactive dye will then be injected into a vein. You may have pain when the needle is inserted into 
your arm. You will have to wait 2-3 hours after the injection before the scan can be performed. You will lie on 


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your back on a table within the scanner, and you must be as still as possible during the test. You may be asked to 
assume various positions on the table in order for all of the necessary images to be taken. The scanner will move back 
and forth slowly, recording images for about 1 hour. After the test, you should drink plenty of fluids. You will be 
exposed to a small amount of radiation from the injection given for the bone scan. 
 
 
Risks of the Chest X-Ray 
A chest x-ray is done to detect and rule out lesions in the lung. During the test, you may be asked to stand and hold 
your breath as they take an image of your chest. It is very important during a chest x-ray to not move in order to 
produce a clear picture of your lungs. The procedure will only take a few minutes, and the time you will be asked to 
hold your breath is a matter of a few seconds. You will be exposed to a small amount of radiation during this test. 
 
Risks of the CT scan 
A CT scan takes about 30 to 60 minutes. If a contrast dye is to be used for the scan, you must not drink or eat 
anything for 4 hours before the test. You will be asked to remove all jewelry. A tourniquet will be applied to your 
arm, and a dye will be injected. You may have pain when the needle is inserted into your arm. When the contrast 
medium is injected during the CT scan, you may experience nausea, flushing, warmth and/or a salty taste. You might 
be allergic to the contrast medium. During the test, you will lie on your back on an x-ray table. A strap will be placed 
across the body part to be scanned; this is done to prevent movement so that the x-ray picture will be clear. The 
table will then slide into a large, tunnel-shaped machine. You might be uncomfortable while you are in the tunnel-
shaped machine. Some patients have felt claustrophobic during this test. When the CT scan is  finished, you may 
immediately resume your usual activities and diet. You will be exposed to radiation during this test. 
 
Risks of the MRI 
An MRI scan is performed like a CT scan. It is in a large, tunnel-shaped machine but it does not use x-rays. The MRI 
uses radio frequency waves, like those in an AM/FM radio, and has a powerful magnet. You must not have any metal 
objects on or in your body, for example, brain aneurysm clips or a pacemaker, and remove all jewelry to be able to 
have a MRI scan. Similar to CT scans, IV contrast dye may be used for MRI scans. Rarely, patients can have allergic 
reactions to MRI contrast agents. 
 
Risks of Colonoscopy 
A colonoscopy poses few risks however in rare instance, complications of this procedure may include: 
 
Adverse reaction to the sedative used during the examination 
 
Bleeding from the site where a tissue sample (biopsy) was taken or a polyp or other abnormal tissue was 
removed from site 
 
A tear in the colon or rectum wall (perforation) 
 
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 a female who is able to have children, you must have a negative pregnancy test before receiving 
investigational drug . You are considered able to have children if you have not completed menopause or are not 
surgically sterile. 


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If you are not surgically sterile or postmenopausal, or are a male patient, you must agree and commit to the use of a 
highly effective non-hormonal method of birth control while enrolled in the study. Your doctor can discuss highly 
effective non-hormonal birth control methods with you. After your last dose of the investigational drug you must 
continue to use medically highly effective non-hormonal 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 investigational drug, 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.   Male patients with a female partner of childbearing potential must agree and commit to use 
condoms and in addition the female partner must agree and commit to use a highly effective method of 
contraception (ie, hormonal contraception associated with inhibition of ovulation) 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. 
 
COMPENSATION 
 
You will receive no payment or other compensation for taking part in this study. 
 
COST 
 
There will be no additional costs to you as a result of being in this study. However, routine medical care for your 
condition (care you would have received whether or not you were in this study) will be charged to you or your 
insurance company. You may wish to contact your insurance company to discuss this further. 
 
CONFLICT OF INTEREST STATEMENT 
 
[If the Principal Investigator, research staff, or their family members have conflicting interest associated with this 
research, insert Conflict of Interest information here. Explain how the conflict will be managed to ensure that the 
integrity of the study data. If there is no conflict or potential conflict, delete this section.] 
 
PRIVACY AND CONFIDENTIALITY 
 
Your signature on this consent form gives permission for the research study staff to collect and use information 
that can identify you. Your identity will be kept as confidential as possible as required by law. Except as required 
by law, you will not be identified on any study form by name, social security number, address, telephone number 
or any other direct personal identifier. Instead, the research study doctor will use your initials and you will be 
assigned a patient identification number. The study doctor will keep a list that matches patient identification 
numbers to patient names, but the study doctor will not send that list to the study sponsor.  However, the study 


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forms will contain other information about you, such as your age, sex and medical history.  It is possible that this 
other information could be used to identify you even though your name does not appear. 
 
The results of this research may be presented at scientific or medical meetings or published in scientific journals. 
In this case, your identity will not be made known. 
 
Other groups may need to look at your medical records and study forms to make sure that the information is 
correct and to evaluate the conduct of this research study. These include the following: 
 
 
The sponsor of this study (Puma Biotechnology, Inc.) and its designees, including any contract research 
organizations helping the sponsor with the research study 
 
Collaborators and other parties working with the study sponsor 
 
The Institutional Review Board that approved this research study 
 
Regulatory agencies in the United States, such as the Food and Drug Administration, Department of Health 
and Human Services and the Office for Human Research Protections, as well as regulatory agencies in other 
countries where the sponsor seeks approval of the study drug or where the study is being conducted. 
 
You can change your mind about being in the study at any time. If you do change your mind about taking part in the 
study, no further data will be collected from you. However, the sponsor needs to retain and use any study results 
that have already been collected in order to maintain the quality of the study. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by US Law. This Web 
site will not include information that can identify you. At most, the Web site will include a summary of the results. 
You can search this Web site at any time. 
 
In addition to this Informed Consent Form, you will be asked to sign an “Authorization for Use and Disclosure of 
Protected Health Information.” This authorization will give more details about how your information will be used for 
this study, and who may see and/or get copies of your information. 
 
BIOLOGICAL SAMPLES 
WHAT WILL HAPPEN TO ANY SAMPLES I GIVE? 
 
Your biological samples (such as blood, urine, or tissue) may be collected, processed and reported as necessary for 
the purposes of the study. Any sample that you provide will be coded to ensure that your identity remains 
confidential. Your samples will be transferred to U.T. MD Anderson Cancer Center, 
 
 and 
the samples will be tested. In order to do this, genetic material (if applicable) from your tumor and blood will be 
tested. 
 
Testing will be done during or after you have participated in this study. The information resulting from the analysis 
will be used anonymously, meaning that your identity will not be revealed. You will not receive the results of this 
testing. Your samples will be stored for up to 20 years after the end of the study. They will be used only for research 
and will not be sold. The research done with your samples may help to develop new products in the future. 
 
The U.S. and some states (including New York) have laws that forbid using your genetic information as a reason to 
fire you or not to give you a job. Under these laws, genetic information cannot be used to deny you health 
insurance or to raise the cost of your current health insurance. However, we cannot fully guarantee you that no one 
will ever use your test results against you, and these laws do not apply to life or disability insurance, or if you are a 
member of the military. 


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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. [If participants are employees, 
include as applicable: “decision to participate or not to participate will not affect your job status.”] 
You will be withdrawn from the study if: 
 
Your disease progresses 
 
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 
 
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 as 
soon as possible if such information becomes available. 
 
WHAT IF YOU GET SICK OR HURT WHILE YOU ARE IN THE STUDY? 
 
If you need emergency care: 
 
Go to your nearest hospital or emergency room right away or call [insert country specific #, if applicable] for 
help. It is important that you tell the doctors at the hospital or emergency room that you are participating 
in a research study. If possible, take a copy of this informed consent form with you when you go. [Insert 
facility name] does not have an emergency room or provide emergency care. 
 
Call the study doctors as soon as you can. They will need to know that you are hurt or ill.  Call [Name of 
Study Doctor at Telephone #] or [alternate telephone #]. 
If you do NOT need emergency care: 
 
Go to your regular doctor. It is important that you tell your regular doctor that you are participating in a 
research study. If possible, take a copy of this informed consent form with you when you go. 
 
The [insert facility name] may not be able to give the kind of help you need. However, let the study 
doctor know of your illness either before or during your next scheduled study visit. 
 
Will I be compensated for research related injuries? 
 
[This section should be modified only as required by the Clinical Study Agreement, the IRB or local laws.] 
If you feel that you have been injured as a result of taking the study drug or any of the anti-diarrhea drugs in this 
study, you should contact your study doctor. If the study doctor and the sponsor determine that the injury is a direct 
result of effects of the study drug or one of the anti-diarrhea drugs or the study procedures performed due to your 
participation in the study, the sponsor will reimburse you for the reasonable cost of emergency and/or acute medical 
care incurred by you for treatment if you do not have commercial medical insurance or to the extent that those 
medical expenses are not covered by your commercial medical insurance. Injury resulting from the use of the study 
drug, or one of the anti-diarrhea drugs or a study procedure does not include the normal progression 


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of your disease or any underlying pre-existing medical conditions. Other compensation (including without 
limitation) for such things as lost wages, disability, or discomfort due to this type of injury is not available. You 
understand, however, that you have not waived any of your legal rights by signing this consent form. 
 
The study doctor will ask to follow up with you if you are injured. 
 
 
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. 
 
We will tell you how to stop safely. We 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. 
 
[Describe the procedures for the orderly termination of participation by the participant.] 
 
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 we find out it is not safe for you to stay in the study or if you are not coming for the 
study visits when scheduled. We 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 [name of principal investigator] at 
[telephone #]. 
If you have questions about your rights, general questions, complaints, or issues as a person taking part in this study, 
call the [insert facility name] Institutional Review Board (IRB) at (###) ##-####. 


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CONSENT TO TAKE PART IN RESEARCH 
 
It is up to you to decide whether you want to take part in this study. If you want to take part, please read the 
statements below and sign the form if the statements are true. 
 
I freely give my consent to take part in this study and authorize that my health information as agreed above, be 
collected/disclosed in this study. I understand that by signing this form I am agreeing to take part in research. I 
have received a copy of this form to take with me. 
 
 
 
 
Signature of Person Taking Part in Study 
Date 
 
 
 
Printed Name of Person Taking Part in Study 
 
 
 
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 Person Obtaining Informed Consent / Research Authorization 
Date 
 
 
 
 
 
Printed Name of Person Obtaining Informed Consent / Research Authorization 


Document Information
Document Name: NER-6201 Am7.1 NA/PAC ICF 2019-08-15
Document Title: NER-6201 Am7.1 NA/PAC ICF 2019-08-15
Document Version: 1.0
Document State: Approved
Page Number: 1 of 1
Signed By: 
Functional Area: Business Development
Meaning Of Signature: I am approving this document
Date/Time: 8/16/2019 10:41:52 AM
Signed By: 
Functional Area: Clinical Development
Meaning Of Signature: I have reviewed and agree with the content of this document
Date/Time: 8/16/2019 10:50:19 AM
Signed By: 
Functional Area: Executives
Meaning Of Signature: I am approving this document
Date/Time: 8/16/2019 12:58:31 PM
Signed By: 
Functional Area: Quality
Meaning Of Signature: I am approving this document
Date/Time: 8/19/2019 11:13:15 AM

Prot_000.pdf: 
An Open-Label Study to Characterize the Incidence and 
Severity of Diarrhea in Patients 
with Early-Stage HER2+ Breast Cancer Treated with 
Neratinib and Loperamide 
 
NCT02400476 
 
Study Protocol – Amendment 7.1 
 
25-Jul-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 Study to Characterize the Incidence and Severity of Diarrhea in Patients 
with Early-Stage HER2+ Breast Cancer Treated with Neratinib and Loperamide  
Study Protocol Number: 
PUMA-NER-6201 
Disease Condition: 
HER2-Positive Breast Cancer 
Sponsor’s Investigational Product 
Name/Formulation: 
Neratinib Tablets 
US IND Number 
066783 
EudraCT Number 
2015-004374-15 
Lead Investigator: 
Carlos Barcenas, MD, MSc 
Assistant Professor 
Department of Breast Medical Oncology 
Division of Cancer Medicine 
The University of Texas MD Anderson Cancer Center 
Houston, TX 
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: 
Richard Bryce, MBChB, MRCGP, MFPM  
Chief Medical & Scientific Officer  
Phone: +1 424.248.6500 
Date of Protocol 
Original 
19-NOV-2014 
Amendment 1 
20-MAY-2015 
Amendment 2 
06-NOV-2015 
Amendment 3 
24-MAR-2016 
Amendment 4 
19-AUG-2016 
Amendment 5 
19-SEP-2017 
Amendment 6 
26-OCT-2017 
Amendment 6.1 (Global) 
30-APR-2018 
Amendment 7 
08-OCT-2018 
Amendment 7.1 
25-JUL-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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CONFIDENTIAL 
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 Study to Characterize the Incidence and Severity of Diarrhea in Patients with 
Early-Stage HER2+ Breast Cancer Treated with Neratinib and Loperamide  
Condition or Disease: HER2-positive Breast Cancer 
Approximate Values 
Number of Patients 
Approximately 750 
Duration of Patient Participation 
1 year 
Number of Centers 
Approximately 74  
Duration of Study 
7 years 
Objectives:  
Primary: The primary objective of this study is to characterize the incidence and severity of diarrhea in patients with 
early-stage HER2 overexpressed/amplified (HER2+) breast cancer treated with neratinib when administered with 
intensive loperamide prophylaxis, after prior treatment with trastuzumab.  
Secondary: The secondary objectives of this study are:  
 
To assess the incidence of serious adverse events (SAEs) and other adverse events of special interest (AESI).  
 
To assess the incidence and severity of diarrhea after the administration of an anti-inflammatory agent (for 
patients enrolled under Amendment 3), a bile acid sequestrant (for patients enrolled under Amendment 4 and 
Amendment 5), or following 2 different dose-escalation regimens of neratinib (for patients enrolled under 
Amendment 6/6.1 and for patients enrolled starting with Amendment 7, respectively). 
Exploratory:  
 
Exploratory objectives include: 
 
For patients enrolled starting with Amendment 2: 
 
To assess patient-reported health outcomes using the EuroQol 5D-5L (EQ-5D-5L) and the Functional 
Assessment of Cancer Therapy Breast (FACT-B) questionnaires. 
 
To collect biomarkers of disease from cell-free DNA (cfDNA) to evaluate their relationship to clinical 
recurrence of disease. 
 
For patients enrolled starting with Amendment 6: 
 
Evaluation of stool bacterial diversity (microbiome)   
 
For patients enrolled starting with Amendment 6.1: 
 
To assess patient-reported health outcomes using the Rotterdam Symptom Checklist (RSCL) 
Study Design: 
This is an open-label, Phase 2 study that will investigate the incidence of diarrhea in HER2+ breast cancer patients 
receiving neratinib with intensive loperamide diarrhea prophylaxis, alone and in combination with an anti-inflammatory 
treatment or a bile acid sequestrant  treatment, who have previously undergone a course of trastuzumab therapy in the 
adjuvant setting. 
Patients will receive:  
 
Neratinib 240 mg orally once daily for thirteen (13) 28-day cycles.  
 
Loperamide daily for two (2) 28-day cycles and then as needed.  


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CONFIDENTIAL 
 
For patients enrolled under Amendment 3, an anti-inflammatory treatment for 1 cycle and loperamide to be 
administered daily for two (2) 28-day cycles and then as needed, thereafter; 
 
For patients enrolled under Amendment 4, colestipol for 1 cycle and loperamide to be administered 1 cycle 
and then as needed, thereafter; 
 
For patients enrolled under Amendment 5, colestipol for 1 cycle and loperamide to be administered on an as-
needed basis only. 
 
For patients enrolled under Amendment 6/6.1, 120 mg neratinib for Week 1 (C1D1 – C1D7), followed by 160 
mg neratinib for Week 2 (C1D8 – C1D14), followed by 240 mg neratinib for Week 3 and thereafter (C1D15 
to End-of-treatment [EOT]). Loperamide will be administered on an as-needed basis only.  
 
For patients enrolled starting with Amendment 7, 160 mg neratinib for the first 2 weeks  (C1D1 – C1D14), 
followed by 200 mg neratinib for the next 2 weeks (C1D15 – C1D28), followed by 240 mg neratinib 
thereafter (C2D1 to End-of-treatment [EOT]). Loperamide will be administered on an as-needed basis only. 
Patients will receive neratinib for 13 cycles (364 days) or until disease recurrence (as determined by the Investigator), 
death, unacceptable toxicity, or other specified withdrawal criterion. 
The effect of the anti-inflammatory treatment budesonide  and the bile acid sequestrant, colestipol, on the incidence, 
severity, and duration of diarrhea will be investigated in sequential patient cohorts using a sample size of approximately 
64 patients per cohort. The anti-inflammatory cohort added in Amendment 3 will be assigned to receive budesonide 
9 mg once daily with or without food for 28 days along with neratinib 240 mg /day (13 cycles) and intensive 
loperamide prophylaxis that will continue through the first 2 cycles (total 56 days), and then on an as-needed basis 
thereafter. 
Following the completion of enrollment of the patients receiving budesonide, neratinib, and intensive loperamide 
prophylaxis, the next cohort will be evaluated after receiving colestipol 2 g twice daily with or without food for 28 
days, to be taken at least 2 hours after, but at least 4 hours before, neratinib 240 mg /day (13 cycles) and intensive 
loperamide prophylaxis. For this cohort, intensive loperamide prophylaxis will continue through the first cycle (total 28 
days); for Cycle 2 and beyond, loperamide may be administered as needed (PRN). 
Following complete enrollment of  the cohort treated with colestipol + intensive loperamide prophylaxis, all patients in 
the next cohort will be evaluated after receiving colestipol and neratinib with loperamide administered on a PRN basis 
only. 
Following complete enrollment of the cohort receiving neratinib + colestipol + loperamide PRN, all patients in the next 
cohort will be evaluated after receiving neratinib administered according to the following dose-escalation scheme: 
120 mg neratinib for 1 week (C1D1 – C1D7), followed by 160 mg neratinib for Week 2 (C1D8 – C1D14), followed by 
240 mg neratinib for Week 3 and thereafter (C1D15 to EOT). Loperamide is to be administered on a PRN basis only.  
Following complete enrollment of all patients in the 120 mg/160 mg/240 mg dose-escalation scheme, patients enrolled 
in the next cohort will be evaluated after receiving neratinib administered according to a second dose escalation 
scheme: 160 mg neratinib to be taken for the first 2 weeks (C1D1 – C1D14), followed by 200 mg neratinib to be taken 
for the next 2 weeks (C1D15 – C1D28), followed by 240 mg neratinib daily dose taken thereafter (C2D1 to EOT). 
Loperamide is to be administered on a PRN basis only. 
The Sponsor will regularly review accumulating safety data (by individual subject and in aggregate). Early termination 
of a cohort or the study may be permitted if data indicate that anti-diarrheal treatment is ineffective. 
Patients in all treatment groups will continue to complete the remaining 12 treatment cycles. 
The final analysis will be conducted after all patients have completed 13 cycles of study treatment or have met other 
specified withdrawal criterion (see Section 10). 
The study will end when all patients have been followed up for 28 days after the last dose of neratinib.  


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Study Endpoints: 
 
The primary endpoint of the study is the incidence of Grade 3 or higher diarrhea.  
 
Secondary endpoints include the frequency distribution of the maximum grade incidence of diarrhea, the 
incidence and severity of diarrhea with and without anti-inflammatory agents, with and without a bile acid 
sequestrant, the effect of lower starting doses and dose escalation of neratinib on the incidence and severity of 
diarrhea; and the incidence of SAEs and AESIs.  
 
The exploratory endpoint of patient-reported health outcomes will be assessed by the EuroQol EQ-5D-5L, the 
FACT-B questionnaires (for patients enrolled starting with Amendment 2), and the RSCL (for patients enrolled 
starting with Amendment 6.1).  
 
The exploratory endpoint of disease biomarkers will consist of the biomarkers of disease recurrence (for patients 
enrolled starting with Amendment 2). 
 
The exploratory endpoint of evaluation of stool bacterial diversity, i.e., microbiome (for patients enrolled starting 
with Amendment 6/6.1). 
Neratinib, Loperamide, Anti-inflammatory, and Bile Acid Sequestrant Treatments, Dose, and Administration:  
 
Neratinib: Six (6) 40 mg tablets (total dose 240 mg) orally, once daily with food, preferably in the morning, 
continuously for 13 cycles (364 days), except for patients enrolled under Amendment 6/6.1 who will receive 
neratinib in the dose escalation scheme detailed above (ie, total dose 120 mg daily for the first week, 160 mg daily 
for Week 2, and 240 mg daily for Week 3 and thereafter, until EOT), and except for patients enrolled under 
Amendment 7/7.1 who will receive neratinib in a second dose escalation scheme (ie, total dose 160 mg daily for 
the first 2 weeks, 200 mg daily for the following 2 weeks, and 240 mg daily thereafter until EOT)..  
 
Loperamide:  
 
For patients enrolled under the Original Protocol: 
o 
Initial dose of 4 mg (2 tablets/capsules) with the first dose of neratinib, followed by 2 mg 
(1 tablet/capsule) every 4 hours for the first 3 days. After the first 3 days, loperamide 2 mg every 6 to 
8 hours through the first 2 cycles of therapy (56 days) from start of neratinib. 
 
For patients enrolled under Amendment 1  Amendment 3: 
o 
For the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered orally by patients 
3 times a day (total 12 mg a day). The initial dose of loperamide 4 mg will be self-administered orally 
with the first dose of neratinib.  
o 
After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered orally twice a day 
(total 8 mg a day) through the first 2 cycles of therapy (Day 56) from start of neratinib dosing 
 
For patients enrolled under Amendment 4: 
o 
For the first 14 days. The initial dose of loperamide 4 mg will be self-administered orally with the first 
dose of neratinib, followed by loperamide 4 mg (2 tablets/capsules) self-administered orally by patients 
3 times a day (total 12 mg a day). 
o 
After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered orally twice a day 
(total 8 mg a day), for 1 cycle [28 days], and then as needed (PRN) (not to exceed 16 mg per day).  
 
For patients enrolled under Amendment 5, Amendment 6, Amendment 6.1, Amendment 7, and 
Amendment 7.1: 
o 
Loperamide 4 mg (2 tablets/capsules) will be self-administered orally by patients on a PRN basis only, 
from the start of neratinib dosing (not to exceed 16 mg per day).  
 
 


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 
Budesonide 
 
For patients enrolled under Amendment 3 and who participate in the evaluation of budesonide, patients will 
self-administer oral budesonide at a dose of 9 mg once daily for the first treatment cycle, to be taken with 
neratinib and intensive loperamide prophylaxis. 
 
Colestipol 
 
For patients enrolled under Amendment 4 and Amendment 5 and who participate in the evaluation of 
colestipol, patients will self-administer colestipol at a dose of 2 g twice daily for the first treatment cycle, to 
be taken at least 2 hours after, but at least 4 hours before neratinib and intensive loperamide prophylaxis 
(Amendment 4) or loperamide PRN (Amendment 5). Colestipol is a bile acid sequestrant anion resin that 
has the potential to interact with co-administered medication. Precaution should be taken around the timing 
of administration to avoid drug-drug interaction. Please refer to Section 7.6 and Appendix 10 of the protocol 
for additional specific recommendations regarding the administration of concomitant medication including 
neratinib and loperamide, the investigation products in this protocol. 
Patients must use a diary to record their intake of medicinal product as supplied by sponsor. 
 
Diagnosis and Main Criteria for Inclusion:  
Study Population:  
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 3c 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 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. The last dose of trastuzumab must have been given >2 weeks and ≤1 year (365 days) from enrollment.  
6. Physician assessment confirming that the patient is negative for local or regional recurrence of disease or 
metastatic disease at the time of study entry, including: 
a. 
Per standard of care, bone scan or positron emission tomography (PET) scan; required only if alkaline 
phosphatase (ALP) is ≥2 x upper limit of normal (ULN) and/or there are symptoms of metastatic 
bone disease. A confirmatory imaging study is required if the results from the bone scan are 
questionable.  
b. Per standard of care, computed tomography (CT), magnetic resonance imaging (MRI) or ultrasound 
of the abdomen and chest; required only if aspartate aminotransferase (AST)/alanine 
aminotransferase (ALT) or ALP is ≥2 x ULN. 
Other radiologic assessments may be performed  to rule out underlying breast cancer recurrence if 
indicated and as per standard of care (for patients enrolled starting with Amendment 6.1). 
7. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or 
echocardiogram (ECHO).  
8. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1.  
9. 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 


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menopause. [Women are considered postmenopausal if they are ≥12 months without menses, in the absence of 
endocrine or anti-endocrine therapies.] 
10. Women of childbearing potential must agree and commit to the use of a highly effective non-hormonal method 
of contraception, ie, 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.  Man (male patient) with 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 (ie, 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. 
11. Recovery (ie, to Grade 1 or baseline) from all clinically significant AEs related to prior therapies (excluding 
alopecia, neuropathy, and nail changes).  
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. Clinical or radiologic evidence of local or regional recurrence of disease or metastatic disease prior to or at the 
time of study entry.  
2. Currently receiving chemotherapy, radiation therapy, immunotherapy, or biotherapy for breast cancer.  
3. Major surgery within <30 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.  
4. 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.  
5. QTc interval >0.450 seconds (males) or >0.470 (females), or known history of QTc prolongation or Torsade 
de Pointes (TdP). 
6. 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  
<100,000/µl (<100 x 109/L) 
Hemoglobin  
<9 g/dL 
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  
Creatinine  
Creatinine clearance <30 mL/min (as calculated by 
Cockcroft-Gault formulaa or Modification of Diet in Renal 
Disease [MDRD] formulab) 
a.  Cockcroft and Gault, 1976. 
b. Levey et al, 1999. 
7. Active, unresolved infections.  
8. 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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9. Currently pregnant or breast-feeding.  
10. 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).  
11. Clinically active infection with hepatitis B or hepatitis C virus.  
12. 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.  
13. Known hypersensitivity to any component of the investigational products; known allergies to any of the 
medications or components of medications used in the trial. 
14. Unable or unwilling to swallow tablets. 
Safety Assessments: 
The primary endpoint is the incidence of Grade 3 or higher diarrhea. AEs and AESIs will be graded according to the 
National Cancer Institute Common Terminology Criteria (NCI CTCAE), version 4.0. SAEs and AESIs will be reported 
through 28 days after the last dose of investigational product and 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 neratinib’s administration, it should be promptly reported. Safety will also be assessed based on 
medical history, vital sign measurements, physical examination findings, electrocardiogram results, MUGA or ECHO, 
and laboratory assessments.  
Other Assessments: 
Patient Reported Health Outcomes Assessments  
The following questionnaires will be used to collect patient-reported health outcomes data:  
1) EQ-5D-5L Health Questionnaire (for patients enrolled starting with Amendment 2) 
2) FACT-B (for patients enrolled starting with Amendment 2) 
3) RSCL (for patients enrolled starting with Amendment 6.1) 
Patient-reported outcomes assessments will be performed at C1D1, C2D1, C4D1, C7D1, C10D1, and C13D28/EOT. 
Biomarkers (for patients enrolled starting with Amendment 2) 
cfDNA will be obtained from plasma samples collected at Screening, C7D1, C13D28 and/or at time of treatment 
discontinuation, and at disease recurrence; cfDNA will undergo molecular profiling to identify biomarkers of disease 
recurrence. 
Microbiome Evaluation (for patients enrolled starting with Amendment 6)   
At select study centers, a stool swab will be collected at Screening, C2D1, and C4D1 and/or at time of treatment 
discontinuation if earlier than C4D1 for possible future assessments of microbiome to assess the effect that neratinib 
has on the microbiome (currently in US only). 
Disease Recurrence 
Clinical documentation of recurrence, including recurrence site, radiographic, and/or pathologic procedures will be 
collected at end-of -treatment (EOT). 


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Statistical Methods: 
Sample Size:  
The first 120 patients will be under the Original Protocol, Amendment 1, and Amendment 2. The incidence of Grade 3 
or higher diarrhea is assumed to be 15% in this study. A sample size of 120 patients will ensure that the width of the 
95% Clopper-Pearson CI of the incidence of Grade 3 or higher diarrhea is no more than 18.5%. For example, if 18 out 
of the 120 patients are observed to have Grade 3 or higher diarrhea, the incidence and its 95% (2-sided) CIs will be 
15.0% (9.1%, 22.7%) where the width of the CI is 13.5%.  
In addition to the analyses of the overall safety population, anti-diarrheal prophylaxis regimen-specific subgroup 
analyses will be performed as needed. Precision of the estimated 95% CIs for the regimen-specific subgroup(s) will be 
lower than what is provided above for the overall safety population.  
To further investigate treatments, cohorts were added. For patients enrolled under Amendment 3, the effect of 
budesonide + mandatory loperamide prophylaxis on the incidence, severity, and duration of diarrhea will be assessed.  
For patients enrolled under Amendment 4 and Amendment 5, the effect of colestipol + mandatory loperamide 
prophylaxis (Amendment 4) and colestipol + PRN loperamide (Amendment 5) will be assessed; for patients enrolled 
under Amendment 6/6.1 and under Amendment 7/7.1, the effect of the dose escalation regimen of neratinib will be 
assessed. The incidence of Grade 3 or higher diarrhea will be evaluated. A sample size of 64 patients will ensure that 
the width of the 95% Clopper-Pearson CI of the incidence of Grade 3 or higher diarrhea is no more than 26%. For 
example, if 7 out of the 64 patients are observed to have Grade 3 or higher diarrhea, the incidence and its 95% (2-sided) 
CI will be 10.9% (4.5–21.2%) where the width of the CI is 17%.  
For each additional cohort, a sample size of 100 patients will ensure that the width of the 95% Clopper-Pearson CI of 
the incidence of Grade 3 or higher diarrhea is no more than 21%. For example, if 15 out of the 100 patients are 
observed to have Grade 3 or higher diarrhea, the incidence and its 95% (2-sided) CI will be 15.0% (8.7–23.5%) where 
the width of the CI is 15%. 
Cohorts will continue to enroll without interruption, in sequence. Thus enrollment may exceed initial projections. 
Statistical Analysis: 
The primary endpoint is the incidence of Grade 3 or higher diarrhea. The accompanying 2-sided 95% Clopper-Pearson 
CIs will be computed.  
Safety: 
All patients who receive a dose of neratinib will be analyzed for safety.  Treatment emergent AEs, SAEs, and AESIs, as 
well as select laboratory tests will be summarized. Deaths and discontinuation from study treatment will also be 
summarized.  
Exploratory: 
Patient-related outcomes data (scores from the EQ-5D-5L, FACT-B, and RSCL questionnaires) will be summarized 
and plotted over time. Changes from baseline will be provided with both point estimates and CIs. 
Exploratory analyses will be conducted to evaluate the relationship between disease biomarkers identified from 
molecular profiling and indications of clinical disease recurrence. 
Microbiome evaluation from participating sites will be summarized at baseline, C2D1, C4D1, and/or at time of 
treatment discontinuation. No formal statistical analyses are planned of the microbiome data.  
All analyses of exploratory endpoints are descriptive and no formal testing is planned. 
Interim Analysis: 
An interim analysis is planned when approximately 120 patients enrolled under the Original protocol, Amendment 1, 
and Amendment 2, have completed at least 2 cycles (56 days) of neratinib with loperamide prophylaxis. The interim 
analysis will only include those 120 patients enrolled under the Original Protocol, Amendment 1, and Amendment 2. 
Other additional analyses by cohort, in addition to the interim analysis, may be carried out as required.  


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Final Analysis: 
The final analysis is planned when all patients have completed 13 cycles (364 days) of neratinib therapy or have 
discontinued the study.  
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.............................16 
2. 
INTRODUCTION ......................................................................................................19 
2.1. 
Background .................................................................................................................19 
2.2. 
ERBB2 Gene and Cancer ...........................................................................................19 
2.2.1. 
The Epidermal Growth Factor Receptor Family (ERBB) ..........................................19 
2.2.2. 
ERBB2-positive Cancers ............................................................................................20 
2.3. 
Current Therapies Targeting ERBB Receptors ..........................................................20 
2.3.1. 
Trastuzumab ...............................................................................................................20 
2.3.2. 
Pertuzumab .................................................................................................................20 
2.3.3. 
Pertuzumab in Combination with Trastuzumab .........................................................20 
2.3.4. 
Ado-trastuzumab Emtansine .......................................................................................21 
2.3.5. 
Other HER2-targeted Therapies .................................................................................22 
2.4. 
Neratinib .....................................................................................................................22 
2.4.1. 
Safety Profile of Neratinib in Monotherapy and Combination Therapy 
Studies.........................................................................................................................22 
2.4.2. 
Diarrhea Prophylaxis in Neratinib Clinical Studies ....................................................22 
2.4.3. 
Preliminary Clinical Activity of Neratinib .................................................................24 
2.5. 
Study Rationale ...........................................................................................................24 
2.5.1. 
Neratinib Dose Escalation Rationale ..........................................................................25 
2.5.2. 
Results of Preclinical Investigations ...........................................................................25 
2.5.3. 
Rationale for use of an Anti-inflammatory Agent ......................................................25 
2.5.4. 
Rationale for Use of a Bile Acid Sequestrant .............................................................26 
2.5.5. 
Enrollment ..................................................................................................................26 
3. 
STUDY OBJECTIVES ..............................................................................................27 
3.1. 
Primary Objective .......................................................................................................27 
3.2. 
Secondary Objectives .................................................................................................27 
3.3. 
Exploratory Objectives ...............................................................................................27 
4. 
INVESTIGATIONAL PLAN .....................................................................................28 
4.1. 
Overall Study Design ..................................................................................................28 


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4.2. 
Study Duration and Termination of Study ..................................................................31 
4.3. 
Randomization and Blinding ......................................................................................32 
5. 
STUDY POPULATION .............................................................................................33 
5.1. 
Inclusion Criteria ........................................................................................................33 
5.2. 
Exclusion Criteria .......................................................................................................34 
5.3. 
Patient Enrollment ......................................................................................................35 
6. 
ADMINISTRATION OF NERATINIB, LOPERAMIDE,  ANTI-
INFLAMMATORY, AND BILE ACID SEQUESTRANT TREATMENTS ...........36 
6.1. 
Neratinib .....................................................................................................................36 
6.1.1. 
Neratinib Dose Adjustment ........................................................................................36 
6.2. 
Loperamide .................................................................................................................37 
6.2.1. 
Loperamide Dose Adjustment ....................................................................................39 
6.3. 
Budesonide .................................................................................................................39 
6.4. 
Colestipol ....................................................................................................................40 
6.5. 
Packaging, Labeling, and Storage ..............................................................................41 
6.5.1. 
Neratinib .....................................................................................................................41 
6.5.2. 
Loperamide .................................................................................................................41 
6.5.3. 
Budesonide .................................................................................................................41 
6.5.4. 
Colestipol ....................................................................................................................42 
6.6. 
Drug Accountability and Treatment Compliance* .....................................................42 
7. 
CONCOMITANT MEDICATIONS ..........................................................................43 
7.1. 
Permitted Concomitant Treatment ..............................................................................43 
7.2. 
Required Loperamide Antidiarrheal Therapy .............................................................43 
7.3. 
Anti-inflammatory Treatment .....................................................................................47 
7.4. 
Colestipol (Amendment 4 and Amendment 5) ...........................................................48 
7.5. 
Prohibited Concomitant Treatment .............................................................................48 
7.6. 
Potential for Drug-Drug Interactions ..........................................................................49 
7.6.1. 
Potential Drug-Drug Interactions with Neratinib .......................................................49 
7.6.2. 
Potential for Drug-Drug Interactions with Budesonide ..............................................49 
7.6.3. 
Potential for Drug-Drug Interactions with Colestipol ................................................50 
7.7. 
Treatment Compliance ................................................................................................50 
8. 
STUDY ASSESSMENTS ..........................................................................................51 
8.1. 
Efficacy Assessment ...................................................................................................51 


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8.2. 
Safety Assessments .....................................................................................................51 
8.2.1. 
Clinical Endpoints and Definitions .............................................................................51 
8.2.2. 
Laboratory Assessments .............................................................................................51 
8.2.3. 
Vital Signs ..................................................................................................................52 
8.2.4. 
Physical Examination .................................................................................................53 
8.2.5. 
Electrocardiogram .......................................................................................................53 
8.2.6. 
Left Ventricular Ejection Fraction (LVEF) ................................................................53 
8.3. 
Other Study Assessments ...........................................................................................53 
8.3.1. 
Health Outcomes Assessments ...................................................................................53 
8.3.2. 
Biomarkers ..................................................................................................................54 
8.3.3. 
Disease Recurrence .....................................................................................................54 
8.3.4. 
Microbiome Evaluation (for patients enrolled starting with Amendment 6) .............54 
8.4. 
Protocol Deviations ....................................................................................................55 
8.5. 
Study Drug Accountability/Patient Diary ...................................................................55 
8.5.1. 
Study Medication Accountability ...............................................................................55 
8.5.2. 
Patient Diary ...............................................................................................................55 
9. 
STUDY CONDUCT ...................................................................................................56 
9.1. 
Screening/Baseline .....................................................................................................56 
9.2. 
Active Treatment Phase ..............................................................................................57 
9.3. 
Treatment Discontinuation or End-of-Treatment Assessments ..................................58 
9.4. 
Safety Follow-up Visit ................................................................................................59 
9.5. 
Long-term Follow-up ..................................................................................................59 
9.6. 
End of Study ...............................................................................................................59 
10. 
PATIENT WITHDRAWAL AND REPLACEMENT ...............................................60 
10.1. 
Investigational Product Discontinuation .....................................................................60 
10.2. 
Withdrawal from the Study ........................................................................................60 
10.3. 
Procedures for Investigational Product Discontinuation/Study Withdrawal ..............61 
10.4. 
Patient Replacement ...................................................................................................61 
11. 
PREMATURE TERMINATION OF STUDY ...........................................................62 
12. 
STATISTICAL METHODS .......................................................................................63 
12.1. 
General Considerations ...............................................................................................63 
12.1.1. 
Subgroups/Cohorts .....................................................................................................63 
12.2. 
Study Patients .............................................................................................................63 


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12.2.1. 
Disposition of Patients ................................................................................................63 
12.2.2. 
Demographic Data, Medical History, Baseline Characteristics, and 
Concomitant Medications ...........................................................................................63 
12.2.3. 
Treatment Compliance ................................................................................................63 
12.3. 
Efficacy Analyses .......................................................................................................63 
12.4. 
Safety Analysis ...........................................................................................................63 
12.4.1. 
Statistical Methods ......................................................................................................64 
12.4.2. 
Adverse Events ...........................................................................................................64 
12.4.3. 
Laboratory Results ......................................................................................................64 
12.5. 
Exploratory Endpoints Analyses ................................................................................64 
12.5.1. 
Health Outcomes Assessments ...................................................................................64 
12.5.2. 
Biomarkers Analyses ..................................................................................................64 
12.5.3. 
Microbiome Analyses .................................................................................................65 
12.6. 
Interim Analysis ..........................................................................................................65 
12.7. 
Determination of Sample Size ....................................................................................65 
13. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING....................66 
13.1. 
Definitions ..................................................................................................................66 
13.1.1. 
Adverse Events ...........................................................................................................66 
13.1.2. 
Abnormal Laboratory Results .....................................................................................66 
13.1.3. 
Serious Adverse Events ..............................................................................................67 
13.1.4. 
Hospitalization ............................................................................................................67 
13.1.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................68 
13.1.6. 
Severity Assessment ...................................................................................................68 
13.1.7. 
Causality Assessment .................................................................................................69 
13.1.8. 
Special Reporting Situations .......................................................................................70 
13.2. 
Reporting Adverse Events ..........................................................................................70 
13.3. 
Reporting Serious Adverse Events .............................................................................70 
13.4. 
Pregnancy ...................................................................................................................71 
13.5. 
Sponsor Reporting Requirements to Health Authorities and IRB/IEC ......................72 
14. 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ....................................73 
14.1. 
Data Collection, Processing, and Monitoring .............................................................73 
14.1.1. 
Case Report Forms and Source Documentation .........................................................73 
14.1.2. 
Study Monitoring and Access to Source Documentation ...........................................73 


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14.1.3. 
Data Quality Assurance ..............................................................................................74 
14.1.4. 
Data Processing ..........................................................................................................74 
14.1.5. 
Retention of Data and Study Records .........................................................................74 
14.2. 
Ethical Aspects ...........................................................................................................75 
14.2.1. 
Good Clinical Practice and Ethical Conduct of the Study ..........................................75 
14.2.2. 
Informed Consent Responsibilities .............................................................................75 
14.3. 
Other Study Administrative Aspects ..........................................................................76 
14.3.1. 
Protocol Approval and Protocol Amendment.............................................................76 
14.3.2. 
Investigator Responsibilities .......................................................................................76 
14.3.3. 
Patient Responsibilities ...............................................................................................77 
14.3.4. 
Financial Disclosure ...................................................................................................78 
14.3.5. 
Publication Policy .......................................................................................................78 
15. 
REFERENCE LIST ....................................................................................................79 
16. 
SIGNATURE PAGES ................................................................................................84 
17. 
APPENDICES ............................................................................................................87 
 
LIST OF TABLES 
Table 1: 
Neratinib Diarrhea Incidence Without Loperamide Prophylaxis ...............................23 
Table 2: 
Neratinib Diarrhea Incidence Using Loperamide Prophylaxis ...................................24 
Table 3: 
Dose Reduction Levels for Neratinib-Related Toxicity .............................................36 
Table 4: 
Loperamide Dosing ....................................................................................................38 
Table 5: 
Loperamide Dose Reduction Levels for Constipation ................................................39 
Table 6: 
Budesonide Dosing .....................................................................................................40 
Table 7: 
Colestipol Dosing .......................................................................................................41 
Table 8: 
Laboratory Parameters ................................................................................................52 
 
LIST OF FIGURES 
Figure 1: 
Study Design (Starting with Amendment 7) ..............................................................30 
 
 


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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 
Akt 
protein kinase B 
ALP 
alkaline phosphatase 
ALT  
alanine aminotransferase 
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 
cfDNA 
cell-free DNA 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CRA 
clinical research associate 
CRF 
case report form 
CSR 
clinical study report 
CT  
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 enzyme 
D 
Day 
DM1 
Emtansine 
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 (formerly EMEA) 
EOS 
end of study 
EOT 
end of treatment 
EQ-5D-5L 
EuroQol 5D-5L 
ERBB  
epidermal growth factor family of trans-membrane receptors (also known as HER) 
ERBB2 V-erb-b2  avian erythroblastic leukemia viral oncogene homolog 2, neuro/glioblastoma derived 
oncogene homolog (avian), HER2 
EU  
European Union 
FACT-B 
Functional Assessment of Cancer Therapy Breast Cancer 
FDA 
Food and Drug Administration (United States) 


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GCP  
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
Hb 
Hemoglobin 
hCG  
β-human chorionic gonadotropin 
Hct 
Hematocrit 
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 
HIPAA  
Health Insurance Portability and Accountability Act 
HR 
hormone receptor 
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) 
IRB 
Institutional Review Board 
IV 
intravenous(ly) 
LDH  
lactate dehydrogenase 
LFT 
liver function test 
LLN 
lower limit of normal 
LVEF  
left ventricular ejection fraction 
MBC  
metastatic breast cancer 
MDRD 
modification of diet in renal disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters mercury 
MRI 
magnetic resonance imaging 
MUGA 
multiple-gated accession scan 
NCI 
National Cancer Institute 
NSCLC 
non-small cell lung cancer 
OS 
overall survival 
PB-272 
Neratinib 
PET 
positron emission tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PI3K  
phosphoinositide 3-kinase 
PO 
by mouth 
PT  
preferred term 
PRN 
Pro re nata (as needed) 
QOL 
Quality of Life 
QTc  
QT interval, corrected for heart rate 
RBC  
red blood cell 


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RSCL 
Rotterdam Symptom Checklist 
SAE 
serious adverse event 
SC  
subcutaneous(ly) 
SmPC 
Summary of Product Characteristics 
SOC 
system organ class 
SUSAR  
suspected unexpected serious adverse reaction 
T-DM1  
trastuzumab emtansine 
TdP  
Torsade de Pointes 
TID  
three times daily 
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 the leading cause of 
cancer mortality in women worldwide. Breast cancer accounted for approximately 522,000 
deaths worldwide in 2012, and the global incidence of new cases in women was approximately 
1.67 million (International Agency for Research on Cancer, GLOBOCAN 2012). 
2.2. 
ERBB2 Gene and Cancer 
2.2.1. 
The Epidermal Growth Factor Receptor Family (ERBB)  
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, 1989). 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. 
Current Therapies Targeting ERBB Receptors 
2.3.1. 
Trastuzumab  
Trastuzumab (Herceptin® Package Insert, Herceptin Summary of Product Characteristics 
[SmPC], Herceptin Product Monograph), the first agent approved for treatment of HER2+ breast 
cancer, is a monoclonal antibody that binds to the juxtamembrane portion of the HER2/neu 
receptor, resulting in inhibition of tumor proliferation (Goldenberg, 1999). While the exact 
mechanism of action is uncertain, Junttila et al (2009) reported that trastuzumab induced 
dissociation of ligand independent HER2-HER3 heterodimers resulting in dephosphorylation of 
HER3 and inhibition of downstream signaling, and Park et al (2010) reported that the antitumor 
effects of trastuzumab also involved antibody-dependent, cell-mediated cytotoxicity.  
2.3.2. 
Pertuzumab  
Pertuzumab (Perjeta® Package Insert) is a humanized monoclonal antibody that binds HER2 at a 
different epitope of the HER2 extracellular domain (subdomain II) than trastuzumab (Baselga et 
al, 2012) thereby preventing HER2 from dimerizing with other ligand-activated HER receptors, 
most notably HER3 (Baselga and Swain, 2009; Agus et al, 2002). The HER2-HER3 heterodimer 
is considered to be the most potent signaling pair (Agus et al, 2002), driving cell proliferation in 
HER2+ cancer (Lee-Hoeflich et al, 2008; Hsieh and Moasser, 2007). In recent studies, the 
addition of pertuzumab to combination therapy has led to improvements in PFS in patients with 
HER2+ metastatic breast cancer (MBC) and higher response rates in the preoperative setting 
(Murphy and Morris, 2012). 
2.3.3. 
Pertuzumab in Combination with Trastuzumab 
Although treatment with trastuzumab in addition to chemotherapy (as compared with 
chemotherapy alone) significantly improves PFS and OS among patients with HER2+ MBC, in 
most patients, the disease progresses (Nahta and Esteva, 2007).  
Because pertuzumab and trastuzumab bind to different HER2 epitopes and have complementary 
mechanisms of action, the combination of these two agents, provide a more comprehensive 
blockade of HER2 signaling and result in greater antitumor activity than either agent alone in 


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HER2+ tumor models (Lee-Hoeflich et al, 2008; Scheuer et al, 2009). In Phase 2 studies, a 
pertuzumab plus trastuzumab regimen showed activity in patients with HER2+ MBC (Baselga et 
al, 2010; Portera et al, 2008) and in patients with early breast cancer (Gianni et al, 2010).  
The Clinical Evaluation of pertuzumab and trastuzumab (CLEOPATRA) study assessed the 
efficacy and safety of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo 
plus trastuzumab plus docetaxel (control group), as first-line treatment for patients with HER2+ 
MBC who had not received chemotherapy or biologic therapy for their metastatic disease 
(Baselga et al, 2012). At the final analysis (median follow-up of 50 months), treatment with 
pertuzumab plus trastuzumab plus docetaxel resulted in significant improvement in PFS and OS 
with an unprecedented increase of 15.7 months in median OS, compared with the control group 
(Swain et al, 2014). CLEOPATRA findings suggest that targeting HER2+ tumors with two 
anti-HER2 monoclonal antibodies that have complementary mechanisms of action results in a 
more comprehensive blockade of HER2 and highlights the clinical importance of preventing the 
ligand-dependent formation of HER2 dimers in order to silence HER2 signaling to the greatest 
extent possible (Baselga and Swain, 2009; Yarden and Sliwkowski, 2001).  
Pertuzumab received approval in the US in 2012 for use in combination with trastuzumab and 
docetaxel for the treatment of patients with HER2+ MBC who have not received prior anti HER2 
therapy or chemotherapy for metastatic disease. In 2013, pertuzumab received approval for use 
in combination with trastuzumab and docetaxel for the neoadjuvant treatment of patients with 
HER2-positive, locally advanced, inflammatory or early-stage breast cancer (either greater than 
2 cm in diameter or node positive) as part of a complete treatment regimen for early breast 
cancer. 
2.3.4. 
Ado-trastuzumab Emtansine  
Ado-trastuzumab emtansine (T-DM1, Kadcyla® Package Insert) is an antibody-drug conjugate 
that combines HER2-targeted delivery of the potent microtubule polymerization inhibitor 
emtansine (DM1), a derivative of maytansine, with the antitumor activity of trastuzumab (Lewis 
Phillips et al, 2008; Remillard et al, 1975; Cassady et al, 2004; Widdison et al, 2006; Junttila et 
al, 2011). In T-DM1, trastuzumab and DM1 are covalently linked via a stable thioether linker 
(N-maleimidomethyl) cyclohexane-1-carboxylate, which is thought to limit the exposure of 
normal tissue to DM1 (Krop et al, 2010; Burris et al, 2011). Antitumor activity was established 
in a proof of concept Phase 2 study of single-agent T-DM1 in patients with HER2+ MBC, who 
had progressed while receiving HER2-directed therapy (Burris et al, 2011). Furthermore, in a 
single-arm Phase 2 study, T-DM1 demonstrated efficacy in patients with HER2+ MBC who 
previously received all standard HER2-directed therapies (trastuzumab, lapatinib, an 
anthracycline, a taxane, and capecitabine) (Krop et al, 2012).  
Primary results from the EMILIA study (a Phase 3, randomized, multicenter study of T-DM1 
compared with lapatinib plus capecitabine in patients with HER2+ locally advanced or MBC 
previously treated with a trastuzumab-based regimen and a taxane) showed a significant and 
clinically meaningful improvement with T-DM1 in PFS compared with lapatinib plus 
capecitabine (Verma et al, 2012). Other end points supported T-DM1 as an active and well-
tolerated novel therapy for HER2+ advanced breast cancer. T-DM1 is approved in the US for 
patients with HER2-positive MBC who have previously received trastuzumab and a taxane 
separately or in combination.  


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2.3.5. 
Other HER2-targeted Therapies 
Other HER2-targeted agents include lapatinib, a small molecule tyrosine kinase inhibitor that 
targets the tyrosine kinase domains of both EGFR and HER2 (Rusnak and Gilmer, 2011). 
Trastuzumab and lapatinib have received approval from the United States (US) Food and Drug 
Administration (FDA) for the treatment of patients with advanced or metastatic HER2-
overexpressing breast cancer who have previously been treated with an anthracycline, a taxane, 
and trastuzumab.  
2.4. 
Neratinib  
Neratinib (PB-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 will have antitumor activity in 
ERBB1- and/or ERBB2-expressing carcinoma cell lines, with cellular IC50 <100 nM (Rabindran 
et al, 2004). 
Neratinib may have advantages over other HER2 inhibitors due to its ability to irreversibly 
inhibit both HER1 and HER2. Breast cancer cells may become resistant to trastuzumab 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+ breast cancer are provided in the neratinib Investigator’s 
Brochure (IB). 
2.4.1. 
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 IB Version 5.0 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.  
2.4.2. 
Diarrhea Prophylaxis in Neratinib Clinical Studies 
Although patients in studies 3144A1-201-WW, 3144A2-3003-WW, I-SPY2 and early cohorts of 
10-005 received standard-of-care diarrhea management on occurrence of diarrhea, the studies did 
not mandate concomitant treatment with loperamide or other anti-diarrheal agents at the outset of 


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neratinib therapy for prevention of neratinib-related diarrhea. In these studies, 28-39% of patients 
experienced Grade 3 or Grade 4 diarrhea Table 1).  
In ongoing neratinib clinical studies that are currently enrolling patients with solid tumors, 
prophylactic use of antidiarrheal medication is mandatory. Data for ongoing study 
PUMA-NER-4201 and the later cohorts of 10-005 are shown in Table 2. Among patients 
receiving prophylactic antidiarrheal medication in these studies, 12-16% of patients experienced 
Grade 3 or Grade 4 diarrhea.  
Table 1 illustrates diarrhea incidence in neratinib studies without loperamide prophylaxis. 
Table 2 illustrates diarrhea incidence in neratinib studies that use intensive loperamide 
prophylaxis. 
Table 1: 
Neratinib Diarrhea Incidence Without Loperamide Prophylaxis  
Study 
Patients 
Investigational Product 
Patients 
N 
Grade 3-4 
Diarrhea 
n (%) 
3144A1-201-WWa 
Locally 
advanced  
or HER2+ MBC 
neratinib 240 mg 
66b 
21 (32%) 
3144A2-3003-WW
a 
Locally 
advanced  
or HER2+ MBC 
neratinib 240 mg  
(monotherapy arm) 
116 
33 (28%)  
3144A2-3004-WW 
Early stage 
HER2+ breast 
cancer 
neratinib 240 mg 
(monotherapy arm) 
1408 
562 (39.9%) 
10-005c 
Triple-negative  
or HER2+ MBC 
neratinib (240 mg) +  
temsirolimus IV (once per 
week) 
35 
10 (29%) 
I-SPY2d 
HER2+/HR-  
Breast Cancer 
neratinib (240 mg) +  
paclitaxel (once per week) 
116 
45 (39%) 
HER = human epidermal growth factor receptor; HR = hormone receptor; IV = intravenously; MBC = metastatic 
breast cancer  
a  Data from 3144A1-201-WW CSR and 3144A2-3003-WW interim CSR.  
b Includes patients in Arm A with prior adjuvant trastuzumab therapy.  
c Patients without diarrhea prophylaxis; data cut-off 22-AUG-2014.  
d AACR Annual Meeting, Park et al, 2014. 


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Table 2: 
Neratinib Diarrhea Incidence Using Loperamide Prophylaxis  
Study 
Patients 
Investigational Product 
Patients 
N 
Grade 3-4 
Diarrhea 
n (%) 
PUMA-NER-
4201a 
Advanced or 
metastatic 
HER2-mutant 
NSCLC 
neratinib (240 mg)  
17 
2 (12%)b 
neratinib (240 mg) +  
temsirolimusc  
28 
4 (14%)b 
10-005a 
Triple-negative or  
HER2+ MBC 
neratinib (240 mg) +  
temsirolimusc  
51 
8 (16%)d 
Data cut-off 22-AUG-2014  
HER = human epidermal growth factor receptor; IV = intravenously; MBC = metastatic breast cancer; 
NSCLC = non-small cell lung cancer  
a To be compliant, patients with intensive diarrhea prophylaxis were to receive loperamide 4 mg with first dose of 
neratinib followed by loperamide 2 mg every 4 hours for the first 3 days. Thereafter, loperamide 2 mg every 
6 to 8 hours until the end of the first cycle of therapy.  
b One (1) patient in each arm had Grade 3 diarrhea during Cycle 1; both patients were non-compliant with 
loperamide prophylaxis.  
c Temsirolimus 8 or 15 mg IV once per week.  
d  Five (5) patients had Grade 3 diarrhea during Cycle 1; three (3) of these patients were non-
compliant with loperamide prophylaxis. 
Refer to the neratinib IB Version 5.0 for more detailed information.  
2.4.3. 
Preliminary 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 randomized Phase 3 
ExteNET trial (Extended Adjuvant Treatment with Neratinib [3144A2-3004-WW], Chan et. al., 
2015) 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 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. 
2.5. 
Study Rationale 
The results shown in Table 1 and Table 2 suggest that the implementation of the intensive 
diarrhea management has resulted in a lower incidence of Grade 3 diarrhea. The rationale of this 
study is to collect safety data in patients with early-stage HER2-positive breast cancer who have 
completed a prior course of adjuvant trastuzumab in order to expand the safety profile of 


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neratinib when given concomitantly with intensive antidiarrheal prophylaxis for 2 cycles. As of 
Amendment 4, starting with the group receiving colestipol, intensive loperamide prophylaxis is 
to be administered for 1 cycle (28 days), and then as needed (PRN) during Cycle 2 and 
thereafter. The duration for the administration of intensive loperamide prophylaxis was changed 
from 2 cycles to 1 cycle (28 days) in Amendment 4 since review of data for the incidence of new 
diarrhea indicated that the majority of episodes occur within the first 28 days of starting neratinib 
treatment. 
In Amendment 5, the study will investigate a bile acid sequestrant (colestipol) given in addition 
to the antidiarrheal medication loperamide, administered on a PRN basis, that may be effective in 
further lowering the incidence of Grade 3 diarrhea. The results will guide how to better manage 
neratinib-related diarrhea in this patient population. 
2.5.1. 
Neratinib Dose Escalation Rationale 
Amendments 6 and 6.1, will investigate the effect on the incidence and severity of diarrhea of a 
lower dose of neratinib starting at 120 mg/day with a dose-escalation regimen. This dose 
escalation scheme is based on (1) a logistic regression model using ExteNET data that suggests 
the odds of having Grade 2 or higher diarrhea increase with increasing average daily dose of 
neratinib; and (2) the observation that Grade 3 diarrhea occurs most frequently in the first month 
after neratinib initiation, suggesting intestinal adaptation to neratinib exposure. By starting 
administration of neratinib at the lower dose of 120 mg in the first week (C1D1 to C1D7), 
followed by 160 mg in Week 2 (C1D8 to C1D14), reaching full treatment dose of 240 mg at 
Week 3 and then thereafter (C1D15 to EOT), patients may experience less early and severe 
episodes of neratinib-associated diarrhea and thereby achieve increased tolerability and 
adherence to neratinib treatment. Starting with Amendment 7, the study will investigate the 
effects of an alternate neratinib dose escalation regimen, starting with the introduction of 160 mg 
neratinib for the first two weeks of treatment.  Subsequently, 200 mg neratinib will start for the 
next two weeks, allowing a stepwise approach that leads to reaching full dose neratinib 240 mg. 
By having a longer duration of 2 weeks at each dose level patients have the opportunity to 
acclimate to neratinib, which may increase tolerability and optimize the management of adverse 
effects. Accumulating data from PUMA-NER-6201 suggest that many patients who remain on 
neratinib therapy through the first month are able to remain on neratinib for the complete one 
year treatment course. Gut bacterial biodiversity will be evaluated from a stool swab at 
Screening, C2D1, and C4D1 and/or at time of treatment discontinuation to assess the effect that 
neratinib has on the microbiome. 
2.5.2. 
Results of Preclinical Investigations 
A rat model to investigate neratinib-associated diarrhea was developed and histopathology 
showed infiltration of polymorphonuclear cells and lymphocytes in the ileum and colon 
(unpublished data on file). This may suggest an inflammatory process that could be ameliorated 
with anti-inflammatory agents. Ongoing investigations into several interventions are proceeding 
in the rat model. 
2.5.3. 
Rationale for use of an Anti-inflammatory Agent 
Budesonide will be investigated in the first pilot cohort as a proof-of-principle for the anti-
inflammatory effect. Budesonide has a high glucocorticosteriod (GCS) activity and substantial 


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first-pass elimination (Package Insert-Uceris® (budesonide) tablets, Santarus, Inc.). The 
formulation contains budesonide in an extended release tablet core. The tablet core is enteric 
coated to protect dissolution in gastric juice which delays budesonide release until exposure to a 
pH ≥ 7 in the small intestine. Upon disintegration of the coating, the core matrix provides 
extended release of budesonide in a time dependent manner. Budesonide has a high 
glucocorticoid effect and a weak mineralocorticoid effect.  
2.5.4. 
Rationale for Use of a Bile Acid Sequestrant 
The bile acid sequestrant colestipol is a lipid lowering agent for oral use, that binds bile acids in 
the intestine forming a complex that is excreted in the feces (Package Insert-Colestid® 
[colestipol], Pfizer). This non-systemic action results in a partial removal of bile acids from 
enterohepatic circulation, preventing their reabsorption. The formation of this complex may 
counteract neratinib induced diarrhea by slowing gastrointestinal transit time and by attenuating 
the possible irritant effect of bile acids on inflamed gastrointestinal lumen. Constipation is the 
major single adverse effect of colestipol and most instances are mild and transient. In animal 
model studies investigating neratinib induced diarrhea, initial observations suggest that there is a 
reduction in severe diarrhea when rats were administered a bile acid sequestrant during neratinib 
administration. 
2.5.5. 
Enrollment 
The projected numbers for enrollment have increased as of Amendment 5. The planned number 
had been 40 patients per additional cohort. Amendment 3 over-enrolled patients due to plans for 
continued investigation to a total of 64 patients. Amendment 4 over-enrolled, exceeding 40 
patients to finally include a total of 136 patients. Amendment 5 though originally planned to  
include 64 patients enrolled 104 patients. Amendment 6 and Amendment 6.1 are currently 
enrolling patients and are projected to enroll approximately 64 patients. Amendment 7 and 
Amendment 7.1 are planned to enroll approximately 100 additional patients. Cohorts will 
continue to enroll without interruption, in sequence. Thus enrollment may exceed initial 
projections.  


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3. 
STUDY OBJECTIVES  
3.1. 
Primary Objective 
The primary objective of this study is to characterize the incidence and severity of diarrhea in 
patients with early-stage HER2 overexpressed/amplified (HER2+) breast cancer treated with 
neratinib when administered with intensive loperamide prophylaxis, after prior treatment with 
trastuzumab.  
3.2. 
Secondary Objectives 
The secondary objectives of this study are:  
 To assess the incidence of serious adverse events (SAEs) and other adverse events of 
special interest (AESI).  
 To assess the incidence and severity of diarrhea after the administration of an anti-
inflammatory agent (for patients enrolled under Amendment 3), a bile acid 
sequestrant (for patients enrolled under Amendment 4 and Amendment 5), or 
following 2 different dose escalation regimens of neratinib (for patients enrolled 
under Amendment 6 and for patients enrolled starting with Amendment 7, 
respectively). 
3.3. 
Exploratory Objectives 
The exploratory objectives of this study are to evaluate: 
For patients enrolled starting with Amendment 2: 
 To assess patient reported outcomes using the EQ-5D-5L Health Questionnaire 
(EQ-5D-5L) and the Functional Assessment of Cancer Therapy Breast (FACT-B) 
questionnaires. 
 To collect plasma biomarkers to evaluate their relationship to clinical recurrence of 
disease. 
For patients enrolled starting with Amendment 6: 
 Evaluation of stool bacterial diversity (microbiome) 
For patients enrolled starting with Amendment 6.1: 
 To assess patient-reported outcomes using the RSCL (for patients enrolled starting 
with Amendment 6.1) 


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4. 
INVESTIGATIONAL PLAN 
4.1. 
Overall Study Design 
This is an open-label, Phase 2 study that will investigate the incidence of diarrhea in HER2+ 
breast cancer patients receiving neratinib with intensive loperamide diarrhea prophylaxis, with 
and without an anti-inflammatory treatment or a bile acid sequestrant treatment and who have 
previously completed trastuzumab therapy in the adjuvant setting.  
Patients will receive:  
 Neratinib 240 mg orally once daily with food for thirteen (13) 28-day cycles.  
 Loperamide daily for two (2) 28-day cycles and then as needed. 
 For patients enrolled under Amendment 3, an anti-inflammatory treatment for 1 cycle 
and loperamide to be administered daily for two (2) 28-day cycles and then as 
needed, thereafter; 
 For patients enrolled under Amendment 4, colestipol for 1 cycle and loperamide to be 
administered 1 cycle and then as needed, thereafter; 
 For patients enrolled under Amendment 5, colestipol for 1 cycle and loperamide to be 
administered on an as-needed basis only. 
 For patients enrolled under Amendments 6 and 6.1, 120 mg neratinib for Week 1 
(C1D1 – C1D7), followed by 160 mg neratinib starting for Week 2 (C1D8 – C1D14), 
followed by 240 mg neratinib starting at Week 3 and thereafter (C1D15 to EOT). 
Loperamide will be administered on an as-needed basis only. 
 For patients enrolled starting with Amendment 7, 160 mg neratinib for the first 
2 weeks  (C1D1 – C1D14), followed by 200 mg neratinib for the next 2 weeks 
(C1D15 – C1D28), followed by 240 mg neratinib thereafter (C2D1 to End-of-
treatment [EOT]). Loperamide will be administered on an as-needed basis only. 
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 thirteen (13) 28-day treatment cycles (Section 9.2). 
Neratinib and loperamide will be administered orally by patients as described in Section 6. 
Neratinib is to be taken continuously, in 28-day cycles, with no rest between cycles.  
The effect of the anti-inflammatory treatment, budesonide and the bile acid sequestrant colestipol 
on the incidence, severity, and duration of diarrhea will be investigated in sequential patient 
cohorts using a sample size of approximately 64 patients per cohort (Figure 1). The 
anti-inflammatory cohort added in Amendment 3 will be assigned to receive budesonide tablets 
9 mg once daily with or without food for 28 days along with neratinib 240 mg/day (13 cycles) 
and intensive loperamide prophylaxis that will continue through the first 2 cycles (total 56 days), 
and on an as-needed basis thereafter.  
Following the planned completion of enrollment of the 40 patients receiving budesonide, 
neratinib, and intensive loperamide prophylaxis (final enrollment was 64 patients), the next 


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cohort will be evaluated after receiving colestipol 2 g twice daily with or without food for 
28 days, to be given at least 2 hours after, but at least 4 hours before,  neratinib 240 mg/day 
(13 cycles) and intensive loperamide prophylaxis. For this cohort, intensive loperamide 
prophylaxis will continue only through the first cycle (28 days); for Cycle 2 and beyond, 
loperamide may be administered as needed (PRN).  
Following complete enrollment of the cohort treated with colestipol and intensive loperamide 
prophylaxis, all patients in the next cohort (approximately 64) will be evaluated after receiving 
colestipol and neratinib with loperamide administered on a PRN basis only. (Note: For 
Amendment 5 and Amendment 6, enrollment into the budesonide cohort and the first colestipol 
cohort is complete and the administration of mandatory loperamide prophylaxis is now also 
complete). 
Patients enrolled under Amendment 6/6.1 will be evaluated after receiving neratinib 
administered according to the following dose-escalation scheme: 120 mg neratinib for Week 1 
(C1D1 – C1D7), followed by 160 mg neratinib starting at Week 2 (C1D8 – C1D14), followed by 
240 mg neratinib starting at Week 3 and thereafter (C1D15 to EOT). Loperamide is to be 
administered on a PRN basis only.  
Following complete enrollment of all patients in the 120 mg/160 mg/240 mg dose-escalation 
scheme, patients enrolled under Amendment 7/7.1 will be evaluated after receiving neratinib 
administered according to a second dose escalation scheme: 160 mg neratinib to be taken for the 
first 2 weeks (C1D1 – C1D14), followed by 200 mg neratinib to be taken for the next 2 weeks 
(C1D15 – C1D28), followed by 240 mg neratinib daily dose taken thereafter (C2D1 to EOT). 
Loperamide is to be administered on a PRN basis only. 
The Sponsor will regularly review accumulating safety data (by individual subject and in 
aggregate). Early termination of a cohort or the study may be permitted if data indicate that 
anti-diarrheal treatment is ineffective. 
Patients in all treatment groups will continue to complete the remaining 12 treatment cycles. 
Analyses are further described in Section 12.4.1. Cohorts will continue to enroll without 
interruption, in sequence. Thus enrollment may exceed initial projections.


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Figure 1: 
Study Design (Starting with Amendment 7) 


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Clinic visits during the active treatment phase are planned on Day 1 of Cycle 1, 2, 3, 4, 7, and 
Cycle 10. End of Treatment (EOT) Visit is planned on Day 28 of Cycle 13, followed by Safety 
Follow-up Visit 28 days after the last dose of neratinib. Assessments required throughout the 
study are summarized in the Schedule of 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 the incidence of Grade 3 or higher diarrhea. Secondary 
endpoints include the frequency distribution of the maximum grade incidence of diarrhea over 
time, the incidence and severity of diarrhea by anti-diarrheal treatment exposure; and the 
incidence of SAEs and AESIs. Additional exploratory endpoints consisting of patient-reported 
health outcomes and biomarkers of disease recurrence will be evaluated (for patients enrolled 
starting with Amendment 2). 
An interim analysis is planned when approximately 120 enrolled under the Original Protocol, 
Amendment 1, and Amendment 2 have completed at least 2 cycles (56 days) of neratinib with 
loperamide prophylaxis. The analysis will only include those 120 patients enrolled under the 
Original Protocol, Amendment 1, and Amendment 2. Other additional analyses by cohort may be 
carried out as required (Section 12.5). The final analysis is planned when all patients have either 
completed 13 cycles (364 days) of neratinib therapy or have discontinued from the study.  
For the Original protocol, Amendment 1, and Amendment 2, approximately 120 patients were to 
be enrolled at approximately 35-45 centers. See Section 12.7 for a discussion of sample size. 
For the 5 cohorts evaluating additional treatments added in Amendment 3 (budesonide), 
Amendment 4 and Amendment 5 (colestipol), Amendment 6/6.1 (neratinib dose escalation from 
120 mg/day), and Amendment 7/7.1 (neratinib dose escalation from 160 mg/day), approximately 
450 additional patients will be enrolled at approximately 74 centers. The approximate total 
enrollment will be 750 patients total.   
Patients 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, and safety 
follow-up visit 28 days after the last dose of neratinib. 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).  
4.2. 
Study Duration and Termination of Study 
The approximate duration of the study is 7 years. 
Patients receive neratinib for 13 cycles (364 days) or until disease recurrence (as determined by 
the Investigator), death, unacceptable toxicity, or other specified withdrawal criterion.  
The final analysis will be conducted after all patients have completed 13 cycles of study 
treatment or have met other specified withdrawal criterion (see Section 10).  
The study will end when all patients have been followed up for 28 days after the last dose of 
neratinib.  


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In the event that end of treatment (EOT) is declared earlier by the Sponsor, patients will be 
offered the opportunity to complete the 1-year course of treatment either through a treatment 
extension study or through a managed access program. 
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 3c 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 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. The last dose of trastuzumab must have been given >2 weeks and ≤1 year (365 days) 
from enrollment.  
6. Physician assessment that the patient is negative for local or regional recurrence of 
disease or metastatic disease at the time of study entry, including  
 Per standard of care, bone scan or positron emission tomography (PET) scan; 
required only if ALP is ≥2 x upper limit of normal (ULN) and/or there are 
symptoms of metastatic bone disease. A confirmatory imaging study is required if 
the results from the bone scan are questionable.  
 Per standard of care computed tomography (CT), MRI or ultrasound of the 
abdomen and chest; required only if aspartate aminotransferase (AST)/alanine 
aminotransferase (ALT) or ALP is ≥2 x ULN. 
 Other radiologic assessments may be performed to rule out underlying breast 
cancer recurrence if indicated and as per standard of care (for patients enrolled 
starting with Amendment 6.1). 
7. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition 
scan (MUGA) ECHO.  
8. ECOG status of 0 to 1.  
9. Negative 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]. 
10. Women of childbearing potential must agree and commit to the use of a highly effective 
non-hormonal method of contraception, ie, 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.  Man (male patient) with 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 (ie, any of the above methods, or for females, 


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hormonal contraception associated with inhibition of ovulation) while on treatment and 
for 3 months after last dose of investigational products. 
11. Recovery (ie, to Grade 1 or baseline) from all clinically significant AEs related to prior 
therapies (excluding alopecia, neuropathy, and nail changes).  
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. 
1. Clinical or radiologic evidence of local or regional recurrence of disease or metastatic 
disease prior to or at the time of study entry.  
2. Currently receiving chemotherapy, radiation therapy, immunotherapy, or biotherapy for 
breast cancer.  
3. Major surgery within <30 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.  
4. 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.  
5. QTc interval >0.450 seconds (males) or >0.470 (females), or known history of QTc 
prolongation or Torsade de Pointes (TdP). 
6. 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  
<100,000/µl (<100 x 109/L) 
Hemoglobin  
<9 g/dL 
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  
Creatinine  
Creatinine clearance <30 mL/min (as calculated by 
Cockcroft-Gault formulaa or Modification of Diet in 
Renal Disease [MDRD] formulab) 
a Cockcroft and Gault, 1976. 
b Levey et al, 1999. 


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7. Active, unresolved infections.  
8. 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.  
9. Currently pregnant or breast-feeding.  
10. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (eg, 
Crohn’s disease, malabsorption, or Grade ≥2 National Cancer Institute [NCI] CTCAE 
v.4.0 diarrhea of any etiology at baseline).  
11. Clinically active infection with hepatitis B or hepatitis C virus.  
12. 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.  
13. Known hypersensitivity to any component of the investigational products; known 
hypersensitivity to salicylates; known allergies to any of the medications or components 
of medications used in the trial.  
14. 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, LOPERAMIDE,  ANTI-
INFLAMMATORY, AND BILE ACID SEQUESTRANT 
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; however, neratinib may be taken in the evening. Neratinib will be given continuously 
for one year (364 days) in thirteen (13) 28-day cycles, with no rest between cycles. Patients 
enrolled under Amendment 6 and Amendment 6.1 will receive neratinib at a starting dose of 
120 mg/day with dose escalation (ie, total dose 120 mg daily for Week 1, 160 mg daily for the 
Week 2, and 240 mg daily for Week 3 and thereafter, until EOT). Patients enrolled starting with 
Amendment 7 will receive neratinib 160 mg neratinib for the first 2 weeks (C1D1 – C1D14), 
followed by 200 mg neratinib for the next 2 weeks (C1D15 – C1D28), followed by 240 mg 
neratinib thereafter (C2D1 to EOT). Daily dosing should continue until a criterion for treatment 
withdrawal is met (see Section 10).  
For patients starting with Amendment 7, patients must use a diary to record intake of neratinib 
for every cycle (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.  
For patients enrolled under the dose-escalation schemes of Amendment 6/6.1, Amendment 7/7.1, 
during the dose escalation phase (240 mg neratinib), for any patient who experiences Grade ≥ 2 
AE(s) leading to neratinib dose interruption which do not resolve to Grade ≤ 1, a review of the 
patient and the patient’s adverse event profile must occur with the Sponsor’s Medical Monitor to 
determine whether the patient should be allowed to continue in the study. 
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 
Starting Dose 
240 mg 
-1 
160 mg 
-2 
120 mg 
mg = milligrams 
Note:  Dose reduction applies following completion of dose escalation to 240 mg (after C1D15) for patients enrolled 
starting with Amendment 6. 


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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 (ie, 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 (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  
 For patients enrolled under the Original Protocol: 
 Initial dose of 4 mg (2 tablets/capsules) with the first dose of neratinib, followed 
by 2 mg (1 tablet/capsule) every 4 hours for the first 3 days. After the first 3 days, 
loperamide 2 mg every 6 to 8 hours through the first 2 cycles of therapy (56 days) 
from start of neratinib. 
 For patients enrolled under Amendment 1  Amendment 3: 
 For the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered 
orally by patients 3 times a day (total 12 mg a day). The initial dose of loperamide 
4 mg will be self-administered orally with the first dose of neratinib.  
 After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered 
orally twice a day (total 8 mg a day) through the first 2 cycles of therapy (Day 56) 
from start of neratinib dosing  
 For patients enrolled under Amendment 4: 
 For the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-
administered orally by patients 3 times a day (total 12 mg a day). The initial dose 
of loperamide 4 mg will be self-administered orally with the first dose of 
neratinib. 
 After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-administered 
orally twice a day (total 8 mg a day) with the first dose of neratinib, for 1 cycle 
[28 days], and then as needed (not to exceed 16 mg per day).  


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 For patients enrolled under Amendment 5, Amendment 6, Amendment  6.1, 
Amendment 7, and Amendment 7.1: 
 Loperamide 4 mg (2 tablets/capsules) will be self-administered orally by patients 
on a PRN basis, from the start of neratinib dosing with a goal of titrating to 1-2 
bowel movements a day (not to exceed 16 mg per day). 
Patients enrolled under the Original Protocol can maintain the loperamide prophylaxis dose 
already initiated with a goal of titrating to 1-2 bowel movements a day. 
Recommended loperamide dosing by amendment is listed below in Table 4.  
Table 4: 
Loperamide Dosing  
Day 
Loperamide Dose 
Amendment 1 – Amendment 3 
 
1-14 
Daily dose of 12 mg in 3 divided doses of 4 mg 
15-56 
Daily dose of 8 mg in 2 divided doses of 4 mg 
57+ 
Daily dose as needed (not to exceed 16 mg per day) 
Amendment 4 
 
Colestipol + loperamide intensive 
prophylaxis cohort : 
 
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) 
Amendment 5 
 
Colestipol + loperamide PRN 
 
All cycles 
Loperamide 4 mg PRN 
Amendment 6, Amendment 6.1, 
Amendment 7, Amendment 7.1 
 
Neratinib dose escalation + 
loperamide PRN 
 
All cycles 
Initial dose 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 (≤16 mg/day); continue loperamide at this frequency 
until diarrhea-free for 12 hours. 
Then titrate loperamide (4 mg PRN) to keep diarrhea controlled (1-2 
bowel movements/day). 
For patients starting with Amendment 6.1, patients must use a diary to record intake of 
loperamide for the first 2 cycles (56 days) of the study. Loperamide pill counts will be conducted 
only during the first 2 cycles (56 days) of therapy (only during the first cycle [28 days], starting 
with the colestipol cohort under Amendment 4).  


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6.2.1. 
Loperamide Dose Adjustment 
Patients are expected to take loperamide prophylaxis as directed. However, patients may require 
individualization of loperamide prophylaxis dose with the goal of titrating to 1-2 bowel 
movements a day.  
 For patients who develop diarrhea during Cycles 1-2, loperamide should be increased 
up to a maximum of 16 mg a day (or during Cycle 1 or after, for patients enrolled 
under Amendment 4; thereafter, loperamide may be administered up to 16 mg per 
day, as described above in Section 6.2). 
 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 
6.3. 
Budesonide 
For patients enrolled under Amendment 3 and who participate in the initial cohort that will 
evaluate budesonide, patients will self-administer oral budesonide at a dose of 9 mg once daily 
with or without food, for the first treatment cycle (28 days), to be taken with neratinib and 
intensive loperamide prophylaxis (Table 6). If a patient experiences an intolerable Grade 2 or 
higher AE deemed related to budesonide, dosing of budesonide should be held until the AE 
resolves to Grade 1 or lower and then restarting dosing will be considered. Neratinib and 
loperamide should be continued while budesonide dosing is being held. If the intolerable AE 
recurs, budesonide dosing should be discontinued and neratinib and loperamide continued. 


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Table 6: 
Budesonide Dosing 
 
 
Suggested Dosing Time 
 
7 a.m 
3 p.m 
9 p.m. 
Treatment Cohort 
(budesonide) 
Budesonidea 9 mg 
 
 
C1D1 through 28 days 
 
 
 
 
Neratinib 240 mg with 
food 
 
 
 
Loperamide 4 mgb 
Loperamide 4 mgb 
Loperamide 4 mgb 
a Budesonide tablets 9 mg should be swallowed whole with water and not chewed, crushed, or broken. Patients 
should be advised to avoid the consumption of grapefruit juice for the duration of their budesonide therapy. The total 
daily dosage is 9 mg tablet taken orally in the morning. 
b Amendment 1 – Amendment 3: For the first 14 days, loperamide 4 mg is to be self-administered 3 times a day. 
After the first 14 days, loperamide 4 mg is to be self-administered twice a day through the first 2 cycles of therapy 
(Day 56). Thereafter, loperamide will be administered as needed (not to exceed 16 mg per day). Amendment 4: 
After the first 14 days, loperamide 4 mg is to be self-administered twice a day through the first cycle only of therapy 
(Day 28). Amendment 5: loperamide is to be self-administered on an as-needed basis only from the beginning of 
neratinib treatment 
6.4. 
Colestipol 
 For patients who participate in the evaluation of colestipol, patients will 
self-administer colestipol at a dose of 2 g twice daily for the first treatment cycle, to 
be taken at least 2 hours after, but at least 4 hours before, neratinib and intensive 
loperamide prophylaxis (Table 7). Colestipol is a bile acid sequestrant anion resin that 
has the potential to interact with co-administered medication. Precaution should be 
taken around the timing of administration to avoid drug-drug interaction. Please refer 
to Section 7.6 and Appendix 10 of the protocol for specific recommendations 
regarding the administration of concomitant medication. 
If a patient experiences an AE leading to dose interruption of any study treatment, all study 
treatments should be held until the AE resolves to Grade 1 or lower. 


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Table 7: 
Colestipol Dosing 
 
 
Suggested Dosing Times 
 
7 a.m. 
9 a.m. 
2 p.m. 
5 p.m. 
9p.m. 
Treatment 
Cohort 
(colestipol) 
C1D1 through 
28 days 
 
Colestipola 2 g   
Colestipola 2 g  
 
 
Neratinib 240 mg 
with food 
 
 
 
 
 
Loperamide 
4 mgb  
 
Loperamide 
4 mgb 
 
Loperamide 
4 mgb 
a Colestipol tablets two (2) 1 g tablets should be taken orally twice daily for a total daily dose of 4 g. Important 
precautions are provided in Appendix 10. 
b Amendment 1 – Amendment 3: Loperamide intensive prophylaxis is to be given during Cycle 1, during the initial 
14-day dosing period. After Day 14, loperamide 4 mg twice daily, intensive prophylaxis is to be given during the 
balance of Cycle 1. For Cycle 2, loperamide may be administered PRN. Amendment 4: After the first 14 days, 
loperamide 4 mg is to be self-administered twice a day through the first cycle only of therapy (Day 28). 
Amendment 5: loperamide is to be self-administered on an as-needed basis only from the beginning of neratinib 
treatment. 
 
6.5. 
Packaging, Labeling, and Storage  
6.5.1. 
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.  
6.5.2. 
Loperamide  
Commercially available loperamide will be provided to study sites by the Sponsor. Loperamide 
will be relabeled by the Sponsor, “For investigational use.” 
6.5.3. 
Budesonide 
Commercially available budesonide will be provided to study sites by the Sponsor. Budesonide 
will be relabeled by the Sponsor, “For investigational use.” 


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6.5.4. 
Colestipol 
Commercially available colestipol will be provided to study sites by the Sponsor. Colestipol will 
be relabeled by the Sponsor, “For investigational use.” 
6.6. 
Drug Accountability and Treatment Compliance* 
The study site must maintain accurate records documenting dates and quantities of 
investigational product: neratinib, loperamide, budesonide, and colestipol received from the 
Sponsor. Records must also be maintained documenting dates and quantities (ie, pill counts) of 
neratinib, loperamide, budesonide and colestipol 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 products, neratinib, 
loperamide, anti-inflammatory, or bile acid sequestrant treatments accidentally or deliberately 
destroyed must also be documented.  
Throughout the study, reconciliation will be made between the amounts of investigational 
product: neratinib, loperamide, anti-inflammatory, and bile acid sequestrant treatments supplied, 
dispensed, returned, and subsequently destroyed or returned to the Sponsor. All investigational 
products, neratinib, loperamide, anti-inflammatory, and bile acid sequestrant treatments 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). 
*reference to loperamide, budesonide and colestipol investigational product accountability and 
treatment compliance are related to the specific protocol amendment cohorts. 
 


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7. 
CONCOMITANT MEDICATIONS 
All concomitant medications and concomitant nonpharmacological treatments/therapies will be 
recorded from 30 days prior to the signing of the informed consent form (ICF) until the Safety 
Follow-up Visit occurring 28 days after the last dose of neratinib. 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 
30 days, which medications are ongoing at the time of screening, any medical conditions that 
require medication, and all prior cancer therapies. At each subsequent study visit, patients will be 
asked what concomitant medications they are currently taking.  
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 7.5), or drugs with potential for drug-drug 
interactions (Section 7.6), or in the associated Appendices (Appendix 4, Appendix 5,  
Appendix 6,  Appendix 9, and Appendix 10), 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. 
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). Prior to Amendment 5, primary 
prophylactic use of antidiarrheal medication was mandatory for all enrolled patients taking 
neratinib; starting with Amendment 5, and continuing in Amendment 6, Amendment 6.1, 
Amendment 7, and Amendment 7.1 primary prophylactic use of loperamide is no longer 
required.  
As noted in Section 6.2, loperamide is the recommended standard therapy to treat diarrhea in this 
study, and it is provided to the sites by the Sponsor. 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 and adjunctive therapies (eg, octreotide 
[SANDOSTATIN®] (or equivalent as approved by the Sponsor) are also recommended for use 
when appropriate. 
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 2 


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cycles (56 days) of the study (see Section 8.5.2). Both the patient and the Investigator must sign 
the 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.  
Intensive Prophylactic dosing instructions (patients enrolled in Amendment 1 to 
Amendment 4)  
 Inform patients that they will experience diarrhea while taking neratinib. 
 Administer loperamide:  
 For the first 14 days, loperamide 4 mg (2 tablets/capsules) will be 
self-administered orally by patients three times a day (total 12 mg a day). The 
initial dose of loperamide 4 mg will be self-administered orally with the first dose 
of neratinib.  
 After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be 
self-administered orally twice a day (total 8 mg a day) through the first 2 cycles of 
therapy (Day 56) from start of neratinib dosing.  
o For patients in the treatment group receiving colestipol under Amendment 4, 
this regimen would be for the rest of the first cycle of therapy [Day 28], from 
the start of neratinib dosing.  
 Patients enrolled under the Original Protocol can maintain the loperamide 
prophylaxis dose already initiated with a goal of titrating to 1-2 bowel movements 
a day. 
 Thereafter, loperamide will be administered as needed (not to exceed 16 mg per 
day)  (during Cycle 2 and beyond for patients in the treatment group receiving 
colestipol under Amendment 4). 


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 For patients who develop diarrhea during Cycles 1-2, loperamide should be increased 
up to a maximum of 16 mg a day (or during Cycle 1 or after, for patients enrolled 
under Amendment 4).  
 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 Cycle 1 or Cycle 2 (4 to 6 stools per day above baseline, 
despite intensive anti-diarrheal therapy), consider adding octreotide (short-acting) 
150 µg subcutaneous [SC] injection 3 times a day, or after initial dose of 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.  
PRN dosing instructions (patients enrolled in Amendment 5,  Amendment 6,  
Amendment 6.1, Amendment 7, and Amendment 7.1) 
 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. 
 Then titrate the amount of loperamide used to keep diarrhea controlled (1-2 bowel 
movements/day). 
Other instructions (all protocol versions) 
 The sites must contact the patient by phone at 1 day, 2 days, and 3 days after the first 
dose of neratinib: 
1. to inquire about any diarrhea and about potential AEs;  
2. to provide guidance to the patients for immediate and appropriate management of 
AEs, including diarrhea as specified in this protocol;  
3. to confirm that the patients have loperamide available 
4. to inquire about the first date of neratinib dosing; the Investigator/research staff must 
update the electronic CRF (eCRF) within 3 days of receipt of this information. 
These phone calls are mandatory and must be recorded in the study chart together with 
response from the patient and action taken.  
 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). 
 


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For new onset uncomplicated Grade 1 or Grade 2 diarrhea 
For Cycle 3 and beyond for patients enrolled prior to Amendment 4; for Cycle 2 and beyond for 
the treatment group receiving colestipol under Amendment 4; after the start of dosing for the 
treatment group receiving colestipol under Amendment 5, and for treatment groups under 
Amendment 6, Amendment 6.1, Amendment 7, and Amendment 7.1:   
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.  
 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 Grade 2 diarrhea (4 to 6 stools per day above baseline, despite intensive 
antidiarrheal therapy), consider adding octreotide (short-acting) 150 µg 
subcutaneously (SC) three times daily (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 patients enrolled starting with Amendment 6, other measures to consider for 
Grade 2 diarrhea (4 to 6 stools per day above baseline, despite intensive antidiarrheal 
therapy) should include: 
 Budesonide 9 mg orally (PO) once daily (QD) for 14 to 28 days. 
 Colestipol 2 g twice daily (PO, BID) for 14 to 28 days. 


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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 12 hours. Then titrate the amount of loperamide used to keep 
diarrhea controlled (<4 stools/day). 
 Administer octreotide [100-150 µg SC twice daily (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. Colonoscopy with biopsy should be strongly considered 
for patients who have significant diarrhea. Results for appearance, histology, pathology, and 
cultures 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. 
Anti-inflammatory Treatment 
For patients enrolled under Amendment 3, the effect of an anti-inflammatory treatment, 
specifically budesonide, will be tested to determine the effect on the incidence, severity, and 
duration of diarrhea. 
Following the completion of Cycle 1 by the first approximately 64 patients in the first treatment 
cohort who receive neratinib and intensive loperamide prophylaxis plus budesonide anti-
inflammatory treatment, the treatment cohort will be evaluated. The Sponsor will regularly 
review accumulating safety data (by individual subject and in aggregate). Early termination of a 
treatment cohort or the study may be permitted if data indicate that anti-inflammatory treatment 
is ineffective. Once enrollment in the cohort testing budesonide is complete, the next cohort will 
begin enrollment, to evaluate the bile acid sequestrant colestipol.  
The Patient Diary will be used by patients to record the daily use of budesonide  treatment. Also, 
the daily dose of the anti-inflammatory treatment noted on the diary will be reviewed and 
recorded on the CRF. 


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Budesonide (along with neratinib and loperamide) 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 budesonide concomitantly with the first dose of neratinib and loperamide to 
minimize the occurrence and severity of diarrhea. 
Anti-inflammatory dosing instructions: 
 Budesonide  
 For the first treatment cycle, budesonide will be self-administered orally by 
patients at a dose of 9 mg once daily either with or without food, for the first 
treatment cycle, and to be taken with neratinib and loperamide on the intensive 
prophylaxis schedule. Budesonide should be swallowed whole and not chewed, 
crushed or broken.  
7.4. 
Colestipol (Amendment 4 and Amendment 5) 
For patients enrolled under Amendment 4 and Amendment 5, the effect of the bile acid 
sequestrant, colestipol, on the incidence, severity, and duration of diarrhea will be investigated in 
a treatment cohort of 40 patients. 
Following the completion of Cycle 1 by the first approximately 40 patients in the first cohort 
who receive neratinib and intensive loperamide prophylaxis plus budesonide, patients in the next 
cohort will receive colestipol 2 g, twice daily, for 28 days. The Sponsor will regularly review 
accumulating safety data (by individual patient and in aggregate). Early termination of a cohort 
or the study may be permitted if data indicate that bile acid sequestrant treatment is ineffective 
for the treatment of diarrhea. 
The Patient Diary will be used by patients to record daily the use of colestipol. Also, the daily 
dose of colestipol noted on the diary will be reviewed and recorded onto the CRF. 
Colestipol (along with neratinib and loperamide) will be dispensed directly by the site on or 
before Cycle 1/Day 1 and during subsequent visits as needed. It is important to initiate treatment 
with the colestipol concomitantly with the first dose of neratinib to minimize the occurrence and 
severity of diarrhea. 
7.5. 
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.   
 Systemic steroid use, by oral or parenteral route.  


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7.6. 
Potential for Drug-Drug Interactions 
7.6.1. 
Potential Drug-Drug Interactions with Neratinib 
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 
summary of drugs known to have a risk of causing QT/QTc prolongation, potentially causing 
Torsades 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 coumarin-derivative anticoagulants (ie, 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), 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. 
7.6.2. 
Potential for Drug-Drug Interactions with Budesonide 
For patients participating in Amendment 3, when taking budesonide with neratinib and 
loperamide during the first 28 days (Cycle 1) there should be close monitoring during the 
concomitant administration with ketoconazole (and itraconazole, ritonavir, saquinavir, or 
erythromycin), or any other CYP3A4 inhibitor for increased signs and/or symptoms of 
hypercorticism. Refer to Appendix 9 for contraindications, warnings, and precautions for 
budesonide. 
Avoid grapefruit juice, which is a known CYP3A4 inhibitor.  
Since the dissolution of the coating of budesonide is pH dependent, the release properties and 
uptake of the compound may be altered when budesonide is used after treatment with gastric 
acid reducing agents (PPI's, H2-receptor antagonists and antacids). 


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7.6.3. 
Potential for Drug-Drug Interactions with Colestipol 
For patients participating in Amendment 4, when taking colestipol with neratinib and lopermide 
during the first 28 days (Cycle 1), there should be attention to the time interval between the 
administration of colestipol tablets and any other medication. The interval for colestipol 
administration should be as long as possible from other concomitant medication. Patients should 
take other drugs at least one hour before or four hours after colestipol to avoid impeding their 
administration. Since colestipol is an anion exchange resin, this effect may be related to a strong 
affinity for anions other than the bile acids. In vitro studies have indicated that colestipol binds a 
number of drugs.  
Repeated doses of colestipol given prior to a single dose of propranolol in human trials have 
been reported to decrease propranolol absorption. Patients on propranolol and possibly other 
beta-blockers should be monitored when colestipol is added or deleted from the therapeutic 
regimen.  Effects of the absorption of other beta-blockers have not been determined.  
Studies in humans show that the absorption of chorothiazide as reflected in urinary excretion is 
markedly decreased even when administered one hour before colestipol. The absorption of 
tetracycline, furosemide, penicillin G, hydrochlorothiazide, and gemfibrozil was significantly 
decreased when given simultaneously with colestipol. These drugs were not tested to determine 
the effect of administration one hour before colestipol.   
No lowering effect on blood levels in humans was noted when colestipol was administered with 
any of the following drugs: aspirin, clindamycin, clofibrate, methyldopa, nicotinic acid (niacin), 
tolbutamide, phenytoin or warfarin. Particular caution should be observed with digoxin 
preparations since ther are conflicting results for the effect of colestipol on the availability of 
digoxin and digitoxin. The potential for binding of these drugs if given concomitantly is present. 
Discontinuing colestipol could pose a hazard to health if a potentially toxic drug that is 
significantly bound to the resin has been titrated to a maintenance level while the patient was 
taking colestipol.   
Bile acid bind resins such as coletipol may also interfere with the absorption of oral phosphate 
supplements and hydrocortisone.  
A study has shown that cholestyramine binds bile acids and reduces mycophenolic acid 
exposure. As colestipol also binds bile acids, colestipol may reduce mycophenolic acid exposure 
and potentially reduce efficacy of mycophenolate mofetil.   
Refer to Appendix 10 for contraindications, warnings, and precautions for colestipol.  
7.7. 
Treatment Compliance 
Refer to Section 6.6. 


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8. 
STUDY ASSESSMENTS 
8.1. 
Efficacy Assessment 
Not applicable for this study.  
8.2. 
Safety Assessments 
8.2.1. 
Clinical Endpoints and Definitions 
Safety Endpoints: 
 The primary endpoint of the study is the incidence of Grade 3 diarrhea in patients 
with early-stage HER2+ breast cancer.  
 Secondary safety endpoints include the frequency distribution of the maximum grade 
incidence of diarrhea, the incidence and severity of diarrhea by loperamide exposure, 
with and without anti-inflammatory treatment; and the incidence of SAEs and AESIs.  
Refer to the Schedule of Procedures (Appendix 1) for time points. The following safety 
endpoints will be assessed: medical history, AEs, vital signs, detailed/brief (symptom-guided) 
physical examinations, 12-lead ECGs, LVEF (ECHO or MUGA), and laboratory evaluations. 
AEs and AESIs will be graded according to the NCI CTCAE, version 4.0. Serious AEs and 
AESIs will be reported until 28 days after the last dose of the investigational product and will be 
followed until resolution. Should an Investigator be made aware of any SAEs occurring any time 
after the reporting period that may be causally related to neratinib’s administration, it should be 
promptly reported. More details on AEs can be found in Section 13. 
For patients starting with Amendment 6.1, the diary used for recording of investigational product 
intake will also be used by patients to document any other study treatment for the first 2 cycles 
(56 days) of the study (see Section 8.5.2). 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. 
Laboratory Assessments 
Laboratory testing will be performed in accordance with the Schedule of Procedures 
(Appendix 1).  
The institutional laboratory will analyze all hematology and routine blood chemistry samples 
collected. Samples will be analyzed at a facility meeting Good Laboratory Practice (GLP) 
requirements and using methods documented in a methods validation report.  
Screening laboratory results may be accepted as the baseline assessment if they are performed 
within 72 hours of initiation of protocol therapy. 
The following laboratory endpoints will be determined, as summarized in Table 8. 


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Table 8: 
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 or urine pregnancy 
test 
In women of child-bearing capacity (at screening and within 72 hours prior to 
C1D1, and monthly, including at the End-of-Treatment Visit and at the 
Safety Follow-up Visit). 
For Amendment 4 and Amendment 5 patients who will be receiving colestipol, a baseline 
(occurring at Screen or C1D1) and C2D1 fasting lipid panel is required to assess total 
cholesterol, HDL-C, and triglycerides. 
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 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 
approximately 40 mL, corresponding to approximately 10 mL blood during screening and 5 mL 
blood at subsequent visits. 
8.2.3. 
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) 


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Vital signs will be measured after resting in a seated position for 5 minutes, prior to dosing.  
8.2.4. 
Physical Examination 
Physical examinations will be performed in accordance with the Schedule of Procedures 
(Appendix 1).  
The brief (symptom-guided) physical examination will evaluate any clinically significant 
abnormalities; including worsening of medical history conditions. 
8.2.5. 
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. 
8.2.6. 
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), ie, within 4 weeks before Day 1 of Cycle 1 and at EOT, 
Cycle 13/Day 28.  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 
Assessments for health outcomes and biomarkers will only be collected for patients enrolled 
starting with Amendment 2.  
8.3.1. 
Health Outcomes Assessments 
The exploratory endpoint of patient-reported health outcomes will be assessed by the EuroQol 
EQ-5D-5L and by the FACT-B questionnaires (for patients enrolled starting with Amendment 2) 
and the RSCL (for patients enrolled starting with Amendment 6.1). 
Health outcomes will be assessed by patient-reported responses to the EQ-5D-5L multi- 
dimensional health status questionnaire (Appendix 7) and by the FACT-B (Appendix 8), and by 
the RSCL (Appendix 11). These assessments will be administered in accordance with the 
Schedule of Procedures (Appendix 1). 
The patient-reported assessments are for the purpose of exploring the subject’s own perceptions 
about their symptoms and health-related quality of life and thus a proxy (ie, a caregiver or study 
personnel) should not complete the questionnaires. Additionally, the investigator must not 
influence the subject’s assessments. Every effort should be made to maintain an unbiased 
assessment. Questionnaires should be administered before any other study procedures on the day 
of the study visit. If questionnaires can only be completed after the study visit, they should be 
administered no later than 5 days from the visit. Both assessments need to be completed on the 
same day. On the day of treatment discontinuation, it is acceptable for questionnaires to be 


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performed after study procedures. If assessments were completed within the previous 7 days at a 
regularly scheduled visit, assessments do not need to be administered at the EOT visit. 
EQ-5D-5L: 
The EQ-5D-5L is a standardized instrument for use as a measure of general health states 
preferences and provides a simple descriptive profile and index value for health status and 
measures 5 dimensions of health including mobility, self-care, usual activities, pain/discomfort, 
anxiety, and general health is measured via a vertical visual analog scale. Applicable to a wide 
range of health conditions and treatments, it provides a simple descriptive profile and a single 
index value for health status. 
FACT-B: 
The FACT-B (version 4) is a 37-item questionnaire with 5 subscales assessing physical, social, 
emotional, and functional well-being and additional concerns more specific to women with 
breast cancer. Subjects will be asked to indicate how true a statement had been for them over the 
past 7 days using a 5-point scale as follows: 0, not at all; 1, a little bit; 2, somewhat; 3, quite a 
bit; and 4, very much. All items receive equal weighting. 
Rotterdam Symptom Checklist: 
The RSCL measures both physical and psychological aspects of quality of life (QOL) in cancer 
patients. The instrument assesses symptom-related distress among patients for physical 
symptoms, psychological symptoms, and activities of daily living. The 3 domains are assessed in 
a 4-point scale (not at all, a little, quite a bit, very much) for 38 items. Patients are asked to 
indicate the degree to which they have been bothered by the indicated symptoms in the past 
week. 
8.3.2. 
Biomarkers 
The exploratory endpoint of disease biomarkers will consist of biomarkers of disease recurrence 
(for patients enrolled starting with Amendment 2). 
cfDNA will be obtained from plasma samples collected several times during the study and at 
disease recurrence (if applicable), in accordance with the Schedule of Procedures (Appendix 1). 
cfDNA will undergo molecular profiling to identify biomarkers of disease recurrence 
8.3.3. 
Disease Recurrence 
Clinical documentation of recurrence, including recurrence site, radiographic, and/or pathologic 
procedures will be collected at end-of-treatment. 
8.3.4. 
Microbiome Evaluation (for patients enrolled starting with Amendment 6) 
At select study centers, a stool swab will be collected at Screening, C2D1, and C4D1 and/or at 
time of treatment discontinuation if earlier than C4D1 for possible future assessments of 
microbiome to assess the effect that neratinib has on the microbiome. 


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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 patient diary will be provided by the Investigator for the patient to record daily study 
medication intake for every cycle. The number of stools per day and the use of antidiarrheal 
treatment will also be required to be recorded in the patient diary during the first 2 treatment 
cycles.  
Individual patient dosing compliance should be reviewed 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.  
For the first 2 cycles, eDiaries will be implemented, either hand-held or web-based, to collect the 
number of daily bowel movements, neratinib self-administration (number of tablets taken), and 
anti-diarrheal intake (number of loperamide capsules or tablets, and as applicable, the number of 
doses of other anti-diarrheal medications). If the use of an eDiary, either hand-held or web-
based, is not feasible, the alternative of a paper diary will be considered on a case-by-case basis.  
After 2 cycles, the hand-held or web-based diary will continue to be available to patients, or 
alternatively, they may switch to a paper diary to be completed on a daily basis and returned to 
the clinic (site) for review and evaluation at scheduled study visits. 


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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 9 in 
Section 5.1), which should be performed, both, at screening and within 72 hours prior to 
Cycle 1/Day 1.  
Documented HER2 overexpression or gene-amplified tumor by a validated approved method 
(Wolff et al, 2013) must be retrieved. 
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.  
 Cancer history, including but not limited to, date of first diagnosis, nodal status 
(based on pathologic assessment of nodes at the time of surgery, either before 
adjuvant chemotherapy or after completion of neoadjuvant chemotherapy), 
histology, tumor stage at diagnosis, previous 
chemotherapy/biotherapy/immunotherapy, previous adjuvant therapy, drug 
names, start and stop dates, reason for treatment discontinuation, previous 
radiation, and prior cancer related surgical therapies. 
 Other previous and concomitant medication will be documented, as described in 
Section 7. 
 Demography: date of birth, sex, ethnicity, and race (Asian, Black or African 
American, White, Other).  
 Physical examination. Refer to Section 8.2.4. 
 Vital signs, including height and weight. Refer to Section 8.2.3. 
 ECG. Refer to Section 8.2.5. 
 LVEF. Refer to Section 8.2.6. 
 Laboratory tests. Refer to Section 8.2.2. 
 Health outcomes assessments. Refer to Section 8.3.1 


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 Biomarkers. Refer to Section 8.3.2. 
 Microbiome evaluation. Refer to Section 8.3.4. 
 Per standard of care, bone scan or positron emission tomography (PET) scan 
performed within 28 days prior to the date of enrollment; only required if ALP is ≥2x 
upper limit of normal (ULN) and/or there are symptoms of metastatic bone disease. A 
confirmatory imaging study is required if the results from the bone scan are 
questionable (see Section 5.1)  
 Per standard of care, computed tomography (CT), magnetic resonance imaging (MRI) 
or ultrasound of the abdomen and chest performed within 28 days prior to the date of 
enrollment; only required if aspartate aminotransferase (AST)/ALT or ALP is ≥2x 
ULN (see Section 5.1)  
 Other radiologic assessments may be performed within 28 days prior to the date of 
enrollment, unless a CT scan has already been performed, to rule out underlying 
breast cancer recurrence if indicated and as per standard of care (for patients enrolled 
starting with Amendment 6.1). 
 ECOG status will be assessed in accordance with the Schedule of Procedures 
(Appendix 1). The ECOG categories are summarized in Appendix 3.  
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.  
For patients enrolled under Amendment 3, the anti-inflammatory treatment budesonide will be 
administered for 1 cycle during Cycle 1 for patients in this treatment cohort. For patients enrolled 
under Amendment 4, colestipol will be administered for 1 cycle during Cycle 1 (colestipol + 
intensive loperamide prophylaxis), and colestipol will also be administered for patients enrolled 
under Amendment 5 (colestipol + PRN loperamide). All patients enrolled under Amendment 6 
and  Amendment 6.1 will be evaluated after receiving neratinib administered according to the 
following dose-escalation scheme: 120 mg neratinib for Week 1 (C1D1 – C1D7), followed by 
160 mg neratinib for Week 2 (C1D8 – C1D14), followed by 240 mg neratinib for Week 3 and 
thereafter (C1D15 to EOS). All patients enrolled under Amendment 7 and Amendment 7.1 will 
be evaluated after receiving neratinib administered according to a second dose escalation 
scheme: 160 mg neratinib to be taken for the first 2 weeks (C1D1 – C1D14), followed by 200 
mg neratinib to be taken for the next 2 weeks (C1D15 – C1D28), followed by 240 mg neratinib 
daily dose taken thereafter (C2D1 to EOT). Loperamide is to be administered on a PRN basis 
only. For both dose escalation regimens, the Investigator or research staff must call patients at 
the end of the first and second weeks of treatment (ie, Day 7 or Day 8, and Day 14 or Day 15) to 
confirm that the patient has increased the dose of neratinib from 120 mg to 160 mg, and from 
160 mg to 240 mg, respectively. 
The following will be performed in accordance with the Schedule of Procedures (Appendix 1): 
 AE assessment. Refer to Section 13. 


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 Monthly serum or urine pregnancy testing.  Refer to Inclusion Criterion 9 in 
Section 5.1 and Section 8.2.2. The Investigator or designee must contact patients on 
months that do not have a scheduled visit to confirm that the patient has performed 
the pregnancy test, is not pregnant, and this is noted in the clinical progress notes. 
 Concomitant medication assessment. Refer to Section 7. 
 Brief symptom-guided physical examination. Refer to Section 8.2.4. 
 Vital signs, including weight. Refer to Section 8.2.3. 
 ECG. Refer to Section 8.2.5. 
 Laboratory tests. Refer to Section 8.2.2. 
 Health outcomes assessments. Refer to Section 8.3.1. 
 Biomarkers. Refer to Section 8.3.2. 
 Microbiome evaluation. Refer to Section 8.3.4. 
 Treatment compliance assessment. Refer to Section 6.6. 
 Collect Patient Diary at C2D1 and at C3D1 visits, and at clinic visits when applicable. 
9.3. 
Treatment Discontinuation or End-of-Treatment Assessments  
The EOT visit will occur within 5 business days of Cycle 13/Day 28. 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.  
 Serum or urine pregnancy test.  Refer to Inclusion Criterion 9 in Section 5.1. 
 Concomitant medication assessment. Refer to Section 7.  
 Physical examination. Refer to Section 8.2.4. 
 Vital signs, including weight. Refer to Section 8.2.3. 
 ECG. Refer to Section 8.2.5. 
 LVEF. Refer to Section 8.2.6.  
 Laboratory tests (hematology, chemistry, LFT). Refer to Section 8.2.2. 
 Health outcomes assessments. Refer to Section 8.3.1 . 
 Biomarkers. Refer to Section 8.3.2. 
 Microbiome evaluation. Refer to Section 8.3.4. 
 Disease recurrence as applicable. Refer to Section 8.3.3. 
 Collect Patient Diary for treatment compliance assessment. 


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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 AESIs/SAEs 
and to obtain a serum or urine pregnancy test.  
9.5. 
Long-term Follow-up  
Not applicable for this study. 
9.6. 
End of Study  
The 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 end of study (EOS) is declared earlier, patients will be offered the opportunity to 
complete the 1-year course of treatment either through a treatment extension study or through a 
managed access program.  


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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 a AESIs/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 (ie, 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. 
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 at least one week of study therapy 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 the 1-year course of 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. Before database lock, a separate statistical analysis plan will be finalized, providing 
detailed methods for the analyses outlined below.  
Any deviations from the planned analyses will be described and justified in the final integrated 
study report. 
12.1. 
General Considerations 
12.1.1. 
Subgroups/Cohorts 
Unless otherwise specified, all analyses will be done by the following cohorts:  (1) the Original 
Protocol, (2) Amendment 1 or Amendment 2, (3) Amendment 3, (4) Amendment 4, (5) 
Amendment 5, (6) Amendment 6 and Amendment 6.1, or (7) Amendment 7 and Amendment 7.1 
by treatment cohort.  
12.2. 
Study Patients 
12.2.1. 
Disposition of Patients 
The number and percentage of patients entering and completing the study will be presented. 
Reasons for withdrawal will also be summarized.  
12.2.2. 
Demographic Data, Medical History, Baseline Characteristics, and Concomitant 
Medications 
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.  
12.2.3. 
Treatment Compliance 
Duration of treatment will be summarized. In addition, the cumulative dose, dose intensity 
(quantity per time unit) and the relative dose intensity (dose intensity/scheduled dose per time 
unit) will be summarized. The number of patients with dose holds or dose reductions will be 
tabulated. 
12.3. 
Efficacy Analyses 
Not applicable for this study.  
12.4. 
Safety Analysis 
All patients who receive a dose of neratinib will be analyzed for safety.  


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12.4.1. 
Statistical Methods 
The primary endpoint is the incidence of Grade 3 or higher diarrhea. The accompanying 
Clopper-Pearson 2-sided 95% CIs will be computed. The primary endpoint will be estimated for 
the overall safety population and, if needed, for subgroups of patients with specific anti-diarrheal 
prophylaxis regimens per protocol.  
12.4.2. 
Adverse Events 
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 and AESIs will also be summarized.  
Serious AE and deaths will be provided in a listing. All AEs resulting in discontinuation, dose 
modification, dosing interruption, and/or treatment delay of investigational product will also be 
listed and tabulated by PT.  
12.4.3. 
Laboratory Results 
Laboratory test results will be collected pretreatment through 28 days after the last dose of 
investigational product. Standard reference ranges will be used for missing or discrepant normal 
ranges. 
Mean change from baseline in laboratory test values at each visit will be provided. On-study 
laboratory test abnormalities will be summarized. Shifts in laboratory test values will also be 
summarized.  
12.5. 
Exploratory Endpoints Analyses 
Exploratory analyses will be conducted on all patients in the safety population who were enrolled 
starting under Amendment 2. 
12.5.1. 
Health Outcomes Assessments 
Patient-reported health outcomes data (scores on the EQ-5D-5L, FACT-B, and RSCL 
questionnaires) will be summarized and plotted over time. Analyses will be descriptive only; 
changes from baseline will be provided with both point estimates and CIs. 
12.5.2. 
Biomarkers Analyses 
Exploratory analyses will be conducted to evaluate the relationship between disease biomarkers 
identified from molecular profiling and indications of clinical disease recurrence. No formal 
statistical analyses are planned, however, of biomarker data. 


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12.5.3. 
Microbiome Analyses 
Results of microbiome evaluation from participating sites, if available, will be summarized at 
baseline, C2D1, C4D1, and/or at time of treatment discontinuation if earlier than C4D1. No 
formal statistical analyses are planned of the microbiome data. 
12.6. 
Interim Analysis 
An interim analysis is planned when approximately 120 patients enrolled under the Original 
protocol, Amendment 1, and Amendment 2, all patients have completed at least 2 cycles 
(56 days) of neratinib with loperamide prophylaxis. The interim analysis will only include those 
120 patients enrolled under the Original Protocol, Amendment 1, and Amendment 2. Other 
additional analyses by cohort may be carried out as required. 
12.7. 
Determination of Sample Size 
The first 120 patients will be under the Original Protocol, Amendment 1, and Amendment 2.  
The incidence of Grade 3 or higher diarrhea is assumed to be 15% in this study. A sample size of 
120 patients will ensure that the width of the 95% Clopper-Pearson CI of the incidence of 
Grade 3 or higher diarrhea is no more than 18.5%. For example, if 18 out of the 120 patients are 
observed to have Grade 3 or higher diarrhea, the incidence and its 95% (2-sided) CIs will be 
15.0% (9.1%, 22.7%) where the width of the CI is 13.5%.  
In addition to the analyses of the overall safety population, anti-diarrheal prophylaxis 
regimen-specific subgroup analyses will be performed as needed.  
For patients enrolled under Amendment 3, the effect of anti-inflammatory treatment budesonide 
on the incidence, severity, and duration of diarrhea will be assessed. For patients enrolled under 
Amendment 4, the effect of a bile acid sequestrant colestipol was to be assessed, with either 
intensive loperamide prophylaxis, or loperamide given on a PRN basis (Amendment 5); for 
patients enrolled under Amendment 6/6.1, under Amendment 7/7.1, the effect of 2 different 
dose-escalation schemes of neratinib will be assessed. The incidence of Grade 3 or higher 
diarrhea will be evaluated. For each additional cohort, a sample size of 64 patients will ensure 
that the width of the 95% Clopper-Pearson CI of the incidence of Grade 3 or higher diarrhea is 
no more than 26%. For example, if 7 out of the 64 patients are observed to have Grade 3 or 
higher diarrhea, the incidence and its 95% (2-sided) CI will be 10.9% (4.5–21.2%) where the 
width of the CI is 17%. 
For each additional cohort, a sample size of 100 patients will ensure that the width of the 95% 
Clopper-Pearson CI of the incidence of Grade 3 or higher diarrhea is no more than 21%. For 
example, if 15 out of the 100 patients are observed to have Grade 3 or higher diarrhea, the 
incidence and its 95% (2-sided) CI will be 15.0% (8.7–23.5%) where the width of the CI is 15%. 


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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 Version 5.0) 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, ie, 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’s 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. However, if necessary and only if requested by the Sponsor, data capture may be 
performed using paper CRFs. 
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. The data should be reviewed, signed 
and dated by the Investigator electronically for accuracy and completeness. 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. 
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. 


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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 
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. 
Query/correction sheets for unresolved queries will be sent to the study monitors for resolution 
with the Investigator. The database will be updated on the basis of signed corrections.  
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 


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region and until there are no pending or contemplated marketing applications in an ICH region or 
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 and in keeping with local 
legal requirements. 
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, ie, 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. 
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.  


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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. 
14.3. 
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 
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. 


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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. 
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 


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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 
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-6201. 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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15. 
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Genentech, Inc.;2014.  


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Krop IE, Beeram M, Modi S, et al. Phase I study of trastuzumab-DM1, an HER2 antibody-drug 
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with human epidermal growth factor receptor 2-positive metastatic breast cancer who were 
previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J 
Clin Oncol 2012;30:3234-3241.  
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combined with pertuzumab in patients with [corrected] human epidermal growth factor receptor 
2-positive metastatic breast cancer. Clin Cancer Res 2008;14:2710-2716.  
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active, irreversible inhibitor of the HER-2 tyrosine kinase. Cancer Res. 2004;64:3958-3965. 
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epidermal growth factor receptor expression in primary breast cancer. Adv Anat Pathol 
2005;12:271-273.  
Remillard S, Rebhun LI, Howie GA and Kupchan SM. Antimitotic activity of the potent tumor 
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Rosen LS, Ashurst HL, Chap L. Targeting signal transduction pathways in metastatic breast 
cancer: a comprehensive review. Oncologist. 2010;15:216-235. 
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Yarden Y, Sliwkowski MX. Untangling the ErbB signalling network. Nat Rev Mol Cell Biol. 
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SIGNATURE PAGES 


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Declaration of Sponsor or Responsible Medical Officer 
Title of Study:  An Open-Label Study to Characterize the Incidence and Severity of Diarrhea in 
Patients with Early-Stage HER2+ Breast Cancer Treated with Neratinib and Loperamide. 
Study Number: PUMA-NER-6201 
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 Study to Characterize the Incidence and Severity of Diarrhea in 
Patients with Early-Stage HER2+ Breast Cancer Treated with Neratinib and Loperamide. 
Study Number: PUMA-NER-6201 
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 
 
_____________________________________ 
______________________________ 
Title 
 
 
 
 
 
 
Institution (block letters) and site number 
 
_____________________________________ 
______________________________ 
Address 
 
 
 
 
 
Phone number 


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17. 
APPENDICES 
 






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g 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).  
h Complete blood count (CBC) to include hematocrit (Hct), hemoglobin (Hb), platelet count, red blood cell (RBC) count, and white blood cell (WBC) count 
plus differential.  CBCs must be tested at screening and on Day 1 of Cycle 1 (-3 days), Cycle 2 (±5 days), Cycle 3 (±10 days), Cycle 4 (±10 days), Cycle 7 
(±14 days), Cycle 10 (±14 days), as well as on Day 28 of Cycle 13/EOT Visit (±5 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.  
i 
Serum chemistry tests include sodium, potassium, chloride, calcium, magnesium, blood urea nitrogen (BUN) or urea, serum creatinine, albumin, lactate 
dehydrogenase (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. For Amendment 4 and Amendment 5 patients who will be receiving colestipol, a baseline (occurring at Screen or C1D1) and C2D1 
fasting lipid panel is required to assess total cholesterol, HDL-C, and triglycerides. 
j 
Liver function tests (LFTs) must include total bilirubin, alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST).  
LFTs must be tested at screening, and on Day 1 of Cycle 1, Cycle 2, Cycle 3, Cycle 4, Cycle 7, and Cycle 10, as well as on Day 28 of Cycle 13/EOT Visit 
(±5 days), 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 
(see Appendix 2).  
k For patients enrolled starting with Amendment 2 only:  cfDNA will be obtained from plasma samples collected at screening, C7D1, C13D28, and/or at time 
of treatment discontinuation and at disease recurrence; cfDNA will undergo molecular profiling to identify biomarkers of disease recurrence. 
l 
At selected centers, a small stool swab from toilet paper, inserted into a tube that is provided, will be collected by the patient at Screening, C2D1, and C4D1 
or at time of treatment discontinuation if earlier than C4D1 for possible future assessments of microbiome. The tube is to be inserted into a bag then labeled 
for return in packaging. 
m During trial participation, ECHO or MUGA will be performed at Screening and on Day 28 of Cycle 13/EOT Visit. It is strongly recommended to use the 
same method of measurement for the same patient throughout the duration of the study.  
n Per standard of care, bone scan or positron emission tomography (PET) scan performed within 28 days prior to the date of enrollment; only required if 
alkaline phosphatase (ALP) is ≥2x upper limit of normal (ULN) and/or there are symptoms of metastatic bone disease. A confirmatory imaging study is 
required if the results from the bone scan are questionable (see Section 5.1).  
o Per standard of care, computed tomography (CT), magnetic resonance imaging (MRI) or ultrasound of the abdomen and chest performed within 28 days prior 
to the date of enrollment; only required if aspartate aminotransferase (AST)/alanine aminotransferase (ALT) or ALP is ≥2x ULN (see Section 5.1).  
p For patients enrolled starting with Amendment 2 only:  Health outcomes assessments consist of the Functional Assessment of Cancer Therapy for Breast 
Cancer (FACT-B) and the EQ-5D-5L questionnaires. For patients enrolled starting with Amendment 6.1: the Rotterdam Symptom Checklist (RSCL) will be 
added to the health outcomes questionnaires that the patient will complete. Questionnaires should be completed before any other study procedures on the day 
of the study visit. At the final or EOT visit, it is acceptable for questionnaires to be completed after study procedures. Questionnaires are to be completed by 
the patient at C1D1, C2D1, C4D1, C7D1, C10D1, and C13D28. 
 
q Concomitant medications and concomitant nonpharmacologic treatments/therapies are recorded from 30 days before signing of the informed consent form 
until the Safety Follow-up Visit.  


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r 
Patients enrolled starting with Amendment 6 will receive neratinib at a starting dose of 120 mg/day with dose escalation (ie, total dose 120 mg daily for the 
first week, 160 mg daily for the Week 2, and 240 mg daily for Week 3 and thereafter, until EOT. For patients receiving budesonide, loperamide is to be 
administered daily for two (2) 28-day cycles and then as needed (PRN). For patients in Amendment 4, loperamide is to be administered for one 28-day cycle 
and then as needed (PRN) thereafter. For patients enrolled under Amendment 5, Amendment 6, Amendment 6.1, Amendment 7, and Amendment 7.1, 
loperamide is to be administered as needed (PRN) for the entire study. Patients are asked to document administration of neratinib and loperamide on a diary 
on a daily basis (for patients starting with Amendment 6.1, this will be for the first 2 cycles (56 days) of the study; for patients starting with Amendment 7, 
after 2 cycles only neratinib administration is to be recorded, until EOT), and to return this diary to the site at appropriate visits (for patients starting with 
Amendment 6.1, the diary will be collected at C3D1, or at EOT if earlier). Individual patient dosing compliance should be reviewed at each study visit by 
study site staff. Investigators must ensure that patients have loperamide on hand when starting to take neratinib. Loperamide and 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.  
s 
The effect of anti-inflammatory treatment (for patients enrolled under Amendment 3 and a bile acid sequestrant, colestipol, (for patients enrolled under 
Amendment 4 and Amendment 5) on the incidence and severity of Grade 3 or higher diarrhea will be investigated in 3 sequential patient cohorts. The first 
treatment cohort will receive budesonide + intensive loperamide prophylaxis, the next cohort will receive colestipol + intensive loperamide prophylaxis, and 
the subsequent cohort will receive colestipol + loperamide on a PRN only basis. 
t 
From the signing of the informed consent form to 28 days after the last dose, adverse events (AEs) and serious adverse events (SAEs) are monitored 
continuously and recorded in the electronic case report form (eCRF) at every visit.  Patients must be instructed to contact the site to report and discuss the 
severity of diarrhea and the appropriate course of treatment.  Patients must use the diary to document any episodes of diarrhea for the first 2 cycles (56 days) 
of the study.  On this diary, patients also record the baseline number of stools per day, and in case of diarrhea, the number of loose stools per day and use of 
loperamide and/or other antidiarrheals, if applicable. Patients are asked to return this diary to the site at each visit.  Patient instructions for the management of 
diarrhea are reviewed with the patients and handed to the patient at the time of enrollment.  Should an Investigator be made aware of any SAEs occurring any 
time after the reporting period that may be causally related to neratinib’s administration, it should be promptly reported. 
u The Investigator or research staff must call the patients 1, 2, and 3 days after the first dose of neratinib (i) to inquire about potential adverse events, including 
diarrhea; (ii) to provide guidance to the patients for immediate and appropriate management of AEs, including diarrhea as specified in this protocol; (iii) to 
confirm that the patients have loperamide available, in case needed; (iv) to inquire about the first date of neratinib intake; the Investigator/research staff must 
update the eCRF within 3 days of receipt of this information. In addition, for patients enrolled under Amendment 6, the Investigator or research staff must call 
patients at the end of the first and second weeks of treatment (ie, Day 7 or Day 8, and Day 14 or Day 15) to confirm that the patient has increased the dose of 
neratinib from 120 mg to 160 mg, and from 160 mg to 240 mg, respectively, as required by the protocol. For patients enrolled under Amendment 7 and 
Amendment 7.1, the Investigator or research staff must call patients at the end of the first 2 weeks of treatment (ie, Day 14 or Day 15) and at the end of Cycle 
1 (C1D28 or C2D1) to confirm that the patient has increased the dose of neratinib from 160 mg to 200 mg, and from 200 mg to 240 mg, respectively, as 
required by the protocol.These phone calls are mandatory and must be recorded in the study chart together with response from the patient and action taken 
(See Section 7.2).  
 
 
 


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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 are listed in Table 3 in 
Section 6.1.1. 
For patients enrolled starting with Amendment 6, during the dose escalation phase (240 mg 
neratinib), for any patient who experiences Grade ≥2 AE(s) leading to neratinib dose interruption 
which do not resolve to Grade ≤ 1, a review of the patient and the patient’s adverse event profile 
must occur with the Sponsor’s Medical Monitor to determine whether the patient should be 
allowed to continue in the study. 
2. Toxicities Requiring Investigational Product Dose Adjustments 
General Toxicities: 
The guidelines for general toxicities 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 until event resolves to Grade ≤1; then resume neratinib at the 
starting dose level. 
 2nd appearance 
 
 Hold neratinib until event resolves to Grade ≤1; then resume neratinib at 
160 mg. 
 3rd appearance 
 Hold neratinib until event resolves to Grade ≤1; then resume neratinib at 120 
mg. 
 4th appearance 
 Discontinue neratinib permanently. 
Grade 3 adverse reaction 
 1st appearance 
 
 Hold neratinib until event resolves to Grade ≤1; then resume neratinib at 
160 mg. 
 2nd appearance 
 
 Hold neratinib until event resolves to Grade ≤1; then resume neratinib at 
120 mg. 
 3rd appearance 
 Discontinue neratinib permanently. 
Grade 4 adverse reaction 
 1st appearance 
 Discontinue neratinib permanently OR if Investigator deems it to be in the 
patient’s best interest to continue, hold neratinib until resolved to Grade ≤1; 
then resume neratinib at 160 mg. 
 If the event occurs again despite one dose reduction, permanently discontinued 
neratinib. 
Based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 


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Gastrointestinal Toxicity:  
Guidelines for adjusting doses of neratinib in the event of gastrointestinal toxicity diarrhea are 
shown in Table A2.2. 
Table A2.2. 
Gastrointestinal Toxicities Requiring Dose Adjustment of Neratinib  
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 
Continue neratinib at full dose.  
 Instruct patient to follow dietetic recommendations in the 
guidelines for management of diarrhea.  
 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. 
 Hold neratinib 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.   
o Within 1-4 weeks after withholding treatment, reduce 
neratinib dose to the next lower dose level.  
 If event occurs a 2nd time and the neratinib dose has not 
already been decreased, reduce neratinib dose to the next 
lower dose level. 
 If subsequent events occur, reduce neratinib dose to the next 
lower dose level.  
 Once the event resolved to ≤ Grade 1 or baseline, start 
loperamide 4 mg with each subsequent neratinib 
administration. 
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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. 
Based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0  
Liver Toxicity: 
Guidelines for adjustment of neratinib 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 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 if recovery to 
≤Grade 1 occurs within 4 weeks. If Grade 3 ALT or 
bilirubin occurs again despite one dose reduction, 
permanently discontinue neratinib.  
Grade 4 ALT (>20x ULN) 
OR 
Grade 4 Bilirubin (>10x ULN) 
 Permanently discontinue neratinib. 
 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. 
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. 
NOTE: During evaluation of hepatotoxicity, bilirubin must be fractionated, prothrombin time must be measured, and 
liver imaging should be considered. 
  














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APPENDIX 7. EUROQOL 5D-5L HEALTH QUESTIONNAIRE 
 


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APPENDIX 8. FUNCTIONAL ASSESSMENT OF CANCER THERAPY  
BREAST (FACT-B) 
 


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APPENDIX 9. CONTRAINDICATIONS, WARNINGS, AND 
PRECAUTIONS FOR BUDESONIDE 
Budesonide 
Contraindications  
 
Known hypersensitivity to budesonide or any of the ingredients in budesonide tablets 
 
Warnings and Precautions 
Hypercorticism and adrenal suppression- since budesonide is a glucocorticosteroid, follow 
general warnings concerning glucocorticoids: 
When glucocorticoids are used chronically, systemic effects such as hypercorticism and 
adrenal suppression may occur. Glucocorticoids can reduce the response of the 
hypothalamus-pituitary-adrenal (HPA) axis to stress.  In situations where patients are 
subject to surgery or other stress situations, supplementation with a systemic 
glucocorticosteroid is recommended. Since budesonide is a glucocorticosteroid, general 
warnings concerning glucocorticosteroids should be followed.   
Transferring patients from systemic glucocorticoids: Risk of impaired adrenal function 
when transferring from glucocorticoid treatment with higher systemic effects to 
glucocorticoid treatment with lower systemic effects, such as budesonide. Taper patients 
slowly from systemic corticosteroids if transferring to budesonide.  
Care is needed in patients who are transferred from glucocorticosteroid treatment with 
higher systemic effects to glucocorticosteroids with lower systemic effects, such as 
budesonide, since symptoms attributed to withdrawal of steroid therapy, including those of 
acute adrenal suppression or benign intracranial hypertension, may develop. 
Adrenocortical function monitoring may be required in these patients and the dose of 
glucocorticosteroid treatment with high systemic effects should be reduced cautiously.  
Immunosuppression: Potential worsening of infections (e.g., existing tuberculosis, fungal, 
bacterial, viral or parasitic infection; or ocular herpes simplex). Use with caution in 
patients with these infections. More serious or even fatal course of chickenpox or measles 
can occur in susceptible patients. 
Patients who are on drugs that suppress the immune system are more susceptible to 
infection that healthy individuals. Chicken pox and measles, for example, can have a more 
serious or even fatal course in susceptible patients or patients on immunosuppressant 
doses of glucocorticosteroids. In patients who have not had these diseases, particular care 
should be taken to avoid exposure.  
How the dose, route, and duration of glucocorticosteroid administration affect the risk of 
developing a disseminated infection is not known. The contribution of the underlying 
disease and/or prior glucocorticoid treatment to the risk is also not known. If exposed, 
therapy with varicella zoster immune globulin (VZIG) or pooled intravenous 
immunoglobulin (IVIG), as appropriate, may be indicated. If exposed to measles, 
prophylaxis with pooled intramuscular immunoglobulin (IG) may be indicated. See 
prescribing information for VZIG and IG. If chicken pox develops, treatment with 
antiviral agents may be considered.  


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Budesonide 
Contraindications  
Glucocorticosteroids should be used with caution, if at all, in patients with active or 
quiescent tuberculosis infection, untreated fungal, bacterial, systemic viral or parasitic 
infections.  
 
Replacement of systemic glucocorticosteroids with budesonide tablets may unmask 
allergies (e.g., rhinitis and eczema), which were previously controlled by systemic drug.  
 
Reduced liver function affects the elimination of glucocorticosteroids, and increased 
systemic availability of oral budesonide has been demonstrated in patients with liver 
cirrhosis.  
 
Caution should be taken in patients with hypertension, diabetes mellitus, osteoporosis, 
peptic ulcer, glaucoma or cataracts, or with a family history of diabetes or glaucoma, or 
with any other condition where glucocorticosteroids may have unwanted effects.  


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APPENDIX 10. CONTRAINDICATIONS, WARNINGS, AND 
PRECAUTIONS FOR COLESTIPOL 
Colestipol 
Contraindications  
 
Known hypersensitivity to micronized colestipol hydrochloride tablets or any of the 
ingredients in the tablets 
 
Warnings and Precautions 
Because it sequesters bile acids, colestipol hydrochloride may interfere with normal fat 
absorptions and thus may reduce absorption of folic acid and fat soluble vitamins such a, 
D, and K. 
Chronic use of colestipol hydrochloride may be associated with an increased bleeding 
tendency due to hypoprothrombinemia from vitamin K deficiency. This will usually 
respond promptly to parenteral vitamin K1 and recurrences can be prevented by oral 
administration of vitamin K1. 
Serum cholesterol and triglyceride levels should be determined periodically based on 
NCEP guidelines to confirm a favorable initial and adequate long-term response. 
Micronized colestipol hydrochloride tablets may produce or severely worsen pre-existing 
constipation. The dosage should be increased gradually in patients to minimize the risk of 
developing fecal impaction. In patients with pre-existing constipation, the starting dose 
should be 2 grams once or twice a day. Increased fluid and fiber intake should be 
encouraged to alleviate constipation and a stool softener may occasionally be indicated. If 
the initial dose is well tolerated, the dose may be increased as needed by a further 2 to 4 
grams/day (at monthly intervals) with periodic monitoring of serum lipoproteins. If 
constipation worsens or the desired therapeutic response is not achieved at 2 to 16 
grams/day, combination therapy or alternate therapy should be considered. Particular 
effort should be made to avoid constipation in patients with symptomatic coronary artery 
disease. Constipation associate with micronized colestipol hydrochloride tablets may 
aggravate hemorrhoids. 
While there have been no reports of hypothyroidism induced in individuals with normal 
thyroid function, the theoretical possibility exists, particularly in patients with limited 
thyroid reserve. 
Since colestipol hydrochloride is a chloride form of an anion exchange resin, there is a 
possibility that prolonged use may lead to the development of hyperchloremic acidosis. 
 
Potential for Drug-drug Interactions 
Since colestipol is an anion exchange resin, this effect may be related to a strong affinity 
for anions other than the bile acids. In vitro studies have indicated that colestipol binds a 
number of drugs. 
Repeated doses of colestipol given prior to a single dose of propranolol in human trials 
have been reported to decrease propranolol absorption. Patients on propranolol and 
possibly other beta-blockers should be monitored when colestipol is added or deleted from 


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Colestipol 
Contraindications  
the therapeutic regimen.  Effects of the absorption of other beta-blockers have not been 
determined. 
Studies in humans show that the absorption of chorothiazide as reflected in urinary 
excretion is markedly decreased even when administered one hour before colestipol. The 
absorption of tetracycline, furosemide, penicillin G, hydrochlorothiazide, and gemfibrozil 
was significantly decreased when given simultaneously with colestipol. These drugs were 
not tested to determine the effect of administration one hour before colestipol. 
No lowering effect on blood levels in humans was noted when colestipol was administered 
with any of the following drugs: aspirin, clindamycin, clofibrate, methyldopa, nicotinic 
acid (niacin), tolbutamide, phenytoin or warfarin. Particular caution should be observed 
with digoxin preparations since ther are conflicting results for the effect of colestipol on 
the availability of digoxin and digitoxin. The potential for binding of these drugs if given 
concomitantly is present. Discontinuing colestipol could pose a hazard to health if a 
potentially toxic drug that is significantly bound to the resin has been titrated to a 
maintenance level while the patient was taking colestipol. 
Bile acid bind resins such as coletipol may also interfere with the absorption of oral 
phosphate supplements and hydrocortisone. 
A study has shown that cholestyramine binds bile acids and reduces mycophenolic acid 
exposure. As colestipol also binds bile acids, colestipol may reduce mycophenolic acid 
exposure and potentially reduce efficacy of mycophenolate mofetil. 
Information for Patients 
Micronized colestipol hydrochloride tablets may be larger than pills you have taken 
before. If you have had swallowing problems or choking with food, liquids or other tablets 
or capsules in the past, you should discuss this with your doctor before taking micronized 
colestipol hydrochloride tablets.  
It is important that you take micronized colestipol hydrochloride tablets correctly: 
 
Always take on tablet at a time and swallow promptly 
 
Swallow each tablet whole. Do not cut, crush, or chew the tablets 
 
Micronized colestipol hydrochloride tablets much be taken with water or 
another liquid that you prefer. Swallowing the tablets will be easier if you 
drink plenty of liquid as you swallow each tablet. 
Difficulty swallowing and temporary obstruction of the esophagus (the tube between your 
mouth and stomach) have been rarely reported in patients taking micronized colestipol 
hydrochloride tablets. If a tablet does get stuck after you swallow it, you may notice 
pressure or discomfort. If this happens to you, you should contact your doctor. Do not take 
micronized colestipol hydrochloride tablets again without your doctor’s advice.   
If you are taking other medications, you should take them at least one hour before or four 
hours after taking micronized colestipol hydrochloride tablets.  
 
Adverse Reactions 
Gastrointestinal 
The most common adverse reactions are confined to the gastrointestinal tract. 
Constipation is the major single complaint and at times is severe. Most instances of 


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Colestipol 
Contraindications  
constipation are mild, transient, and controlled with standard treatment. Increased fluid 
intake and inclusion of additional dietary fiber should be the first step; a stool softener 
may be added if needed. Some patients require decreased dosage or discontinuation of 
therapy. Hemorrhoids may be aggravated.  
Other less frequent gastrointestinal complaints consist of abdominal discomfort 
(abdominal pain and cramping) intestinal gas (bloating and flatulence), indigestion and 
heartburn, diarrhea and loose stools, and nausea and vomiting. Bleeding hemorrhoids and 
blood in the stool have been infrequently reported. Peptic ulceration, cholecystitis, and 
cholelithiasis have been rarely reported in patients receiving colestipol hydrochloride 
granules, and are not necessarily drug related.   
Difficulty swallowing and transient esophageal obstruction have been rarely reported in 
patients taking micronized colestipol hydrochloride.  
Transient and modest elevations of aspartate aminotransferase (AST, SGOT), alanine 
aminotransferase (ALT, SGPT) and alkaline phosphatase were observed on one or more 
occasions in various patients treated with colestipol hydrochloride. 
Cardiovascular 
Chest pain, angina, and tachycardia have been infrequently reports and are comparable to 
placebo rates in trials 
Hypersensitivity 
Rash has been infrequently reported. Urticaria and dermatitis have been rarely noted in 
patients receiving colestipol hydrochloride granules. 
Musculoskeletal  
Musculoskeletal pain, aches, and pains in the extremities, joint pain and arthritis, and 
backache have been reported.  
Neurologic 
Headache, migraine headache, and sinus headache have been reported. Other infrequently 
reported complaints include dizziness, light-headedness, and insomnia.  
Miscellaneous 
Anorexia, fatigue, weakness, shortness of breath, and swelling of the hands or feet, have 
been infrequently reported. 
Source:  Colestid (colestipol) US Package Insert. 
 
 


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APPENDIX 11. ROTTERDAM SYMPTOM CHECKLIST 
 
 
 
 
 
 
 
 


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SAP_001.pdf: 
An Open-Label Study to Characterize the Incidence and 
Severity of Diarrhea in Patients 
with Early-Stage HER2+ Breast Cancer Treated with 
Neratinib and Loperamide 
 
NCT02400476 
 
Statistical Analysis Plan – Version 4.0 
 
30-Aug-2019 


Document ID: 093d860c8135cc39
 
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 Study to Characterize the Incidence and 
Severity of Diarrhea in Patients with Early-Stage HER2+ Breast 
Cancer Treated with Neratinib and Loperamide  
 
Study Protocol No. 
PUMA-NER-6201 
Disease Condition 
HER2-Positive 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 
18-September-2015 
 
 
 
    v2.0 
 
                      29-June-2016 
 
 
 
    v3.0 
 
                      06-February-2018 
                                      v4.0                                              30-August-2019 
 


Document ID: 093d860c8135cc39
Statistical Analysis Plan 
 
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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 Objectives ................................................................................. 6 
2.1.2 
Secondary Objectives ............................................................................. 6 
2.1.3 
Exploratory Objectives ........................................................................... 6 
2.2 Study Endpoints ..................................................................................................... 6 
2.2.1 
Primary Endpoint ................................................................................... 6 
2.2.2 
Secondary Endpoints .............................................................................. 7 
2.2.3 
Exploratory Endpoints ............................................................................ 7 
2.3 Overall Study Design and Plan ................................................................................. 7 
2.3.1 
Study Design ......................................................................................... 7 
2.3.2 
Neratinib Adjustments .......................................................................... 10 
2.3.3 
Loperamide-Original Protocol ............................................................... 11 
2.3.4 
Loperamide- Amendment 1 to Amendment 3 .......................................... 11 
2.3.5 
Loperamide- Amendment 4 ................................................................... 11 
2.3.6 
Loperamide- Amendment 5 ................................................................... 12 
2.3.7 
Loperamide- Amendments 6, 6.1, 7, and 7.1 ............................................ 12 
2.3.8 
Loperamide Dose Adjustments-Amendments 1 through 7.1 ....................... 12 
2.3.9 
Anti-inflammatory Treatment-Amendment 3 ........................................... 13 
2.3.10 
Bile Acid Sequestrant-Amendments 4 and 5 ............................................ 13 
2.4 Sample Size Determination .................................................................................... 13 
3. 
DEFINITIONS ........................................................................................................ 15 
4. 
DATA SCREENING, ACCEPTANCE AND PROGRAMMING ............................... 18 
4.1 General Principles ................................................................................................ 18 
4.2 Handling of Missing and Incomplete Data ............................................................... 18 
4.3 Testing/Validation Plan ......................................................................................... 18 
5. 
ANALYSIS POPULATIONS ................................................................................... 19 
5.1 Safety Population ................................................................................................. 19 
5.2 Quality of Life (QOL) Analysis Population ............................................................. 19 
6. 
ANALYSIS METHODS .......................................................................................... 20 
6.1 General Principles ................................................................................................ 20 
6.2 Disposition of Patients .......................................................................................... 20 
6.3 Deviations ........................................................................................................... 20 
6.4 Demographic and Baseline Characteristics .............................................................. 20 
6.5 Medical History ................................................................................................... 21 
6.6 Cancer History ..................................................................................................... 21 
6.6.1 
Summary of Cancer History .................................................................. 21 
6.6.2 
Prior Anti-cancer Therapy ..................................................................... 22 
6.7 Baseline Biomarkers ............................................................................................. 22 
6.8 Study Medication (Neratinib) ................................................................................. 22 
6.9 Concomitant Medications/ Therapy ........................................................................ 22 
6.9.1 
Loperamide During the Mandatory Prophylactic Period ............................ 23 
6.9.2 
Anti-diarrheal Medications During the Mandatory Prophylactic Period ....... 23 


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Statistical Analysis Plan 
 
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6.9.3 
Anti-inflammatory Agents During the First Cycle .................................... 23 
6.9.4 
Bile Acid Sequestrant During the First Cycle ........................................... 24 
6.9.5 
Concomitant Therapy ........................................................................... 24 
6.10 
Adverse Events (AEs) .................................................................................... 24 
6.10.1 
Treatment Emergent Diarrhea ................................................................ 24 
6.10.2 
Treatment-Emergent Adverse Events (TEAEs) ........................................ 26 
6.10.3 
Adverse Events of Special Interest (AESI) .............................................. 26 
6.10.4 
Death .................................................................................................. 27 
6.11 
Clinical Laboratory Parameters ....................................................................... 27 
6.12 
Vital Signs .................................................................................................... 27 
6.13 
ECG Abnormality ......................................................................................... 27 
6.14 
Left Ventricular Ejection Fraction (LVEF) ....................................................... 28 
6.15 
Disease Recurrence ........................................................................................ 28 
6.16 
Health Outcome Assessments ......................................................................... 28 
6.17 
Exploratory Biomarker Analysis ..................................................................... 30 
6.18 
Exploratory Microbiome Analysis ................................................................... 30 
7. 
INTERIM ANALYSES ........................................................................................... 31 
8. 
LIST OF PLANNED TABLES, FIGURES, AND LISTINGS .................................... 32 
8.1 TABLES ............................................................................................................. 32 
8.2 FIGURES ............................................................................................................ 35 
8.3 LISTINGS ........................................................................................................... 35 
9. 
REFERENCES ....................................................................................................... 37 
 


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Statistical Analysis Plan 
 
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LIST OF ABBREVIATIONS 
 
Abbreviation 
Term/Definition 
AE 
adverse event 
AESI 
adverse events of special interest 
ATC 
Anatomical Therapeutic Chemical 
CI 
confidence interval 
CRF 
case report form 
CSR 
clinical study report 
CT  
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
ECG 
Electrocardiogram 
ECHO  
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
ER 
estrogen receptor 
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 
IHC 
Immunohistochemistry 
IP 
Investigational Product 
ISH 
in situ hybridization 
K-M 
Kaplan-Meier 
LVEF  
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MUGA 
multiple-gated accession scan 
NCI 
National Cancer Institute 
PR 
progesterone receptor 
PT  
preferred term 
QOL 
quality of life 
QTc  
QT interval, corrected for heart rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SOC 
system organ class 
TDM-1 
trastuzumab emtansine 
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 
through Amendment 7.1 of the protocol “An Open-Label Study to Characterize the 
Incidence and Severity of Diarrhea in Patients with Early-Stage HER2+ Breast 
Cancer Treated with Neratinib and Loperamide” (PUMA-NER-6201), dated 25 July 
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 
Clinical Study Report (CSR).  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2. PROTOCOL SUMMARY 
2.1 
Study Objectives 
2.1.1 Primary Objectives  
The primary objective of this study is to characterize the incidence and severity of 
treatment-emergent diarrhea in patients with early-stage HER2 overexpressed/amplified 
(HER2+) breast cancer treated with neratinib after prior treatment with trastuzumab. 
 
2.1.2 Secondary Objectives 
The secondary objectives of this study are: 
 To assess the incidence of serious adverse events (SAEs) and other adverse events 
of special interest (AESI).  
 To assess the incidence and severity of diarrhea. 
 
 
2.1.3 Exploratory Objectives 
Exploratory objectives include: 
 For patients enrolled starting with Amendment 2: 
 To assess patient-reported health outcomes using the EuroQol 5D-5L (EQ-
5D-5L) and the Functional Assessment of Cancer Therapy Breast (FACT-B) 
questionnaires. 
 To collect biomarkers of disease from cell-free DNA (cfDNA) to evaluate 
their relationship to clinical recurrence of disease. 
 For patients enrolled under Amendment 6: 
 
Evaluation of stool bacterial diversity (microbiome)   
 
 
For patients enrolled starting with Amendment 6.1: 
 To assess patient-reported health outcomes using the Rotterdam Symptom 
Checklist (RSCL) 
 
2.2 
Study Endpoints 
2.2.1 Primary Endpoint 
The primary endpoint is the incidence of Grade 3 or higher diarrhea.  
 
 


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2.2.2 Secondary Endpoints 
Secondary endpoints include the incidence and severity of diarrhea and the incidence of 
SAEs and AESIs. 
 
 
2.2.3 Exploratory Endpoints 
The exploratory endpoint of patient-reported health outcomes will be assessed by the 
EuroQol EQ-5D-5L, the FACT-B questionnaires (for patients enrolled starting with 
Amendment 2), and the RSCL (for patients enrolled starting with Amendment 6.1). The 
exploratory endpoint of disease biomarkers will consist of the biomarkers of disease 
recurrence (for patients enrolled starting with Amendment 2). The exploratory endpoint 
of evaluation of stool bacterial diversity, i.e., microbiome (for patients enrolled starting 
with Amendment 6/6.1). 
 
 
2.3 
Overall Study Design and Plan 
2.3.1 Study Design 
This is an open-label, Phase 2 study that will investigate the incidence of diarrhea in 
HER2+ breast cancer patients receiving neratinib with intensive loperamide diarrhea 
prophylaxis, with and without an anti-inflammatory treatment or a bile acid sequestrant 
treatment and who have previously completed trastuzumab therapy in the adjuvant 
setting.  
Patients will receive:  
 Neratinib 240 mg orally once daily with food for thirteen (13) 28-day cycles.  
 For patients enrolled Original Protocol, Amendment 1 or 2, loperamide daily 
for two (2)  28-day cycles and then as needed. 
 For patients enrolled under Amendment 3, an anti-inflammatory treatment for 
1 cycle and loperamide to be administered daily for two (2) 28-day cycles and 
then as needed, thereafter; 
 For patients enrolled under Amendment 4, colestipol for 1 cycle and 
loperamide to be administered 1 cycle and then as needed, thereafter; 
 For patients enrolled under Amendment 5, colestipol for 1 cycle and 
loperamide to be administered on an as-needed basis only. 
 For patients enrolled under Amendment 6 and 6.1, 120 mg neratinib for Week 
1 (C1D1 – C1D7), followed by 160 mg neratinib starting for Week 2 (C1D8 – 
C1D14), followed by 240 mg neratinib starting at Week 3 and thereafter 
(C1D15 to EOT). Loperamide will be administered on an as-needed basis 
only. 


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 For patients enrolled starting with Amendment 7, 160 mg neratinib for the 
first 2 weeks (C1D1 – C1D14), followed by 200 mg neratinib for the next 2 
weeks (C1D15 – C1D28), followed by 240 mg neratinib thereafter (C2D1 to 
End-of-treatment [EOT]). Loperamide will be administered on an as-needed 
basis only. 
 
Patients will participate in the active treatment phase, consisting of thirteen (13) 28-day 
treatment cycles. Neratinib and loperamide will be administered orally by patients. 
Neratinib is to be taken continuously, in 28-day cycles, with no rest between cycles.   
The effect of the anti-inflammatory treatment, budesonide and the bile acid sequestrant 
colestipol on the incidence, severity, and duration of diarrhea will be investigated in 
sequential patient cohorts using a sample size of approximately 64 patients per cohort. 
The anti-inflammatory cohort added in Amendment 3 will be assigned to receive 
budesonide tablets 9 mg once daily with or without food for 28 days along with neratinib 
240 mg/day (13 cycles) and intensive loperamide prophylaxis that will continue through 
the first 2 cycles (total 56 days), and on an as-needed basis thereafter.  
Following the completion of enrollment of the patients receiving budesonide, neratinib, 
and intensive loperamide prophylaxis, the next cohort will be evaluated after receiving 
colestipol 2 g twice daily with or without food for 28 days, to be given at least 2 hours 
after, but at least 4 hours before, neratinib 240 mg/day (13 cycles) and intensive 
loperamide prophylaxis. For this cohort, intensive loperamide prophylaxis will continue 
only through the first cycle (28 days); for Cycle 2 and beyond, loperamide may be 
administered as needed (PRN).  
Following complete enrollment of the cohort treated with colestipol and intensive 
loperamide prophylaxis, all patients in the next cohort will be evaluated after receiving 
colestipol and neratinib with loperamide administered on a PRN basis only. 
Following complete enrollment of the cohort receiving neratinib + colestipol + 
loperamide PRN, all patients in the next cohort will be evaluated after receiving neratinib 
administered according to the following dose-escalation scheme: 120 mg neratinib for 
Week 1 (C1D1 – C1D7), followed by 160 mg neratinib starting at Week 2 (C1D8 – 
C1D14), followed by 240 mg neratinib starting at Week 3 and thereafter (C1D15 to 
EOT). Loperamide is to be administered on a PRN basis only.  
Following complete enrollment of all patients in the 120 mg/160 mg/240 mg dose-
escalation scheme, patients enrolled in the next cohort will be evaluated after receiving 
neratinib administered according to a second dose escalation scheme: 160 mg neratinib to 
be taken for the first 2 weeks (C1D1 – C1D14), followed by 200 mg neratinib to be taken 
for the next 2 weeks (C1D15 – C1D28), followed by 240 mg neratinib daily dose taken 
thereafter (C2D1 to EOT). Loperamide is to be administered on a PRN basis only.  
The Sponsor will regularly review accumulating safety data (by individual subject and in 
aggregate). Early termination of a cohort or the study may be permitted if data indicate 
that anti-diarrheal treatment is ineffective. 


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Patients in all treatment groups will continue to complete the remaining 12 treatment 
cycles. Cohorts will continue to enroll without interruption, in sequence. Thus enrollment 
may exceed initial projections. 


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Clinic visits during the active treatment phase are planned on Day 1 of Cycle 1, 2, 3, 4, 7, 
and Cycle 10. End of Treatment (EOT) Visit is planned on Day 28 of Cycle 13, followed 
by Safety Follow-up Visit 28 days after the last dose of neratinib.  
Patients may be discontinued from investigational product or from the study.  
An interim analysis is planned when approximately 120 enrolled under the Original 
Protocol, Amendment 1, and Amendment 2 have completed at least 2 cycles (56 days) of 
neratinib with loperamide prophylaxis. The analysis will only include those 120 patients 
enrolled under the Original Protocol, Amendment 1, and Amendment 2. Other additional 
analysis by cohort may be carried out as required. The final analysis is planned when all 
patients have either completed 13 cycles (364 days) of neratinib therapy or have 
discontinued from the study.  
For the Original protocol, Amendment 1, and Amendment 2, approximately 120 patients 
were to be enrolled at approximately 35-45 centers.  
For the 5 cohorts evaluating additional treatments added in Amendment 3 (budesonide), 
Amendment 4 and Amendment 5 (colestipol), Amendment 6/6.1 (neratinib dose 
escalation from 120 mg/day), and Amendment 7/7.1 (neratinib dose escalation from 160 
mg/day), approximately 450 additional patients will be enrolled at approximately 74 
centers. The approximate total enrollment will be 750 patients total.   
Patients 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, and 
safety follow-up visit 28 days after the last dose of neratinib. 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).  
 
 
2.3.2 Neratinib Adjustments 
Neratinib may be dose-adjusted/reduced due to neratinib-related toxicity from 240 mg 
down 160 mg or 120 mg. If doses of neratinib are held, study procedures for that cycle 
will proceed on schedule as planned, without delay. 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.  
 
For patients enrolled under the dose-escalation schemes of Amendment 6/6.1, 
Amendment 7/7.1, during the dose escalation phase (<240 mg neratinib), for any patient 
who experiences Grade ≥ 2 AE(s) leading to neratinib dose interruption which do not 
resolve to Grade ≤ 1, a review of the patient and the patient’s adverse event profile must 
occur with the Sponsor’s Medical Monitor to determine whether the patient should be 
allowed to continue in the study. 
 


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2.3.3 Loperamide-Original Protocol 
Under the original protocol, initial dose of loperamide 4 mg (2 tablets/capsules) will be 
self-administered orally by patients with the first dose of neratinib, followed by 2 mg 
(1 tablet/capsule) every 4 hours for the first 3 days.  After the first 3 days, loperamide 2 
mg every 6 to 8 hours through the first 2 cycles of therapy (56 days) from start of 
neratinib. Thereafter, loperamide will be administered as needed. Patients are expected to 
take loperamide prophylaxis as directed and it is expected that all patients will comply 
with the initial 3-day loading dose of loperamide. Following the initial 3 days of 
loperamide, if a patient is unable to tolerate loperamide due to constipation, it should be 
held until the first bowel movement and then resumed at a dose reduced by one level. 
After a recurrent event, resume loperamide after the first bowel movement and reduce to 
the next lower dose level. At the third occurrence of 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 -1 (2mg every 12 hours or 2 tablets a day), Dose Level -2 (2mg once a day or 
1 tablets a day).  
 
 
2.3.4 Loperamide- Amendment 1 to Amendment 3 
Starting from amendment 1, loperamide dosing was changed to improve effectiveness 
and compliance. The updated loperamide dosing schedule is as follows:  
 
• 
For the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-
administered orally by patients 3 times a day (total 12 mg a day).  
• 
The initial dose of loperamide 4 mg will be self-administered orally with the first 
dose of neratinib.  
• 
After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-
administered orally twice a day (total 8 mg a day) through the first 2 cycles of therapy 
(Day 56) from start of neratinib dosing.  
• 
Thereafter, loperamide will be administered as needed (not to exceed 16 mg per 
day). 
 
 
 
 
2.3.5 Loperamide- Amendment 4 
With amendment 4, loperamide dosing was reduced to 1 cycle. The updated loperamide 
dosing schedule is as follows:  
 
• 
For the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-
administered orally by patients 3 times a day (total 12 mg a day).  
• 
The initial dose of loperamide 4 mg will be self-administered orally with the first 
dose of neratinib.  


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• 
After the first 14 days, loperamide 4 mg (2 tablets/capsules) will be self-
administered orally twice a day (total 8 mg a day) through the first cycle (Day 28) from 
start of neratinib dosing.  
• 
Thereafter, loperamide will be administered as needed (not to exceed 16 mg per 
day). 
 
 
2.3.6 Loperamide- Amendment 5  
Starting with amendment 5, loperamide dosing was changed to be given as prescribed. 
The updated loperamide dosing schedule is as follows:  
 
• 
Loperamide 4 mg (2 tablets/capsules) will be self-administered orally by patients 
on a PRN basis, from the start of neratinib dosing with a goal of titrating to 1-2 bowel 
movements a day (not to exceed 16 mg per day). 
 
 
2.3.7 Loperamide- Amendments 6, 6.1, 7, and 7.1  
With amendments 6 through 7.1, the updated loperamide dosing schedule is as follows:  
 
• 
Initial dose 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 
0(≤16 mg/day); continue loperamide at this frequency until diarrhea-free for 12 hours. 
• 
Then titrate loperamide (4 mg PRN) to keep diarrhea controlled (1 2 bowel 
movements/day). 
 
 
2.3.8 Loperamide Dose Adjustments-Amendments 1 through 7.1 
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) with the goal of titrating to 1-2 bowel movements a day. For patients who 
develop diarrhea during Cycles 1-2, loperamide should be increased up to a maximum of 
16 mg a day (or during Cycle 1 or after, for patients enrolled under Amendment 4; 
thereafter, loperamide may be administered up to 16 mg per 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, loperamide should be held 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. 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), or Dose 
Level -4 (2 mg once a day or 1 tablet/capsule a day). Neratinib dosing should continue if 


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loperamide is held. 
 
 
2.3.9 Anti-inflammatory Treatment-Amendment 3 
Under amendment 3, the use of anti-inflammatory agent was added to Cycle 1 of the 
neratinib-loperamide dosing regimen. The anti-inflammatory agent is as follows: 
 
o Budesonide 
 For patients enrolled in Amendment 3 and who participate in the evaluation of 
budesonide, patients will self-administer oral budesonide at a dose of 9 mg once 
daily for the first treatment cycle, to be taken with neratinib and intensive 
loperamide prophylaxis. 
 
 
2.3.10 Bile Acid Sequestrant-Amendments 4 and 5 
Under amendments 4 and 5, the use of bile acid sequestrant was added to Cycle 1 of the 
neratinib-loperamide dosing regimen. The bile acid sequestrant is as follows: 
 
o Colestipol 
 For patients enrolled in Amendments 4 and 5 and who participate in the 
evaluation of colestipol, patients will self-administer colestipol at a dose of 2 g 
twice daily for the first treatment cycle, to be taken with neratinib and intensive 
loperamide prophylaxis. 
 
 
2.4 
Sample Size Determination 
A sample size of 120 patients was originally planned for the Loperamide Cohort. A 
sample size of 40 was originally planned for the Budesonide Cohort. A sample size of 64 
was planned for the Colestipol, Colestipol+Loperamide PRN, and Neratinib Dose 
Escalation Cohorts. A sample size of 100 was planned for the Neratinib Dose Escalation 
Scheme 2 Cohort. For Grade 3 or higher treatment-emergent diarrhea, both incidence and 
exact confidence intervals are calculated (Clopper and Pearson, 1934). The below table 
presents several incidence and associated CI by planned sample sizes. 
 
 


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Incidence 
CI for Sample 
Size N=120 
CI for Sample 
Size N=40 
CI for Sample 
Size N=64 
CI for Sample 
Size N=100 
15.0% 
(9.1%, 22.7%) 
(5.7%, 29.8%) 
(7.3%, 26.1%) 
(8.6%, 23.5%) 
20.0% 
(13.3%, 28.3%) 
(9.1%, 35.7%) 
(11.0%, 31.9%) 
(12.7%, 29.2%) 
25.0% 
(17.5%, 33.7%) 
(12.7%, 41.2%) 
(15.0%, 37.4%) 
(16.9%, 34.7%) 
30.0% 
(22.0%, 39.0%) 
(16.6%, 46.5%) 
(19.2%, 42.7%) 
(21.2%, 40.0%) 
35.0% 
(26.5%, 44.2%) 
(20.6%, 51.7%) 
(23.5%, 47.9%) 
(25.7%, 45.2%) 
40.0% 
(31.2%, 49.3%) 
(24.9%, 56.7%) 
(27.9%, 53.0%) 
(30.3%, 50.3%) 
 
 


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3. DEFINITIONS 
Baseline 
The baseline value for a parameter of interest (e.g. labs) is the last measurement obtained 
prior to or on the date of the first dose of neratinib. 
 
Cycle 
A cycle in this protocol is 28 days.  
 
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 (daily dosing) 
 
 
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. For neratinib, the planned dose intensity is described in Section 
6.8. For loperamide, it is described in Section 6.9.1. 
 
Prescribed Dose Intensity  
The prescribed dose intensity is defined as the cumulative prescribed dose divided by 
treatment duration. 
 
Treatment-Emergent Adverse Event (TEAE) 
 
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 last administration of neratinib. 
 
Investigational Product (IP) 


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Investigational product (IP) is used to reference neratinib. 
 
Functional Assessment of Cancer Therapy- Breast Cancer (FACT-B) 
FACT-B is a validated instrument used to measure disease-specific quality of life in 
breast cancer patients (Brady et al., 1997). Subjects will be asked to indicate how true a 
statement had been for them over the past 7 days using a 5-point scale: 0, not at all; 1, a 
little bit; 2, somewhat; 3, quite a bit; and 4, very much. All items on the questionnaire 
receive equal weighting. 
The FACT-B (version 4) is a 37-item questionnaire with 5 subscales. The FACT-B 
(version 4) consists of two parts: 
(1) The general questionnaire on cancer (FACT-G), which includes the following 
4 subscales: 
a. Physical well-being (PWB) consisting of 7 statements (GP1 – GP7) 
b. Social/Family well-being (SWB) consisting of 7 statements (GS1 – GS7) 
c. Emotional well-being (EWB) consisting of 6 statements (GE1 – GE6) 
d. Functional well-being (FWB) consisting of 7 statements (GF1 – GF7) 
(2) An additional breast cancer-specific subscale (BCS) consisting of 10 statements 
of which 9 are used in scoring (B1 – B9) 
 
 
EQ-5D-5L 
The EQ-5D-5L is a standardized instrument that provides a simple descriptive profile and 
index value for health status. The EQ-5D-5L consists of 6 items: 5 dimensions (mobility, 
self-care, usual activity, pain/discomfort, and anxiety/depression) and a health state score.  
Each dimension has 5 levels: 
(1) No problems 
(2) Slight problems 
(3) Moderate problems 
(4) Severe problems 
(5) Extreme problems 
and subjects are asked to select the level most descriptive of their current state of function 
or experience on each dimension.  
 


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Rotterdam Symptom Checklist (RSCL) 
The RSCL measures both physical and psychological aspects of quality of life (QOL) in 
cancer patients. The instrument assesses symptom-related distress among patients for 
physical symptoms, psychological symptoms, and activities of daily living. The 3 
domains are assessed in a 4-point scale (not at all, a little, quite a bit, very much) for 38 
items. Patients are asked to indicate the degree to which they have been bothered by the 
indicated symptoms in the past week. 
(1) The 3 domains, which includes the following 3 subscales: 
a. Physical Symptom Distress (23 items) (not collected for this study) 
b. Psychological Distress (7 items) (not collected for this study) 
c. Activities of Daily Living (8 items) 
(2) An additional single Overall Valuation of Life item consisting of 7 possible 
responses. 
 
 
 


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4. DATA SCREENING, ACCEPTANCE AND PROGRAMMING 
4.1 
General Principles 
Clinical data are entered into the InForm 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. 
 
Subjects missing baseline assessments for FACT-B, EQ-5D, or RSCL questionnaires will 
not be included in the analysis of these health outcomes assessments. 
 
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 9.3 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.  Unless otherwise specified, all analyses will be done by the following 
subgroups:  (1) the Original Protocol, (2) Amendment 1 or Amendment 2, (3) 
Amendment 3 (Budesonide cohort), (4) Amendment 4 (Colestipol cohort), (5) 
Amendment 5 (Colestipol+Loperamide PRN cohort),  (6) Amendment 6/6.1 (Neratinib 
Dose Escalation cohort), and (7) Amendment 7/7.1 (Neratinib Dose Escalation Scheme 2 
cohort).Subgroups (1) and (2) may be combined into the Loperamide cohort. 
 
5.2 
Quality of Life (QOL) Analysis Population 
The QOL analysis population is defined as all enrolled patients who are in the safety 
population and who also have a baseline QOL assessment as well as at least 1 post-
baseline QOL assessment. 
  
 
 
 


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6. ANALYSIS METHODS 
6.1 
General Principles 
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.  Safety 
analyses will be performed by subgroups specified in section 5.2 when appropriate. 
Patient incidence will be provided for AEs, as specified in Section 6.10.2.  
 
 
6.2 
Disposition of Patients 
Disposition of patients will be summarized into two general categories: Investigational 
Product Accounting and Study Completion Accounting. For each type of accounting, 
summaries will include the number of patients continuing either the treatment or study, 
and the number of patients who have discontinued treatment or study, along with the 
reasons for discontinuation of treatment or study. A listing will be provided for patient 
disposition. 
 
 
6.3 
Deviations 
Protocol deviations will be classified and monitored during the study.  All important 
deviations will be summarized and grouped into the following categories: 
 those who entered the study even though they did not satisfy the entry 
criteria;  
 those who developed withdrawal criteria during the study but were 
not withdrawn;  
 those who received the wrong treatment or incorrect dose;  
 those who received an excluded concomitant treatment.  
All important protocol deviations will be summarized and in addition listed by center. 
 
6.4 
Demographic and Baseline Characteristics 
Demographic and baseline summaries will include: 
 Age (years at enrollment) 
 Age group (<=65, > 65),  


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 Sex  
 Ethnicity (Hispanic or Latino, Not Hispanic or Latino) 
 Race (American Indian or Alaska Native, Asian, Black or African-American, 
Native Hawaiian or other Pacific Islander, White, Other) 
 Height (cm) 
 Weight (kg) 
 Menopausal status 
 Number of Baseline Bowel Movements 
 BMI 
Body mass index (BMI) will be calculated as: 
BMI (kg/m2) = Weight (kg)/ (Height(cm) * 0.01)2 
 
 
A listing will be provided for demographics. 
 
 
 
6.5 
Medical History 
 Medical history will be summarized by system organ class and preferred terms. 
 
 
6.6 
Cancer History 
6.6.1 Summary of Cancer History 
ECOG performance status, breast tumor stage at diagnosis, histology, tumor stage at 
diagnosis, grade at diagnosis, cell type at diagnosis, and time from diagnosis to 
enrollment will be summarized. The number of patients who achieved pathological 
complete response will also be presented.   
  
 


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6.6.2 Prior Anti-cancer Therapy  
Prior anti-cancer medication (yes/no), prior radiotherapy (yes/no), and prior cancer-
related surgery (excluding diagnostic biopsies) will be summarized   
For prior anticancer medication, the following summaries will be provided:  number of 
patients who had prior neo-adjuvant therapy, the number of patients who had prior 
trastuzumab use in neo-adjuvant therapy and adjuvant therapy setting correspondingly, 
the number of patients who had prior anthracycline use, prior taxane use, prior 
pertuzumab use, and prior TDM-1 use. In addition, the duration of prior trastuzumab use, 
and the time from last prior trastuzumab use to enrolment will also be summarized.  
 
6.7 
Baseline Biomarkers 
Biomarkers will be summarized: HER2 (ISH) type (FISH/CISH/SISH), HER2 (ISH) 
status, HER2 (IHC) status, ER status, PR status, will also be summarized. For each HER2 
(ISH) type, the result (Amplified, Non-amplified, Unknown/not done) will be 
summarized. 
 
6.8 
Study Medication (Neratinib) 
Exposure to neratinib during the study will be summarized by 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. 
The number of dose reductions, the lowest dose reduction level, dose reduction due to AE 
(yes/no), will be summarized. In addition, the dose withheld due to AE (yes/no), and the 
number of dose withheld due to AE will be presented. 
Refer to Section 3 for general endpoint definitions of dose intensities.  
 
6.9 
Concomitant Medications/ Therapy 
Concomitant medications will be summarized by Anatomical Therapeutic Chemical 
(ATC) category and preferred term. In addition, loperamide and anti-diarrhea medication 
exposure will be summarized for the first two cycles; and anti-inflammatory agents’ 
exposure will be summarized for the first cycle.  
 
 


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6.9.1 Loperamide During the Mandatory Prophylactic Period 
Exposure to loperamide during the first mandatory prophylactic period (first 2 cycles for 
Amendment 3 or earlier, first cycle for Amendment 4) will be summarized by treatment 
duration (days), cumulative actual dose (mg), actual dose intensity (mg/day) and relative 
actual dose intensity. In addition, the summary on the initial loading dose will also be 
provided. 
The highest daily dose and lowest daily dose will be summarized. In addition, the 
following will also be summarized: 
1. Dose reduction due to AE and the number of dose reduction due to AE 
2. Dose increase due to AE and the number of dose increase due to AE 
3. Dose hold due to AE and the number of dose hold due to AE. 
For loperamide (original protocol) , for the first 3 days, the planned dose intensity is 
12mg/day; for days 4 through 56, the planned dose intensity is 6-8 mg/day. For example, 
the planned dose intensity for loperamide for the first two cycle is (12mgx3days + 
6mgx53days)/56 = 6.3mg/day. 
For loperamide (amendment 1 to 3), for the first 14 days, the planned dose intensity is 
12mg/day; for days 15 through 56, the planned dose intensity is 8 mg/day. For example, 
the planned dose intensity for loperamide for the first two cycle is (12mgx14days + 
8mgx42days)/56 = 9mg/day. 
For loperamide (amendment 4), 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. For example, 
the planned dose intensity for loperamide for the first cycle is (12mgx14days + 
8mgx14days)/28 = 10mg/day. 
 
6.9.2 Anti-diarrheal Medications During the Mandatory Prophylactic Period 
All anti-diarrhea medication (including loperamide and any other concomitant 
medication for diarrhea) during the mandatory prophylactic period, will be summarized 
by number of patients taking anti-diarrheal medication, the anti-diarrhea medication 
name, anti-diarrheal medication use duration. 
 
 
 
6.9.3 Anti-inflammatory Agents During the First Cycle 
Anti-inflammatory medication (budesonide) during the first cycle (28 days), will be 
summarized by treatment duration (days), cumulative actual dose (mg), actual dose 
intensity (mg/day), and relative actual dose intensity.  


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The highest daily dose and lowest daily dose will be summarized. In addition, the 
following will also be summarized: 
1. 
Dose reduction due to AE and the number of dose reduction due to AE 
2. 
Dose hold due to AE and the number of dose hold due to AE. 
 
6.9.4 Bile Acid Sequestrant During the First Cycle 
Bile acid sequestrant (colestipol) during the first cycle (28 days), will be summarized by 
treatment duration (days), cumulative actual dose (mg), actual dose intensity (mg/day), 
and relative actual dose intensity.  
The highest daily dose and lowest daily dose will be summarized. In addition, the 
following will also be summarized: 
1. 
Dose reduction due to AE and the number of dose reduction due to AE 
2. 
Dose hold due to AE and the number of dose hold due to AE. 
 
6.9.5 Concomitant Therapy 
Concomitant therapy will be listed.  
 
6.10  
Adverse Events (AEs) 
AEs are graded by the investigators according to the NCI CTCAE v.4.0. AEs will be 
coded using MedDRA v. 17.0 or later. Summaries will focus on treatment-emergent 
adverse events (TEAEs). 
 
 
6.10.1 Treatment Emergent Diarrhea 
The primary endpoint is the incidence of grade 3 or higher treatment-emergent diarrhea. 
The incidence of grade 3 or higher treatment-emergent diarrhea with accompanying 
Clopper-Pearson 2-sided 95% CI will be computed (Clopper and Pearson, 1934).  
 
 
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, will be 


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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. 
 
Diarrhea incidence by grade in each treatment cycle (28 days) will be plotted against the 
corresponding treatment cycle.   


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6.10.2 Treatment-Emergent Adverse Events (TEAEs) 
A high-level summary of TEAE will be provided, including the incidence of any TEAE, 
any treatment-related TEAE, any Grade 3 or 4 TEAE, any serious TEAE, any serious 
treatment-related TEAE, any TEAE leading to treatment discontinuation, any TEAE 
leading to dose reduction, any TEAE leading to dose interruption, and fatal TEAE.   
TEAEs will also be presented in incidence tables by system organ class (SOC), preferred 
term (PT), and grade for the following: 
 Any TEAE 
 
 Treatment-related TEAE 
 
 Serious TEAE 
 
 Serious treatment-related TEAE 
 
 Grade 3 or 4 TEAE 
 
 Fatal TEAE 
 
 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, TEAE>=10%, serious TEAE, Grade 3 or 4 TEAE, and fatal TEAE. 
Listings will be provided for SAEs, TEAEs, and TEAEs leading to study drug 
discontinuation. 
 
 
6.10.3 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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6.10.4 Death 
Deaths will be summarized by number of deaths, number of on-study deaths (within 28 
days after last dose of neratinib), and cause of death. A listing of deaths will be provided. 
 
6.11 Clinical Laboratory Parameters 
Laboratory data will be summarized combining all cohorts in the safety population. 
Descriptive statistics provided will include the actual values at baseline, last post-
baseline, minimum post-baseline, maximum post-baseline, change for baseline to 
minimum, and change from baseline to maximum. 
Shifts between baseline CTCAE grade and worst CTCAE grade post-treatment will be 
summarized for select lab parameters. 
Listings of laboratory values for blood chemistry parameters, and hematology parameters 
will be provided. 
In addition, abnormalities in liver function tests will be summarized for  baseline 
assessments and any post-baseline assessments. A plot of liver function test abnormality 
results will also be provided.  
 
6.12 Vital Signs  
Vital sign measures (systolic and diastolic blood pressure, pulse,  respiratory rate, oral 
temperature and weight) will be summarized for baseline, last post-baseline, minimum 
post-baseline, maximum post-baseline, change for baseline to minimum, and change 
from baseline to maximum, in addition to the incidence of abnormalities. Vital signs will 
be summarized combining all cohorts in the safety population.  
 
6.13 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. 
Descriptive statistics of all the above ECG parameters will be summarized at baseline, 
and maximum post-baseline. 
 
Additionally, the overall ECG evaluation will be summarized at baseline and worst post-
baseline. ECG results will be summarized combining all cohorts in the safety population.  
 
 


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A listing of ECGs will be provided.  
 
6.14 Left Ventricular Ejection Fraction (LVEF) 
LVEF will be summarized descriptively for baseline, and worst (lowest) post-baseline. 
Descriptions will be by summary statistics and also by category cutoffs. LVEF and LVEF 
change from baseline will also be summarized by visit by summary statistics. Incidence 
of absolute decrease of LVEF>10% from baseline and below 50% will be provided. A 
plot of LVEF by visit will also be provided.  A listing of ECHO/MUGA results will also 
be provided. LVEF results will be summarized combining all cohorts in the safety 
population.  
6.15 Disease Recurrence 
Disease recurrence will be summarized by type (ductal carcinoma in situ, invasive 
ipsilateral breast tumor recurrence, local/regional invasive recurrence, distant recurrence, 
or invasive contralateral breast cancer). For distant recurrence, the disease recurrence site 
will be provided. 
 
6.16 Health Outcome Assessments 
Health outcomes in this study consist of the three questionnaires: FACT-B, EQ-5D-5L, 
and RSCL.  
The FACT-B (version 4) is a 37-item questionnaire with 5 subscales, PWB, SWB, EWB, 
FWB and BCS.  The overall total score is the sum of the 5 subscale scores based upon the 
following formulas*: 
PWB = [(4-GP1)+(4-GP2)+(4-GP3)+ (4-GP4)+(4-GP5)+ (4-GP6)+(4-GP7)]×7/(# responses) 
SWB = [GS1+GS2+GS3+GS4+GS5+GS6+GS7]×7/(# responses) 
EWB = [(4-GE1)+GE2+(4-GE3)+ (4-GE4)+(4-GE5)+ (4-GE6)]×6/(# responses) 
FWB = [GF1+GF2+GF3+GF4+GF5+GF6+GF7]×7/(# responses) 
BCS = [(4-B1)+(4-B2)+(4-B3)+B4+(4-B5)+(4-B6)+(4-B7)+(4-B8)+B9]×9/(# responses) 
*An item is only used if the patient responded to the question, ie, an item is not used in 
scoring when there is no response to the question. 
These formulas account for missing responses via proration, ie, multiplying the sum of 
the subscale by the number of items in the subscale, then dividing by the number of items 
responded to by the patient.  
The total score is calculated as the sum of the subscale scores: 


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FACT-B = FACT-G + BCS = (PWB + SWB + EWB + FWB) + BCS. 
The greater the FACT-B score, the better the breast cancer patient’s quality of life. 
The Trial Outcome Index formularies are: 
TOI-PFB=PWB+FWB+BCS 
TOI-ESB=EWB+SWB+BCS 
 
The EQ-5D-5L consists of 6 items: 5 dimensions (mobility, self-care, usual activity, 
pain/discomfort, and anxiety/depression) and a health state score.  Each of the 5 
dimensions has 5 levels. The combination of 1 level from each of the 5 dimensions (e.g. 
12234) will be used to obtain the health index score. The EQ-5D-5L cross-walk value set 
for UK will be used (Van Hout et al 2012) in the derivation of health index scores.  
 
The RSCL is a 38-item questionnaire with 3 subscales Physical Symptom Distress (PSD), 
Psychological Distress (PD), and Activities of Daily Living (ADL), plus a single-item 
Overall Valuation of Life (OVL) question. Each distress subscale question has 4 
responses (not at all, a little, quite a bit, very much), while each activity question has 4 
responses (unable, only with help, without help/with difficulty, without help), and the 
valuation of life question has 7 responses (extremely poor, poor, rather poor, neither good 
nor bad, moderately good, good, and excellent). 
PSD=S1+S3+S5+S7+S8+S10+S12+S13+S14+S15+S16+S18+S20+S21+S22+S23+S24+
S25+S26+S27+S28+S29+S30 (not collected for this study) 
PD=S2+S4+S6+S9+S11+S17+S19 (not collected for this study) 
ADL=ACT1+ACT2+ACT3+ACT4+ACT5+ACT6+ACT7+ACT8 
OVL=ALL1 
 
For scoring consistency across subscales, the ADL score can be reversed based on the 
following formula: 32-SUM OF (ACT1 TO ACT8). After application of this reversal, for 
all 4 scales, the greater the RSCL score, the worse the breast cancer patient’s quality of 
life. 
 
In the case of missing questions, if at least 50% of the questions for a patient’s subscale 
have been answered, then replace the missing questions with the subscale mean. 
 
Physical Symptom Distress range is from 23 to 92. 


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Psychological Distress range is from 7 to 28. 
Activity Level range is from 0 to 24. 
 
Overall Valuation of Life= 1 to 7. 
 
Finally, scores for RSCL can be standardized using the formula  
[(RAW SUBSCALE SCORE – MINIMUM RAW SCORE)/(MAXIMUM SCORE – 
MINIMUM SCORE)] x 100 
 
QOL completion rates for FACT-B, EQ-5D-5L, and RSCL will be summarized. 
Descriptive statistics (n, mean, std dev, median, minimum and maximum) will be 
presented for FACT-B subscales (PWB, SWB, EWB, FWB, and BCS) and total scores 
(FACT-G, FACT-B, TOI-PFB, and TOI-ESB),EQ-5D-5L  health index and health state 
score at each visit,  and RSCL-ADL and RSCL-OVL standardized scores at each visit, 
for both the raw scores and the change-from-baseline. These variables will also be 
summarized by plotting mean score versus visit.   
 
6.17 Exploratory Biomarker Analysis 
Biomarker analysis will follow the general analysis and reporting conventions described 
in Section 6.1. All analyses will be descriptive and no formal testing planned. Descriptive 
statistics (n, mean, std dev, median, minimum and maximum) will be presented for 
biomarker plasma cfDNA sample data at each visit for both the raw scores and the 
change-from-baseline.  
 
6.18 Exploratory Microbiome Analysis 
Results of microbiome evaluation from participating sites will be summarized at baseline, 
C2D1, C4D1, and/or at time of treatment discontinuation.  
 
 


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7. INTERIM ANALYSES 
An interim analysis was originally planned when approximately 120 patients enrolled 
under the Original protocol, Amendment 1, and Amendment 2, have completed (or had 
the opportunity to complete) at least 2 cycles (56 days) of neratinib with loperamide 
prophylaxis. When this analysis was conducted, there were a total of 133 patients in the 
safety population and consisted of Original Protocol, Amendment 1, and Amendment 2. 
Additional analyses by cohort when the follow-up of a cohort is complete are considered 
planned analyses. Ad hoc analyses of data from ongoing cohort(s) may also be 
performed. 


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8. LIST OF PLANNED TABLES, FIGURES, AND LISTINGS 
8.1 
 TABLES 
 
Tables 
Study populations 
Patient disposition  
Protocol deviations 
Inclusion/exclusion criteria  
Demographics and baseline characteristics 
Medical history 
Breast cancer history 
Prior anti-cancer therapy 
Baseline biomarkers 
Summary of IP exposure 
Summary of dose changes-neratinib 
Summary of loperamide exposure during the first mandatory prophylactic period 
Summary of dose changes-loperamide during the mandatory prophylactic period 
Summary of anti-diarrhea medication use during the mandatory prophylactic period 
Summary of budesonide exposure during the first cycle 
Summary of dose changes-budesonide 


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Tables 
Summary of colestipol exposure during the first cycle 
Summary of dose changes-colestipol 
Summary of other concomitant medications (non anti-diarrheal) 
Incidence of grade 3 or higher diarrhea (with CI)  
Summary of treatment-emergent diarrhea characteristics 
Summary of IP dose reduction due to treatment-emergent diarrhea 
Summary of IP dose hold due to treatment-emergent diarrhea 
Summary of IP dose discontinuation due to treatment-emergent diarrhea 
TEAE (high-level summary) 
TEAE by SOC, PT, and Grade 
Treatment-related TEAE by SOC, PT, and Grade 
Serious TEAE by SOC, PT, and Grade 
Serious treatment-related TEAE by SOC, PT, and Grade 
Grade 3 or 4 TEAE by SOC, PT, and Grade 
Fatal TEAE by SOC, PT, and Grade 
TEAE leading to dose reduction by SOC, PT, and Grade 
TEAE leading to dose interruption by SOC, PT, and Grade 
TEAE leading to treatment discontinuation by SOC, PT, and Grade 


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Tables 
TEAE in descending order of incidence by PT 
TEAE in descending order of incidence>=10% by PT 
Serious 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 
Summary of death 
Lab summary tables for the key lab parameters 
Lab shift tables for the key lab parameters 
Incidence of liver function test abnormality 
Vital sign summary  
Summary of ECG abnormality (for each ECG parameter) 
Summary of overall ECG evaluation 
Summary of LVEF  
Summary of LVEF by visit 
Summary of disease recurrence 
QOL compliance (FACT-B, EQ-5D-5L, and RSCL) 
Summary of QOL scores (FACT-B, EQ-5D-5L, and RSCL) 


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8.2 
FIGURES 
 
Figures 
Incidence of treatment-emergent diarrhea by worst grade and 
treatment cycle 
Plot of liver function test abnormality  
Plot of LVEF % by visit 
Plot of QOL mean scores by visit 
 
 
8.3 
LISTINGS 
 
Listings 
Listing of SAEs 
Listing of TEAEs 
Listing of TEAEs leading to IP discontinuation 
Listing of deaths 
Listings of demographics 
Listing of concomitant therapy 
Listing of laboratory values, blood chemistry 
Listing of laboratory values, hematology 


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Listing of liver function test values 
Listing of ECGs 
Listing of ECHO/MUGA 
 


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9. REFERENCES 
Agresti, A. Categorical Data Analysis. New York: Wiley, 1990. 
 
Brady MJ, Cella DF, Mo F, et al. Reliability and validity of the Functional Assessment of 
Cancer Therapy-Breast (FACT-B) quality of life instrument. J Clin Oncol 1977; 15:974-
86. 
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in the case of 
the binomial. Biometrika 1934, 26 (4): 404-413. 
de Haes JC, Olschewski M, Fayers P, Visser M, Cull A, Hopwood P, Sanderman R. The 
Rotterdam Symptom Checklist (RSCL): A manual. Second revised edition. UMCG / 
University of Groningen, Research Institute SHARE. 1996. 
 
Study Protocol Number PUMA-NER-6201: An Open-Label Study to Characterize the 
Incidence and Severity of Diarrhea in Patients with Early-Stage HER2+ Breast Cancer 
Treated with Neratinib and Intensive Loperamide Prophylaxis. PUMA Biotechnology, 
Amendment 6, 26 October 2017. 
Van Hout B, Janssen MF, et al. Interim scoring for the EQ-5D-5L: Mapping the EQ-5D-
5L to EQ-5D-3L value sets. Value in Health 2012 Jul-Aug;15(5):708-15 
 


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