Conditions: Solid Tumors Harboring Somatic HER2 or EGFR Exon 18 Mutations
Keywords: Neratinib Nerlynx Breast Solid Tumors Cancer HER2 mutations EGFR mutations Fulvestrant Trastuzumab Cervical Salivary ERBB2 Exon 18 Metastatic HR Positive Lung Non-Small Cell Lung Cancer (NSCLC)
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 582
Healthy volunteers: no

Brief summary:
This is an open-label, multicenter, multinational, Phase 2 basket study exploring the efficacy and safety of neratinib as monotherapy or in combination with other therapies in participants with HER (EGFR, HER2) mutation-positive solid tumors.

Detailed description:
This is an open-label, multicenter, multinational, Phase 2 basket study exploring the efficacy and safety of neratinib as monotherapy or in combination with other therapies in participants with HER (EGFR, HER2) mutation-positive solid tumors. The study has a basket design and includes several cohorts, either defined by an actionable somatic mutation or by actionable mutation and tumor histology, including HER2 mutant breast, HER2 mutant cervical, HER2 mutant salivary gland, and EGFR Exon 18 mutant Non-small cell lung cancers.

The trial will consist of a screening period, a treatment period, and an end of treatment visit occurring when neratinib is discontinued for any reason, a safety follow-up visit occurring 28 days after the last dose of neratinib and a survival follow-up period.

Arms:
arm 1: Neratinib monotherapy in HER2 mutated cancers including cervical, salivary gland, and lung cancers containing EGFR exon 18 mutations.

Cohorts closed to enrollment in prior amendments: HER2 mutant cancers including bladder/urinary, colorectal, endometrial, breast HR-positive, TNBC HR-negative, lung, gastroesophageal, biliary, and ovarian; HER3 mutant solid tumor NOS; HER4 mutant solid tumor NOS; fibrolamellar carcinoma and EGFR brain. arm 2: Neratinib and Trastuzumab in HER2 mutated (TNBC, HR-negative) breast cancers.

Cohorts closed to enrollment in in prior amendments: colorectal, lung cancer HER2 mutant. arm 3: Neratinib, Fulvestrant and Trastuzumab or Fulvestrant and Trastuzumab or Fulvestrant alone in HER2 mutated (HR-positive with prior CDK4/6i) breast cancers. arm 4: Neratinib, Fulvestrant and Trastuzumab in HER2 mutated (HR-positive with or without CDK4/6i) breast cancers. arm 5: Neratinib and Paclitaxel in HER2 mutated bladder/urinary tract cancers. arm 6: Neratinib and Fulvestrant in HER2 mutated (HR-positive) breast cancers.

Interventions: intervention 1: Neratinib intervention 2: Fulvestrant intervention 3: Trastuzumab intervention 4: Paclitaxel
Intervention descriptions: intervention 1: 240 mg administered orally, once daily with food, continuously in 28 day cycles intervention 2: 500 mg administered as two 5 mL injections on Days 1, 15, and 29; then once every 4 weeks thereafter month, then Day 1 of every 4 week cycle intervention 3: Initial dose of 8 mg/kg of trastuzumab administered IV on Day 1, followed by 6 mg/kg IV once every 3 weeks thereafter intervention 4: 80mg/m\^2 administered IV on Days 1, 8, and 15 of every 4 week cycle

Protocol document:
ICF_002.pdf: 
Oﬃcial Title 
AN OPEN-LABEL, PHASE 2 BASKET STUDY OF NERATINIB IN 
PATIENTS WITH SOLID TUMORS WITH SOMATIC ACTIVATING 
HER MUTATIONS  
 
NCT Number 
NCT01953926 
 
Version Date  
30-MAR-2021 
 
 
 
 


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Information to Consider Before Taking Part in This Research Study 
 
 
Protocol Title & Number: PUMA-NER-5201, An Open-Label, Phase 2 Basket Study of Neratinib in Patients With 
Solid Tumors With Somatic Activating HER Mutations 
 
Consent for ERBB2 mutated HR positive and HR negative Breast Cancer Patients 
 
Investigator Name: 
 
 
 
You are being asked to take part in a research study.  Research studies include only people who choose to take 
part.  This document is called an informed consent form [Ex-US only: and includes an information sheet and a 
consent form].   Please read this information carefully and take your time making your decision.  Ask the person in 
charge of this research study or study staff to discuss this consent form with you.  Please ask him/her to explain 
any words or information that you do not clearly understand.  We encourage you to talk with your family and 
friends before you decide to take part in this research study.  The nature of the study, risks, inconveniences, 
discomforts, and other important information about the study will be reviewed with you.  Once you understand 
the study and you agree to participate, you will be asked by the study staff to sign this form.  Additionally, the 
study staff will provide you with a copy of the signed form.  
 
Please tell the study doctor or study staff if you are taking part in another research study. 
 
We are asking you to take part in a research study called:  
 
An Open-Label, Phase 2 Basket Study of Neratinib in Patients With Solid Tumors With Somatic Activating HER 
Mutations   
 
The person who is in charge of this research study is [Insert PI name].  This person is called the Principal 
Investigator.  However, other research staff may be involved and can act on behalf of the Principal Investigator.   
 
The research will be conducted at [List the site(s) where the participant will be expected to take part in the 
research]. 
 
This research is being sponsored by Puma Biotechnology, Inc. which means that Puma Biotechnology, Inc. is paying 
to conduct the study and may be referred to as the Sponsor in this consent. 
 
PURPOSE OF THE STUDY 
 
The purpose of this study is to find out what effects; good and/or bad, neratinib, either by itself (monotherapy) or 
in combination with other drugs has in solid tumors harboring somatic mutations in the ERBB gene family (EGFR, 
ERBB2). A mutation is an alteration of the genetic material and, in case of cancer, it is believed it contributes to the 
growth of tumor, replication and/or resistance to therapy. Neratinib may decrease the effects of the mutations in 
the growth of the tumor which harbor the mentioned mutations. 
 
Neratinib is an experimental drug in this study and is being studied as monotherapy or in combination with other 
drugs. An experimental or investigational drug means it has not been approved by the national health authorities 
in your country for these indications.   
 
This study enrolls patients who have any solid tumors harboring somatic EGFR or ERBB2 mutations including but 
not limited to breast cancer, cervical cancer, EGFR Exon 18 lung cancer, and salivary cancer.  The combination of a 
mutation with a tumor type constitutes a cohort and it is independent of the other cohorts. The 
inclusion/exclusion criteria may differ, one cohort can stop, and the others will continue, based on response and 
tolerability. 
 
All patients in the breast cohort will harbor an ERBB2 mutation and some are HR positive (also expressing on their 
surface the estrogen and/or progesterone receptors also called hormone positive). Neratinib has been already 
tested as monotherapy in the course of this study. Now the study wants to find out the good and bad effects of 


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neratinib given in combination with fulvestrant, a medicine commonly used in persons with recurrent hormone 
receptor positive breast cancer and the addition of trastuzumab for patients who have not been previously treated 
with CDK4/6 inhibitors (CDK4/6i). CDK4/6i are a class of drugs that target enzymes called CDK4 and CDK6. These 
enzymes are important in cell division. CDK4/6i are designed to interrupt the growth of cancer cells. 
 
Patients with hormone receptor positive breast cancer who have been previously treated with CDK4/6i will be 
randomized (like the toss of a coin) to one of three treatment groups as follows: 1) fulvestrant alone; 2) fulvestrant 
in combination with trastuzumab; or 3) neratinib in combination with trastuzumab and fulvestrant. Patients 
randomized to receive fulvestrant alone or fulvestrant plus trastuzumab will be able to receive triple combination 
therapy (neratinib, fulvestrant, trastuzumab) upon disease progression. 
 
In patients with breast cancers that are hormone receptor negative, neratinib has been already tested as 
monotherapy in the course of this study. Now the study wants to find out the good and bad effects of neratinib 
given in combination with trastuzumab. 
SHOULD YOU TAKE PART IN THIS STUDY? 
• 
This form tells you about this research study.  After reading through this form and having the research 
explained to you by someone conducting this research, you can decide if you want to take part in it.  You 
do not have to take part in this research to receive medical care. 
• 
You may have questions this form does not answer.  If you do have questions, feel free to ask the study 
doctor or the person explaining the study, as you go along.   
• 
Take your time to think about the information that is being provided to you.       
• 
Feel free to talk it over with your regular doctor. 
 
This form explains: 
• 
Why this study is being done 
• 
What will happen during this study and what you will need to do 
• 
Whether there is any chance of benefit from being in this study   
• 
What risks are involved in this study 
• 
How the information collected about you during this study will be used and with whom it may be shared 
 
Providing informed consent to participate in this research study is up to you.  If you choose to be in the study, then 
you should sign the form.  If you do not want to take part in this study, you should not sign this form.  
WHY ARE YOU BEING ASKED TO TAKE PART? 
We are asking you to take part in this research study because you have either a hormone receptor positive or 
hormone receptor negative breast cancer carrying an ERBB2 mutation.  
For patients with HR positive breast cancer: Fulvestrant is a commercial drug in the United States, but not in 
several other countries. Trastuzumab is approved in the USA for metastatic breast cancer, gastric and 
gastroesophageal tumors which overexpressed the HER2 mutation. The combination of neratinib, fulvestrant and 
trastuzumab is an experimental drug combination which is studied as a potential new treatment for patients with 
hormone positive cancers that have a mutation in ERBB2.   An experimental or investigational drug means it has 
not been approved by the national health authorities in your country for a particular indication.   
 
For patients with triple negative breast cancer (TNBC) (HR negative):   The combination of neratinib and 
trastuzumab is an experimental drug combination which is studied as a potential new treatment for patients with 
hormone negative breast cancer that has a mutation in ERBB2.   An experimental or investigational drug means it 
has not been approved by the national health authorities in your country for a particular indication.   
 
WHAT WILL HAPPEN DURING THIS STUDY?  
 
Prior to participating in this study you must 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 copy will be provided 
to you for your files.  You will participate in a screen period to determine your eligibility.  


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Before You Begin the Study (Screening Period) 
A schedule of procedure is provided in the table below (Study Calendar).  In addition to the procedures listed 
below, unscheduled clinic visits and procedures may be performed should your study doctor feel that it is 
necessary to assess symptoms and concerns that you may have reported and to confirm or rule out potential 
recurrence, and or for your safety.  
 
You will need to have the following exams, tests or procedures to find out if you can be in the study.  These exams, 
tests or procedures are generally part of regular cancer care and may be done even if you do not join the study.  If 
you have had some of them recently, they may not need to be repeated.  This will be up to your study doctor. 
• 
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 4-5 teaspoons) 
o 
Measure your blood counts  
o 
See how well your liver, kidneys and other organs are working 
• 
Whole blood sample for germline DNA research 
• 
Research blood sample for exploratory biomarker testing. “Biomarkers” are laboratory tests related 
to your disease.  Four test tubes of blood (about 8-10 teaspoons) will be drawn  
o 
It is expected that these banked plasma specimens will subsequently be used for cell -free 
DNA (cfDNA) mutational analysis to investigate mechanisms of primary and/or acquired 
resistance to neratinib therapy 
• 
Urine tests will be taken to make sure your kidneys are functioning normally 
• 
Electrocardiogram (ECG) will be obtained to make sure you heart is functioning normally 
• 
Echocardiogram (an ultrasound of the heart) or MUGA (a special x-ray) to make sure your heart is 
pumping normally 
• 
Radiographic tumor assessment to measure your tumor using CT or MRI and PET/CT (required) and 
tumor marker (blood) analysis to see how your tumor responds to treatment.  The tumor markers 
will be collected as part of your standard of care. 
• 
Pregnancy test (blood or urine) – if you are a woman who can have children 
• 
A pretreatment fresh tissue biopsy within 28 days before starting treatment 
• 
Patient-reported health outcomes questionnaire (FACT-G)  
 
The Day 1 physical examination, ECOG performance status assessment, urine and blood sample may be omitted if 
the screening values were obtained within 72 hours prior to initiation of treatment. 
If your genetic mutation was confirmed by a liquid biopsy, a fresh tumor biopsy will be required if the leftover tissue 
sample cannot be provided.  
During the Active Treatment Stage (Cycle 1 Day 1 & greater) 
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. 
The following tests and procedures will be performed at each cycle (every 4 weeks for patients receiving 
fulvestrant alone and every 3 weeks for patients receiving the combination treatment of fulvestrant and 
trastuzumab or neratinib, fulvestrant and trastuzumab).  In addition to the procedures listed below, unscheduled 
clinic visits and procedures may be performed should your study doctor feels that it is necessary to assess 
symptoms and concerns that you may have reported and to confirm or rule out potential recurrence, and or for 
your safety:  
• 
Vital signs, weight, physician exam 
• 
Routine blood tests (about 4-5 teaspoons) 


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• 
Performance status - an evaluation of how well you perform normal daily activities  
• 
Phone call on Cycle 1, days 2, 3, and 4 after starting neratinib to see how you are feeling 
• 
Review of symptoms and side effects  
• 
Medication review – a review of all medications you are currently taking, including the study 
medication  
• 
Patient-reported health outcome questionnaire (FACT-G). You will be required to complete the 
questionnaire at cycle 1 day 1 and monthly (per study visit and prior to drug administration) for up to 
6 months or at the end of treatment, whichever comes first. 
• 
Dispense and collect study medication at the beginning and end of each cycle visit. 
• 
You will be given a diary to track the study medication (neratinib and loperamide pills) you take each 
day.  You will also record the number of stools per day and the dose of loperamide taken each day for 
the first two cycle of therapy only.  You will be required to record all doses of neratinib for the entire 
duration of the study. 
For patients receiving fulvestrant treatment (4-week cycles): 
The following test will be performed at cycle 3 (beginning of week 9), every 2 cycles and end of treatment: 
• 
Research blood sample (about 8-10 teaspoons) for biomarker testing 
The following procedure will be performed at cycle 3 (beginning of week 9) day 1 and then every 2 cycles for 
1 year. After one year (13 cycles) on therapy, scans may move to every 3 months. After two years (26 cycles) 
on therapy, scans may move to every 4 months thereafter: 
• 
Radiographic tumor assessment to measure your tumor using CT or MRI and PET/CT and tumor 
marker (blood) analysis to see how your tumor responds to treatment.  The tumor markers will be 
collected as part of your standard of care. 
If during treatment your disease progresses, you will be eligible to have neratinib and trastuzumab added to your 
treatment regimen and will then follow the procedures outlined below. 
For patients receiving fulvestrant and trastuzumab or combination treatment with neratinib (3-week cycles): 
The following test will be performed at cycle 4 (beginning of week 10), every 3 cycles and at the end of treatment: 
• 
Research blood sample (about 8-10 teaspoons) for biomarker testing 
The following procedure will be performed at cycle 4 (beginning of week 10), every 3 cycles for 1 year. After one 
year (13 cycles) on therapy, scans may move to every 4 cycles. After two years (26 cycles) on therapy, scans 
may move to every 5 cycles: 
• 
Radiographic tumor assessment to measure your tumor using CT or MRI and PET/CT and tumor 
marker (blood) analysis to see how your tumor responds to treatment.  The tumor markers will be 
collected as part of your standard of care.  
The following procedure will be performed before starting treatment at cycle 5 (beginning of week 13), every 4 
cycles (12 weeks) and then at the end of treatment:  
• 
Echocardiogram (an ultrasound of the heart) or MUGA (a special x-ray) to make sure your heart is 
pumping normally 
For all treatment groups: 
The following procedure will be performed and collected for research purposes during screening or within the first 
cycle of treatment: 
• 
Most recent metastatic tumor tissue: a sample of your tumor tissue from a surgery or biopsy you 
have had in the past (if it is available) will be requested as part of this study during screening or 
within the first cycle of neratinib   
The following procedure will be performed at the time of disease progression and/or end of treatment: 
• 
An optional fresh tumor tissue biopsy: Your study doctor may perform an optional fresh core tumor 
tissue biopsy if possible, at the time of disease progression and/or end of treatment   
 


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The following test and procedures will be performed for research purposes and will be collected only once 
(preferably during screening or within the first cycle): 
• 
Blood sample for DNA testing (1 test tube of blood, about 2 teaspoons). 
o 
The purpose of this addition research is to: 
 
Re-test your tumor to make sure it has an ERBB2 mutation 
 
Look at genetic reasons why neratinib may or may not work in your tumor 
o 
This DNA testing will be done during or after you have participated in this study. In 
order to do this, genetic material from your tumor and 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 products in the future 
o 
The U.S. and individual states 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 your 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. 
 
This testing will be done 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.  
This study will be open label which means that you and your study doctor will know exactly the treatment you will 
receive.  
Randomized Cohort Treatment Arms: 
Tumor Group 
Randomized Treatment 
Breast  
HR Positive (with prior CDK4/6i) 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; once every 28 
days thereafter  
Or 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; once every 28 
days thereafter  
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks 
 
If you are assigned to the fulvestrant or fulvestrant and trastuzumab arm, 
you will be eligible to have neratinib or neratinib and trastuzumab added to 
your treatment regimen upon disease progression and will be assigned the 
treatment below. 
 
Or 
• 
Neratinib: 240 mg daily 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; once every 28 
days thereafter  
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks  
 
Non-randomized Treatment Groups: 
Tumor Group 
Assigned Treatment 
Breast 
HR Positive (CDK4/6i naive) 
• 
Neratinib: 240 mg daily 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; once every 28 
days thereafter  
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks 
Breast  
• Neratinib: 240 mg daily 
• Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV every 3 weeks  


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Tumor Group 
Assigned Treatment 
TNBC (HR Negative) 
 
 
 


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All treatment groups: 
The cycle will be repeated until your study doctor tells you to stop. Each cycle is numbered in order. You will take 
the study medications as long as you are not having serious side effects, your cancer is not getting worse or you 
withdraw consent. If your doctor believes that fulvestrant and/or trastuzumab is causing adverse effects but you 
may benefit by continuing neratinib alone, you may do so with sponsor approval. If your cancer is getting worse, 
but in the opinion of the study doctor you may benefit from continuing study treatment you may continue 
protocol therapy if approved by the sponsor.  
In addition to taking neratinib, you need to take loperamide (Imodium™), for the first two cycles 56 days for 4 
week cycles and 42 days for 3 week cycles to prevent or lessen diarrhea caused by neratinib.  You will take 2 
tablets (4mg) of loperamide by mouth three times a day for the first 14 days, with the first dose (2 tablets) taken 
at the same time with the first treatment of neratinib. After two weeks on study, you will take 2 tablets (4mg) of 
loperamide by mouth two times a day until the end of cycle 2. Thereafter, loperamide will be administered as 
needed throughout neratinib treatment. Your doctor or nurse will contact you each of the first three days after 
you start taking neratinib to ask how much diarrhea you have and make any treatment adjustments.  If diarrhea 
continues despite taking loperamide, call your doctor or nurse. If you are constipated, call your study doctor but 
do not discontinue Loperamide unless specifically instructed by your doctor. 
NOTE: Your study doctor will provide you with a separate instruction sheet which will review how to manage 
diarrhea.  
You will be given a patient calendar (diary) to complete through the study.  You will use this to record the time and 
number of neratinib and loperamide pills you take each day.  Additionally, your study doctor will instruct you to 
record the number of stools per day and the dose of loperamide taken each day for the first two cycle of therapy.  
You will be required to record all doses of neratinib for the entire duration of the study. 
You will need to bring the calendar to the doctor’s office before each cycle. You must also bring any unused study 
medications and pill bottles (even if empty) to the doctor’s office before each cycle. 
When I am finished taking study drug (End of Treatment Visit) 
You will need the following tests and procedures within 28 days (+14 days) after stopping treatment.  They are 
part of regular cancer care. These tests or procedures are detailed below: 
• 
Vital signs, weight, physician exam 
• 
Medication review – a review of all medications you are currently taking, including the study 
medication  
• 
Review of symptoms and side effects 
• 
Routine blood tests (about 4-5 teaspoons) 
• 
Electrocardiogram (ECG) will be obtained to make sure you heart is functioning normally 
• 
Echocardiogram (an ultrasound of the heart) or MUGA (a special x-ray) to make sure your heart is 
pumping normally 
• 
Radiographic tumor assessment: to measure your tumor using CT or MRI and PET/CT (required), if 
you are stopping neratinib for any reason other than your tumor growing, you did not have another 
radiologic assessment in the prior 4 weeks and we need to see if your tumor responded or continued 
to respond to the therapy  
• 
Research blood sample (about 8-10 teaspoons) for biomarker testing 
• 
Patient-reported health outcomes questionnaire (FACT-G) 
• 
Collect study medication 
• 
Optional tumor biopsy 
• 
Collect medication diary 
 
Long-term Follow-up 
After you stop taking the study medication(s) the following test and procedures will be performed: 
• 
Your study doctor will continue to monitor you for any symptoms or side effects until the 28th day 
after taking the last dose of study medication(s). 
• 
If you stopped taking the study medication(s) for any reason other than your tumor growing, a 
radiographic tumor assessment will be collected every 2 cycles if you are on the Fulvestrant alone 
arm  or every 3 cycles if you are on combination therapy with fulvestrant and trastuzumab or 


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neratinib, fulvestrant and trastuzumab (±7 days) until your tumor grows. You will be contacted via 
phone call, office visit or email every 12 weeks (±14 days) to discuss your overall health status until 
you start a new anti-cancer therapy. 
• 
After your last dose of trastuzumab, cardiac safety assessments (echocardiogram or MUGA) will be 
performed every 6 months up to 24 months. 
 
Study Calendar for patients on fulvestrant treatment: This study calendar is a summary of the events that will 
occur at each scheduled visit.  It is not intended to capture duplicate information from the list above. 
Event 
Before Treatment 
Treatment – 4 Week Cycles 
After 
Treatment 
Visit 
Within 28 
days of Cycle 
1 Day 1 
Within 14 
days of Cycle 
1 Day 1 
Cycle 1, 
Day 1  
Each 
Additional 
Cycle Day 
1  
End of 
Treatment 
Long Term 
Follow-up 
Informed consent 
X 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
Medical, cancer, and 
medication history  
 
X 
 
 
 
 
Physical examination  
 
X 
X (only if not 
done 72 hours 
before 
starting Cycle 
1) 
X 
X 
 
Vital signs  
 
X 
X 
X 
X 
 
Electrocardiogram 
 
X 
 
 
X  
 
Echocardiogram or MUGA  
X 
 
 
 
X 
 
Urine Test 
 
X 
 
 
 
 
Pregnancy test (if you are 
capable of getting 
pregnant) 
 
X 
X  
(only if not 
done 72 hours 
before 
starting Cycle 
1) 
 
 
 
Routine Blood Test 
 
X 
X  
(only if not 
done 72 hours 
before 
starting Cycle 
1) 
X  
X  
 
Performance Status 
 
X 
X  
(only if not 
done 72 hours 
before 
starting Cycle 
1) 
X 
 
 
MD/RN Phone Call 
 
 
X 
(only Cycle 1, 
day 2, 3, & 4) 
 
 
X 
(every 12 Weeks) 


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Event 
Before Treatment 
Treatment – 4 Week Cycles 
After 
Treatment 
Visit 
Within 28 
days of Cycle 
1 Day 1 
Within 14 
days of Cycle 
1 Day 1 
Cycle 1, 
Day 1  
Each 
Additional 
Cycle Day 
1  
End of 
Treatment 
Long Term 
Follow-up 
Radiographic tumor 
assessment (CT or MRI and 
PET/CT (required)) and 
tumor marker assessments 
X 
 
 
X 
(done every 2 
cycles starting 
from the first 
dose of IP) 
X 
(if you stop 
neratinib before 
your tumor grows) 
X  
(every 8 weeks, if 
you stop 
neratinib before 
your tumor 
grows) 
Blood Sample for cfDNA 
Biomarker Research 
 
X 
 
X  
(done every 2 
cycles) 
X 
 
Most recent metastatic 
tumor tissue sample for 
research 
X 
 
 
 
 
Required fresh 
pretreatment tumor biopsy  
X 
 
 
 
 
 
Optional fresh core tumor 
tissue biopsy for research  
 
 
 
 
X (and/or at time of 
progression) 
 
Patient-reported health 
outcomes questionnaire 
(FACT-G)  
X 
 
X 
(cycle 1) 
 
X (monthly 
for up to 6 
months) 
 
X 
 
Blood Sample for DNA 
Testing 
 
X 
X 
(if not 
obtained 
during 
screening) 
 
 
 
Fulvestrant 
 
 
X 
(given on cycle 1, days 1 and 15, and 29 and then day 1 
of every cycle) 
 
Loperamide 
 
 
X (mandatory for C1-C2) 
 
 
Patient Diary 
 
 
X 
 
Collect/Review of 
Medications 
X 
 
Collect/Review of Side 
Effects 
X 
 
 
 
 


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Study Calendar for patients receiving fulvestrant and trastuzumab or combination treatment with neratinib: 
This study calendar is a summary of the events that will occur at each scheduled visit.  It is not intended to capture 
duplicate information from the list above. 
Event 
Before Treatment 
Treatment – 3 Week Cycles 
After Treatment 
Visit 
Within 28 
days of 
Cycle 1 Day 
1 
Within 14 
days of Cycle 
1 Day 1 
Cycle 1, 
Day 1  
Each 
Additional 
Cycle Day 
1  
End of 
Treatment 
Long Term 
Follow-up 
Informed consent 
X 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
Medical, cancer, and 
medication history  
 
X 
 
 
 
 
Physical examination  
 
X 
X (only if not 
done 72 hours 
before 
starting Cycle 
1) 
X 
X 
 
Vital signs  
 
X 
X 
X 
X 
 
Electrocardiogram 
 
X 
 
 
X  
 
Echocardiogram or MUGA  
X 
 
 
X 
(every 12 
weeks) 
X 
 
Urine Test 
 
X 
X  
(only if not 
done 72 hours 
before 
starting Cycle 
1) 
 
 
 
Pregnancy test (if you are 
capable of getting pregnant) 
 
X 
X  
(only if not 
done 72 hours 
before 
starting Cycle 
1) 
 
 
 
Routine Blood Test 
 
X 
X  
(only if not 
done 72 hours 
before 
starting Cycle 
1) 
X  
X  
 
Performance Status 
 
X 
X  
(only if not 
done 72 hours 
before 
starting Cycle 
1) 
X 
 
 
MD/RN Phone Call 
 
 
X 
(only Cycle 1, 
day 2, 3, & 4) 
 
 
X 
(every 12 Weeks) 
Radiographic tumor 
assessment (CT or MRI and 
X 
 
 
X 
(done every 3 
cycles starting 
X 
 
X  
(every 9 weeks, if 
you stop neratinib 


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Event 
Before Treatment 
Treatment – 3 Week Cycles 
After Treatment 
Visit 
Within 28 
days of 
Cycle 1 Day 
1 
Within 14 
days of Cycle 
1 Day 1 
Cycle 1, 
Day 1  
Each 
Additional 
Cycle Day 
1  
End of 
Treatment 
Long Term 
Follow-up 
PET/CT (required)) and 
tumor marker assessments 
from the first 
dose of IP) 
before your tumor 
grows) 
Blood Sample for cfDNA 
Biomarker Research 
 
X 
 
X  
(done every 3 
cycles) 
X 
 
Most recent metastatic 
tumor tissue sample for 
research 
X 
 
 
 
 
Required fresh pretreatment 
tumor biopsy  
X 
 
 
 
 
 
Optional fresh core tumor 
tissue biopsy for research  
 
 
 
 
X (and/or at time of 
progression) 
 
Patient-reported health 
outcomes questionnaire 
(FACT-G) 
X 
 
X 
(cycle 1) 
X  
(monthly for 
up to 6 
months) 
 
X 
 
Blood Sample for DNA 
Testing 
 
X 
X 
(if not 
obtained 
during 
screening) 
 
 
 
Neratinib, Fulvestrant and 
Trastuzumab 
 
 
X 
(neratinib taken every day, trastuzumab administered at 
the beginning of each cycle and fulvestrant given on 
cycle 1, days 1, 15 and 29 and then once every 4 weeks) 
 
Loperamide 
 
 
X (mandatory for C1-C2) 
 
 
Patient Diary 
 
 
X 
 
Collect/Review of 
Medications 
X 
 
Collect/Review of Side 
Effects 
X 
 
TOTAL NUMBER OF PARTICIPANTS AND STUDY DURATION 
• 
About 650 individuals will take part in this study.  The study will be conducted at several centers and in 
multiple countries. 
• 
A total of [number of participants] individuals will participate in the study at this site. 
• 
It is anticipated that you will be on study for approximately 18 months.  The exact length of time will 
depend on how you are doing.  If you agree, you can remain in the study as long as you are not having 
uncontrollable side effects and your cancer is not progressing. If your cancer appears to worsen but, in 
the opinion of the study doctor, you may benefit from continuing study treatment you may continue 
protocol therapy if approved by the Sponsor.  
• 
Overall study duration is approximately 102 months. 


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ALTERNATIVES 
You do not have to participate in this research study. Your other choices may include: 
• 
Getting treatment or care for your cancer without being in a study 
• 
Taking part in another study 
• 
Getting no treatment 
• 
Getting comfort care, also called palliative care.  This type of care helps reduce pain, tiredness, appetite 
problems and other problems caused by the cancer.  It does not treat the cancer directly, but instead tries 
to improve how you feel.  Comfort care tries to keep you as active and comfortable as possible. 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
 
FALSE POSITIVE RISK 
 
Risk of Incorrect Laboratory Diagnosis: 
 
There is a low risk that your tumor may have been incorrectly diagnosed as having a specific gene mutation and 
that you may therefore be mistakenly selected for participating into this study. If you are misdiagnosed as having 
the correct gene mutation for this study, you may be exposed unnecessarily to neratinib treatment.  As with all 
patients participating in this research study, it is unclear if you will receive any benefits.  You will be exposed to 
same safety risks as any other appropriately identified patient receiving neratinib as described in the risk section 
below. 
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.  This information may help future 
cancer patients.   
 
RISKS OR DISCOMFORT 
 
Risks of Neratinib 
 
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] ≥10% 
• Diarrhea   
 
 
 
 
 
 
 
 
 
• Nausea 
 
 
 
 
 
 
 
 
 
 
• Abdominal pain  
• Vomiting  
• 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 enzyme that measures the function of the liver) 
• Increased blood levels of aspartate aminotransferase (an enzyme that measures the function of the liver) 
• Increased blood levels of creatinine (an increase in a byproduct of proteins that measures the function of 
the kidney) 
• Dyspepsia (indigestion) 
• Abdominal distension 
• Urinary tract infection 
• Weight loss 


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• Dehydration 
• Nosebleed 
• 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 a byproduct of your red blood cells that measures the 
function of the liver) 
• Renal failure (damage to the kidney which decreases its functioning) 
 
Diarrhea and vomiting can quickly lead to a loss of too much water from your body (dehydration). If you get very 
dehydrated, this could make your blood pressure low and could make it hard for your kidneys to clean your 
blood.  If the dehydration is not treated, this could lead to a subtype of kidney failure called pre-renal failure. This 
kidney failure gets better when fluids are given. Patients who suffered from pre-renal failure in neratinib trials 
have all fully recovered their renal function. 
 
Symptoms of mild dehydration include thirst, decreased urine volume, abnormally dark urine, unexplained 
tiredness or fatigue, irritability and negative mood,  headache, dry mouth and dry skin, dizziness when standing, 
and in some cases can cause insomnia. Other possible symptoms include cloudy urine and 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 the study doctor immediately to prevent the signs of dehydration 
described above. 
 
Other Potential Side Effects of Neratinib 
 
The side effects listed below have been reported with neratinib, however; the relationship of these events to 
treatment with neratinib is unknown at this time. They occurred uncommonly (≥0.1% - <1%) between 1 and 9 
subjects in 1000 but can be ultimately life-threatening if not treated rapidly.  Call your study doctor immediately if 
you experience any of the symptoms described in the section below. 
 
 Severe liver damage: 
There have been reports of patients taking neratinib, who have had severe changes in liver function 
tests, which may indicate 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 liver 
function tests. 
 
 Interstitial lung disease: 
One patient with non-small cell lung cancer who was treated with neratinib experienced interstitial 
lung disease (an inflammation 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 
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. 
 
Risks of Fulvestrant 
 
 
When taking fulvestrant alone or in combination you may experience some or none of the side effects associated to 
the treatment with either drug alone. Additional unknown side effects may occur. You will be monitored closely for 


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all side effects including any that are unexpected. Make sure to let your study doctor know if you develop any side 
effects while taking the drug(s). If symptoms develop, your study doctor will start appropriate treatment to prevent 
or treat these side effects. 
 
 


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Very common side effects 
• 
Nausea 
• 
Increased liver enzymes which could indicate liver damage 
• 
Weakness 
• 
Injection site reactions excluding injection site bleeding, injection site hematoma (blood pooling under 
the skin at the site of injection 
• 
Hot flashes 
• 
Allergic reactions (including chills, rashes, hives, itching, redness, swelling, low blood pressure, cough and 
shortness of breath) 
• 
Rash 
• 
Joint and muscle pain 
 
Common side effects 
• 
Decreased number of blood platelet cells (which can increase the risk of bleeding) 
• 
Vaginal bleeding 
• 
Urinary tract infections 
• 
Loss of appetite 
• 
Headache 
• 
Blood clots 
• 
Vomiting  
• 
Diarrhea 
• 
Back pain 
• 
Nerve pain radiating from the back down the leg 
• 
Prickling of tingling in the hands or feet 
• 
Increased blood levels of bilirubin (an increase in a byproduct of your red blood cells that measures the 
function of the liver) 
 
Uncommon side effects 
• 
Liver failure 
• 
Hepatitis 
• 
Increased gamma-GT (an increase in an enzyme that measures the function of the liver) 
• 
Vaginal yeast infection 
• 
Whitish or yellowish vaginal discharge 
 
• 
Injection site bleeding, hematoma (blood pooling under the skin at the site of injection) 
• 
Nerve pain 
 
Risks of Trastuzumab 
 
When taking trastuzumab in combination with either fulvestrant or neratinib, you may experience some or none 
of the side effects associated to the treatment with either drug alone. Additional unknown side effects may 
occur. You will be monitored closely for all side effects including any that are unexpected. Make sure to let your 
study doctor know if you develop any side effects while taking the drug(s). If symptoms develop, your study 
doctor will start appropriate treatment to prevent or treat these side effects. 
 
Very common side effects of trastuzumab:  which may affect more than 1 in 10 subjects (≥ 10%) 
 
• infections 
•  diarrhea  
 
 
 
• constipation 
• heartburn 
• weakness  
• skin rashes 
• chest pain 
• abdominal pain 
• joint pain 
• low counts of red blood cells and white blood cells 
(which help fight infection) sometimes with fever 
• muscle pain 
• conjunctivitis 
• watery eyes 
• nose bleeds 
• runny nose 
• hair loss 
• tremor 
• hot flush 
• dizziness 
• nail disorders 
• weight loss 


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• loss of appetite 
• inability to sleep (insomnia) 
• altered taste 
• low platelet count 
• numbness or tingling of the fingers and toes 
• redness, swelling or sores in your mouth and/or 
throat 
• pain, swelling, redness or tingling of hands and/or 
feet 
• breathlessness 
• headache 
• cough 
• vomiting 
• nausea 
 
 
 
 


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Common side effects of trastuzumab: which may affect up to 1 in 10 subjects (≥ 1%) 
 
• allergic reactions 
 
 
• throat infection 
• bladder and skin infections 
• shingles 
• inflammation of the breast 
• inflammation of the pancreas or liver 
• kidney disorders 
• increased muscle tone or tension (hypertonia) 
• pain in the arms and/or legs 
• itchy rash 
• sleepiness (somnolence) 
• bruising 
• hemorrhoids 
• itchiness 
• dry mouth and skin 
• dry eyes 
• sweating 
• feeling weak and unwell 
• anxiety 
• depression 
• abnormal thinking 
• asthma 
• infection of lungs 
• lung disorders 
• back pain 
• neck pain 
• bone pain 
• acne 
• leg cramps 


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Uncommon side effects of trastuzumab: which may affect up to 1 in 100 subjects ( ≥ 0.1%)   
• deafness 
• bumpy rash 
• blood infection 
 
Rare side effects of trastuzumab: which may affect up to 1 in 1,000 people (> 0.01%) 
• weakness 
• yellow discoloration of the skin and white of the eyes which may indicate liver damage (jaundice) 
• inflammation or scarring of the lungs 
 
Uncommon but Serious side effects of trastuzumab: which may affect up to 1 in 100 subjects (≥ 0.1%)   
• Severe infusion reactions including symptoms such as: 
• difficulty breathing  
• low blood pressure or high blood pressure 
• wheezing 
• spasm or tightening of the breathing airway (bronchospasm) 
• rapid and irregular heart beats  
• reduced level of oxygen in the blood 
• severe allergic reaction which develops rapidly and may cause death. Symptoms include an itchy rash, 
throat swelling, and low blood pressure (anaphylaxis) 
• hives 
• swelling of the lips, throat, eyes and face (angioedema) 
• Severe lung problems including: 
• severe lung infection 
• shortness of breath 
• lungs filling with fluid 
• low levels of oxygen in the blood 
• permanent injury 
• Heart problems including weakening of the heart muscle possibly leading to heart failure, inflammation 
(swollen, red, hot and painful) of the lining around the heart and heart rhythm disturbances. This can lead 
to symptoms such as: 
• breathlessness (including breathlessness at night) 
• cough 
• swelling in the legs or arms (fluid retention) 
• heart fluttering or irregular heartbeat (palpitations) 
 
Information on other risks:  
 
Risks of Taking Neratinib with Acid-Reducing Medication 
 
The absorption of neratinib in the stomach is dependent on stomach acidity. Medications that reduce the 
secretion of acid in the stomach such as antacids, proton pump inhibitors (such as Lansoprazole), and H2-receptor 
antagonists (such as ranitidine) may affect how neratinib dissolves in the stomach. It has been observed that a 
single 240-mg dose of neratinib combined with a proton pump inhibitor lowered the absorption of neratinib up to 
seven-fold. It is not known whether separating the time of taking a proton pump inhibitor and neratinib reduces 
the interaction. If you are required to take a H2-receptor antagonist (such as ranitidine) to reduce stomach acid, 
take neratinib 10 hours after taking the medication and at least 2 hours before the next dose of that medication. If 
antacids are necessary, the antacid dose and the neratinib dose should be separated by 2 to 4 hours. If you have 
any questions, you should consult with your doctor about what type of acid-reducing medication you are taking. 


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Risk of Loperamide 
You will need to take loperamide to treat diarrhea during the course of the study.  Taking loperamide might be 
associated with, but not limited to the following symptoms: constipation (decrease or absence of bowel 
movements), dry mouth, abdominal pain or discomfort, nausea and vomiting.  Drowsiness, dizziness and fatigue 
may occur with loperamide as well.  Difficulty or inability to completely void the bladder (difficulty to urinate) has 
been reported less frequently.  Allergic reactions such as skin rash and itching including severe forms have also 
been reported, however other medications may have caused or contributed to some of these cases.  Please refer 
to the loperamide package insert for additional information. 
 
Risk of other cancer treatment 
If you have disease progression your physician may decide to add a treatment to neratinib therapy. It may include 
the following drug fulvestrant. Please review the package insert of the selected product with your doctor before 
starting the particular medication as to understand the risks and discomforts associated with the product. 
 
Risks of the Blood Collection  
You may have pain, swelling, or bruising around the vein where your blood is collected.  There may be risk of 
infection. You may feel dizzy or you may faint.  You may get an infection at the place on your body from which the 
blood is collected. 
 
Risks of the ECG and ECHO  
Placement of the leads may cause skin irritation, redness, or burning of the skin at the site where the leads were 
attached. 
 
Risks of the MUGA Scan 
A MUGA scan measures how well your heart pumps blood.  During a MUGA scan, a radioactive dye is injected into 
a vein, and special equipment is used to measure the pumping capacity of your heart.  You will be exposed to 
radiation from the injection given for the MUGA scan.  The needle puncture into the vein for the MUGA scan may 
cause bruising, inflammation, or infection at the site of the puncture.  
Risks 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 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, 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.  To 
give you an idea about how much radiation you will get, we will make a comparison with an every-day situation. 
Everyone receives a small amount of unavoidable radiation each year. Some of this radiation comes from space 
and some from naturally-occurring radioactive forms of water and minerals.   The CT scan gives your body the 
equivalent of about 3 extra years' worth of this natural radiation. The radiation dose we have discussed is what 
you will receive from this study only and does not include any exposure you may have received or will receive 
from other tests. 
 
 
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 


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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 the PET-CT 
Positron emission tomography (PET) scan is a test that uses radioactive glucose (sugar) that is injected into a vein. 
In rare instances, this might cause a major allergic reaction. You'll need to wait 30 to 60 minutes for the sugar to be 
absorbed by your body. Sugar is absorbed mainly by organs and tissues that use the most energy. Because cancer 
cells tend to use more energy than healthy cells, they absorb more of the radioactive sugar. It only stays in your 
body for a short time and the risk of negative effects from it is low. When you are ready, you'll lie on a narrow, 
padded table that slides into the tunnel shaped scanner.  If you're afraid of enclosed spaces, you may feel nervous 
while in the scanner. During the scan you'll need to lie very still so that the images aren't blurred. It takes about 30 
minutes to complete the test. The machine makes buzzing and clicking sounds. In some cases you may have a CT 
and PET scan in the same machine during the same appointment. The CT scan will be done first and take about 10 
minutes. You'll need to drink plenty of fluids to help flush the materials from your body.  To give you an idea about 
how much radiation you will get, we will make a comparison with an every-day situation. Everyone receives a small 
amount of unavoidable radiation each year. Some of this radiation comes from space and some from naturally-
occurring radioactive forms of water and minerals. The PET scan gives your body the equivalent of about 6 extra 
years' worth of this natural radiation.  
Risks of Tumor Biopsy 
It is possible that you could have pain during the procedure. Bruising, bleeding, tissue discoloration, infection, 
swelling, or scarring can occur where the biopsy sample is taken is possible. 
 
Risks to Unborn Children 
It is not known whether neratinib may cause side effects to pregnant women, to an unborn child (an embryo or a 
fetus), or to children of nursing women.  In a study with pregnant animals, administration of neratinib caused 
harm, including birth defects and death to the fetuses.  Because of these unknown risks, if you are pregnant or 
trying to become pregnant you cannot enter the study.  If you are nursing a child, you may not be entered in the 
study. 
 
If you are able to have children, you must have a negative pregnancy test before receiving any study medication.  
You are considered able to have children if you have not completed menopause or are not surgically sterile.  
 
If you are not surgically sterile or postmenopausal, you must agree and commit to the use of a reliable method of 
birth control while enrolled in the study.  Your doctor can discuss effective birth control methods with you.   In 
addition, you must continue to use medically effective birth control for the following time periods based upon the 
investigation medication(s) you are taking: 
For neratinib only, birth control must be used for 28 days after the last dose of neratinib. 
Treatments containing trastuzumab, birth control must be used for 7 months after the last dose of trastuzumab. 
Treatments containing fulvestrant, birth control must be used for 1 year after the last dose of fulvestrant. 
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 neratinib, your study doctor will 
ask to follow the outcome of your pregnancy and the condition of your newborn. 
 
The effects of neratinib on an unborn child (embryo or fetus) fathered by a man taking neratinib are unknown.  
Men with partners of childbearing potential must use a medically effective method of birth control throughout the 
study and for 3 months after the last dose of neratinib. 
 


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Unknown Risks 
 
Neratinib, fulvestrant, trastuzumab and study procedures 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.  Your participation in this study 
may contribute to the development of commercial products from which the Sponsor company (Puma 
Biotechnology, Inc.) or others may derive economic benefit.  You will have no rights to any products, patents or 
discoveries arising from this research, and you will receive no economic benefit.  
The study center will be paid to conduct this research 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. You may be 
reimbursed for reasonable accommodations and travel expenses. Please contact the study coordinator for more 
information and to see if you qualify.  
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.] 
[US ONLY] 
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 an assigned 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 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: 


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• 
The Sponsor of this study (Puma Biotechnology, Inc.) and its designees, including any contract 
research organization 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 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 a central laboratory and the samples will be tested.  In order to 
do this, genetic material 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 15 years after the end of the study.  They will be used only for 
research and will not be sold.  The research performed with your samples may help to develop new products in the 
future. 
The U.S. and induvial states 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.  
[EU ONLY] 
PRIVACY AND CONFIDENTIALITY 
Your study doctor and the study staff will collect and use information about you for the study. This may include your 
identification number, location information, health information, and data that is obtained from any biological sample 
taken from you such as your blood, tissue or saliva. This information is referred to as “Personal Data”. 
Your identity will be kept confidential as required by applicable law, but there is always a risk that some of your 
Personal Data may be disclosed.  


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You will not be identified on any study form or study document by name, national identity number, address, 
telephone number, or by any other direct personal identifiers. Instead, you will be identified by an assigned patient 
identification number or code. The study doctor will keep the list that matches the patient identification numbers 
to patient names. That list will not be provided to the Sponsor, and only the study doctor will have access to the list. 
The Personal Data together with other information collected about you during the study is referred to as the “study 
data” and will be coded before it is transferred outside the study center. Study data and the key to the code 
reconnecting the study data to you will be kept by the study center for up to 25 years after the study is completed 
or for a longer time period required under local law.  
The following parties may access your medical records at the study center to ensure the study is being performed 
properly: the Sponsor, parties working with or on behalf of the Sponsor, the ethics committee responsible for 
approving the conduct of the study, local regulatory authorities and regulatory authorities in other countries where 
the Sponsor may seek approval for the study drug (such as the United States Federal Food and Drug Administration). 
These parties may be able to identify you.  
The Personal Data the study doctor and study staff will collect, use, share, and transfer out of the EU as part of your 
coded study data, may include sensitive information about you such as your health information, genetic data and 
biometric data. If you want to consent to the collection, use and sharing of your sensitive Personal Data, then you 
should check the box next to the statement above your signature so we know you understand what your sensitive 
Personal Data may include, and that you specifically consent to the collection, use and sharing of your sensitive 
Personal Data as described in this Patient Information Sheet. If you do not consent to the collection, use and sharing 
of your sensitive Personal Data as described in this Personal Information Sheet, then you may not be in this study. 
If you consent to the use and sharing of your sensitive Personal Data as part of the coded study data by checking the 
box above your signature, you may withdraw that consent at any time.  If you withdraw your consent, the Sponsor 
may continue to use your sensitive Personal Data that has already been collected as part of the coded study data. If 
you wish to withdraw your consent to the collection, use and sharing of your sensitive Personal Data, please contact 
your study doctor. 
The study data will be used by the Sponsor to carry out the study, to develop the study drug, to meet its legal 
obligations in connection with the conduct of the study and to make publications and presentations about the study. 
In addition, the Sponsor and parties working with or on behalf of the Sponsor may use your study data to perform 
additional unknown future research. Although the exact nature of the research that may be performed is not known 
at this time, such research will be in connection with patient care and public health, including the development of 
new drugs and treatments for diseases. The Sponsor will limit and monitor access to your study data and put 
appropriate restrictions in place so that efforts are made to not identify you and to ensure that your study data are 
only used for the purposes described in this Patient Information Sheet. For certain reasons, you may have a right to 
oppose the use of your study data for additional future unknown research. If you wish to object to such use, please 
contact your study doctor. 
If you consent to the use and sharing of your study data by signing the attached Consent Form, you have a right to 
withdraw your consent at any time and for whatever reason. If you do withdraw your consent, the Sponsor may 
continue to use the study data that has already been collected. If you wish to withdraw your consent, please contact 
your study doctor. 
THE SPONSOR AND SOME OF THE RECIPIENTS OF YOUR STUDY DATA MAY BE BASED IN COUNTRIES OUTSIDE THE 
EUROPEAN UNION, SUCH AS THE UNITED STATES, THAT MAY NOT HAVE THE SAME LEVEL OF DATA PROTECTION 
AS IN [COUNTRY] OR IN THE EUROPEAN UNION. HOWEVER, THE SPONSOR AND ITS REPRESENTATIVES WILL TAKE 
REASONABLE MEASURES TO KEEP YOUR STUDY DATA CONFIDENTIAL IN ACCORDANCE WITH APPLICABLE LAWS. 
BY PARTICIPATING IN THIS STUDY, YOU CONSENT TO THE TRANSFER OF YOUR STUDY DATA TO THESE COUNTRIES.  


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The results of this study may be published and presented to the public and used for educational purposes. 
Information that could directly or indirectly identify you (like your name) will not be used in any publication or 
presentation. 
You have certain rights to your study data that are kept by the study center and the Sponsor including the rights to 
access your study data and the right to correct incomplete or inaccurate study data. If you wish to exercise any of 
your rights, you should contact the study doctor who can explain to you what these rights are. You also have a right 
to bring a complaint to the regulatory authority responsible for the protection of Personal Data in your country. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by United States 
Law. This website will not include information that can directly or indirectly identify you. At most, the website will 
include a summary of the results. You can search this website at any time. 
BIOLOGICAL SAMPLES 
WHAT WILL HAPPEN TO ANY SAMPLES I GIVE? 
Biological samples will be collected from you as described in this Patient Information Sheet.  If you do not agree to 
have biological samples collected from you as described in this Patient Information Sheet, you cannot participate 
in the study. 
Some biological samples collected during the study may be tested immediately at a central laboratory. The 
remainder of the samples will be sent to the biorepository determined by the Sponsor and kept for future testing. 
The samples will be identified only by a code and not by your name, national identity number, address, telephone 
number, or by any other direct personal identifier. Only the study doctor [and the study staff] will have access to 
the list that matches names to the codes, and that list will not be provided to the Sponsor.  Some samples will be 
saved for future scientific research by the Sponsor and parties working with the Sponsor on future scientific 
research.  Only the Sponsor, parties working with the Sponsor, and representatives of the regulatory authorities 
will have access to your coded samples.   
If you change your mind about taking part in the study, no further samples will be collected from you.    However, 
the Sponsor may retain and use both any study data derived from the samples already taken from you and any 
samples that have already been collected and sent to the Sponsor by the study center in order to maintain the 
quality of the study and for future scientific research.   
THE SPONSOR AND SOME RECIPIENTS OF YOUR BIOLOGICAL SAMPLES MAY BE BASED IN COUNTRIES OUTSIDE 
THE EUROPEAN UNION, SUCH AS THE UNITED STATES, THAT MAY NOT HAVE THE SAME LEVEL OF DATA 
PROTECTION AS IN [COUNTRY] OR IN THE EUROPEAN UNION. HOWEVER, THE SPONSOR AND ITS AUTHORIZED 
REPRESENTATIVES WILL TAKE REASONABLE MEASURES TO KEEP YOUR SAMPLES CONFIDENTIAL UNDER 
APPLICABLE LAWS. BY PARTICIPATING IN THIS STUDY AND SIGNING THE ATTACHED CONSENT FORM, YOU 
CONSENT TO TRANSFERRING YOUR BIOLOGICAL SAMPLES TO THESE COUNTRIES. 
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 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 


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• 
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  
FOLLOW UP  
It is very important for the success of the study that The Sponsor is able to collect information on your response to 
the study drug throughout the duration of the study.  
If for some reason your study doctor loses contact with you (for example, there is no response after calling or 
mailing information to your home, after contacting the individuals that you provided as additional contact names 
at the start of the study or after contacting your private doctor) the study doctor will try to obtain your updated 
contact information and information about your health which may be referred to as vital statistics by checking 
publicly available sources.   
If updated contact information is not available and your study doctor is unable to contact you, your personal 
information/personal data (name, address, telephone and date of birth) may be given to the Sponsor’s 
representative (a patient finder company) in order to find more accurate contact information and vital statistics for 
you, through publicly available sources. The new information will be provided to your study doctor’s office so they 
may re-establish contact with you and further assess your current health status. No personal information/personal 
data will be provided to the Sponsor from the patient finder service. 
If your personal information/personal data is given to the Sponsor’s representatives, they will not share or 
distribute this information to any other party. They will keep this information in a protected location to help 
prevent unauthorized use, access, or disclosure. The information provided will be limited to information that is 
needed to try to re-establish contact with you or determine your vital statistics. Your personal information will be 
kept confidential by the Sponsor’s representatives until the study is completed, and then the information will be 
destroyed.   
If you choose to no longer participate in the study and you withdrawal your consent completely, you will be asked 
to clarify this decision in writing. 
NEW INFORMATION ABOUT THE STUDY 
During the course of this study, we may find more information that could be important to you.  This includes 
information that, once learned, might cause you to change your mind about being in the study.  We will notify you 
as soon as possible if such information becomes available. 
[US ONLY] 
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 911 [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 #]. 


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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 you be compensated for research related injuries? 
If you feel that you have been injured as a result of taking the study drug 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 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 a study procedure does not include the 
normal progression 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.  
[EU ONLY] 
WHAT IF YOU ARE INJURED WHILE YOU ARE IN THE STUDY?  
You will get medical treatment if you are injured as a result of taking part in this study.  If you experience any injury 
or side effects, you should contact your study doctor at: 
[insert contact name and telephone number] 
Your study doctor will explain the treatment options to you and tell you where you can get treatment.   
The Sponsor has obtained an insurance policy which covers you as a study participant in accordance with the laws 
of [country]. The insurance policy has been taken out with [Insurance name & address], under Policy Number 
[insert number]. Your study doctor can provide more information about this insurance. 
Other compensation (including without limitation) for such things as lost wages, disability, or discomfort due to 
this type of injury is not available. 
You will not lose any of your legal rights by signing the Consent Form.   
WHAT HAPPENS IF YOU DECIDE NOT TO TAKE PART IN THIS STUDY? 
If you decide not to take part in the study, you will not be in trouble or lose any rights you normally have.  You will 
still have the same health care benefits and get your regular treatments from your regular doctor. 
 
You can decide after signing this consent form 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. 
• 
Your study doctor will tell you how to stop safely and 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.  


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• 
If you decided to stop, you will be asked to return all study drug and related study material (e.g., patient 
diary, etc.)  
Even if you want to stay in the study, there may be reasons the study doctor will need to withdraw you from the 
study.  You may be taken out of this study if it is no longer safe for you to stay in the study or if you are not coming 
for the study visits when scheduled.  You will be told 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 [insert (###) ##-####]. 
 
 


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[US ONLY] 
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 (dd/mmm/yyyy) 
 
______________________________________________                                           
Printed Name of Person Taking Part in Study 
 
[EU ONLY] 
 
CONSENT FORM 
STUDY TITLE: 
[insert] 
PROTOCOL NUMBER: 
[insert] 
EUDRACT NUMBER: 
[insert] 
I have received verbal (spoken) information on the above study and have read the attached written information. I 
have been given the chance to discuss the study and ask questions. 
I voluntarily consent to participate in this study, including all assessments, lifestyle restrictions, contraception 
requirements, and taking and use of my biological samples. 
I understand that I am free to withdraw from this study at any time. I understand that if I choose to not participate 
or to withdraw, my current medical care will not be affected by this decision. 
I understand that I will receive and may keep a copy of this signed and dated Patient Information Sheet and 
Consent Form. 
By signing and dating this Consent Form, I have not waived any of the legal rights that I would have if I were not a 
participant in a medical research study. 
I CONSENT TO AND AUTHORIZE THE TRANSFER OF MY STUDY DATA AND BIOLOGICAL SAMPLES WITHIN AND 
OUTSIDE THE EUROPEAN UNION, TO COUNTRIES, INCLUDING THE UNITED STATES, WHICH  MAY NOT HAVE THE 
SAME LEVEL OF DATA PROTECTION AS IN [COUNTRY] OR IN THE EUROPEAN UNION. I AGREE THAT MY STUDY 
DATA SND BIOLOGICAL SAMPLES MAY BE MADE AVAILABLE TO THE SPONSOR AND PARTIES WORKING WITH THE 
SPONSOR AS WELL AS TO OTHER PARTIES/ENTITIES IDENTIFIED IN THE PATIENT INFORMATION SHEET FOR THE 
PURPOSES STATED IN THE PATIENT INFORMATION SHEET. 


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I CONSENT TO AND AUTHORIZE THE USE OF MY STUDY DATA AND BIOLOGICAL SAMPLES FOR THE PURPOSE OF 
ANY FUTURE SCIENTIFIC RESEARCH THAT IS CONDUCTED IN ACCORDANCE WITH RECOGNIZED ETHICAL 
STANDARDS EVEN THOUGH THE NATURE OF THAT FUTURE SCIENTIFIC RESEARCH MAY NOT BE KNOWN TODAY. 
☐ BY CHECKING THIS BOX I CONSENT AND AUTHORIZE THE COLLECTION, USE AND SHARING OF MY SENSITIVE 
PERSONAL DATA AS PART OF THE CODED STUDY DATA WITH THE SPONSOR AND OTHER PARTIES AS DESCRIBED 
IN THIS INFORMED CONSENT FORM. 
__________________________________________________ 
__________________ 
Signature of Person Taking Part in Study 
Date (dd/mmm/yyyy) 
__________________________________________________                                           
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 patient speaks the language that was used to explain this research and is receiving 
an informed consent form in the appropriate language.  Additionally, this patient 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 
patient 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 patient 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 (dd/mmm/yyyy) 
 
 
 
_______________________________________________________________ 
Printed Name of Person Obtaining Informed Consent / Research Authorization 

ICF_003.pdf: 
Oﬃcial Title 
AN OPEN-LABEL, PHASE 2 BASKET STUDY OF NERATINIB IN 
PATIENTS WITH SOLID TUMORS WITH SOMATIC ACTIVATING 
HER MUTATIONS  
 
NCT Number 
NCT01953926 
 
Version Date  
30-MAR-2021 
 
 
 
 


 
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Information to Consider Before Taking Part in This Research Study 
 
Protocol Title & Number: PUMA-NER-5201, An Open-Label, Phase 2 Basket Study of Neratinib in 
Patients With Solid Tumors With Somatic Activating HER Mutations  
 
Consent for Patients with ERBB2 or EGFR Mutations on Neratinib Monotherapy 
 
Investigator Name: 
 
You are being asked to take part in a research study.  Research studies include only people who choose 
to take part.  This document is called an informed consent form [Ex-US only: and includes an 
information sheet and a consent form].  Please read this information carefully and take your time 
making your decision. Ask the person in charge of this research study or study staff to discuss this 
consent form with you. Please ask him/her to explain any words or information that you do not clearly 
understand.  We encourage you to talk with your family and friends before you decide to take part in 
this research study. The nature of the study, risks, inconveniences, discomforts, and other important 
information about the study will be reviewed with you. Once you understand the study and you agree 
to participate, you will be asked by the study staff to sign this form.  Additionally, the study staff will 
provide you with a copy of the signed form. 
Please tell the study doctor or study staff if you are taking part in another research study. We are asking 
you to take part in a research study called: 
An Open-Label, Phase 2 Basket Study of Neratinib in Patients With Solid Tumors With Somatic Activating 
HER Mutations. 
The person who is in charge of this research study is [Insert PI name]. This person is called the Principal 
Investigator.  However, other research staff may be involved and can act on behalf of the Principal 
Investigator. 
The research will be conducted at [List the site(s) where the participant will be expected to take part in 
the research]. 
This research is being sponsored by Puma Biotechnology, Inc. which means that Puma Biotechnology, 
Inc. is paying to conduct the study and may be referred to as the Sponsor in this consent. 
 
 
PURPOSE OF THE STUDY 
Neratinib is an experimental drug in this study and is being studied as a potential new treatment for 
patients with cancers which carry specific mutations in genes of the ERBB family (EGFR or 
ERBB2).  These mutations are believed to have a role in the oncogenesis, which is the 
transformation of a normal cell to a cancer cell.  An experimental or investigational drug 
means it has not been approved by the national health authorities in your country for these 
indications. 
This study will enroll patients who have any solid tumors harboring somatic EGFR mutations or ERBB2 
including but not limited to breast cancer, cervical cancer, salivary cancer and EGFR Exon 18 lung cancer. 
The reason why neratinib is being tested in patients with these types of cancers is because it is believed 
that when an ERBB2 or EGFR mutation occurs in a tumor, it will help the tumor grow and neratinib may 
decrease the effect of these mutations on cancer growth. 
The purpose of this study is to find out what effects, good and/or bad, neratinib, either by itself 


 
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(monotherapy) or in combination with other drugs has in solid tumors harboring somatic EGFR 
or ERBB2 mutations. 
SHOULD YOU TAKE PART IN THIS STUDY? 
• 
This form tells you about this research study. After reading through this form and having the 
research explained to you by someone conducting this research, you can decide if you want to 
take part in it. You do not have to take part in this research to receive medical care. 
• 
You may have questions this form does not answer. If you do have questions, feel free to 
ask the study doctor or the person explaining the study, as you go along. 
• 
Take your time to think about the information that is being provided to you. 
• 
Feel free to talk it over with your regular doctor. 
This form explains: 
• 
Why this study is being done 
• 
What will happen during this study and what you will need to do 
• 
Whether there is any chance of benefit from being in this study 
• 
What risks are involved in this study 
• 
How the information collected about you during this study will be used and with whom it 
may be shared. 
 
Providing informed consent to participate in this research study is up to you. If you choose to be in the 
study, then you should sign the form. If you do not want to take part in this study, you should not sign 
this form. 
WHY ARE YOU BEING ASKED TO TAKE PART? 
We are asking you to take part in this research study because you have a solid tumor with a problem 
related to a cancer-specific gene EGFR or ERBB2 mutation. 
Neratinib is an experimental drug being studied as a potential new treatment for patients with cancers 
that have a mutation in EGFR or ERBB2. An experimental or investigational drug means it has not been 
approved by the national health authorities in your country for that particular indication.   
Patients enrolled in this study will be given neratinib. 
WHAT WILL HAPPEN DURING THIS STUDY? 
Prior to participating in this study, you must 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 copy will be provided to you for your files. You will participate in a screening period to determine 
your eligibility. 
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 procedures may be performed should your study doctor feel 
that it is necessary to assess symptoms and concerns that you may have reported and to confirm or rule 
out potential recurrence, and or for your safety. 
You will need to have the following exams, tests or procedures to find out if you can be in the study. 
These exams, tests or procedures are generally part of regular cancer care and may be done even if 
you do not join the study. If you have had some of them recently, they may not need to be repeated. 
This will be up to your study doctor. 


 
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• 
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 4-5 teaspoons) 
o Measure your blood counts  
o See how well your liver, kidneys and other organs are working 
• 
Whole blood sample for germline DNA research 
• 
Research blood sample for biomarker testing. “Biomarkers” are laboratory tests related to 
your disease.  Four test tubes of blood (about 8-10 teaspoons) will be drawn 
o It is expected that these banked plasma specimens will subsequently be used for 
cell-free DNA (cfDNA) mutational analysis to investigate mechanisms of primary 
and/or acquired resistance to neratinib therapy 
• 
Urine tests will be taken to make sure your kidneys are functioning normally 
• 
Electrocardiogram (ECG) will be obtained to make sure you heart is functioning normally 
• 
Echocardiogram (an ultrasound of the heart) or MUGA (a special x -ray) to make sure 
your heart is pumping normally 
• 
Radiographic tumor assessment to measure your tumor using CT or MRI and PET/CT and 
tumor marker (blood) analysis to see how your tumor responds to treatment. The tumor 
markers will be collected as part of your standard of care 
• 
Pregnancy test (blood or urine) – if you are a woman who can have children 
• 
A pretreatment fresh tissue biopsy within 28 days before starting treatment (Lung EGFR 
exon 18 cohort only) 
• 
Patient-reported health outcomes questionnaire (FACT-G) 
The Day 1 physical examination, ECOG performance status assessment, urine and blood sample may be 
omitted if the screening values were obtained within 72 hours prior to initiation of treatment. 
If your genetic mutation was confirmed by a liquid biopsy, fresh tumor biopsy will be required if leftover 
tissue sample cannot be provided. 
During the Active Treatment Stage (Cycle 1 Day 1 and greater) 
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. 
The following tests and procedures will be performed at each cycle (every 4 weeks). In addition to the 
procedures listed below, unscheduled clinic visits and procedures may be performed should your study 
doctor feels that it is necessary to assess symptoms and concerns that you may have reported and to 
confirm or rule out potential recurrence, and or for your safety : 
• 
Vital signs, weight, physician exam 
• 
Routine blood tests (about 4-5 teaspoons) 
• 
Performance status - an evaluation of how well you perform normal daily activities 
• 
Phone call on Cycle 1, days 2, 3, and 4 after starting neratinib to see  how you are feeling 
• 
Review of symptoms and side effects 
• 
Medication review – a review of all medications you are currently taking, including the study 


 
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medication 
• 
Patient-reported health outcomes questionnaire (FACT-G). You will be required to 
complete the questionnaire at Cycle 1 day 1 and monthly (per study visit and prior to 
drug administration) for up to 6 months, and then at the end of treatment, whichever 
comes first  
• 
Dispense and collect study medication at the beginning and end of each cycle visit 
• 
You will be given a diary to track the study medication (neratinib and loperamide pills) you 
take each day.  You will also record the number of stools per day and the dose of 
loperamide taken each day for the first two cycles of therapy only. You will be required to 
record all doses of neratinib for the entire duration of the study. 
The following test will be performed every 2 cycles and at the end of treatment: 
• 
Research blood samples (about 8-10 teaspoons) for biomarker testing 
The following procedure will be performed at the beginning of cycle 3 day 1 and then every 2 cycles for 1 
year.  After one year (13 cycles) on therapy, scans may move to every 3 months. After two years (26 cycles) 
on therapy, scans may move to every 4 months thereafter: 
• 
Radiographic tumor assessment to measure your tumor using CT or MRI and PET/CT and tumor 
marker (blood) analysis to see how your tumor responds to treatment. The tumor markers 
will be collected as part of your standard of care 
The following will be collected for research purposes during screening or within the first cycle of 
treatment: 
• 
Most recent metastatic tumor tissue: A sample of your tumor tissue from a surgery or 
biopsy you have had in the past (if it is available) will be requested as part of this study 
during screening or within the first cycle of neratinib. 
The following procedure will be performed at the time of disease progression and/or end of treatment: 
• 
Optional fresh core tumor biopsy: Your study doctor may perform an optional fresh 
core tumor tissue biopsy if possible, at the time of disease progression and/or 
treatment discontinuation. 
The following test will be performed for research purposes and will be collected only once 
(preferably during screening or within the first cycle): 
• 
Blood sample for DNA testing (1 test tube of bloods, about 2 teaspoons). 
o The purpose of this additional research is to: 
 
 
Re-test your tumor to make sure it has an ERBB2or EGFR mutation or co-
mutations developed 
 
 
Look at genetic reasons why neratinib may or may not work in your tumor 
o This DNA testing will be done during or after you have participated in this study. In 
order to do this, genetic material from your tumor and 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 products in the future 
o The U.S. and some individual states 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 your health insurance or to raise the 
cost of your current health insurance. However, we cannot fully guarantee you 


 
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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. 
This testing will be done 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. 
This study will be an open-label which means that you and your study doctor will know exactly the 
treatment you will receive. You will take neratinib by mouth once a day for 28 days without any breaks. 
This 28 day period of time is called a cycle. You will take 240mg (six 40mg tablets) dose of neratinib each 
calendar day.  Missed dose(s) of neratinib (i.e., any dose that is not administered per your doctor’s 
instructions) will not be made up. Neratinib should be taken each morning with food. 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. 
The 28-day cycle will be repeated until your study doctor tells you to stop. Each cycle is numbered in 
order. You will take neratinib as long as you are not having serious side effects, your cancer doesn’t 
appear to be getting worse or you withdraw consent. If your cancer appears to be getting worse by 
radiographic assessment, but in the opinion of the study doctor, you may benefit from continuing 
study treatment, you may continue protocol therapy if approved by the Sponsor.  
In addition to taking neratinib, you will need to take loperamide every day during Cycle 1 and 2 (56 
days), to prevent or lessen diarrhea caused by neratinib. The commercial name for loperamide is 
ImodiumTM.  Along with your first dose of neratinib, you will take 2 tablets (4 mg) by mouth three times a 
day for the first 14 days. After two weeks on study, you will take 2 tablets (4mg) of loperamide by 
mouth twice a day  until the end of Cycle 2. Thereafter, loperamide will be administered as needed 
throughout neratinib treatment. Your doctor or nurse will contact you each of the first three days after 
you start taking neratinib to ask how much diarrhea you have and make any treatment adjustments.  If 
diarrhea continues despite taking loperamide, call your doctor or nurse. If you are constipated, call your 
study doctor but do not discontinue loperamide unless specifically instructed by your doctor. 
NOTE: Your study doctor will provide you with a separate instruction sheet which will review how to 
manage diarrhea. 
You will be given a patient calendar (diary) to complete through the study.  You will use this to record 
the time and number of neratinib and loperamide pills you take each day.  Additionally, your study 
doctor will instruct you to record the number of stools per day and the dose of loperamide (Imodium™) 
taken each day for the first two cycles of therapy. You will be required to record all doses of neratinib for 
the entire duration of the study. 
You will need to bring the calendar to the doctor’s office before each cycle. You must also bring any 
unused study medications and pill bottles (even if empty) to the doctor’s office before each cycle. 
When I am finished taking Neratinib (End of Treatment Visit) 
You will need the following tests and procedures within 28 days (+14 days) after stopping 
treatment. They are part of regular cancer care. These tests or procedures are detailed below: 
 
• 
Vital signs, weight, physician exam 
• 
Medication review – a review of all medications you are currently taking, including the 
study medication 
• 
Review of symptoms and side effects 
• 
Routine blood tests (about 4-5 teaspoons) 
• 
Electrocardiogram (ECG) will be obtained to make sure you heart is functioning normally 


 
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• 
Echocardiogram (an ultrasound of the heart) or MUGA (a special x -ray) to make sure your 
heart is pumping normally 
• 
Radiographic tumor assessment: to measure your tumor using CT or MRI and PET/CT, if 
you are stopping treatment for any other reason than your tumor growing an d did not 
have another radiologic assessment in the prior 4 weeks and we need to see if your 
tumor responded, or continued to respond to the therapy and tumor marker (blood) 
analysis to see how your tumor responds to treatment. The tumor markers will be 
collected as part of your standard of care. 
• 
Research blood sample (about 8-10 teaspoons) for biomarker testing 
• 
Patient-reported health outcomes questionnaire (FACT-G)  
• 
Collect study medication 
• 
Optional tumor biopsy 
• 
Collect medication diary 
Long-term Follow-up 
After you stop taking neratinib the following test and procedures will be performed: 
• 
Your study doctor will continue to monitor you for any symptoms or side effects until the 
28th day after the last dose of neratinib. 
• 
If you stopped taking neratinib for any reason other than your tumor growing, a radiographic 
tumor assessment will be collected every 8 weeks (±7 days) until your tumor grows. 
• 
You will be contacted via phone call, office visit or email every 12 weeks (±14 days) to 
discuss your overall health status until you start a new anti -cancer therapy. 
 
 


 
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Study Calendar: This study calendar is a summary of the events that will occur at each scheduled visit. It is not 
intended to capture duplicate information from the list above. 
 
Event 
Before Treatment 
Treatment 
After 
Treatment 
Visit 
Within 
28 days of 
Cycle 1 Day 
1
Within 
14 days of 
Cycle 1 Day 1 
Cycle 1 
Day 1 
Each 
Additional 
Cycle Day 
1
End of 
Treatment 
Long Term 
Follow-up 
Informed consent 
X 
Demographics 
X 
Medical, cancer, 
and medication his 
X 
Physical examination 
X 
X 
X 
X 
Vi ta l signs 
X 
X 
X 
X 
Electrocardiogram 
X 
 
X 
Echocardiogram or MUGA 
X 
X 
Uri ne Test 
X 
Pregnancy test (if you a re 
capable of getting pregnant)
X 
X 
(only if not 
done 72 
hours before 
starting C1) 
Routine Blood Test 
X 
X 
(only if not 
done 72 
hours before 
starting C1) 
X 
X 
Performance Status 
X 
X 
(only if not 
done 72 
hours before 
starting C1) 
X 
 
 
 


 
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Event 
Before Treatment 
Treatment 
After 
Treatment 
Visit 
Within 
28 days of 
Cycle 1 
Day 1 
Within  
14 days of 
Cycle 1 
Day 1 
Cycle 1, 
Day 1 
Each 
Additiona
l Cycle 
Day 1
End of 
Treatment 
Long Term 
Follow-up 
 
 
MD/RN Phone Call 
X 
(only Cycle 1, 
da y 2, 3, 4) 
X 
(every 12 
Weeks) 
 
Radiographic tumor  
assessment (CT or MRI and 
PET/CT) and tumor marker 
assessments 
X 
X 
 
X 
(if you stop 
neratinib 
before your 
tumor 
grows) 
X 
(every 8 wks, 
if you stop 
neratinib 
before your 
tumor grows) 
 
Blood Sample for 
cfDNA Biomarker 
Research 
X 
X 
(beginning 
at week 9 
and done 
every 
2cyles) 
X 
 
Most recent metastatic 
tumor sample for 
research 
X 
 
Required pretreatment 
tumor biopsy (Lung EGFR 
Exon 18 cohort only) 
X 
 
 
 
 
Optional fresh core 
tumor tissue biopsy for 
research 
 
 
 
X (and/or at 
time of 
progression) 
 
Patient-reported health 
outcomes questionnaire 
(FACT-G) 
X 
X 
(cycle 1 and 
monthly for 
up to 6 
months) 
X 
X 
 
Blood Sample for 
DNA Testing 
X 
X 
(if not 
obtained 
during 
screening) 
 
Neratinib  
X 
Loperamide 
 
X (mandatory for C1-C2) 
Patient Diary 
X 


 
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Collect/Review of 
Medications 
X 
Collect/Review of Si de 
effects 
X 
 
 


 
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TOTAL NUMBER OF PARTICIPANTS AND STUDY DURATION 
• 
About 650 individuals will take part in this study. The study will be conducted 
at several centers and in multiple countries. 
• 
A total of [number of participants] individuals will participate in the study at this site. 
• 
It is anticipated that you will be on study for approximately 18 months. The exact length of 
time will depend on how you are doing. I f you agree, you can remain in the study as long as 
you are not having uncontrollable side effects and your cancer is not progressing. If your 
cancer appears to worsen but, in the opinion of the study doctor, you may benefit from 
continuing study treatment you may continue protocol therapy if approved by the Sponsor. 
• 
Overall study duration is approximately 102 months. 
 
ALTERNATIVES 
You do not have to participate in this research study. Your other choices may include: 
• 
Getting treatment or care for your cancer without being in a study 
• 
Taking part in another study 
• 
Getting no treatment 
• 
Getting comfort care, also called palliative care. This type of care helps reduce pain, 
tiredness, appetite problems and other problems caused by the cancer. It does not treat 
the cancer directly, but instead tries to improve how you feel. Comfort care tries to keep 
you as active and comfortable as possible. 
 
Talk to your doctor about your choices before you decide if you will take part in this study. 
FALSE POSITIVE RISK 
Risk of Incorrect Laboratory Diagnosis: 
There is a low risk that your tumor may have been incorrectly diagnosed as having a specific gene 
mutation and that you may therefore be mistakenly selected for participating into this study. If you are 
misdiagnosed as having the correct gene mutation for this study, you may be exposed unnecessarily to 
neratinib treatment. As with all patients participating in this research study, it is unclear if you will 
receive any benefits. You will be exposed to same safety risks as any other appropriately identified 
patient receiving neratinib as described in the risk section below. 
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  
Risks of Neratinib 
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]>10% 
• 
Diarrhea 
• 
Nausea 


 
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• 
Abdominal pain  
• 
Vomiting 
• 
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 aspartate aminotransferase (an increase in an enzyme that measures 
the function of the liver) 
• 
Increased blood levels of alanine aminotransferase (an increased in an enzyme that measures 
the function of the liver) 
• 
Increased blood levels of creatinine (an increase in a byproduct of proteins that measures the 
function of the kidney) 
• 
Dyspepsia (indigestion) 
• 
Abdominal distension 
• 
Urinary tract infection  
• 
Weight loss 
• 
Dehydration 
• 
Nosebleed 
• 
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 a byproduct of your red blood cells that 
measures the function of the liver) 
• 
Renal failure (damage to the kidney which decreases its functioning)  
 
Diarrhea and vomiting can quickly lead to a loss of too much water from your body (dehydration). If you 
get very dehydrated, this could make your blood pressure low and could make it hard for your kidneys 
to clean your blood. If the dehydration is not treated, this could lead to a subtype of kidney failure 
called pre-renal failure. This type of kidney failure usually 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 the study doctor immediately to prevent the signs 
of dehydration described above. 
Other Potential Side Effects of Neratinib 
The side effects listed below have been reported with neratinib however, the relationship of these 


 
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events to treatment with neratinib is unknown at this time. They occurred in uncommon (≥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 bel ow. 
   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 liver function tests. 
   Interstitial lung disease 
One patient with non-small cell lung cancer who was treated with neratinib experienced 
interstitial lung disease (an inflammation 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 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 
You will need to take loperamide to treat diarrhea during the course of the study. Taking loperamide 
might be associated with, but not limited to the following symptoms: constipation (decrease or 
absence of bowel movements), dry mouth, abdominal pain or discomfort, nausea and vomiting. 
Drowsiness, dizziness and fatigue may occur with loperamide as well. Difficulty or inability to 
completely void the bladder (difficulty to urinate) has been reported less frequently. Allergic reactions 
such as skin rash and itching including severe forms have also been reported, however other 
medications may have caused or contributed to some of these cases. Please refer to the loperamide 
package insert for additional information. 
Risks of the Blood Collection 
You may have pain, swelling, or bruising around the vein where your blood is collected. There may be 


 
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risk of infection. You may feel dizzy or you may faint.  You may get an infection at the place on your 
body from which the blood is collected. 
Risks of the ECG and ECHO 
Placement of the leads may cause skin irritation, redness, or burning of the skin at the site where the 
leads were attached. 
Risks of the MUGA Scan 
A MUGA scan measures how well your heart pumps blood.  
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 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, 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. The CT scan gives your 
body the equivalent of about 3 extra years' worth of this natural radiation. The radiation dose we have 
discussed is what you will receive from this study only and does not include any exposure you may have 
received or will receive from other tests. 
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, f or 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 the PET/CT 
Positron emission tomography (PET) scan is a test that uses radioactive glucose (sugar) that is injected 
into a vein. In rare instances, this might cause a major allergic reaction. You'll need to wait 30 to 60 
minutes for the sugar to be absorbed by your body. Sugar is absorbed mainly by organs and tissues that 
use the most energy. Because cancer cells tend to use more energy than healthy cells, they absorb more 
of the radioactive sugar. It only stays in your body for a short time and the risk of negative effects from it 
is low. When you are ready, you'll lie on a narrow, padded table that slides into the tunnel shaped 
scanner. If you're afraid of enclosed spaces, you may feel nervous while in the scanner. During the scan 
you'll need to lie very still so that the images aren't blurred. It takes about 30 minutes to complete the 
test. The machine makes buzzing and clicking sounds. In some cases you may have a CT and PET scan in 
the same machine during the same appointment. The CT scan will be done first and take about 10 
minutes. You'll need to drink plenty of fluids to help flush the materials from your body. To give you an 


 
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idea about how much radiation you will get, we will make a comparison with an every -day situation. 
Everyone receives a small amount of unavoidable radiation each year. Some of this radiation comes 
from space and some from naturally-occurring radioactive forms of water and minerals. The PET scan 
gives your body the equivalent of about 6 extra years' worth of this natural radiation. 
Risks of Tumor Biopsy 
It is possible that you could have pain during the procedure. Bruising, bleeding, tissue discoloration, 
infection, swelling, or scarring can occur where the biopsy sample is taken is possible. 
Risks to Unborn Children 
It is not known whether neratinib may cause side effects to pregnant women, to an unborn child (an 
embryo or a fetus), or to children of nursing women. In a study with pregnant animals, administration 
of neratinib caused harm, including birth defects and death to the fetuses. Because of these unknown 
risks, if you are pregnant or trying to become pregnant you cannot enter the study. If you are nursing a 
child, you may not be entered in the study. 
If you are able to have children, you must have a negative pregnancy test before receiving neratinib. 
You are considered able to have children if you have not completed menopause or are not surgically 
sterile. 
If you are not surgically sterile or postmenopausal, you must agree and commit to the use of a reliable 
method of birth control while enrolled in the study. Your doctor can discuss effective birth control 
methods with you. After your last dose of neratinib you must continue to use medically effective 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 
neratinib, your study doctor will ask to follow the outcome of your pregnancy and the condition of your 
newborn. 
The effects of neratinib on an unborn child (embryo or fetus) fathered by a m an taking neratinib are 
unknown. Men with partners of childbearing potential must use a medically effective birth control throughout 
the study and for 3 months after the last dose of neratinib. 
Unknown Risks 
Neratinib and study procedures 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.  Your participation in 
this study may contribute to the development of commercial products from which the Sponsor 
company (Puma Biotechnology, Inc.) or others may derive economic benefit.  You will have no rights 
to any products, patents or discoveries arising from this research, and you will receive no economic 
benefit.  
The study center will be paid to conduct this research 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 


 
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to you or your insurance company. You may wish to contact your insurance company to discuss this 
further. You may be reimbursed for reasonable accommodations and travel expenses. Please contact 
the study coordinator for more information and to see if you qualify.  
 
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.] 
[US ONLY] 
 
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 an assigned 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 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 organization 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.  


 
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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 a central laboratory and the samples 
will be tested.  In order to do this, genetic material 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 15 years after the end of the 
study.  They will be used only for research and will not be sold.  The research performed with your 
samples may help to develop new products in the future. 
The U.S. and individual states 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.  
[EU ONLY] 
PRIVACY AND CONFIDENTIALITY 
Your study doctor and the study staff will collect and use information about you for the study. This may 
include your identification number, location information, health information, and data that is obtained 
from any biological sample taken from you such as your blood, tissue or saliva. This information is referred 
to as “Personal Data”. 
Your identity will be kept confidential as required by applicable law, but there is always a risk that some 
of your Personal Data may be disclosed.  
You will not be identified on any study form or study document by name, national identity number, 
address, telephone number, or by any other direct personal identifiers. Instead, you will be identified by 
an assigned patient identification number or code. The study doctor will keep the list that matches the 
patient identification numbers to patient names. That list will not be provided to the Sponsor, and only 
the study doctor will have access to the list. The Personal Data together with other information collected 
about you during the study is referred to as the “study data” and will be coded before it is transferred 
outside the study center. Study data and the key to the code reconnecting the study data to you will be 
kept by the study center for up to 25 years after the study is completed or for a longer time period required 
under local law.  
The following parties may access your medical records at the study center to ensure the study is being 
performed properly: the Sponsor, parties working with or on behalf of the Sponsor, the ethics committee 
responsible for approving the conduct of the study, local regulatory authorities and regulatory authorities 
in other countries where the Sponsor may seek approval for the study drug (such as the United States 
Federal Food and Drug Administration). These parties may be able to identify you.  
The Personal Data the study doctor and study staff will collect, use, share, and transfer out of the EU as 


 
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part of your coded study data, may include sensitive information about you such as your health 
information, genetic data and biometric data. If you want to consent to the collection, use and sharing of 
your sensitive Personal Data, then you should check the box next to the statement above your signature 
so we know you understand what your sensitive Personal Data may include, and that you specifically 
consent to the collection, use and sharing of your sensitive Personal Data as described in this Patient 
Information Sheet. If you do not consent to the collection, use and sharing of your sensitive Personal Data 
as described in this Personal Information Sheet, then you may not be in this study. 
If you consent to the use and sharing of your sensitive Personal Data as part of the coded study data by 
checking the box above your signature, you may withdraw that consent at any time.  If you withdraw your 
consent, the Sponsor may continue to use your sensitive Personal Data that has already been collected as 
part of the coded study data. If you wish to withdraw your consent to the collection, use and sharing of 
your sensitive Personal Data, please contact your study doctor. 
The study data will be used by the Sponsor to carry out the study, to develop the study drug, to meet its 
legal obligations in connection with the conduct of the study and to make publications and presentations 
about the study. In addition, the Sponsor and parties working with or on behalf of the Sponsor may use 
your study data to perform additional unknown future research. Although the exact nature of the research 
that may be performed is not known at this time, such research will be in connection with patient care 
and public health, including the development of new drugs and treatments for diseases. The Sponsor will 
limit and monitor access to your study data and put appropriate restrictions in place so that efforts are 
made to not identify you and to ensure that your study data are only used for the purposes described in 
this Patient Information Sheet. For certain reasons, you may have a right to oppose the use of your study 
data for additional future unknown research. If you wish to object to such use, please contact your study 
doctor. 
If you consent to the use and sharing of your study data by signing the attached Consent Form, you have 
a right to withdraw your consent at any time and for whatever reason. If you do withdraw your consent, 
the Sponsor may continue to use the study data that has already been collected. If you wish to withdraw 
your consent, please contact your study doctor. 
THE SPONSOR AND SOME OF THE RECIPIENTS OF YOUR STUDY DATA MAY BE BASED IN COUNTRIES 
OUTSIDE THE EUROPEAN UNION, SUCH AS THE UNITED STATES, THAT MAY NOT HAVE THE SAME LEVEL 
OF DATA PROTECTION AS IN [COUNTRY] OR IN THE EUROPEAN UNION. HOWEVER, THE SPONSOR AND 
ITS REPRESENTATIVES WILL TAKE REASONABLE MEASURES TO KEEP YOUR STUDY DATA CONFIDENTIAL 
IN ACCORDANCE WITH APPLICABLE LAWS. BY PARTICIPATING IN THIS STUDY, YOU CONSENT TO THE 
TRANSFER OF YOUR STUDY DATA TO THESE COUNTRIES.  
The results of this study may be published and presented to the public and used for educational purposes. 
Information that could directly or indirectly identify you (like your name) will not be used in any 
publication or presentation. 
You have certain rights to your study data that are kept by the study center and the Sponsor including the 
rights to access your study data and the right to correct incomplete or inaccurate study data. If you wish 
to exercise any of your rights, you should contact the study doctor who can explain to you what these 
rights are. You also have a right to bring a complaint to the regulatory authority responsible for the 
protection of Personal Data in your country. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by United 
States Law. This website will not include information that can directly or indirectly identify you. At most, 


 
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the website will include a summary of the results. You can search this website at any time. 
BIOLOGICAL SAMPLES 
WHAT WILL HAPPEN TO ANY SAMPLES I GIVE? 
Biological samples will be collected from you as described in this Patient Information Sheet. If you do 
not agree to have biological samples collected from you as described in this Patient Information Sheet, 
you cannot participate in the study. 
Some biological samples collected during the study may be tested immediately at a central laboratory. 
The remainder of the samples will be sent to the biorepository determined by the Sponsor and kept for 
future testing. The samples will be identified only by a code and not by your name, national identity 
number, address, telephone number, or by any other direct personal identifier. Only the study doctor 
[and the study staff] will have access to the list that matches names to the codes, and that list will not be 
provided to the Sponsor.  Some samples will be saved for future scientific research by the Sponsor and 
parties working with the Sponsor on future scientific research.  Only the Sponsor, parties working with 
the Sponsor, and representatives of the regulatory authorities will have access to your coded samples.   
If you change your mind about taking part in the study, no further samples will be collected from you.    
However, the Sponsor may retain and use both any study data derived from the samples already taken 
from you and any samples that have already been collected and sent to the Sponsor by the study center 
in order to maintain the quality of the study and for future scientific research.   
THE SPONSOR AND SOME RECIPIENTS OF YOUR BIOLOGICAL SAMPLES MAY BE BASED IN COUNTRIES 
OUTSIDE THE EUROPEAN UNION, SUCH AS THE UNITED STATES, THAT MAY NOT HAVE THE SAME 
LEVEL OF DATA PROTECTION AS IN [COUNTRY] OR IN THE EUROPEAN UNION. HOWEVER, THE 
SPONSOR AND ITS AUTHORIZED REPRESENTATIVES WILL TAKE REASONABLE MEASURES TO KEEP 
YOUR SAMPLES CONFIDENTIAL UNDER APPLICABLE LAWS. BY PARTICIPATING IN THIS STUDY AND 
SIGNING THE ATTACHED CONSENT FORM, YOU CONSENT TO TRANSFERRING YOUR BIOLOGICAL 
SAMPLES TO THESE COUNTRIES. 
 
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 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 
 
 


 
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FOLLOW UP  
It is very important for the success of the study that the Sponsor is able to collect information on your 
response to the study drug throughout the duration of the study.  
If for some reason your study doctor loses contact with you (for example, there is no response after calling 
or mailing information to your home, after contacting the individuals that you provided as additional 
contact names at the start of the study or after contacting your private doctor) the study doctor will try to 
obtain your updated contact information and information about your health which may be referred to as 
vital statistics  by checking publicly available sources, such as information available on the computer.   
If updated contact information is not available and your study doctor is unable to contact you, your 
personal information/personal data (name, address, telephone and date of birth) may be given to the 
Sponsor’s representative (a patient finder company) in order to find more accurate contact information and 
vital statistics for you, through publicly available sources. The new information will be provided to your 
study doctor’s office so they may re-establish contact with you and further assess your current health 
status. No personal information/personal data will be provided to the Sponsor from the patient finder 
service. 
If your personal information/personal data is given to the Sponsor’s representatives, they will not share or 
distribute this information to any other party. They will keep this information in a protected location to help 
prevent unauthorized use, access, or disclosure. The information provided will be limited to information 
that is needed to try to re-establish contact with you or determine your vital statistics. Your personal 
information will be kept confidential by the Sponsor’s representatives until the study is completed, and then 
the information will be destroyed.   
If you choose to no longer participate in the study and you withdraw your consent completely, you will be 
asked to clarify this decision in writing. 
NEW INFORMATION ABOUT THE STUDY 
During the course of this study, we may find more information that could be important to you. This 
includes information that, once learned, might cause you to change your mind about being in the study. 
We will notify you as soon as possible if such information becomes available. 
[US ONLY] 
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 911 [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 


 
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visit. 
Will you be compensated for research related injuries? 
If you feel that you have been injured as a result taking the study drug 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 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 a study procedure does not include the normal progression 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. 
[EU ONLY] 
WHAT IF YOU ARE INJURED WHILE YOU ARE IN THE STUDY?  
You will get medical treatment if you are injured as a result of taking part in this study.  If you experience 
any injury or side effects, you should contact your study doctor at: 
[insert contact name and telephone number] 
Your study doctor will explain the treatment options to you and tell you where you can get treatment.   
The Sponsor has obtained an insurance policy which covers you as a study participant in accordance 
with the laws of [country]. The insurance policy has been taken out with [insurance name & address], 
under Policy Number [insert number]. Your study doctor can provide more information about this 
insurance. 
Other compensation (including without limitation) for such things as lost wages, disability, or discomfort 
due to this type of injury is not available. 
You will not lose any of your legal rights by signing the Consent Form.   
 
WHAT HAPPENS IF YOU DECIDE NOT TO TAKE PART IN THIS STUDY? 
If you decide not to take part in the study, you will not be in trouble or lose any rights you normally 
have. You will still have the same health care benefits and get your regular treatments from your regular 
doctor. 
You can decide after signing this consent form 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. 
• 
Your study doctor will tell you how to stop safely and 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. 
• 
If you decided to stop, you will be asked to return all study drug and related study material (e.g., 
patient diary, etc.) 


 
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Even if you want to stay in the study, there may be reasons the study doctor will need to withdraw you 
from the study. You may be taken out of this study if it is no longer safe for you to stay in the study or if 
you are not coming for the study visits when scheduled. You will be told 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 [insert phone (###) ##-
####].  
 
[US ONLY] 
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 (dd/mmm/yyyy) 
 
 
 
Printed Name of Person Taking Part in Study 
 
 
 


 
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[EU ONLY] 
CONSENT FORM 
STUDY TITLE: 
[insert] 
PROTOCOL NUMBER: 
[insert] 
EUDRACT NUMBER: 
[insert] 
I have received verbal (spoken) information on the above study and have read the attached written 
information. I have been given the chance to discuss the study and ask questions. 
I voluntarily consent to participate in this study, including all assessments, lifestyle restrictions, 
contraception requirements, and taking and use of my biological samples. 
I understand that I am free to withdraw from this study at any time. I understand that if I choose to not 
participate or to withdraw, my current medical care will not be affected by this decision. 
I understand that I will receive and may keep a copy of this signed and dated Patient Information Sheet 
and Consent Form. 
By signing and dating this Consent Form, I have not waived any of the legal rights that I would have if I 
were not a participant in a medical research study. 
I CONSENT TO AND AUTHORIZE THE TRANSFER OF MY STUDY DATA AND BIOLOGICAL SAMPLES WITHIN 
AND OUTSIDE THE EUROPEAN UNION, TO COUNTRIES, INCLUDING THE UNITED STATES, WHICH  MAY 
NOT HAVE THE SAME LEVEL OF DATA PROTECTION AS IN [COUNTRY] OR IN THE EUROPEAN UNION. I 
AGREE THAT MY STUDY DATA SND BIOLOGICAL SAMPLES MAY BE MADE AVAILABLE TO THE SPONSOR 
AND PARTIES WORKING WITH THE SPONSOR AS WELL AS TO OTHER PARTIES/ENTITIES IDENTIFIED IN 
THE PATIENT INFORMATION SHEET FOR THE PURPOSES STATED IN THE PATIENT INFORMATION SHEET. 
I CONSENT TO AND AUTHORIZE THE USE OF MY STUDY DATA AND BIOLOGICAL SAMPLES FOR THE PURPOSE OF 
ANY FUTURE SCIENTIFIC RESEARCH THAT IS CONDUCTED IN ACCORDANCE WITH RECOGNIZED ETHICAL 
STANDARDS EVEN THOUGH THE NATURE OF THAT FUTURE SCIENTIFIC RESEARCH MAY NOT BE KNOWN TODAY. 
☐ BY CHECKING THIS BOX I CONSENT AND AUTHORIZE THE COLLECTION, USE AND SHARING OF MY 
SENSITIVE PERSONAL DATA AS PART OF THE CODED STUDY DATA WITH THE SPONSOR AND OTHER 
PARTIES AS DESCRIBED IN THIS INFORMED CONSENT FORM. 
 
______________________________________________ 
_________________ 
Signature of Person Taking Part in Study 
Date (dd/mmm/yyyy) 
 
______________________________________________ 
Printed Name of Person Taking Part in Study 
 
 
 


 
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STATEMENT OF PERSON OBTAINING INFORMED CONSENT AND RESEARCH AUTHORIZATION 
 
I have carefully explained to the person taking part in the study what he or she can expect from their 
participation. I hereby certify that when this person signs this form, to the best of my knowledge, 
he/she understands: 
• 
What the study is about; 
• 
What procedures/interventions/investigational drugs or devices will be used; 
• 
What the potential benefits might be; and 
• 
What the known risks might be. 
I can confirm that this research patient speaks the language that was used to explain this research and is 
receiving an informed consent form in the appropriate language.  Additionally, this patient 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 patient 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 patient 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 (dd/mmm/yyyy) 
 
 
 
Printed Name of Person Obtaining Informed Consent / Research Authorization 

Prot_000.pdf: 
 
 Oﬃcial Title 
AN OPEN-LABEL, PHASE 2 BASKET STUDY OF NERATINIB IN 
PATIENTS WITH SOLID TUMORS WITH SOMATIC ACTIVATING 
HER MUTATIONS  
 
NCT Number 
NCT01953926 
 
Version Date  
03-FEB-2021 
 
 
 
 


This document contains confidential information of Puma Biotechnology, Inc. This document must not be disclosed to 
anyone other than the study staff and members of the Independent Ethics Committee/Institutional Review Board. The 
information in this document cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Puma Biotechnology Inc.  
AN OPEN-LABEL, PHASE 2 BASKET STUDY OF NERATINIB IN PATIENTS WITH 
SOLID TUMORS WITH SOMATIC ACTIVATING HER MUTATIONS  
Study Protocol Number: 
PUMA-NER-5201 
Disease Condition: 
Solid tumors harboring somatic HER mutations 
Sponsor’s Investigational Product 
Name/Formulation: 
Neratinib Tablets  
US IND Number 
107931 
EudraCT Number 
2013-002872-42 
Lead Investigators: 
Principal Investigator 
 
  
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 Contacts: 
 
  
Date of Protocol 
Original 
08-JUL-2013 
Amendment 1  
07-NOV-2013 
Amendment 2 
02-APR-2014 
Amendment 3 
17-MAR-2015 
Amendment 4 
20-MAY-2016 
Amendment A4.1 (France) 
27-FEB-2017 
Amendment 5 
04-OCT-2017  
Amendment A5.1 (France) 
26-MAR-2018 
Amendment A5.2 (FLC, select sites) 20-APR-2018 
Amendment 6 
21-JAN-2020 
Amendment A6.1 (France) 
20-APR-2020 
Amendment 7 
03-FEB-2021 


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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 manual.  
 
 


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CONFIDENTIAL 
PROTOCOL SYNOPSIS 
Title: An open-label, Phase 2 basket study of neratinib in patients with solid tumors with somatic activating HER 
mutations 
Condition or Disease: Solid tumors harboring somatic activating HER mutations  
Approximate Values 
Number of Patients 
650  
Duration of Patient Participation 
18 months 
Number of Centers 
90 
Duration of study 
102 months 
Objectives:  
The objectives of this study, applicable to each cohort, are:  
For the randomized hormone receptor positive (HR+), HER2 negative metastatic breast cancer: 
Primary:  
• 
To determine the confirmed objective response rate (ORR) by independent central review according to 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
Secondary: 
• 
To determine the confirmed ORR by investigator 
• 
To determine the duration of response (DOR) by both independent central review and investigator 
• 
To determine the clinical benefit rate (CBR) by both independent central review and investigator 
• 
To determine the progression-free survival (PFS) by both independent central review and investigator 
For the metastatic cervical cancer cohort:  
Primary:  
• 
To determine the confirmed ORR by independent central review according to RECIST v1.1 
Secondary: 
• 
To determine the confirmed ORR by investigator 
• 
To determine the DOR by both independent central review and investigator 
• 
To determine the CBR by both independent central review and investigator 
• 
To determine the PFS by both independent central review and investigator 
• 
To determine overall survival (OS) 
For all other cohorts: 
Primary: 
• 
To determine the first objective response rate (ORRfirst) by investigator at the first post-baseline tumor 
assessment  
Secondary:  
• 
To determine the confirmed ORR by investigator 
• 
To determine the DOR by investigator 
• 
To determine the CBR by investigator 
• 
To determine the PFS by investigator 
• 
To determine OS 
Safety Objectives: 
For all cohorts, including the randomized HR+, HER2 negative metastatic breast cancer and metastatic cervical 
cancer cohorts: 
• 
To assess the safety profile and tolerability of study treatments 


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CONFIDENTIAL 
• 
To assess Patient Reported Outcomes (PRO) 
Exploratory: The exploratory objectives of this study are: 
• 
To collect and retrospectively evaluate somatic mutations or gene aberrations using next-generation 
sequencing (NGS) in the most recent pretreatment tumor biopsy or fresh tumor tissue biopsies at a 
central laboratory.  
• 
To explore genetic modifiers of sensitivity and/or resistance to neratinib using molecular profiling 
techniques in pretreatment archival and/or fresh tumor specimens and paired normal whole blood. 
• 
To evaluate cell-free DNA (cfDNA) from plasma specimens collected at baseline/screening, during the 
course of treatment, and upon disease progression to identify HER2 and EGFR mutations and other gene 
aberrations and to assess any potential associations with neratinib sensitivity and/or primary/acquired 
resistance to neratinib or neratinib-containing therapy. 
• 
To evaluate potential genes or protein biomarkers that may be reported to confer neratinib sensitivity 
and/or primary/acquired resistance to neratinib or neratinib-containing therapy from optional fresh core 
tumor biopsies during time of treatment and/or at the time of treatment discontinuation or disease 
progression.  
Study Design: 
This is an open-label, multicenter, multinational, Phase 2 study exploring the efficacy and safety of neratinib as 
monotherapy or in combination with other therapies in patients with HER (EGFR, HER2) mutation-positive solid 
tumors. Patients with tumors harboring somatic mutations in HER will be identified through previously 
documented mutation testing performed prior to screening. The presence of human HER mutations (EGFR, 
HER2) will be retrospectively confirmed by central testing via next generation sequencing (NGS). The study has a 
basket design and includes several cohorts, either defined by an actionable somatic mutation or by actionable mutation 
and tumor histology (for example HER2 mutant cervical cancer). In the course of the study, enrollment in certain cohorts 
can be completed and enrollment in new cohorts initiated to test the anticancer effect of neratinib in other histologies, 
specific molecular abnormalities, and/or in combination with other drugs. 
Patients with HER2 mutant, HER2 negative breast cancer will be divided into different treatment cohorts on the 
basis of HR status: HR negative (Triple Negative Breast Cancer [TNBC]) and HR+.  
• 
Patients in the HR negative breast cancer cohort (TNBC) will receive neratinib in combination with 
trastuzumab. 
• 
Patients in the HR+, HER2 negative, HER2 mutant breast cancer cohort with RECIST measurable 
tumors and who have been previously been treated with CDK4/6 inhibitors (CDK4/6i) will be 
randomized to receive single agent fulvestrant, fulvestrant in combination with trastuzumab, or neratinib 
in combination with trastuzumab and fulvestrant with a randomization ratio of 1:1:1. Randomization will 
be stratified by the number of lines of prior therapy for metastatic disease (≤ 2 and >2 lines) and by prior 
fulvestrant therapy. 
The randomized HR-positive (HR +), HER2 negative, HER2 mutant metastatic breast cancer cohort is 
designed to investigate the individual contribution of neratinib and/or trastuzumab to fulvestrant via 
Simon’s 2 stage optimal design. The decision to carry over on enrollment of each arm in the cohort will 
be based on stage I and II analysis of Simon’s 2 stage in consultation with the Independent Data 
Monitoring Committee (IDMC).  
o 
Patients in the HR+ cohort who receive single agent fulvestrant or fulvestrant plus trastuzumab 
will be eligible for triplet therapy (neratinib, fulvestrant, trastuzumab) upon progression. 
Patients who have unequivocal evidence of disease progression as documented by imaging, 
clinical examination, or disease related symptoms before the first scan post-treatment are 
eligible for the triplet therapy. Efficacy will be determined based on response to initial regimen 
only. 


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• 
Patients in the HR+ breast cancer cohort who have not received prior CDK4/6i therapy (eg. CDK4/6i 
naïve) will receive neratinib in combination with trastuzumab and fulvestrant as part of an open label 
cohort. 
The trial will consist of a screening period, a treatment period, and a follow-up period after the study therapy is 
discontinued for any reason. An end of treatment (EOT) assessment is performed 28 days (+14 days) after the last 
dose of investigational product(s) and adverse events are collected 28 days after the last dose of investigational 
product(s). 
Neratinib will be administered orally with food once daily (recommended to be taken in the morning), on a 
continuous basis. Dose delays and modifications will be handled as per instructions in the package insert. All 
patients taking neratinib will maintain a patient diary for the study to record each dose of neratinib taken and 
while receiving antidiarrheal prophylaxis with loperamide taken for the first two cycles of treatment. For cohorts 
receiving combination treatment that includes trastuzumab, post-treatment radiographic evaluation of their 
disease will be conducted every 3 cycles. For all other cohorts, post-treatment disease assessment will be 
conducted every 2 cycles.  Treatment should be administered until there is unequivocal evidence of disease 
progression as documented by imaging, clinical examination, or disease-related symptoms. Tumor markers or 
circulating tumor cells should not be used as the sole criteria for determining progression. At the time of decision 
regarding disease progression, radiological exam should be performed. Patients will continue study treatment 
until disease progression, unacceptable toxicity, patient withdrawal of consent, or death. Patients who develop 
disease progression, but in the opinion of the Investigator would still benefit from continuing study, may continue 
per-protocol therapy if approved by the Sponsor. Survival follow-up will be every 12 weeks after treatment 
discontinuation. Enrollment will continue as dictated by the Simon’s 2-stage design in all the histology and 
mutation specific cohorts and/or up to 30 patients per cohort in multi-cancer, mutation specific NOS cohorts. 
Enrollment in the randomized breast cancer, non-randomized breast cancer and cervical cancer cohorts will also 
continue as dictated by the Simon’s 2-stage design up to 50 patients per cohort. 
Tumor Cohorts Open to Enrollment in Amendment 7   
Randomized Breast Cancer Cohort 
Tumor 
Cohort 
Mutation 
Randomized Treatment 
Sample Size (# 
subjects) 
Breast  
HR Positive 
(with prior 
CDK4/6i) 
HER2 
mutant 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; 
once every 28 days thereafter  
Or 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; 
once every 28 days thereafter  
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV 
every 3 weeks 
Or 
• 
Neratinib: 240 mg daily 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; 
once every 28 days thereafter  
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV 
every 3 weeks  
 
 
Up to 18 
 
 
 
Up to 18 
 
 
 
 
 
Up to 50 


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Non-randomized Breast Cancer Cohorts 
Tumor 
Cohort 
Mutation 
Assigned Treatment 
Cohort Sample 
Size (# subjects) 
Breast 
HR Positive 
(CDK4/6i 
naïve) 
HER2 
mutant 
•
Neratinib: 240 mg daily
•
Fulvestrant: 500 mg on Study Day 1, 15, and 29;
once every 28 days thereafter
•
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV
every 3 weeks
Up to 50 
Breast 
TNBC (HR 
Negative) 
 
HER2 
mutant 
• Neratinib: 240 mg daily
• Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV
every 3 weeks
Up to 50 
Cervical Cancer Cohort 
Tumor 
Cohort 
Mutation 
Assigned Treatment 
Cohort Sample 
Size (# subjects) 
Cervical 
HER2 
mutant 
• Neratinib: 240 mg daily
50 
Cohorts Not Receiving Trastuzumab 
Tumor Cohort 
Mutation 
Assigned Treatment 
Salivary Gland 
HER2 mutant 
• Neratinib: 240 mg daily
Non-small Cell Lung EGFR exon 18 
mutations 
• Neratinib: 240 mg daily
Tumor Cohorts Closed to Enrollment in Amendment 7 
The following cohorts were closed to enrollment in Amendment 7: solid tumors (NOS) HER2 mutant 
monotherapy and bladder/urinary HER2 mutant combination therapy of neratinib + paclitaxel.  
Investigational Product, Dose, and Administration: 
•
Neratinib: Patients will receive six 40-mg tablets (total daily dose 240 mg) administered orally, once
daily with food (recommended to be taken in the morning), continuously.
•
Fulvestrant: Patients will receive 500 mg total dose administered as two 5 mL injections, by
intramuscular injection, one in each buttock on Days 1, 15, and 29; then once every 4 weeks thereafter;
see fulvestrant package insert and Schedule of Procedures.
•
Trastuzumab: Patients will receive an initial dose of 8 mg/kg of trastuzumab intravenously (IV)
administered on Cycle 1 Day 1 (C1D1), followed by 6 mg/kg IV once every 3 weeks thereafter; see
Herceptin (trastuzumab) package insert and Schedule of Procedures.
Study Population: 
Inclusion Criteria for All Patients 
Each patient will be entered into this study only if she/he meets all of these criteria: 
1.
Men and women who are ≥18 years old at signing of informed consent.
2.
At the time of screening, histologically confirmed cancers in patients with previously documented
activating EGFR (exon 18) or qualifying HER2 mutation confirmed by a Clinical Laboratory
Improvement Amendments (CLIA)-certified or equivalent laboratory, and who are refractory to standard
therapy or for which standard or curative therapy does not exist or is not considered sufficient or
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3. At least one measurable lesion, as defined by Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST v1.1; Eisenhauer et al, 2009).  
4. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or 
echocardiogram (ECHO). 
5. Eastern Cooperative Oncology Group (ECOG) status of 0 to 2. 
6. Female patients with cancers known to secrete β-human chorionic gonadotropin (hCG), ie germinomas, 
are eligible if the pattern of serum β-hCG is suggestive of the malignancy and the pelvic ultrasound is 
negative for pregnancy. 
7. Male patients must agree and commit to use a barrier method of contraception while on treatment and for 
3 months after the last dose of trastuzumab, fulvestrant, or neratinib monotherapy. Patients of child-
bearing potential must agree and commit to the use of a highly effective double-barrier method of 
contraception (eg, a combination of male condom with an intravaginal device such as the cervical cap, 
diaphragm, or vaginal sponge with spermicide) or a non-hormonal method, from the signing of the 
informed consent until:  
i. 
28 days after the last dose of neratinib monotherapy, or 
ii. 
7 months after last dose of trastuzumab or  
iii. 
1 year after the last dose of fulvestrant. 
8. Provide written, informed consent to participate in the study and follow the study procedures. 
9. Agree to provide most recent metastatic tumor sample or fresh tumor biopsy, and plasma/blood 
specimens for gene sequencing and other biomarker analysis.  
Additional Inclusion Criteria for all Breast Cancer Patients that Harbor HER2 Mutations and NCSLC Patients that 
Harbor EGFR exon 18 Mutations  
10. Must provide a pretreatment fresh biopsy within 28 days prior to starting treatment unless the biopsy 
procedure presents a safety concern for the patient as determined by the Investigator, or other exceptional 
reason upon agreement with the Sponsor  
Additional Inclusion Criteria for HR+ Breast Cancer Patients with Tumors that Harbor HER2 Mutations  
11. HR+ disease defined as ≥1% estrogen receptor (ER) positive and/or progesterone receptor (PR) positive 
cells (performed on the most recent biopsy as assessed locally and consistent with current American 
Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) or European Society of 
Medical Oncology (ESMO) guidelines): 
12. Biopsy from a non-bony metastatic site: preferred, or 
a. 
Biopsy from bony metastasis or if the sample is considered inadequate or unavailable: 
assessment of HR status will be at the Investigator’s discretion. 
13. Postmenopausal, as defined by at least one of the following criteria: 
a. 
Age ≥60 years; 
b. Age <60 years and cessation of regular menses for at least 12 consecutive months with no 
alternative pathological or physiological cause; and serum estradiol and follicle stimulating 
hormone (FSH) level within the laboratory’s reference range for postmenopausal females; 
c. 
Documented bilateral oophorectomy, 
14. Medically confirmed ovarian failure 
OR 
15. Pre/perimenopausal, ie, not meeting the criteria for being postmenopausal: 
a. 
Pre/perimenopausal women can be enrolled if amenable to be treated with a luteinizing 
hormone receptor hormone (LHRH) agonist. Patients must have commenced treatment with an 
LHRH agonist at least 4 weeks prior to the first dose of neratinib.  
16. Prior treatment with chemotherapy or hormonal therapy (including fulvestrant). 


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Exclusion Criteria for All Patients 
A patient will be excluded from this study if she/he meets any of these criteria: 
1. Patients harboring ineligible somatic HER2 mutations, such as those that are subclonal in nature or those 
resulting in the expression of truncated proteins including alterations that result in premature stop codon 
or a change in reading frame (ie, frame shift mutations).  
2. Prior treatment with any pan-HER, HER2-, or EGFR tyrosine kinase inhibitor (TKI) (eg, lapatinib, 
afatinib, dacomitinib, neratinib, tucatinib, poziotinib, gefitinib, erlotinib, osimertinib) is excluded with the 
following exception: patients with EGFR exon 18 mutated non-small cell lung cancer (NSCLC) who may 
have received afatinib, osimertinib, or other pan-HER or EGFR TKIs remain eligible. 
3. Not recovered to at least Grade 1 at screening (Common Terminology Criteria for Adverse Events v4.0 
[CTCAE v4.0]) from all clinically significant adverse events related to prior therapies (excluding 
alopecia). 
4. Received chemotherapy or biologic therapy ≤2 weeks or 5 half-lives (t½) of the agent used, whichever is 
shorter, prior to the initiation of investigational product.  
5. Received radiation therapy ≤14 days prior to initiation of investigational product.  
6. Patients who are receiving any other anticancer agents with the exception of patients on 1) a stable dose 
of bisphosphonates or denosumab or 2) sex hormone therapy in the case of breast, or gynecological 
cancers. 
7. Received prior therapy resulting in a cumulative epirubicin dose >900 mg/m2 or cumulative doxorubicin 
dose >450 mg/m2. If another anthracycline or more than one anthracycline has been used, the cumulative 
dose must not exceed the equivalent of 450 mg/m2 doxorubicin. 
8. Symptomatic or unstable brain metastases. (Note: Asymptomatic patients with metastatic brain disease 
who have been on a stable dose of corticosteroids for at least 14 days are eligible to participate in the 
study.)  
9. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart 
Association functional classification of  ≥2), unstable angina (symptomatic angina pectoris within the past 
180 days that required the initiation of or increase in anti-anginal medication or other intervention), 
myocardial infarction within 12 months of enrollment, or ventricular arrhythmia (except for benign 
premature ventricular contractions).   
10. Demonstrates a QTc interval >450 ms for men or >470 ms for women or known history of congenital 
QT-prolongation or Torsade de pointes (TdP). 
11. Inadequate bone marrow, renal or hepatic function as defined on screening laboratory assessments outside 
the following limits:  
Laboratory Assessments Endpoints 
Laboratory endpoint 
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  
<8 g/dL (transfusion allowed to treat low hemoglobin) 
Transfusion must be at least 7 days prior to C1D1. 
Total bilirubin  
>1.5 x institutional upper limit of normal (ULN) (in case of known 
Gilbert’s syndrome, >2x ULN) 
Aspartate aminotransferase (AST) 
and/or alanine aminotransferase (ALT)  
>3 x institutional ULN  
OR 
>5 x ULN if liver metastases are present 


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Creatinine 
>1.5 x institutional ULN 
OR 
Calculated Creatinine Clearance <30 mL/min (as measured directly 
with a 24-hour urine or calculated by Cockcroft-Gault formula a or 
Modification of Diet in Renal Disease [MDRD] formula b) 
a Cockcroft and Gault, 1976.  
b Levey et al, 1999. 
12. Active infection or unexplained fever >38.5°C (101.3°F).  
13. Women who are pregnant, are planning on becoming pregnant, or are breast-feeding. 
14. 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 version 4.0] diarrhea of any etiology at baseline. 
15. Clinically active infection with a hepatitis virus. 
16. 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. 
17. Known hypersensitivity to any component of the investigational product, required combination therapy, 
or loperamide. 
18. Unable or unwilling to swallow tablets. 
19. Patients with known activating KRAS mutations. 
Additional Exclusion Criteria for Patients with Breast Cancer With HER2 Mutations  
20. Patients with known HER2+ tumors (protein overexpression or gene amplification as defined by 
ASCO/CAP guidelines or HER2 amplifications as determined by copy number alterations by NGS) are 
excluded.  
Additional Exclusion Criteria for Patients With HER2 Mutations Treated With Trastuzumab Combination 
Therapy or Being Randomized into HR+ Breast Cancer Cohorts 
21. Hypersensitivity to trastuzumab, murine proteins or any of the excipients listed in the Herceptin label.  
22. Severe dyspnea at rest due to complications of advanced malignancy or requiring supplementary oxygen 
therapy 
Efficacy Assessments: 
For cohorts receiving combination treatment that includes trastuzumab, post-treatment disease assessment by CT 
or magnetic resonance imaging (MRI) will be conducted at the beginning of Week 10 (ORRfirst), and every 
3 cycles (± 7 days) thereafter (see Schedule of Procedures, Appendix 1 Table A1.1). For all other cohorts not 
receiving trastuzumab, post-treatment disease assessment will be conducted at the beginning of Week 9 (ORRfirst), 
and every 2 cycles (± 7 days) thereafter (see Schedule of Procedures, Appendix 1 Table A1.2). Complete or 
partial response (CR or PR) must be confirmed with a repeat scan performed no sooner than 4 weeks after the 
criteria for response are first met. In cases where the subject discontinues treatment for reasons other than 
progressive disease (eg., adverse event, patient choice, noncompliance, etc.) and the response is either CR or PR, 
then a confirmation scan is required no sooner than 4 weeks after the criteria of response is met. Radiological 
response is assessed by RECIST v1.1. Following one year on therapy, scans may move to every 4 cycles for 
trastuzumab-containing regimens and every 3 cycles for non-trastuzumab containing regimens. Following two 
years on therapy, scans may move to every 5 cycles for trastuzumab-containing regimens and every 4 cycles for 
non-trastuzumab-containing regimens. 
Safety Assessments: 
Patients receiving at least one dose of the investigational products will be evaluable for safety.  
Safety will be assessed based on medical history, vital sign measurements, physical examination findings, 
electrocardiogram (ECG) results, cohort specific MUGA or ECHO, laboratory assessments, and adverse events. 


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Adverse events will be graded according to the National Cancer Institute Common Terminology Criteria (NCI 
CTC) version 4.0. Adverse events and serious adverse events will be reported until 28 days after the last dose of 
investigational product(s) and will be followed until resolution or until condition stabilizes.  
Should an Investigator be made aware of any serious adverse events occurring any time after the reporting period 
that may be causally related to the administration of neratinib, it should be promptly reported. In addition to 
cardiac evaluations conducted during the study, patients who are receiving trastuzumab are required to be 
followed-up for potential cardiac toxicity (as assessed by MUGA or ECHO scans, see Schedule of Procedures, 
Appendix 1 Table A1.1 and Table A1.2) every 6 months and up to 24 months after the last dose of trastuzumab. 
Other Assessments: 
The most recent metastatic tumor tissue will be obtained for all patients and banked by the sponsor for 
retrospective centralized confirmation of somatic mutations in the ERBB gene family (EGFR, HER2). This tumor 
sample should preferably be from the specimens used to detect the initial mutation prior to study enrollment. For 
patients that do not have an archived tumor tissue, a fresh biopsy will be obtained if medically feasible. For all breast cancer 
cohorts and NSCLC exon 18 mutations cohort, a fresh pretreatment tumor biopsy collection is mandated unless the biopsy 
procedure presents a safety concern for the patient. 
Whole blood for germline DNA analysis will be collected once at screening. Cell-free DNA will be obtained from 
plasma samples collected at screening, on-treatment in accordance with the Schedule of Procedures (Schedule of 
Procedures, Appendix 1 Table A1.1 and Table A1.2), and at the time of treatment discontinuation; cfDNA will be 
subject to molecular profiling to identify HER2 and EGFR mutations and other gene aberrations related to 
treatment response and resistance. 
Health-related Quality of Life Assessment 
The following patient-reported outcomes will be assessed for all patients: the FACT-G questionnaire. 
Patient-reported outcome assessments will be collected at screening, and at the beginning of each cycle for up to 
6 months or EOT, whichever comes first. 
Statistical Methods: 
Sample Size Justification for the Randomized HR+ Breast Cancer Study Cohort: 
A Simon’s 2-stage optimal design (Simon, 1989) will be used to determine whether there is sufficient activity to 
warrant further development of the therapy and to minimize the number of patients exposed to therapy if 
ineffective.  For each treatment arm, using Simon’s 2-stage optimal design (with significance level 10% and 
power of 80%), an ORR (confirmed) of 10% or less per RECIST by independent assessment will be considered 
unacceptable (null hypothesis) whereas an ORR (confirmed) of 30% per RECIST by independent  assessment will 
merit further study (alternative hypothesis). In the first stage, 7 patients are enrolled in each treatment arm. If at 
least 1 response is observed in the first stage, the second stage will be opened. In the second stage, 11 additional 
response evaluable patients will be accrued and randomized for a total of 18 patients in the treatment arm. The null 
hypothesis will be rejected (for each arm separately) if at least 4 responses are observed in Stage 2 for each arm. 
Once the Simon’s 2-stage criteria are met, enrollment of the neratinib arm may continue until up to 50 patients 
have been enrolled. 
Sample Size Justification for All Other Cohorts: 
A Simon’s 2-stage optimal design (Simon, 1989) will be used to determine whether neratinib monotherapy has 
sufficient activity to warrant further development in the following cohorts: cervical, salivary gland, and EGFR 
exon 18 non-small cell lung cancers. A similar Simon’s 2-stage design will be used to determine whether 
neratinib combination therapy has sufficient activity to warrant further development in the following cohorts: 
HR+ and CDK4/6i naïve and TNBC.  Early study termination will be permitted if data at the first stage indicate 
that the treatment is ineffective. For each cohort, using Simon’s optimal 2-stage design (with significance level 
10% and power of 80%), an ORRfirst of 10% or less will be considered unacceptable (null hypothesis) whereas an 


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ORRfirst of 30% will merit further study (alternative hypothesis). In the first stage, enrollment will continue until 
7 patients received at least one dose of study treatment and completed the first tumor assessment by the 
investigator (response evaluable). If no responses are observed, the second stage for the cohort must be 
discontinued. Otherwise 11 additional response evaluable patients will be accrued for a total of 18 patients in the 
cohort. The null hypothesis will be rejected (for each cohort separately) if at least 4 responses are observed in 
Stage 2 for each cohort.  
Once the Simon’s 2-stage criteria are met, enrollment into the salivary gland and EGFR exon 18 mutant NSCLC 
cohorts may continue until up to 30 patients; and the enrollment into the cervical, HR+ CDK4/6i naïve, and 
TNBC cohorts may continue up to 50 patients. A new cohort may also be opened separately at any time per 
Sponsor discretion and follow the Simon’s 2-stage criteria. Cohorts may close prior to planned enrollment. 
Statistical Analysis  
In general, efficacy and safety analyses in this study are cohort-specific and will be summarized by monotherapy 
and combination therapy separately. Safety analyses will also be summarized across some cohorts where 
appropriate. Integrated analysis of HR+ metastatic breast cancer patients receiving neratinib, fulvestrant, and 
trastuzumab from either the randomized cohort or the original cohort will be performed. 
Categorical variables will be summarized using counts and percentages. Percentages will be displayed to 1 place 
after the decimal point (xx.x), with the exception of 100%, which will be displayed without additional decimal 
places. Continuous variables will be summarized using number of patients, mean, standard deviation, median, Q1, 
Q3, minimum, and maximum. 
The binary endpoints (eg, ORRfirst, ORR, CBR) will be estimated and its associated two-sided 95% Clopper-
Pearson confidence intervals will be determined.  
Time to event endpoint (eg, PFS, OS, DOR) will be estimated via Kaplan-Meier with its associated two-sided 
95% confidence intervals.  
Patient-reported outcomes will be summarized and plotted over time. Changes from baseline will be provided 
with both point estimates and confidence intervals. 
Safety: 
All patients who receive at least one dose of the investigational product will be analyzed for safety by cohort and 
across some cohorts where appropriate. Safety endpoints will be summarized descriptively for vital signs, adverse 
events, laboratory tests, and ECG. Serious adverse events, deaths, and patients discontinued from study treatment 
will be listed. The IDMC will oversee the safety of patients during the study. 
Interim Analysis 
Interim analyses may be performed at the completion of each stage for cohorts with a Simon's 2-stage design and 
for other cohorts as necessary. An IDMC will be established to regularly review accumulating safety data and 
efficacy data throughout the study. 
Primary Analysis 
The primary analysis will be performed when all enrolled patients have been followed for at least 6 months or 
when all responses have had a chance to be confirmed. 


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TABLE OF CONTENTS 
DISCLOSURE STATEMENT ........................................................................................................2 
STUDY CONTACTS ......................................................................................................................2 
PROTOCOL SYNOPSIS ................................................................................................................3 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ..................................................18 
1.
INTRODUCTION ......................................................................................................21 
1.1. 
The Epidermal Growth Factor Receptor (ERBB) Family ..........................................21 
1.1.1. 
Somatic Mutations in ERBB2 .....................................................................................21 
1.1.2. 
Somatic EGFR Exon 18 Mutations in Lung Cancer ..................................................23 
1.2. 
Neratinib as a Cancer Therapy That Targets ERBB Receptors ..................................25 
1.2.1. 
Neratinib, An Irreversible Inhibitor of EGFR, ERBB2, and ERBB4 Receptor 
Tyrosine Kinases ........................................................................................................25 
1.2.2. 
Neratinib Treatment for ERBB2 Mutant Solid Tumors .............................................25 
1.2.3. 
Neratinib Treatment for EGFR Exon 18 Mutations in Lung Cancer .........................26 
1.3. 
Neratinib Phase 1 and Pharmacokinetic Data .............................................................26 
1.4. 
Adverse Event Profile of Neratinib Monotherapy ......................................................28 
1.5. 
Rationale for Proposed Combination Therapies with Neratinib in Select 
Cohorts ........................................................................................................................29 
1.5.1. 
Rationale for Treatment With Neratinib Combined With Fulvestrant in 
HER2 Mutant Breast Cancer ......................................................................................29 
1.5.1.1. 
Adverse Event Profile of Combination Therapy of Neratinib and Fulvestrant ..........31 
1.5.2. 
Rationale for Treatment With Neratinib Combined With Trastuzumab in 
ERBB2 Mutant Breast Cancer ....................................................................................32 
1.5.3. 
Adverse Event Profile of Combination Therapy of Neratinib and 
Trastuzumab ...............................................................................................................33 
1.6. 
Rationale for Treatment with Neratinib Monotherapy in EGFR Exon 18 
Mutant Lung Cancer ...................................................................................................34 
2.
STUDY OBJECTIVES ..............................................................................................36 
2.1. 
Primary Objectives .....................................................................................................36 
2.2. 
Secondary Objectives .................................................................................................36 
2.3. 
Exploratory Objectives ...............................................................................................37 
3.
OVERALL DESIGN AND PLAN OF THE STUDY ................................................38 
3.1. 
Study Design ...............................................................................................................38 
3.2. 
Randomization and Blinding ......................................................................................41 


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4. 
STUDY POPULATION .............................................................................................42 
4.1. 
Inclusion Criteria ........................................................................................................42 
4.2. 
Exclusion Criteria .......................................................................................................43 
4.3. 
Patient Enrollment ......................................................................................................45 
4.4. 
Cohort Assignment .....................................................................................................46 
5. 
INVESTIGATIONAL PRODUCT AND ADMINISTRATION ...............................47 
5.1. 
Investigational Product Administration ......................................................................47 
5.1.1. 
Neratinib .....................................................................................................................47 
5.1.2. 
Fulvestrant ..................................................................................................................47 
5.1.3. 
Trastuzumab ...............................................................................................................48 
5.2. 
Investigational Product Dose Adjustment for Toxicity ..............................................48 
5.3. 
Packaging, Labeling and Storage ...............................................................................53 
5.3.1. 
Neratinib .....................................................................................................................53 
5.3.2. 
Fulvestrant ..................................................................................................................53 
5.3.3. 
Trastuzumab ...............................................................................................................54 
5.4. 
Drug Accountability ...................................................................................................54 
6. 
CONCOMITANT TREATMENT..............................................................................55 
6.1. 
Required Concomitant Treatment ...............................................................................55 
6.1.1. 
Loperamide .................................................................................................................55 
6.1.2. 
Loperamide Dose Adjustment ....................................................................................56 
6.1.2.1. 
Loperamide Antidiarrheal Therapy ............................................................................56 
6.2. 
Permitted Concomitant Treatment ..............................................................................59 
6.3. 
Prohibited Concomitant Treatment .............................................................................59 
6.4. 
Potential for Drug-Drug Interactions ..........................................................................60 
7. 
STUDY ASSESSMENTS ..........................................................................................61 
7.1. 
Efficacy Assessments .................................................................................................61 
7.1.1. 
Tumor Assessments ....................................................................................................61 
7.1.1.1. 
General Information ....................................................................................................61 
7.1.1.2. 
Radiographic/Imaging Evaluations ............................................................................62 
7.1.2. 
Tumor Assessments – Clinical ...................................................................................62 
7.1.3. 
Quality of Life Assessments .......................................................................................63 
7.1.4. 
ECOG Performance Status .........................................................................................63 
7.2. 
Safety Assessments .....................................................................................................63 


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7.2.1. 
Laboratory Assessments .............................................................................................63 
7.2.2. 
Vital Signs ..................................................................................................................64 
7.2.3. 
Physical Examinations ................................................................................................65 
7.2.4. 
Electrocardiograms .....................................................................................................65 
7.2.5. 
Left Ventricular Ejection Fraction (LVEF) ................................................................65 
7.2.6. 
Archival and Fresh Tumor Tissue, Whole Blood (for Germline DNA), and 
Plasma Collection .......................................................................................................65 
7.3. 
Protocol Deviations ....................................................................................................66 
7.4. 
Patient Diary ...............................................................................................................66 
8.
STUDY CONDUCT ...................................................................................................67 
8.1. 
Informed Consent .......................................................................................................67 
8.2. 
Screening All Cohorts .................................................................................................67 
8.2.1. 
Active Treatment Stage ..............................................................................................68 
8.2.2. 
End of Treatment Visit for All Cohorts ......................................................................69 
8.3. 
Long-term Follow-up for All Cohorts ........................................................................69 
8.4. 
End of Study ...............................................................................................................70 
9.
PATIENT WITHDRAWAL AND REPLACEMENT ...............................................71 
9.1. 
Investigational Product Discontinuation .....................................................................71 
9.2. 
Withdrawal from the Study ........................................................................................71 
9.3. 
Procedures for Investigational Product Discontinuation/Study Withdrawal ..............72 
10.
PREMATURE TERMINATION OF THE STUDY ..................................................73 
11.
STATISTICAL METHODS .......................................................................................74 
11.1. 
Sample Size Justification ............................................................................................74 
11.1.1. 
Sample Size Justification for the Randomized HR+ and with Prior CDK4/6i 
Breast Cancer Study Cohort: ......................................................................................74 
11.1.2. 
Sample Size Justification for All Other Cohorts: .......................................................74 
11.2. 
Statistical Analyses .....................................................................................................75 
11.2.1. 
Populations for Analysis .............................................................................................75 
11.2.2. 
Primary Endpoint ........................................................................................................75 
11.2.3. 
Secondary Endpoints ..................................................................................................75 
11.2.4. 
Exploratory Endpoints ................................................................................................76 
11.2.5. 
Adverse Events, Serious Adverse Events, and Deaths ...............................................76 
11.2.6. 
Laboratory Results ......................................................................................................77 


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12.
SAFETY DATA COLLECTION, RECORDING, AND REPORTING....................78 
12.1. 
Definitions ..................................................................................................................78 
12.1.1. 
Adverse Events ...........................................................................................................78 
12.1.2. 
Abnormal Laboratory Results .....................................................................................78 
12.1.3. 
Serious Adverse Events ..............................................................................................79 
12.1.4. 
Hospitalization ............................................................................................................79 
12.1.5. 
Suspected Unexpected Serious Adverse Reaction .....................................................80 
12.1.6. 
Severity Assessment ...................................................................................................80 
12.1.7. 
Causality Assessment .................................................................................................81 
12.1.8. 
Special Reporting Situations .......................................................................................81 
12.2. 
Reporting Adverse Events ..........................................................................................82 
12.3. 
Reporting Serious Adverse Events .............................................................................82 
12.4. 
Pregnancy ...................................................................................................................83 
12.5. 
Sponsor Reporting Requirements to Health Authorities and IRB/IEC ......................84 
13.
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ....................................85 
13.1. 
Data Collection, Processing, and Monitoring .............................................................85 
13.1.1. 
Case Report Forms and Source Documentation .........................................................85 
13.1.2. 
Study Monitoring and Access to Source Documentation ...........................................85 
13.1.3. 
Data Quality Assurance ..............................................................................................86 
13.1.4. 
Data Processing ..........................................................................................................86 
13.1.5. 
Retention of Data and Study Records .........................................................................86 
13.2. 
Ethical Aspects ...........................................................................................................87 
13.2.1. 
Good Clinical Practice and Ethical Conduct of the Study ..........................................87 
13.2.2. 
Informed Consent Responsibilities .............................................................................87 
13.3. 
Other Study Administration Aspects ..........................................................................88 
13.3.1. 
Protocol Approval and Protocol Amendment.............................................................88 
13.3.2. 
Investigator Responsibilities .......................................................................................88 
13.3.3. 
Patient Confidentiality ................................................................................................89 
13.3.4. 
Financial Disclosure ...................................................................................................90 
13.3.5. 
Publication Policy .......................................................................................................90 
14.
REFERENCE LIST ....................................................................................................91 
15.
SIGNATURE PAGES ................................................................................................96 
16.
APPENDICES ............................................................................................................99 


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APPENDIX 1 SCHEDULE OF PROCEDURES .....................................................................100 
APPENDIX 2 EASTERN COOPERATIVE ONCOLOGY GROUP (ECOG) 
PERFORMANCE STATUS .....................................................................................106 
APPENDIX 3 INHIBITORS AND INDUCERS OF THE CYTOCHROME P450 
ISOENZYMES .........................................................................................................107 
APPENDIX 4 SUBSTRATES AND INHIBITORS OF P-GLYCOPROTEIN (P-GP) ...........109 
APPENDIX 5 DRUGS ASSOCIATED WITH RISK OF QT/QTC PROLONGATION 
LEADING TO TORSADE DE POINTES ...............................................................110 
APPENDIX 6 RECIST V1.1 CRITERIA .................................................................................112 
APPENDIX 7 SPECIFIC GUIDANCE ON EGFR AND ERBB2 MUTATIONS ...................117 
APPENDIX 8 PATIENT-REPORTED HEALTH OUTCOMES ASSESSMENT 
(FACT-G): ................................................................................................................119 
LIST OF TABLES 
Table 1: 
Overall Response Rate (ORR), Disease Control (DC), Progression-free 
Survival (PFS, Weeks), and Overall Survival (OS, Weeks) According to 
Drug Type ...................................................................................................................33 
Table 2: 
Randomized Breast Cancer Cohort ............................................................................39 
Table 3: 
Non-randomized Breast Cancer Cohorts ....................................................................40 
Table 4: 
Cervical Cancer Cohort ..............................................................................................40 
Table 5: 
Cohorts Not Receiving Trastuzumab ..........................................................................40 
Table 6: 
Investigational Product Administration Schedule ......................................................47 
Table 7: 
Dose Reduction Levels for Investigational Product-Related Toxicity .......................48 
Table 8: 
General Toxicity Related to Neratinib and Requiring Dose Adjustmenta ..................49 
Table 9: 
Diarrhea Related to Neratinib and Requiring Dose Adjustment ................................50 
Table 10: Pulmonary Toxicity Related to Neratinib or Trastuzumab Requiring Dose 
Adjustment ..................................................................................................................51 
Table 11: Dose Adjustment for Neratinib or Fulvestrant for Patients With Hepatic 
Impairment ..................................................................................................................51 
Table 12: Liver Toxicity Requiring Dose Adjustment ...............................................................52 
Table 13: Left Ventricular Ejection Fraction Toxicity Related to Trastuzumab 
Requiring Dose Adjustment .......................................................................................53 
Table 14: Symptomatic Cardiac Failure Toxicity Related to Neratinib or Trastuzumab 
Requiring Dose Adjustment .......................................................................................53 
Table 15: Infusion Reactions Related to Trastuzumab Requiring Dose Adjustment .................53 


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Table 16: Loperamide Dosing for Neratinib Treatment .............................................................55 
Table 17: Loperamide Dose Reduction Levels for Constipation ................................................56 
Table 18: Laboratory Parameters ................................................................................................64 
 
LIST OF FIGURES 
Figure 1: 
Frequency and Location of ERBB2 Mutations in Cancer Biopsy Samples 
(ERBB2 Amplification and Mutations across Cancer Types) ....................................22 
Figure 2: 
Frequency and Location of ERBB2 Mutations in Cancer Biopsy Samples 
(ERBB2 Mutation Hotspots across Cancer Types) .....................................................23 
Figure 3: 
Distribution of EGFR Mutations in Lung Cancers (Aichi Cancer Center) ................24 
Figure 4: 
Distribution of EGFR Exon 18 Mutations (COSMIC Database) ...............................24 
Figure 5: 
Distribution of Mutations at Codons 709 and 719 in EGFR Exon 18 
(COSMIC Database) ...................................................................................................25 
Figure 6: 
Neratinib Monotherapy or Neratinib Plus Fulvestrant Displays Enhanced 
Tumor Growth Inhibition in HER2+/ER+ Breast Patient-Derived Xenograft 
Model ..........................................................................................................................30 
Figure 7: 
Neratinib Monotherapy or Neratinib Plus Fulvestrant Displays Enhanced 
Tumor Growth Inhibition in Breast Cell-Derived Xenograft Model ..........................31 
Figure 8: 
Combined Treatment With Neratinib and Trastuzumab Has an Additive 
Effect in Reducing BT474 and SKBR3 Cell Numbers ..............................................33 
Figure 9: 
Sensitivity of Ba/F3 Cells Expressing Exon 18 Mutations to Various EGFR 
Tyrosine Kinase Inhibitors .........................................................................................34 
Figure 10: Percent Change in Measurable Tumor for EGFR Mutation-Positive NSCLC 
Patients Treated with Neratinib ..................................................................................35 
 
LIST OF APPENDIX TABLES 
Table A1.1. Schedule of Study Procedures for Cohorts Receiving Trastuzumab 
Combination Therapy ...............................................................................................101 
Table A1.2. Schedule of Study Procedures for Cohorts Not Receiving Trastuzumab .................104 
Table A6.1. Evaluation Criteria ....................................................................................................115 
Table A7.1. Eligible ERBB2 Mutations ........................................................................................117 
Table A7.2. Eligible EGFR exon 18 Mutations ...........................................................................118 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
ADL 
activities of daily living  
ADR 
adverse drug reaction  
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology  
AST 
aspartate aminotransferase 
AUC 
area under the plasma drug concentration-versus-time curve; exposure 
BID 
twice a day 
BUN 
blood urea nitrogen 
C1D1 
Cycle 1 Day 1 
CBR 
clinical benefit rate 
cfDNA 
cell-free DNA 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma drug concentration 
CR 
complete response  
CRF 
case report form 
CS 
clinically significant 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 enzyme 
DLT 
dose limiting toxicity 
DOR 
duration of response 
ECG 
electrocardiogram 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
epidermal growth factor receptor (also known as HER1) 
EIU 
exposure-in-utero 
EORTC 
European Organization for Research and Treatment of Cancer 
EOS 
end of study 
EOT 
end of treatment 
18F-FDG 
18F-fluorodeoxyglucose 
ER 
estrogen receptor 
ERBB 
human protein product of the ERBB gene (also known as HER) 
ERBB2 
v-erb-b2 avian erythroblastic leukemia viral oncogene homolog 2 
EU 
European Union 
FLC 
fibrolamellar carcinoma 
GCP 
Good Clinical Practice 
Hb 
hemoglobin 
hCG  
human chorionic gonadotropin 
Hct 
hematocrit 
HER 
human epidermal growth factor receptor 
HR 
hormone receptor 


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IB 
Investigator’s Brochure 
IC50 
concentration at which there is 50% inhibition 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation or International Council for 
Harmonisation  
IDMC 
Independent Data Monitoring Committee 
IEC 
Independent Ethics Committee 
IM 
intramuscular(ly) 
IP 
investigational product 
IRB 
Institutional Review Board 
ITT 
intent-to-treat; intention-to-treat 
IV 
intravenous(ly) 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LV 
left ventricle 
LVEF 
left ventricular ejection fraction 
MDRD 
Modification of Diet in Renal Disease 
MedDRA 
Medical Dictionary for Regulatory Activities 
mmHg 
millimeters mercury 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multi-gated acquisition scan 
NCI 
National Cancer Institute 
NCS 
not clinically significant 
NGS 
next-generation sequencing 
NOS 
not otherwise specified 
NSCLC 
non-small cell lung cancer 
ORR 
objective response rate 
ORRfirst 
objective response rate at the first post-baseline tumor assessment timepoint 
OS 
overall survival 
PAC 
Picture Archival Communication 
PB-272 
neratinib 
PD 
progressive disease 
PET 
positron emission tomography 
PET/CT 
18F-fluorodeoxyglucose positron emission tomography combined with 
computerized tomography 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PI3K 
phosphoinositide-3 kinase 
PK 
pharmacokinetic  
PLC 
phospholipase C 
PPI 
proton pump inhibitor 
PR 
partial response 
QID 
four times a day 


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QTc 
corrected QT interval 
RANK 
receptor activator of nuclear factor kappa-B 
RAS 
rat sarcoma (family of ras genes) 
RBC 
red blood cell 
RECIST 
Response Evaluation Criteria in Solid Tumors 
ROI 
region of interest 
RTK 
receptor tyrosine kinase 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous 
SD 
stable disease 
SOC 
system organ class 
SUL 
standard uptake value normalized by lean body mass  
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
half-life 
TdP 
Torsade de Pointes 
TEAE 
treatment-emergent adverse event 
TID 
three times a day 
TKI 
tyrosine kinase inhibitor 
Tmax 
time to peak concentration  
ULN 
upper limit of normal 
US 
United States (of America) 
WBC 
white blood cell  
WHO Drug 
World Health Organization Drug Reference List 
WT 
wild type 


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1. 
INTRODUCTION 
1.1. 
The Epidermal Growth Factor Receptor (ERBB) Family  
The epidermal growth factor receptor (EGFR) class of receptor tyrosine kinases (RTKs) 
comprises four receptor proteins encoded by four genes (in parentheses): EGFR (EGFR), HER2 
(ERBB2[Neu]), HER3 (ERBB3) and HER4 (ERBB4), together known as the HER protein family. 
Canonically, HER family proteins exist as inactive monomers until bound to ligand. Ligand 
binding prompts a conformational change and enables homodimerization or heterodimerization 
with another HER protein, leading to transphosphorylation and downstream signaling (reviewed 
by Yarden and Sliwkowski, 2001). EGFR binds to and is activated by a number of ligands, 
including EGF, TGFα, HB-EGF, amphiregulin, betacellulin, epiregulin, and epigen (Yarden and 
Sliwkowski, 2001; Jones et al, 1999). HER3 and HER4 bind to ligands in the neuregulin family, 
including heregulin (reviewed in Stove and Bracke, 2004). A ligand for HER2 has not been 
identified; however HER2 can still homodimerize (Ghosh et al, 2011; Peckys et al, 2015) and has 
been characterized as the preferred dimerization partner for EGFR and HER3 (Graus-Porta et al, 
1997; Zaczek et al, 2005). In contrast, HER3 does bind ligand, but lacks intrinsic kinase activity 
(Pinkas-Kramarski et al, 1996). Despite the lack of ligand binding and kinase activity in HER2 
and HER3, respectively, HER2-HER3 heterodimers possess the most potent mitogenic activity 
among the HER family hetero- and homodimer combinations (Okines et al, 2011). Alterations 
within the HER family of RTKs have been reported in a number of tumor types. Oncogenic HER 
kinase alterations include receptor overexpression, elevated ligand levels, and somatic activating 
mutations. Sustained activation of HER signaling due to such alterations can result in oncogene 
or pathway-addicted tumors, and selective HER kinase inhibitors are now a component of 
standard treatment for several malignancies.  
1.1.1. 
Somatic Mutations in ERBB2 
Mutations in the ERBB2 gene have been identified in multiple tumor types (Figure 1), and cluster 
primarily in the kinase domain at exons 19 and 20 (between amino acids 737-831) and the 
extracellular domain at exon 8 (amino acids 301-340) (Figure 2). The latter induce kinase 
activation by elevating C-terminal tail phosphorylation or by covalent dimerization via 
intermolecular disulfide bond formation (Greulich et al, 2012). 
Activating point mutations in the ERBB2 gene that have been associated with primary breast 
cancer include but are not limited to amino acid positions G309, S310, R678, L755, D769, V777, 
V842, and E930. Activating insertions/deletions associated with breast cancer include but are not 
limited to L755_T759del, and 774-755 and 776 in-frame insertions. Activating mutations in the 
ERBB2 gene associated with colorectal cancer may include S310F, L755S, V777L, V842I, and 
L866M (Kavuri et al, 2015).  


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Figure 1: 
Frequency and Location of ERBB2 Mutations in Cancer Biopsy Samples 
(ERBB2 Amplification and Mutations across Cancer Types) 
 
 


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Figure 2: 
Frequency and Location of ERBB2 Mutations in Cancer Biopsy Samples 
(ERBB2 Mutation Hotspots across Cancer Types) 
 
Reference: Figures duplicated with permission from Dr. Solit (www.iom.edu/Activities/Disease/NCPF/2013-FEB-
11/Day%201/Session%204/17-Solit.aspx [accessed 21OCT2013]). 
1.1.2. 
Somatic EGFR Exon 18 Mutations in Lung Cancer  
Somatic mutations in the EGFR kinase domain have been identified in approximately 40% and 
17% of patients with NSCLC in Asian and American patients, respectively (Yatabe et al, 2015; 
Kris et al, 2014).  
EGFR exon 18 mutations, which are much less common, occur in 3-5% of all EGFR-mutant 
lung cancers (Kris et al, 2014; Cheng et al, 2015; Kobayashi et al, 2015; Lai et al, 2017).  
At the Aichi Cancer Center, mutation analyses of tumor samples identified 1,402 EGFR 
mutation-positive lung cancers (Kobayashi et al, 2015, Figure 3). Most tumors harbored 
mutations such as deletion of exon 19 (40%) or L858R (47%). Exon 18 mutations, comprising of 
G719X (n=41), E709X+G719X (n=1), and deletion of exon 18 (n=3), were present in 3.2% 
(n=45) of tumor samples.  


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Figure 3: 
Distribution of EGFR Mutations in Lung Cancers (Aichi Cancer Center)  
 
EGFR exon 18 mutations accounted for 4.1% of all EGFR mutations spanning from exons 18 
through 21 from analysis of the publicly available COSMIC database (Kobayashi et al, 2015). 
Furthermore, mutations at codon 709 and 719 accounted for 84% of mutations in exon 18 
(Figure 4). At codon 709, the delE709_T710insD mutation was the most frequently reported 
deletion, and the E709K and G719A mutations were the most frequent point mutations at codon 
709 and 719, respectively (Figure 5).  
Figure 4: 
Distribution of EGFR Exon 18 Mutations (COSMIC Database)  
 


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Figure 5: 
Distribution of Mutations at Codons 709 and 719 in EGFR Exon 18 
(COSMIC Database)  
 
1.2. 
Neratinib as a Cancer Therapy That Targets ERBB Receptors 
1.2.1. 
Neratinib, An Irreversible Inhibitor of EGFR, ERBB2, and ERBB4 Receptor 
Tyrosine Kinases 
Neratinib (PB-272) is an orally available, small molecule, irreversible tyrosine kinase inhibitor 
(TKI) of EGFR, ERBB2, and ERBB4. Preclinical characterization showed that neratinib inhibits 
EGFR and ERBB2 phosphorylation, downstream signaling, and cell growth in EGFR- and 
HER2-dependent cell lines, and decreased tumor formation in HER2-dependent xenograft 
models (Rabindran et al, 2004).  
A summary of preclinical studies, human pharmacokinetic studies, and previous clinical studies 
of neratinib for treatment of HER2+ breast cancer is provided in the Investigator’s Brochure 
(Neratinib IB).  
On 17-JUL-2017, the United States (US) Food and Drug Administration (FDA) approved 
neratinib (NERLYNX™) for the extended adjuvant treatment of adult patients with early stage 
HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. On 
25-FEB-2020, the FDA approved neratinib for use in combination with capecitabine, for the 
treatment of adult patients with advanced or metastatic HER2+ breast cancer who have received 
two or more prior anti-HER2 based regimens in the metastatic setting. 
1.2.2. 
Neratinib Treatment for ERBB2 Mutant Solid Tumors 
Several preclinical studies have shown utility of neratinib in ERBB2-mutant, tumor models. 
Survival of Ba/F3 cells transformed by ERBB2 wild type (WT) or G309E, S310F, S310Y, 
S312G, or A775_G776insYVMA mutant alleles was inhibited by neratinib 
(Greulich et al, 2012).  


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A seminal publication by Ron Bose and colleagues (Bose et al, 2013) identified 25 cases of 
breast cancer patients with ERBB2 mutations reported in American Society of Clinical Oncology 
(ASCO) Group Z1031 Clinical Trial or The Cancer Genome Atlas (TCGA) Breast Cancer 
Database. Seven of these mutations, including five in the kinase domain (V777L, D769H, V842I, 
L755S, L755_T759del), one in the extracellular domain (G309A), and one in the intracellular 
juxtamembrane region (R687Q) were introduced into MCF10A, MCF7, and NIH 3T3 cell lines 
using retroviral vectors. The V777L, D769H, and V842I mutants strongly increased ERBB2 
autophosphorylation and substrate protein (phospholipase C1, PLC) phosphorylation relative to 
WT ERBB2. Modest increases in ERBB2, PLC, and EGFR phosphorylation were reported with 
G309A, L755S, and R678Q. ERBB2 L755_T759del showed a marked decrease in ERBB2 and 
PLC phosphorylation, but an increase in EGFR phosphorylation, suggesting that L755_T759del 
may have the ability to activate other ERBB family members. Soft agar growth of cells 
expressing these mutants with the tyrosine kinase inhibitors lapatinib or neratinib revealed that 
all mutants were sensitive to neratinib, even the lapatinib-resistant L755S and L755_T759del 
mutations (Bose et al, 2013). 
Examination of HER2-targeted therapies on the growth of colorectal cancer patient-derived 
xenografts harboring ERBB2 mutations (S310Y, L866M, and V777L) showed that single agent 
therapy (trastuzumab, neratinib, or lapatinib) delayed tumor growth while dual HER2-targeted 
therapy with trastuzumab plus tyrosine kinase inhibitors caused tumor regression 
(Kavuri et al, 2015). 
In summation, the preclinical experience suggests that cancer patients with solid tumors 
harboring activating ERBB2 mutations could potentially benefit from treatment with neratinib.  
1.2.3. 
Neratinib Treatment for EGFR Exon 18 Mutations in Lung Cancer  
Neratinib has potent irreversible EGFR binding properties. EGFR exon 18 mutations, including 
G719, E709, and Del18 mutations, are observed less frequently (3%) in lung cancers and have 
poor response to first generation tyrosine kinase inhibitors (Kobayashi et al, 2015; 
Greulich et al, 2005). Preclinical studies suggest that EGFR exon 18 mutations display enhanced 
sensitivity to irreversible pan-HER inhibitors, including neratinib, as compared to approved 
benchmark EGFR TKIs including gefitinib and erlotinib (Kobayashi et al, 2015). Clinical 
responses to neratinib treatment have been previously reported in NSCLC patients harboring 
EGFR exon 18 mutations (Sequist et al, 2010). Here, we propose targeting these rare mutations 
in non-small cell lung cancer patients that may not benefit from currently approved EGFR TKIs.  
1.3. 
Neratinib Phase 1 and Pharmacokinetic Data 
Clinical pharmacokinetic (PK) results from the first-in-human study with ascending single and 
multiple doses in subjects with cancer showed that absorption of neratinib was slow with time to 
peak concentration (Tmax) ranging from 3-6.5 hours post dose. After single or multiple daily oral 
doses of neratinib with food, the maximum plasma drug concentration (Cmax) and the area under 
the plasma concentration-versus-time curve (AUC) increased with increasing dose. Furthermore, 
no major accumulation was observed when comparing Day 14 exposure with Day 1 exposure 
following once-daily dosing of neratinib 240 mg and 360 mg with food. The mean half-life (t1/2) 
following a single dose on Day 1 ranged from 8 to 17 hours, which supports once-daily dosing of 
neratinib. Fecal excretion of radiolabeled neratinib accounted for approximately 97% of the total 


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dose administered and is the major route of elimination. Data suggested no sex-related effect on 
the PK profile of neratinib (Neratinib IB).  
Data from a Phase 1 dose-escalation study in patients with advanced solid tumors demonstrated 
the safety and feasibility of once-daily oral treatment with neratinib. The maximum tolerated 
dose (MTD) was initially determined to be 320 mg. The higher frequency of high-grade diarrhea 
for subjects who received neratinib 320 mg in a subsequent Phase 2 study (46.2% at 320 mg 
daily vs 22.7% at 240 mg daily) led to the decision to reduce the recommended dose for neratinib 
to 240 mg (Neratinib IB).  
In healthy subjects, a high-fat meal increased neratinib peak and total exposure (Cmax and 
AUCinf) by approximately 2-fold, and a standard breakfast increased neratinib exposure by 
13%-17%, compared with exposure under fasting conditions (Neratinib IB).  
Neratinib, a substrate of cytochrome P450 enzyme (CYP), is susceptible to interaction with 
potent CYP3A4 inducers or inhibitors such as rifampin and ketoconazole, respectively. In a 
clinical study in healthy subjects, exposures of neratinib were substantially reduced when 
neratinib was coadministered with rifampin. Ketoconazole was found to increase exposure to 
neratinib by ~481% in healthy subjects. Nonclinical in vitro experiments indicate that neratinib 
inhibits the transport of P-glycoprotein (P-gp) substrates, which may decrease the clearance of 
drugs that are P-gp substrates. This P-gp interaction of neratinib would only be clinically 
relevant for P-gp substrate drugs with a narrow therapeutic window, such as digoxin. In a study 
with healthy subjects, neratinib was not associated with prolongation of the QTc interval at either 
the 240 mg daily dose of neratinib with food or under conditions of supratherapeutic plasma 
concentrations (neratinib 240 mg with ketoconazole 400 mg) (Neratinib IB).  
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. Once-daily doses of lansoprazole, a PPI, administered with a single dose of neratinib 
to healthy subjects resulted in decrease of neratinib Cmax by 71% and AUC by 65% compared 
with when neratinib was administered alone; there was a delay in tmax of 1.5 hours. The potential 
PK interaction of H2-receptor antagonists with neratinib has not been evaluated. It is unknown 
whether separating PPI or H2-receptor antagonist and neratinib doses reduce the interaction. If 
antacids are necessary, the antacid dose and the neratinib dose should be separated by 3 hours 
(Neratinib IB).  
In clinical studies conducted in patients with advanced tumors who received neratinib 240 mg 
daily with weekly paclitaxel 80 mg/m2, the PK data analysis suggested no meaningful 
differences in neratinib or paclitaxel exposure when administered as monotherapy compared 
with exposure when neratinib and paclitaxel were administered in combination (Study 3144A2-
1115-JA and 3144A1-203-WW; Neratinib IB). In a clinical study conducted in women with 
advanced ERBB2-positive breast cancer who received neratinib 240 mg daily in combination 
with trastuzumab (a loading dose of 4 mg/kg, followed by 2 mg/kg weekly thereafter), the PK 
data analysis suggested no interactions between neratinib and trastuzumab (Study 3144A1-202-
WW; Neratinib IB).  


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1.4. 
Adverse Event Profile of Neratinib Monotherapy  
In neratinib monotherapy (240 mg/day) studies conducted in patients with early-stage 
HER2-positive, or locally advanced, or metastatic solid malignancies, the most frequently 
reported treatment-emergent adverse events (TEAEs) were associated with gastrointestinal 
disorders, and included diarrhea, nausea, abdominal pain, and vomiting (Neratinib IB).  
In the Phase 3 Study 3144A2-3004-WW, in the extended adjuvant breast cancer setting, the 
intent-to-treat (ITT) population consisted of a total of 2840 subjects (1420 subjects in each arm) 
who had early stage HER2-positive breast cancer and had received prior adjuvant trastuzumab. 
The safety sample consisted of subjects who received at least 1 dose of study drug (neratinib or 
placebo), 1408 subjects in each arm. Subjects had a median age of 52 years (range, 23 to 
83 years). Prophylactic loperamide was not mandated.  
In the neratinib arm (N = 1408), Grade 3 TEAEs were reported for 684 (48.6%) patients and 
Grade 4 TEAEs for 15 (1.1%) patients. The most commonly reported Grade 3 TEAEs were 
diarrhea (561 subjects, 39.8%), vomiting (47 subjects, 3.3%), nausea (26 subjects, 1.8%), 
abdominal pain (24 subjects, 1.7%), and fatigue (23 subjects, 1.6%). The most common (>5%) 
adverse drug reactions (ADRs) occurring in patients receiving neratinib monotherapy are 
diarrhea, nausea, abdominal pain, abdominal pain upper, fatigue, vomiting, rash, stomatitis, 
decreased appetite, muscle spasms, dyspepsia, alanine aminotransferase (ALT) increased, 
aspartate aminotransferase (AST) increased, nail disorder, dry skin, abdominal distension, and 
urinary tract infection (see Neratinib IB).  
In the placebo arm (N = 1408), Grade 3 TEAEs were reported for 169 (12.0%) patients and 
Grade 4 TEAEs for 14 (1.0%) patients. The most commonly reported Grade 3 TEAEs were 
diarrhea (23 subjects, 1.6%) and electrocardiogram QT prolonged (7 subjects, 0.5%).  
During Study 3144A2-3004-WW, cardiac associated adverse events (AEs) were reported in 
10.5% of subjects in the neratinib arm and 12.9% of subjects in the placebo arm. In contrast to 
treatment with other HER2-targeted agents, such as trastuzumab, 4 patients treated with neratinib 
reported nonserious Grade 3 AEs pertaining to left ventricular ejection fraction (LVEF). Three 
out of the 4 neratinib-treated patients had LVEF ≤50% that resolved after treatment interruption, 
and 1 patient had an absolute decrease of 9% from baseline of 54% to 45% that resolved after 
treatment discontinuation. One patient who discontinued due to LVEF decreased had 
comorbidities of Grade 1 diarrhea and Grade 3 hyperglycemia prior to the event.  
Interstitial lung disease, which can sometimes be fatal, has been reported with other oral tyrosine 
kinase inhibitors that target EGFR and/or HER2, including lapatinib, gefitinib, and erlotinib. 
Rare cases of pneumonitis, which was considered to be drug related according to the 
Investigator’s assessment, have been reported in clinical studies of neratinib. Patients receiving 
neratinib should be monitored for acute onset or worsening of pulmonary symptoms such as 
dyspnea, cough, and fever, and treated appropriately. Neratinib clinical safety data show no 
consistent pattern of hematologic toxicity and no biologic mechanism has been currently defined.  
In Study 3144A2-3004-WW neratinib monotherapy arm, treatment-emergent serious adverse 
events (SAEs) that occurred in more than 4 patients were diarrhea (22 patients, 1.6%); vomiting 
(12 patients, 0.9%); dehydration (9 patients, 0.6%); cellulitis (6 patients, 0.4%); and erysipelas 
(5 patients, 0.4). Grade 4 ALT increased, and AST increased was reported for 3 (0.2%) patients 
each.  


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Refer to the most recent version of the IB for a summary of findings from nonclinical studies that 
potentially have clinical significance and from clinical studies that are relevant to the study 
(Neratinib IB). Also, refer to the IB for a summary of the known and potential risks and benefits 
to human patients.  
1.5. 
Rationale for Proposed Combination Therapies with Neratinib in Select Cohorts 
This open-label, multicenter, multinational, Phase 2 study has a basket design and as such it is 
predicated on the hypothesis that the presence of a molecular marker predicts response to the 
investigational products (Mandrekar et al, 2015).  
In addition to the typical “basket” cohorts, identified mainly by mutation, this study includes 
cohorts recognizing the role of tumor histology, especially in the case of combination therapies. 
These cohorts are defined by tumor type and actionable mutations. The tumor type, the mutation 
and the combination therapy are identified prospectively, with patients assigned in a 
nonrandomized way to a specific treatment arm. As a result, the study is composed of multiple 
parallel “small’ Phase 2 trials, with the cohorts defined by histology and mutations enrolling 
patients following a Simon’s design based on response. During the conduct of the study, cohorts 
may be closed and new ones may be opened in new histologies, new molecular abnormalities 
and/or different treatment strategies may be examined based on data emerging from the trial 
itself, from other neratinib trials, or from clinical or preclinical data generated by the Sponsor or 
reported in literature.  
The following sections will discuss the rationale of patient selection on the basis of mutations 
and the rationale for the use of diverse therapeutic approaches in the different cohorts. Recent 
clinical studies have shown that dual inhibition of HER2, such as the combination of lapatinib 
and trastuzumab or trastuzumab and pertuzumab, is more effective than trastuzumab treatment 
alone (Baselga et al, 2012; Swain et al, 2013; Gianni et al, 2012). The rationale underlying the 
combination therapies in the lung, colon, and breast cancer cohorts is essentially to overcome the 
resistance due to oncogenic switches (Erjala et al, 2006) with dual ERBB blockade (neratinib 
and trastuzumab in lung, breast and colon cancer) or a blockade of a second oncogenic pathway 
(neratinib and fulvestrant in hormone receptor positive breast cancer). Notably, trastuzumab is 
effective in patients with advanced ERBB2-mutated lung cancer (Mazieres et al, 2016) and the 
combination of trastuzumab and lapatinib, another anti-EGFR TKI, was recently reported as 
effective in colorectal cancer (Siena et al, 2015). In addition, taxanes are extensively used with 
the anti-HER2 trastuzumab in breast cancer; clinical data suggest that their anticancer activity 
may be enhanced by ERBB mutations (Park et al, 2012).  
1.5.1. 
Rationale for Treatment With Neratinib Combined With Fulvestrant in HER2 
Mutant Breast Cancer 
The ‘cross-talk’ between the estrogen and HER2 receptors has been previously reported, with 
HER2 amplification resulting in reduced estrogen-receptor signaling (De Laurentiis et al, 2005; 
Dowsett et al, 2001). HER2 overexpression increases the aggressiveness of breast cancer cells, 
lowering their response to endocrine therapies and resulting in a poorer prognosis. A review of 
patients with HER2 overexpression who were treated with fulvestrant suggested these patients 
may receive benefit from dual HER2-ER targeting (Charif et al, 2014).  


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Endocrine responsiveness may also be limited by resistance potentially due to upregulation of 
HER2/EGFR signaling. Preclinical evidence suggests that combining fulvestrant and an EGFR 
blocker may be an effective anti-tumor strategy in HER2-overexpressing/positive cells 
(Emde et al, 2011). Therapies aimed at inhibiting the ‘cross-talk’ between ER and HER2 using 
combinations of endocrine and HER2-directed therapies to overcome any potential ER signalling 
resistance mechanisms have been shown to improve anti-tumor efficacy compared to single 
agent treatments alone in preclinical studies. For example, in HER2+/ER+ breast cancer patient-
derived xenograft (Figure 6) and cell-derived xenograft models (Figure 7), the combination of 
neratinib plus fulvestrant resulted in significant inhibition of tumor growth compared to single 
agent treatments (internal Puma data).  
Figure 6: 
Neratinib Monotherapy or Neratinib Plus Fulvestrant Displays Enhanced 
Tumor Growth Inhibition in HER2+/ER+ Breast Patient-Derived Xenograft 
Model 
 


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Figure 7: 
Neratinib Monotherapy or Neratinib Plus Fulvestrant Displays Enhanced 
Tumor Growth Inhibition in Breast Cell-Derived Xenograft Model 
 
A retrospective chart analysis of 85 patients with metastatic breast cancer treated with fulvestrant 
with and without the HER2 antibody treatment, trastuzumab, was recently conducted by 
Charif et al (2014); 13% of patients had documented HER2+ primary tumors that were treated 
with both fulvestrant and trastuzumab. The combination was associated with a longer clinical 
response (median duration of therapy 772 days [51-1911]) than HER2 negative patients who 
received fulvestrant alone (median duration of therapy 360 days [60-2739]), suggesting 
that trastuzumab may help overcome resistance to fulvestrant (Charif et al, 2014).  
1.5.1.1. 
Adverse Event Profile of Combination Therapy of Neratinib and Fulvestrant 
Few clinical studies have explored the combination of fulvestrant with tyrosine kinase inhibitors 
in the clinical setting. Lapatinib was combined with fulvestrant in a randomized Phase 3 trial in 
patients with metastatic estrogen receptor (ER) positive, HER2+ breast cancer resistant to 
aromatase inhibitors (Burstein et al, 2014). The combination of fulvestrant plus lapatinib 
exhibited an overall response rate of 20% compared to 9% in the fulvestrant plus placebo arm 
alone. The combination regimen did not appear to decrease the tolerability of either agent alone. 
In the Phase 3 ExteNET study (NCT00878709), in a pre-specified subgroup analysis in the 
hormone receptor positive cohort in which >93% received concurrent hormone therapy, an 
enhanced neratinib benefit in improving disease free survival was observed (Chan et al, 2015). 
Diarrhea was the most common AE in neratinib-treated patients with 40% of patients reporting 
Grade 3 diarrhea (1 patient reported Grade 4 diarrhea). Other individual AEs ≥Grade 3 occurred 
in <4% of neratinib-treated patients. LVEF decrease ≥Grade 2 was seen in 1.3% of 


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neratinib-treated patients vs. 1.1% of placebo-treated patients. The mean relative dose intensity 
was 88% in neratinib-treated patients vs. 98% in placebo-treated patients.  
As of the data cutoff date of 01-MAY-2017 for the Neratinib IB, there were 27 patients with 
ERBB2 mutant breast cancer in the neratinib+fulvestrant combination therapy cohort of Study 
PUMA-NER-5201. At least 1 TEAE of Grade 1 to Grade 4 was reported for 25 (92.6%) patients. 
In this cohort, the most commonly reported (≥20% incidence) TEAEs of Grade 1 to 4 were: 
diarrhea (20 patients, 74.1%); nausea (10 patients, 37.0%); and constipation and decreased 
appetite (7 patients, 25.9%, each). Diarrhea was the only Grade 3 TEAE that occurred in more 
than 1 patient (3 patients, 11.1%). No TEAEs of Grade 4 or 5 were reported (Neratinib IB). No 
new safety signals from the neratinib+fulvestrant combination cohort have been observed.  
Preclinical studies have shown that neratinib did not alter the mRNA or activity levels of any 
cytochrome P450 enzyme (CYP) studies at concentrations 7 times that of the 240 mg dose used 
in clinical trials. Based on these in vitro findings, it is improbable that neratinib will be involved 
in induction mediated drug-drug interactions with concomitant medications that are metabolized 
by CYP1A2, CYP2B6, CYP3A4 or CYP2C9. Given that fulvestrant is metabolized by CYP3A4, 
neratinib is unlikely to be involved in any drug-drug interactions with fulvestrant.  
1.5.2. 
Rationale for Treatment With Neratinib Combined With Trastuzumab in 
ERBB2 Mutant Breast Cancer  
For HER2-positive breast cancer, there has been a focus in recent years to develop therapeutic 
agents to potentiate the effect of trastuzumab on target cells that have become resistant to 
trastuzumab. Preclinical evidence suggest that co-inhibition of HER2, other members of the HER 
family and/or the downstream pathway by giving trastuzumab/lapatinib in combination with 
other targeted therapies might prevent or at least prolong time to resistance and treatment failure 
(Baselga, 2010; O’Donovan et al, 2011).  
There is clinical evidence that dual HER2 blockade with trastuzumab in combination in women 
with metastatic HER2-positive breast cancer resulted in significant clinical benefit in a heavily 
pre-treated population (prior exposure to trastuzumab, lapatinib, T-DM1, a taxane, and multiple 
lines of chemotherapy; Jankowitz et al, 2013). Additionally in the clinic, lapatinib in 
combination with trastuzumab significantly improved overall survival and progression-free 
survival compared to lapatinib alone despite disease progression on prior trastuzumab-based 
therapy (Blackwell et al, 2010; Blackwell et al, 2012).  
The combination of neratinib and trastuzumab had a greater growth inhibitory effect than either 
drug alone in both HER2 over-expressing cell lines and cell lines that had acquired resistance to 
trastuzumab (Canonici et al, 2013; Figure 8). This result also held true in the mouse BT474 
xenograft model. The xenograft experiment showed that the combination treatment lead to the 
greatest decrease in pHER2 with decreased activation of pAkt and pERK, correlating with 
increased efficacy compared to the single agents (Mazieres et al, 2016).  
These examples support the notion that dual blockade using combination therapy is more 
effective than treatment with trastuzumab alone under conditions where HER2 is 
over-expressed/amplified; the same approach may also work in a setting where ERBB2 is 
mutated.  


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Figure 8: 
Combined Treatment With Neratinib and Trastuzumab Has an Additive 
Effect in Reducing BT474 and SKBR3 Cell Numbers  
 
 
Table 1: 
Overall Response Rate (ORR), Disease Control (DC), Progression-free 
Survival (PFS, Weeks), and Overall Survival (OS, Weeks) According to Drug 
Type 
Treatment 
n 
ORR 
DC 
PFS median 
(95% CI) 
OS median 
(95% CI) 
First-line; without HER2-targeting treatment 
93 
43.5% 
70.7% 
6 (5; 7.1) 
24 (19.1; 36.4) 
Second-line; without HER2-targeting 
treatment 
52 
10% 
36% 
4.3 (3.1; 5) 
19.4 (9.6; 24.7) 
EGFR-TKIa 
26 
7.6% 
26.8% 
2.99 
 (1.87; 4.47) 
20.14 
 (7.14; 32.95) 
Trastuzumab combination, T-DMIa 
58 
50.9% 
75.5% 
4.8 (3.4; 6.5) 
13.3 (8.1; 15) 
Neratinib, lapatinib, and afatiniba 
29 
7.4% 
55.5% 
3.4 (2.4; 4) 
6.5 (4.7; 30.6)a 
a If the same drug has been given more than one time, the results presented here are from their first administration.  
1.5.3. 
Adverse Event Profile of Combination Therapy of Neratinib and Trastuzumab  
Dual blockade with trastuzumab and neratinib was assessed in a Phase 1/2 clinical trial to 
determine the MTD and safety of the combination in patients with advanced breast cancer (Study 
3144A1-202-WW, Neratinib IB). In Part 1 of the study, 4 patients received neratinib 160 mg and 
4 patients received neratinib 240 mg in combination with trastuzumab 4 mg/kg as a loading dose 
and trastuzumab 2 mg/kg weekly thereafter. No dose limiting toxicity (DLT) was reported. In 
Part 2, all 37 patients received neratinib 240 mg in combination with trastuzumab 4 mg/kg as a 
loading dose and trastuzumab 2 mg/kg weekly thereafter. No MTD was defined for this study 
because no DLT was reported.  


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All 45 patients (100.0%) in the safety population reported at least 1 AE. The most commonly 
reported TEAEs of Grade 1 to 4 were diarrhea (42 patients, 93.3%), nausea (23 patients, 51.1%), 
decreased appetite (22 patients, 48.9%), vomiting (18 patients, 40.0%), and asthenia (13 patients, 
28.9%). Grade 3 TEAEs that occurred in more than 1 patient were diarrhea (7 patients, 15.6%); 
and nausea, vomiting, AST increased, and dyspnea (2 patients, 4.4% each). Grade 4 TEAEs of 
metastases to the central nervous system and hyperbilirubinemia were reported for 1 patient 
each. Grade 5 TEAE of disease progression was reported for 1 patient.  
Based on the above safety data and the low risk of drug-drug interactions with the combination 
of trastuzumab and neratinib, the risk of additional toxicities using a single 8 mg/kg loading dose 
followed by 6 mg/kg every 3 weeks is small.  
1.6. 
Rationale for Treatment with Neratinib Monotherapy in EGFR Exon 18 Mutant 
Lung Cancer  
In a preclinical study, NIH-3T3 cells transfected with EGFR exon 18 mutations (Del18, E709K, 
and G719A) were observed to form foci with marked pile-up (Kobayashi et al, 2015). This 
indicated that EGFR Del18, E709K, and G719A were oncogenic drivers. Furthermore, Ba/F3 
cells transfected with EGFR exon 18 mutations (Del18, E709K, and G719A) exhibited higher 
sensitivity to neratinib (25-fold for G719A, 5-fold for E709K, and by comparable extent for 
Del18) compared to control cells (Kobayashi et al, 2015). Compared with various EGFR tyrosine 
kinase inhibitors, including irreversible pan-HER TKIs (eg, afatinib), neratinib demonstrated the 
most sensitivity for blocking cell proliferation in exon 18 mutant Ba/F3 cells in vitro (Figure 9; 
Kobayashi et al 2015).  
Figure 9: 
Sensitivity of Ba/F3 Cells Expressing Exon 18 Mutations to Various EGFR 
Tyrosine Kinase Inhibitors  
 


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In a Phase 2 trial of neratinib in patients with advanced NSCLC who previously benefited from 
first-generation TKI and developed acquired resistance, it was ascertained that a response to 
neratinib was observed in patients harboring the EGFR exon 18 G719X point mutation 
(Sequist et al, 2010; Figure 10). Three of the 4 patients harboring G719X mutations had a partial 
response and the fourth had SD that lasted for 40 weeks (PFS: 52.7 weeks, 90% CI: 25.6 to 
57 weeks). It was noted that one of the patients who demonstrated a partial response and the 
patient with SD had transitioned from receiving erlotinib (due to lack of treatment response) to 
neratinib.  
Figure 10: 
Percent Change in Measurable Tumor for EGFR Mutation-Positive NSCLC 
Patients Treated with Neratinib  
 
More recently, the incidence and natural epidemiology of lung cancer patients with tumors 
harboring EGFR exon 18 mutations were reviewed at Memorial Sloan Kettering Cancer Center 
to better understand the clinical-pathological characteristics and outcomes to TKI therapy 
(Lai et al, 2017). Patients with EGFR exon 18 mutations appeared to have a shorter median 
overall survival (OS; 22 months vs. 31 months) when compared to patients with more common 
sensitizing EGFR mutations (Lai et al, 2017).  
The above preclinical and clinical results suggest that NSCLC patients with tumors harboring 
EGFR exon 18 mutations may benefit with neratinib monotherapy. Part of the primary objective 
of this study will be to determine whether neratinib monotherapy induces tumor regression in 
NSCLC patients with tumors harboring EGFR exon 18 mutations.  


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2. 
STUDY OBJECTIVES 
2.1. 
Primary Objectives 
The primary objectives of this study, applicable to each cohort, are:  
For the randomized hormone receptor positive (HR+), HER2 negative metastatic breast 
cancer: 
• To determine the confirmed objective response rate (ORR) by independent central 
review according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
For the metastatic cervical cancer cohort:  
• To determine the confirmed ORR by independent central review according to 
RECIST v1.1 
For all other cohorts: 
• To determine the first objective response rate (ORRfirst) by investigator at the first 
post-baseline tumor assessment  
2.2. 
Secondary Objectives 
The secondary objectives of this study, applicable to each cohort, are:  
For the randomized hormone receptor positive (HR+), HER2 negative metastatic breast 
cancer: 
• To determine the confirmed ORR by investigator 
• To determine the duration of response (DOR) by both independent central review and 
investigator 
• To determine the clinical benefit rate (CBR) by both independent central review and 
investigator 
• To determine the progression-free survival (PFS) by both independent central review 
and investigator 
For the metastatic cervical cancer cohort:  
• To determine the confirmed ORR by investigator 
• To determine the DOR by both independent central review and investigator 
• To determine the CBR by both independent central review and investigator 
• To determine the PFS by both independent central review and investigator 
• To determine overall survival (OS) 
For all other cohorts: 
• To determine the confirmed ORR by investigator 
• To determine the DOR by investigator 


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• To determine the CBR by investigator 
• To determine the PFS by investigator 
• To determine OS 
For all cohorts including the randomized HR+, HER2 negative metastatic breast cancer and 
metastatic cervical cancer cohorts, the safety objectives are: 
• To assess the safety profile and tolerability of study treatments 
• To assess Patient Reported Outcomes (PRO) 
2.3. 
Exploratory Objectives 
For all cohorts including the randomized HR+, HER2 negative metastatic breast cancer and 
metastatic cervical cancer cohorts, the exploratory objectives are: 
• To collect and retrospectively evaluate somatic mutations or gene aberrations using 
next-generation sequencing (NGS) in the most recent pretreatment tumor biopsy or 
fresh tumor tissue biopsies at a central laboratory.  
• To explore genetic modifiers of sensitivity and/or resistance to neratinib using 
molecular profiling techniques in pretreatment archival and/or fresh tumor specimens 
and paired normal whole blood. 
• To evaluate cell-free DNA (cfDNA) from plasma specimens collected at 
baseline/screening, during the course of treatment, and upon disease progression to 
identify HER2 and EGFR mutations and other gene aberrations and to assess any 
potential associations with neratinib sensitivity and/or primary/acquired resistance to 
neratinib or neratinib-containing therapy. 
• To evaluate potential genes or protein biomarkers that may be reported to confer 
neratinib sensitivity and/or primary/acquired resistance to neratinib or neratinib-
containing therapy from optional fresh core tumor biopsies during time of treatment 
and/or at the time of treatment discontinuation or disease progression. 


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3. 
OVERALL DESIGN AND PLAN OF THE STUDY 
3.1. 
Study Design 
This is an open-label, multicenter, multinational, Phase 2 study exploring the efficacy and safety 
of neratinib as monotherapy or in combination with other therapies in patients with HER (EGFR, 
HER2) mutation-positive solid tumors. Patients with tumors harboring somatic mutations in HER 
will be identified through previously documented mutation testing performed prior to screening. 
The presence of human HER mutations (EGFR, HER2) will be retrospectively confirmed by 
central testing NGS sequencing. The study has a basket design and includes several cohorts, either 
defined by an actionable somatic mutation or by actionable mutation and tumor histology (for 
example HER2 mutant cervical cancer). In the course of the study, enrollment in certain cohorts can 
be completed and enrollment in new cohorts initiated to test the anticancer effect of neratinib in other 
histologies, specific molecular abnormalities and/or in combination with other drugs. 
Patients with HER2 mutant, HER2 negative breast cancer will be divided into different treatment 
cohorts on the basis of HR status: HR negative (Triple Negative Breast Cancer [TNBC]) and 
HR+.  
• Patients in the HR negative cohort (TNBC) will receive neratinib in combination with 
trastuzumab (Table 3).  
• Patients in the HR+, HER2 negative, HER2 mutant breast cancer cohort with RECIST 
measurable tumors and who have been previously treated with CDK4/6 inhibitors 
(CDK4/6i) will be randomized to receive single agent fulvestrant, fulvestrant in 
combination with trastuzumab, or neratinib in combination with trastuzumab and 
fulvestrant with a randomization ratio of 1:1:1. Randomization will be stratified by 
the number of lines of prior therapy for metastatic disease (≤ 2 and >2 lines) and prior 
fulvestrant therapy (Table 2). 
• The randomized HR-positive (HR +), HER2 negative, HER2 mutant metastatic breast 
cancer cohort is designed to investigate the individual contribution of neratinib and/or 
trastuzumab to fulvestrant via Simon’s 2 stage optimal design. The decision to carry 
over on enrollment of each arm in the cohort will be based on stage I and II analysis 
of Simon’s 2 stage in consultation with the Independent Data Monitoring Committee 
(IDMC).  
− Patients in the HR+ cohort who receive single agent fulvestrant or fulvestrant plus 
trastuzumab will be eligible for triplet therapy (neratinib, fulvestrant, 
trastuzumab) upon progression. Patients who have unequivocal evidence of 
disease progression as documented by imaging, clinical examination, or disease 
related symptoms before the first scan post-treatment are eligible for the triplet 
therapy. Efficacy will be determined based on response to initial regimen only. 
• Patients in the HR+ cohort who have not received prior CDK4/6i therapy (eg. 
CDK4/6i naïve) will receive neratinib in combination with trastuzumab and 
fulvestrant as part of an open label cohort (Table 3). 
The cervical cancer cohort and cohorts not receiving trastuzumab are summarized in Table 4 and 
Table 5, respectively. 


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The trial will consist of a screening period, a treatment period, and a follow-up period after the 
study therapy is discontinued for any reason. An end of treatment (EOT) assessment is 
performed 28 days (+14 days) after the last dose of investigational product(s) and adverse events 
are collected 28 days after the last dose of investigational product(s). 
Neratinib will be administered orally with food once daily (recommended to be taken in the 
morning), on a continuous basis. Dose delays and modifications will be handled as per 
instructions in the package insert. All patients taking neratinib will maintain a patient diary for 
the study to record each dose of neratinib taken and while receiving antidiarrheal prophylaxis 
with loperamide taken for the first two cycles of treatment. For cohorts receiving combination 
treatment that includes trastuzumab, post-treatment radiographic evaluation of their disease will 
be conducted every 3 cycles. For all other cohorts, post-treatment disease assessment will be 
conducted every 2 cycles. Treatment should be administered until there is unequivocal evidence 
of disease progression as documented by imaging, clinical examination, or disease-related 
symptoms. Tumor markers or circulating tumor cells should not be used as the sole criteria for 
determining progression. At the time of decision regarding disease progression, radiological 
exam should be performed. Patients will continue on study treatment until disease progression, 
unacceptable toxicity, patient withdrawal of consent, or death. Patients who develop disease 
progression, but in the opinion of the Investigator would still benefit from continuing study, may 
continue on per-protocol therapy if approved by the Sponsor. Survival follow-up will be every 
12 weeks after treatment discontinuation. Enrollment will continue as dictated by the Simon’s 
2-stage design in all the histology and mutation specific cohorts and/or up to 30 patients per 
cohort in multi-cancer, mutation specific NOS cohorts. Enrollment in the randomized breast 
cancer, non-randomized breast cancer and cervical cancer cohorts will also continue as dictated 
by the Simon’s 2-stage design up to 50 patients per cohort. 
Table 2: 
Randomized Breast Cancer Cohort 
Tumor 
Cohort 
Mutation 
Randomized Treatment 
Sample Size (# 
subjects) 
Breast 
HR 
Positive 
(with prior 
CDK4/6i) 
HER2 
mutant 
• 
Fulvestrant: 500 mg IM on Study Day 1, 15, and 
29; once every 28 days thereafter  
Or 
• 
Fulvestrant: 500 mg IM on Study Day 1, 15, and 
29; once every 28 days thereafter  
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg 
IV every 3 weeks 
Or 
• 
Neratinib: 240 mg PO daily 
• 
Fulvestrant: 500 mg IM on Study Day 1, 15, and 
29; once every 28 days thereafter  
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg 
IV every 3 weeks  
 
Up to 18 
 
 
 
Up to 18 
 
 
 
 
 
Up to 50 
 


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Table 3: 
Non-randomized Breast Cancer Cohorts 
Tumor 
Cohort 
Mutation 
Assigned Treatment 
Cohort 
Sample Size (# 
subjects) 
Breast 
HR 
Positive 
(CDK4/6i 
naïve) 
HER2 
mutant 
• 
Neratinib: 240 mg PO daily 
• 
Fulvestrant: 500 mg IM on Study Day 1, 15, and 
29; once every 28 days thereafter 
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg 
IV every 3 weeks 
Up to 50 
Breast 
TNBC 
(HR 
Negative)  
HER2 
mutant 
• 
Neratinib: 240 mg PO daily 
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg 
IV every 3 weeks 
Up to 50 
 
Table 4: 
Cervical Cancer Cohort 
Tumor 
Cohort 
Mutation 
Assigned Treatment 
Cohort 
Sample Size (# 
subjects) 
Cervical 
HER2 
mutant 
• 
Neratinib: 240 mg PO daily 
50 
 
Table 5: 
Cohorts Not Receiving Trastuzumab  
Tumor Cohort 
Mutation 
Assigned Treatment 
Salivary Gland 
HER2 mutant 
• 
Neratinib: 240 mg PO daily 
Non-small Cell 
Lung 
EGFR exon 18 
mutations 
• 
Neratinib: 240 mg PO daily 
 
 
 


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Tumor Cohorts Closed to Enrollment in Amendment 7 
The following cohorts were closed to enrollment in Amendment 7: solid tumors (NOS) HER2 
mutant treated with neratinib monotherapy and HER2 mutant bladder/urinary tract cancer treated 
with neratinib + paclitaxel. 
The approximate duration of the study is 90 months and approximate duration for patient’s 
participation is 18 months. 
The end-of-study (EOS) is defined as the last visit of the last patient or the completion of any/all 
follow-up monitoring and data collection described in the protocol (ie, survival). 
The EOS will occur when all patients have been followed for OS or death, withdrawal of 
consent, or are lost to follow-up. The Sponsor reserves the right to terminate the study early for 
any reason and offer patients receiving treatment benefit the option to continue to receive 
neratinib via a separate treatment extension study or an expanded access protocol.  
3.2. 
Randomization and Blinding 
Patients in the HER2-negative, HER2 mutant, HR positive breast cancer cohort with RECIST 
measurable tumors who have previously been treated with CDK4/6 inhibitors (CDK4/6i) will be 
randomized to receive single agent fulvestrant, fulvestrant in combination with trastuzumab, or 
neratinib in combination with trastuzumab and fulvestrant with a randomization ratio of 1:1:1. 
Randomization will be stratified by the number of lines of prior therapy for metastatic disease 
(≤ 2 and >2 lines) and by prior exposure to fulvestrant. 
Randomization will be suspended after the 21st patient unless the decision has been made 
previously to drop any cohort earlier for futility/safety, and further patients will be enrolled into 
the T+N+F arm until the ‘final’ decision on expansion into the second stage has been made, 
randomization has been reintroduced (if 2 or 3 cohorts remain) or sufficient data are present to 
reconvene with the Independent Data Monitoring Committee (IDMC).  
For all other cohorts, this is an open-label, single arm study.  


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
Each patient will be entered into this study only if she/he meets all of these criteria: 
1. Men and women who are ≥18 years old at signing of informed consent.  
2. At the time of screening, histologically confirmed cancers in patients with previously 
documented activating EGFR (exon 18) or qualifying HER2 mutation confirmed by a 
Clinical Laboratory Improvement Amendments (CLIA)-certified or equivalent 
laboratory, and who are refractory to standard therapy or for which standard or curative 
therapy does not exist or is not considered sufficient or appropriate. 
3. At least one measurable lesion, as defined by Response Evaluation Criteria in Solid 
Tumors version 1.1 (RECIST v1.1; Eisenhauer et al, 2009).  
4. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition 
scan (MUGA) or echocardiogram (ECHO). 
5. Eastern Cooperative Oncology Group (ECOG) status of 0 to 2. 
6. Female patients with cancers known to secrete β-human chorionic gonadotropin (hCG), 
ie germinomas, are eligible if the pattern of serum β-hCG is suggestive of the malignancy 
and the pelvic ultrasound is negative for pregnancy. 
7. Male patients must agree and commit to use a barrier method of contraception while on 
treatment and for 3 months after the last dose of trastuzumab, fulvestrant, or neratinib 
monotherapy. Patients of child-bearing potential must agree and commit to the use of a 
highly effective double-barrier method of contraception (eg, a combination of male 
condom with an intravaginal device such as the cervical cap, diaphragm, or vaginal 
sponge with spermicide) or a non-hormonal method, from the signing of the informed 
consent until:  
i. 
28 days after the last dose of neratinib monotherapy, or 
ii. 
7 months after last dose of trastuzumab or  
iii. 
1 year after the last dose of fulvestrant. 
8. Provide written, informed consent to participate in the study and follow the study 
procedures. 
9. Agree to provide most recent metastatic tumor sample or fresh tumor biopsy, and 
plasma/blood specimens for gene sequencing and other biomarker analysis.  
Additional Inclusion Criteria for all Breast Cancer Patients that Harbor HER2 Mutations and 
NCSLC Patients that Harbor EGFR exon 18 Mutations  
10. Must provide a pretreatment fresh biopsy within 28 days prior to starting treatment unless 
the biopsy procedure presents a safety concern for the patient as determined by the 
Investigator, or other exceptional reason upon agreement with the Sponsor  


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Additional Inclusion Criteria for HR+ Breast Cancer Patients with Tumors that Harbor HER2 
Mutations  
11. HR+ disease defined as ≥1% estrogen receptor (ER) positive and/or progesterone 
receptor (PR) positive cells (performed on the most recent biopsy as assessed locally and 
consistent with current American Society of Clinical Oncology/College of American 
Pathologists (ASCO/CAP) or European Society of Medical Oncology (ESMO) 
guidelines): 
12. Biopsy from a non-bony metastatic site: preferred, or 
a. Biopsy from bony metastasis or if the sample is considered inadequate or unavailable: 
assessment of HR status will be at the Investigator’s discretion. 
13. Postmenopausal, as defined by at least one of the following criteria: 
a. Age ≥60 years; 
b. Age <60 years and cessation of regular menses for at least 12 consecutive months 
with no alternative pathological or physiological cause; and serum estradiol and 
follicle stimulating hormone (FSH) level within the laboratory’s reference range for 
postmenopausal females; 
c. Documented bilateral oophorectomy, 
14. Medically confirmed ovarian failure 
OR 
15. Pre/perimenopausal, ie, not meeting the criteria for being postmenopausal: 
a. Pre/perimenopausal women can be enrolled if amenable to be treated with a 
luteinizing hormone receptor hormone (LHRH) agonist. Patients must have 
commenced treatment with an LHRH agonist at least 4 weeks prior to the first dose of 
neratinib.  
16. Prior treatment with chemotherapy or hormonal therapy (including fulvestrant). 
4.2. 
Exclusion Criteria 
A patient will be excluded from this study if she/he meets any of these criteria: 
1. Patients harboring ineligible somatic HER2 mutations, such as those that are subclonal in 
nature or those resulting in the expression of truncated proteins including alterations that 
result in premature stop codon or a change in reading frame (ie, frame shift mutations).  
2. Prior treatment with any pan-HER-, HER2-, or EGFR tyrosine kinase inhibitor (TKI) 
(eg, lapatinib, afatinib, dacomitinib, neratinib, tucatinib, poziotinib, gefitinib, erlotinib, 
osimertinib) is excluded with the following exception: patients with EGFR exon 18 
mutated NSCLC who may have received afatinib, osimertinib, or other pan-HER or 
EGFR TKIs remain eligible. 
3. Not recovered to at least Grade 1 at screening (Common Terminology Criteria for 
Adverse Events v4.0 [CTCAE v4.0]) from all clinically significant adverse events related 
to prior therapies (excluding alopecia). 


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4. Received chemotherapy or biologic therapy ≤2 weeks or 5 half-lives (t½) of the agent 
used, whichever is shorter, prior to the initiation of investigational product.  
5. Received radiation therapy ≤14 days prior to initiation of investigational product.  
6. Patients who are receiving any other anticancer agents with the exception of patients on 
1) a stable dose of bisphosphonates or denosumab or 2) sex hormone therapy in the case 
of breast, or gynecological cancers. 
7. Received prior therapy resulting in a cumulative epirubicin dose >900 mg/m2 or 
cumulative doxorubicin dose >450 mg/m2. If another anthracycline or more than one 
anthracycline has been used, the cumulative dose must not exceed the equivalent of 450 
mg/m2 doxorubicin. 
8. Symptomatic or unstable brain metastases. (Note: Asymptomatic patients with metastatic 
brain disease who have been on a stable dose of corticosteroids for at least 14 days are 
eligible to participate in the study.)  
9. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure 
(New York Heart Association functional classification of  ≥2), unstable angina 
(symptomatic angina pectoris within the past 180 days that required the initiation of or 
increase in anti-anginal medication or other intervention), myocardial infarction within 
12 months of enrollment, or ventricular arrhythmia (except for benign premature 
ventricular contractions).  
10. Demonstrates a QTc interval >450 ms for men or >470 ms for women or known history 
of congenital QT-prolongation or Torsade de pointes (TdP). 
11. Inadequate bone marrow, renal or hepatic function as defined on screening laboratory 
assessments outside the following limits:  
Laboratory Assessments Endpoints 
Laboratory endpoint 
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  
<8 g/dL (transfusion allowed to treat low hemoglobin) 
Transfusion must be at least 7 days prior to C1D1. 
Total bilirubin  
>1.5 x institutional upper limit of normal (ULN) (in case of 
known Gilbert’s syndrome, >2x ULN) 
Aspartate aminotransferase 
(AST) and/or alanine 
aminotransferase (ALT)  
>3 x institutional ULN  
OR 
>5 x ULN if liver metastases are present 


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Laboratory endpoint 
Required limit for exclusion 
Creatinine 
>1.5 x institutional ULN 
OR 
Calculated Creatinine Clearance <30 mL/min (as measured 
directly with a 24-hour urine or calculated by Cockcroft-
Gault formula a or Modification of Diet in Renal Disease 
[MDRD] formula b) 
a Cockcroft and Gault, 1976.  
b Levey et al, 1999. 
12. Active infection or unexplained fever >38.5°C (101.3°F).  
13. Women who are pregnant, are planning on becoming pregnant, or are breast-feeding. 
14. 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 version 4.0] diarrhea of 
any etiology at baseline). 
15. Clinically active infection with a hepatitis virus. 
16. 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. 
17. Known hypersensitivity to any component of the investigational product, required 
combination therapy, or loperamide. 
18. Unable or unwilling to swallow tablets. 
19. Patients with known activating KRAS mutations. 
Additional Exclusion Criteria for Patients with Breast Cancer With HER2 Mutations  
20. Patients with known HER2+ tumors (protein overexpression or gene amplification as 
defined by ASCO/CAP guidelines or HER2 amplifications as determined by copy 
number alterations by NGS) are excluded.  
Additional Exclusion Criteria for Patients With HER2 Mutations Treated With Trastuzumab 
Combination Therapy or Being Randomized into HR+ Breast Cancer Cohorts 
21. Hypersensitivity to trastuzumab, murine proteins or any of the excipients listed in the 
Herceptin label.  
22. Severe dyspnea at rest due to complications of advanced malignancy or requiring 
supplementary oxygen therapy. 
4.3. 
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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4.4. 
Cohort Assignment 
Patients will be assigned to cohorts based on tumors harboring somatic mutations in EGFR or 
HER2 identified through previously documented mutation testing performed prior to screening 
and by the tumor type and approved by the Sponsor (Appendix 7).  
Mutation status of a tumor should be documented using molecular assays available at study sites 
(Appendix 7).  


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5. 
INVESTIGATIONAL PRODUCT AND ADMINISTRATION 
5.1. 
Investigational Product Administration 
The investigational product administration schedule is outlined in Table 6, and is described in the 
subsections below. For patients enrolled to a HER2-mutant bladder cohort treated with neratinib 
in combination with paclitaxel reference Protocol Amendment 6/6.1 for paclitaxel investigational 
product administration details. 
Table 6: 
Investigational Product Administration Schedule 
Study Drug  
Total Initial Dose 
Administration 
Dosing Schedule 
Neratinib 
240 mg  
Oral (PO) 6 x 40 mg 
tablets 
Daily, continuously  
Fulvestranta 
500 mg 
IM 2 x 250 mg injections 
Days 1, 15, and 29; then once 
every 4 weeks thereafter; see 
Schedule of Procedures, 
Appendix 1 Table A1.1 and 
Table A1.2. 
Trastuzumabb 
8 mg/kg on C1D1, 
then 6 mg/kg 
IV 
C1D1 then  
once every 3 weeks 
thereafter; see Schedule of 
Procedures, Appendix 1 Table 
A1.1. 
a Dosing schedule will include a window of ±2 days. For dosing outside the window, the Medical Monitor needs to 
be informed. For rate of administration, premedication, treatment of infusion reactions, and for dose adjustments, 
consult the label of fulvestrant . For patients with hepatic impairment defined by the Childs-Turcott-Pugh Class B 
criteria, the dose of fulvestrant should be reduced to 250 mg as one 5 mL injection on the same schedule. 
b Dosing schedule will include a window of ±7 days. For dosing outside the window, the Medical Monitor needs to 
be informed. If rounding is necessary, trastuzumab should be rounded to the nearest 20 mg. Infusion of 
trastuzumab should be performed in accordance with local guidelines and/or prescribing information, consult the 
label of trastuzumab.  
5.1.1. 
Neratinib  
Neratinib is self-administered as six 40-mg tablets (total daily dose 240 mg) orally, once daily 
with food (recommended to be taken in the morning), continuously.  
Daily dosing should continue until a criterion for treatment withdrawal is met (see Section 9.1).  
5.1.2. 
Fulvestrant  
Patients receiving fulvestrant (see Table 2) will receive 500 mg total dose of fulvestrant 
administered as two 5 mL intramuscular (IM) injections, one in each buttock, on Day 1, 15, and 
29; then once every 4 weeks thereafter (Appendix 1 Table A1.1 and Table A1.2). For patients 
with hepatic impairment defined by the Childs-Turcott-Pugh Class B criteria, the dose of 
fulvestrant should be reduced to 250 mg as one 5 mL injection on the same schedule.  
Dosing should continue until a criterion for treatment withdrawal is met (see Section 9.1).  


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5.1.3. 
Trastuzumab  
Patients receiving trastuzumab combination therapy (see Table 2) will receive an initial dose of 
8 mg/kg of trastuzumab IV administered on C1D1, followed by 6 mg/kg IV once every 3 weeks 
thereafter (Appendix 1 Table A1.1 and Table A1.2). 
Trastuzumab infusion should be interrupted in all patients experiencing significant 
signs/symptoms, and intervention of medical therapy should be administered, which may include 
epinephrine, corticosteroids, diphenhydramine, bronchodilators, and oxygen. Patients should be 
evaluated and carefully monitored until complete resolution of signs and symptoms. Permanent 
discontinuation should be strongly considered in all patients with severe infusion reactions 
(follow Herceptin [trastuzumab] package insert).  
Dosing should continue until a criterion for treatment withdrawal is met (see Section 9.1). 
5.2. 
Investigational Product Dose Adjustment for Toxicity 
Dose adjustment and/or discontinuation for fulvestrantand trastuzumab should follow dosing 
guidelines provided in Section 5.3.1 through Section 5.3.3 and the respective country-approved 
label. If, in the opinion of the investigator, the patient will be discontinued from combination 
therapy with fulvestrant or trastuzumab but may benefit from neratinib single agent, patient may 
remain on study after consulting the medical monitor. 
Recommended dose reductions for the -1 and -2 dose levels are listed in Table 7.  
Table 7: 
Dose Reduction Levels for Investigational Product-Related Toxicity 
Study Drug 
Initial Dose 
Dose Level -1 
Dose Level -2 
Neratinib 
240 mg 
160 mg 
120 mg 
Fulvestrant 
500 mg 
250 mg 
NA 
Trastuzumab 
8 mg/kg for Cycle 1 and then 6 mg/kg 
for the remaining cycles  
NA 
NA 
If doses of the IPs are held, study procedures for that cycle will proceed on schedule as planned, 
without any delay. This also applies to tumor assessments, which should continue as per cohort 
schedule regardless of any changes in dose or occurrence of AEs. Missed dose(s) of IPs (ie, any 
dose that is not administered within the protocol-defined administration window; Table 6) will 
not be made up. Note: Patients should take one dose of neratinib 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. If other toxicities are observed, consult the approved country label and 
the medical monitor. 
Once a 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. 


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Patients should discontinue IP if a criterion for withdrawal is met (see Section 9.1).  
Detailed rules for dose adjustments of IP in case of toxicity, including the dose levels to which IP 
should be adjusted, are provided in Table 8 to Table 15.  
For infusion reactions requiring dose adjustment, follow the country-approved label for 
trastuzumab as appropriate.  
Table 8: 
General Toxicity Related to Neratinib and Requiring Dose Adjustmenta 
NCI CTCAE v.4.0b 
Action with Neratinib 
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. 
a For fulvestrant and trastuzumab, follow the country-approved label.  
b  Based on National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0  
 


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Table 9: 
Diarrhea Related to Neratinib and Requiring Dose Adjustment  
NCI CTCAE V4.0 
Action with Neratinib 
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. (see 
Section 6.1.2.1 ) 
• Instruct patient to follow dietetic recommendations in 
the guidelines for management of diarrhea (see 
Section 6.1.2.1 for dietetic measures) 
• Fluid intake of ~2L should be maintained to avoid 
dehydration. 
• Once the event resolved to ≤ Grade 1 or baseline, 
continue loperamide as per the guidelines for 
management of diarrhea at the first onset of diarrhea. 
Continue neratinib at full dose. (see Section 6.1.1) 
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 
 
• Adjust anti-diarrheal treatment, as per the guidelines 
for management of diarrhea at the first onset of 
diarrhea. (see Section 6.1.2.1 pharmacological 
treatment) 
• Hold neratinib until recovery to ≤ Grade 1 or baseline. 
• Instruct patient to follow dietetic recommendations of 
the guidelines for management of diarrhea (see 
Section 6.1.2.1 for dietetic measures)  
• Fluid intake of ~2L should be maintained, 
intravenously if needed. 
• If diarrhea resolves to Grade 0-1:  
• 
≤1 week after withholding treatment, resume 
same dose of neratinib.  
• 
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. 
Any Grade 4 diarrhea [Life-threatening 
consequences; urgent intervention indicated] 
• Permanently discontinue neratinib  


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Table 10: 
Pulmonary Toxicity Related to Neratinib or Trastuzumab Requiring Dose 
Adjustment  
NCI CTCAE V4.0 
Action with Neratinib 
Action with Trastuzumab 
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.
•
Hold trastuzumab until
recovery to ≤ Grade 1 or
baseline; then resume
dosing.
Grade 3 Pneumonitis/Interstitial 
Lung Disease [Severe symptoms; 
limiting self-care ADL; oxygen 
indicated] 
•
Discontinue neratinib permanently
•
Discontinue trastuzumab
permanently.
Table 11: 
Dose Adjustment for Neratinib or Fulvestrant for Patients With Hepatic 
Impairment  
LIVER FUNCTION 
TOXICITY 
Action with Neratinib 
Action with Fulvestrant 
Childs-Turcott-Pugh Class A 
•
No dose adjustment required.
•
Continue 500 mg
Childs-Turcott-Pugh Class B 
•
No dose adjustment required.
•
Reduce dose to 250 mg on same
schedule of administration
Childs-Turcott-Pugh Class C 
•
Reduce starting dose to 80 mg in
patients with severe hepatic
impairment
•
No data in this patient population;
consult with medical monitor


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Table 12: 
Liver Toxicity Requiring Dose Adjustment 
NCI CTCAE 
V4.0 
Action with 
Neratinib 
Action with 
Fulvestrant 
Action with Trastuzumab 
Grade 3 
ALT/AST 
(>5-20x 
ULN) 
OR 
Grade 3 
bilirubin 
(>3-10x 
ULN) 
•
Hold neratinib until recovery to
≤ Grade 1 for patients with
ALT/AST ≤ Grade 1 at baseline
OR ≤ Grade 2 for patients with
Grade 2 ALT/AST at baseline.
•
Evaluate alternative causes.
•
For patients with ALT/AST
≤ 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, AST or bilirubin occurs
again despite one dose reduction,
permanently discontinue
neratinib. For patients with
Grade 2 ALT/AST at baseline
due to liver metastases: contact
the Sponsor for guidance on
appropriate dose adjustments.
Refer to Table 11. 
•
No dose adjustment
required
Grade 4 
ALT/AST 
(>20x ULN) 
OR 
Grade 4 
Bilirubin 
(>10x ULN) 
•
Permanently discontinue
neratinib.
•
Evaluate alternative causes.
•
Permanently discontinue
•
Evaluate alternative
causes
•
Permanently discontinue
•
Evaluate alternative causes
ALT/AST 
>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 by clinical laboratory
tests as soon as possible,
preferably within 48 hours from
awareness of the abnormal
results.
•
No dose adjustment
required unless Childs-
Turcott-Pugh Class B
criteria met
•
No dose adjustment
required
•
Contact the Sponsor immediately to discuss next steps, including evaluation of alternative
causes, and management of IP.
•
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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Table 13: 
Left Ventricular Ejection Fraction Toxicity Related to Trastuzumab 
Requiring Dose Adjustment  
 
Absolute Decrease from Baseline 
Relationship of LVEF to LLN 
<10% 
10%-15% 
>16% 
Within normal limits 
Continue 
Continue 
Holda 
1% - 5% below LLN 
Continue 
Holda 
Holda 
>6% below LLN 
Continue 
Holda 
Holda 
a Repeat LVEF assessment after 4 weeks. If criteria for continuation were met, trastuzumab is resumed. If not 
(ie, 2 consecutive holds) or a total of 3 holds occurred, trastuzumab is permanently discontinued.  
Table 14: 
Symptomatic Cardiac Failure Toxicity Related to Neratinib or Trastuzumab 
Requiring Dose Adjustment  
NCI CTCAE V4.0 
Action with Neratinib 
Action with Trastuzumab 
Symptomatic cardiac failure 
Neratinib should be discontinued. 
Trastuzumab should be discontinued 
Table 15: 
Infusion Reactions Related to Trastuzumab Requiring Dose Adjustment  
NCI CTCAE V4.0 
Action with Trastuzumab 
Grade 1 / 2  
Hypersensitivity reactions  
• 
Decrease the rate of infusion for mild to moderate infusion reaction.  
• 
Interrupt the infusion if necessary.  
• 
Treat as per institutional policy. Patients should be evaluated and carefully 
monitored. When symptoms resolve to ≤ Grade 1, infusion may be resumed 
(maintain dose) later that day at a slower rate or on the next day at slower 
rate with premedication.  
• 
Premedication should be used for all subsequent treatments. 
Grade 3 Severe infusion 
reactions 
• 
Discontinue trastuzumab infusion permanently. 
5.3. 
Packaging, Labeling and Storage 
Detailed packaging information is available in the study manual. The IPs will be labeled 
according to local regulations. 
5.3.1. 
Neratinib 
Neratinib will be supplied as 40-mg film-coated tablets packaged in opaque, plastic bottles with 
desiccant and a child-proof lid. 
Neratinib will be stored at 25°C (77°F) or below with desiccant; do not freeze. Excursions are 
permitted 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. 
5.3.2. 
Fulvestrant 
The Sponsor may provide commercial supply of fulvestrant, labeled for clinical trial use. Clinical 
sites that are not allowed to accept commercially available product may utilize their own 


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commercial supply. The pharmaceutical form of fulvestrant is clear, colorless to yellow, viscous 
solution.  
Pre-filled syringe of fulvestrant should be stored in the original packaged container to protect 
from light in refrigerator at (2C-8C). 
The commercially available fulvestrant is supplied in two clear Type 1 glass pre-filled syringe 
presentation. 
5.3.3. 
Trastuzumab  
The Sponsor may provide commercial supply of trastuzumab vials labeled for clinical trial use. 
Clinical sites that are not allowed to accept commercially available product may utilize their own 
commercial supply. Trastuzumab is supplied as a lyophilized sterile powder to be reconstituted 
for IV infusion. Trastuzumab should be stored in a refrigerator at (2C-8C).  
5.4. 
Drug Accountability 
The study site must maintain accurate records documenting dates and quantities of IP received 
from the Sponsor. Records must be maintained on a per-patient basis documenting dates and 
quantities of IP dispensed and returned at the beginning and end of each visit. Any IP 
accidentally or deliberately destroyed must be documented. Records also must be maintained of 
all IPs received and dispensed such that the amount of IP present within the pharmacy is accurate 
at any point in time against this record.  
Reconciliation will be made throughout the study between the amounts of IP supplied, 
dispensed, returned, and subsequently destroyed or returned to Sponsor. All IPs 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 at each study visit by study site staff. If 
patient noncompliance is noted, the patient should be re-instructed regarding proper dosing 
procedures in order to continue in the study. If repeated noncompliance is noted, additional steps 
may be taken, including withdrawal of the patient from the study (see Section 9.2).  


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6. 
CONCOMITANT TREATMENT 
All combination therapies, concomitant treatments, non-drug interventions, and medications will 
be captured from the signing of the informed consent form (ICF) until the end of the treatment 
(EOT). This will include the start date, stop date, generic name, route of administration, dose, 
frequency and indication for treatment.  
At screening, patients will be asked 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 or 
have taken since their last visit.  
6.1. 
Required Concomitant Treatment 
Diarrhea is the major dose-limiting toxicity of neratinib with onset typically occurring during the 
first few weeks of treatment. In particular, after the implementation of diarrhea prophylaxis with 
loperamide, most episodes of Grade 3 diarrhea occur during the first cycle of therapy 
(Neratinib IB; Ustaris et al, 2015). Primary prophylactic use of antidiarrheal medication is 
mandatory for all enrolled patients taking neratinib. Loperamide is the recommended standard 
therapy to prevent and treat diarrhea in this study. If alternative antidiarrheal medication is 
proposed, this should be discussed with the Medical Monitor and the reason documented in the 
source documents. Second-line antidiarrheal treatments and adjunctive therapies 
(ie, diphenoxylate hydrochloride and atropine sulfate [Lomotil], or octreotide 
[SANDOSTATIN®]) (or equivalent, as approved by the Sponsor) are also recommended for use 
when appropriate. 
6.1.1. 
Loperamide  
All patients receiving neratinib will take loperamide for the first 2 cycles of neratinib treatment. 
Patients will take 4 mg three times a day (TID) on Days 1-14 of Cycle 1 with the first dose of 
loperamide given concomitantly with the first dose of neratinib. After two weeks on study, 
patients will take loperamide 4 mg twice a day (BID) until the completion of Cycle 2 (42 days 
for trastuzumab containing regimens and 56 days for non-trastuzumab-containing regimens). 
Thereafter, loperamide will be administered as needed throughout neratinib treatment. 
Recommended loperamide dosing is listed below in Table 16.  
Patients randomized to fulvestrant or fulvestrant and trastuzumab will not be required to take 
loperamide. 
Table 16: 
Loperamide Dosing for Neratinib Treatment 
Loperamide Dose 
Day 
4 mg TID with a total daily dose of 12 mg  
Days 1-14  
4 mg BID with a total daily dose of 8 mg 
Days 15-end of Cycle 2  
Daily dose as needed (not to exceed 16 mg per day)  
Day 42+ for trastuzumab-containing 
regimens 
Day 56+ for non-trastuzumab-containing 
regimens 


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Patients must use a diary to record intake of loperamide during the first 2 cycles. Loperamide pill 
counts will be conducted only during the first 28 days of therapy. 
6.1.2. 
Loperamide Dose Adjustment 
Patients are expected to take loperamide prophylaxis as directed. However, patients may require 
individualization of loperamide prophylaxis dose (up to a maximum dose of 16 mg per day) with 
the goal of titrating to 1-2 bowel movements a day. 
• Diarrhea 
− For patients who develop diarrhea during Cycle 1, loperamide should be increased 
up to a maximum of 16 mg a day. 
• Constipation 
 
− 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 constipation due to loperamide are listed in Table 17.  
Table 17: 
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  
6.1.2.1. 
Loperamide Antidiarrheal Therapy 
The Investigator must review with the patient the Patient Instructions for the management of 
diarrhea and the Patient Diary for the patient’s daily recording of IP dose, any adverse 
reactions, the number of stools, and the use of loperamide and/or other antidiarrheals. A copy of 
the Patient Instructions are to be handed to the patient before leaving the site with IP on or before 
the first day on neratinib, 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. 


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Documentation of the number of stools at baseline should be captured in the patient’s record. 
Any occurrences of loose stools, diarrhea or constipation must be documented by the patient as 
precisely as possible and captured in the Patient Diary. The entries in the Patient Diary should be 
reviewed by the study staff together with the patient at the end of the first month of neratinib 
therapy. 
The Patient Diary will contain details of the daily number of unformed stools the patient has 
experienced since the last visit. Documenting the toxicity grade of the diarrhea or constipation by 
the study staff needs to be reported accurately on the Case Report Form (CRF) using an adjusted 
NCI CTCAE version 4.0 criteria (see Section 5.2). Also, the daily dose of loperamide (or other 
antidiarrheals, if applicable) noted on the diary will be reviewed and recorded on the CRF. 
Loperamide will be provided and dispensed directly by the site on or before C1D1 with 
neratinib. It is very important to initiate treatment with loperamide concomitantly with the first 
dose of neratinib to minimize the occurrence and severity of diarrhea.  
Prophylactic dosing instructions (Cycles 1 and 2) 
• Inform patients that they will experience diarrhea while taking neratinib. 
• Administer loperamide: 4 mg TID for the first 14 days, with the first dose 
administered concomitantly with the first dose of neratinib. After two weeks, take 
loperamide 4 mg BID until the end of the second cycle of therapy regardless of 
whether the patient is experiencing diarrhea or not.  
• For patients with persistent Grade 1 diarrhea (<4 stools per day above baseline) on 
loperamide, increase loperamide up to 16mg daily (4 mg four times a day [QID]).  
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 (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 IM injection 
(equivalent medication may be used with approval of the Sponsor). 
• The sites must contact the patient by phone 1 day, 2 days, and 3 days after the first 
dose of neratinib in Cycle 1 to inquire about any diarrhea and ensure the patient is 
compliant with anti-diarrheal therapy. 
(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 on the Patient Diary the number of stools per day and the 
dose of any anti-diarrheal medication taken each day for the first cycle of therapy (see 
Section 5). Patients must record all doses of neratinib for the entire duration of the 
study.  


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For new onset, uncomplicated Grade 1 or Grade 2 diarrhea in Cycle 3 and beyond 
Dietetic measures 
• Stop all lactose-containing products. 
• Drink 8 to 10 large glasses of clear liquids per day. 
• Eat frequent small meals. 
• Recommend a low-fat regimen enriched with bananas, rice, applesauce and toast until 
the 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 or 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, increase loperamide up 
to 16 mg (4 mg QID) and 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 SC TID; or 
after initial dose of short-acting octreotide, if well tolerated, a single dose of 
octreotide LAR 20 mg IM (equivalent medication may be used with approval of the 
Sponsor). 
For Grade 3 or Grade 4 diarrhea with complicating features (dehydration, fever, and/or 
Grade 3-4 neutropenia) 
Dietetic measures (same as above) 
Pharmacologic treatment 
• Administer loperamide: initial dose of 4 mg (2 tablets or capsules) with the first bout 
of diarrhea followed by 2 mg (1 tablet or 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). 
• For patients with Grade 3-4 diarrhea on loperamide, consider administration of 
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). 
• Administer octreotide (100 to150 µg SC BID or IV (25 to 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 to4 neutropenia. 


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Stool cultures should be done to exclude infectious causes of Grade 3 or 4 diarrhea or diarrhea of 
any grade with complicating features (dehydration, fever, and/or Grade 3 or 4 neutropenia) per 
the Investigator’s discretion. Results from occult blood, fecal leukocyte stain, Clostridium 
difficile, Campylobacter, Salmonella, and Shigella testing, when performed, should be reported 
using the appropriate CRF. 
Patients with significant diarrhea who are unresponsive to medical treatment may require 
treatment interruption and/or dose reduction.  
6.2. 
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 6.3), or drugs with potential for drug-drug 
interactions (Section 6.4), or in the associated Appendices 3 (cytochrome P450 inhibitors and 
inducers), 4 (p-glycoprotein substrates and inhibitors) and 5 (drugs associated with QT/QTc 
prolongation), is permitted at the Investigator’s discretion. 
Specifically, the following treatments are permitted during the study:  
• Standard therapies for preexisting medical conditions, medical and/or surgical 
complications, and palliation. All medication(s) as well as previous hormonal 
therapy, dose and length of therapy should be recorded in the CRF. 
• Bisphosphonates and receptor activator of nuclear factor kappa-B (RANK) 
ligand inhibitors (eg, denosumab), regardless of indication, provided patients have 
been on stable doses for at least 2 weeks prior to enrollment. The stable dose should 
be maintained during the IP treatment period. Patients requiring initiation of 
bisphosphonate treatment during the course of the study should be discontinued due 
to progressive disease (PD), unless disease progression can be completely ruled out 
and clearly documented in the patient’s source documentation. 
• Secondary prophylactic use of growth factors (eg, granulocyte colony-stimulating 
factor or granulocyte macrophage colony-stimulating factor) may be implemented per 
the currently applicable ASCO and the European Organization for Research and 
Treatment of Cancer (EORTC) (Aapro et al, 2011) guidelines at the Investigator’s 
discretion, if significant neutropenia or febrile neutropenia/infection is observed. 
6.3. 
Prohibited Concomitant Treatment 
The following treatments are prohibited throughout the duration of the active (treatment) phase 
of the study:  
Other than as specified in protocol, any concurrent chemotherapy, radiotherapy (including 
palliative radiotherapy), surgery related to cancer, anticancer immunotherapy, or other anticancer 
treatments including other investigational agents are prohibited. Megestrol®, bisphosphonates, 
and RANK-ligand inhibitors are permitted provided the patient has been on a stable dose for at 
least 2 weeks prior to the start of neratinib. Patients with breast cancer on a stable dose of 
hormonal therapy will be permitted to remain on this regimen through their participation in the 
study.  


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6.4. 
Potential for Drug-Drug Interactions 
Patients should avoid agents known to be strong cytochrome P450 (CYP) 3A4 inducers or 
inhibitors (eg, ketoconazole) for the duration of the active phase of the study. Patients should 
also avoid grapefruit and herbal remedies, including St John's Wort. Refer to Appendix 3 for a 
list of inhibitors and inducers of CYP isoenzymes. If unavoidable, patients taking such agents 
should be monitored closely. 
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 4 for a list of substrates and 
inhibitors of P-gp. 
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 5 for a 
summary of drugs known to have a risk of causing QT/QTc prolongation, potentially causing 
TdP. 
Patients taking oral coumarin-derivative anticoagulants (eg, 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 reduces the interaction. If an H2-receptor antagonist such as ranitidine is 
required, neratinib should be taken 10 hours after the H2-receptor antagonist dosing and at least 
2 hours before the next dose of the H2-receptor antagonist. If antacids are necessary, the antacid 
dose and the neratinib dose should be separated by 2 to 4 hours.  


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7. 
STUDY ASSESSMENTS 
7.1. 
Efficacy Assessments 
For cohorts receiving combination treatment that includes trastuzumab (Table 2 and Table 3), 
post-treatment disease assessment by CT or magnetic resonance imaging (MRI) will be 
conducted at the beginning of Week 10 (ORRfirst), and every 3 cycles (± 7 days) thereafter 
(Appendix 1 Table A1.1 and Table A1.2). For all other cohorts not receiving trastuzumab 
(Table 4 and Table 5), post-treatment disease assessment will be conducted at the beginning of 
Week 9 (ORRfirst), and every 2 cycles (± 7 days) thereafter (Appendix 1 Table A1.1 and 
Table A1.2). Complete or partial response (CR or PR) must be confirmed with a repeat scan 
performed no sooner than 4 weeks after the criteria for response are first met. In cases where the 
subject discontinues treatment for reasons other than progressive disease (eg., adverse event, 
patient choice, noncompliance, etc.) and the response is either CR or PR, then a confirmation 
scan is required no sooner than 4 weeks after the criteria of response is met. Radiological 
response is assessed by RECIST v1.1. Following one year on therapy, scans may move to every 
4 cycles for trastuzumab-containing regimens and every 3 cycles for non-trastuzumab 
containing regimens. Following two years on therapy, scans may move to every 5 cycles for 
trastuzumab-containing regimens and every 4 cycles for non-trastuzumab containing regimens. 
For patients who enrolled prior to Amendment 6, the same method of measurement 
(eg PET/CT) and same method of disease assessment (eg metabolic response by PET Response 
Criteria) should continue through final assessments 
7.1.1. 
Tumor Assessments 
Radiographic tumor assessments use CT (or MRI or PET/CT) and tumor markers will be 
performed in accordance with the Schedule of Procedures (Appendix 1 Table A1.1 and 
Table A1.2). Following one year  on therapy, scans may move to every 4 cycles for trastuzumab-
containing regimens and every 3 cycles for non-trastuzumab containing regimens. Following two 
years on therapy scans may move to every 5 cycles for trastuzumab-containing regimens and 
every 4 cycles for non-trastuzumab containing regimens. 
7.1.1.1. 
General Information  
All target and nontarget sites of disease (see Appendix 6) identified at screening must be 
followed for the duration of the study. Their size, presence, and absence should be noted 
throughout follow-up. Overall response for each patient is based on the combined results for 
target and nontarget lesions and the presence or absence of new lesions. 
Tumor-based efficacy endpoints (ie, PFS, ORRfirst, and confirmed ORR) will be based on tumor 
assessments performed by the Investigator. Response and progression will be evaluated using 
RECIST version 1.1 (see Appendix 6). 
Tumor assessments will be performed for all patients as described in Section 7.1 and in 
(Appendix 1 Table A1.1 and Table A1.2) throughout the treatment phase until the occurrence of 
documented disease progression, death or patient withdrawal from the study (ie, lost to 
follow-up, withdrawal of consent), whichever occurs first (refer to Section 9 for a complete list 
of reasons for withdrawal from the study). Additional tumor evaluations may be performed as 
clinically indicated. Missed tumor assessments must be performed as soon as possible. As soon 


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as evaluations for each tumor assessment are completed, the Investigator should assess the 
patient’s overall response (target and nontarget lesions) based on appropriate disease response 
criteria and overall response algorithms (see Appendix 6). Scans must be assessable for all 
evaluations.  
The longest diameters (LD) for all target lesions will be recorded (short axis for target 
pathological lymph nodes) within the source documentation. The LD for all target lesions will be 
added and reported as the baseline sum LD (SLD). Per RECIST version 1.1, for determining CR 
or PR, all post-baseline tumor measurements will be compared with the baseline SLD; for 
determining PD, the post-baseline measurement is compared with the smallest SLD recorded 
since initiation of treatment, including baseline (Appendix 6). 
Patients who discontinue study treatment and do not have PD will be asked to remain on study 
for tumor evaluation per protocol and for determination of progression free survival (PFS; see 
Section 8.3). 
7.1.1.2. 
Radiographic/Imaging Evaluations 
The same method of measurement (eg, CT or MRI) and the same technique of assessment should 
be used to characterize each identified and reported lesion at baseline through the final visit. All 
measurements should be taken, recorded, and measured on computer screens of Picture Archival 
Communication (PAC) systems or on hard-copy images using a ruler or calipers. All baseline 
evaluations should be performed as closely as possible to the beginning of the active drug phase 
and never more than 28 days before the beginning of the active drug phase. As often as possible, 
lesions should be assessed by the same Investigator or same radiologist using the same method 
of measurement. Physical examination may not be the sole method of assessment for a solitary 
lesion. For patients with measurable and evaluable skin lesions, photographs should be taken, 
inclusive of a ruler.  
All patients must have a CT of the chest, abdomen and pelvis at baseline. Additional areas of 
assessment at baseline would include additional possible target or non-target lesion.  On-study 
scans should be repeated at the appropriate interval for areas with known target or non-target 
disease. Additional fields of imaging should be repeated as clinically indicated. Patients with a 
history of brain metastasis must receive a Brain MRI or CT at baseline. Follow-up Brain MRI or 
CT scans should only be completed as clinically indicated. 
Definitions of measurable disease and measurable lesions, documentation of “target” and 
“nontarget” lesions, and evaluation of response are summarized in Appendix 6 
(Eisenhauer, et al, 2009). 
Baseline screening radiographic studies and all subsequent radiographic studies and their 
associated reports will be collected and stored by the Sponsor for possible future independent 
review. 
7.1.2. 
Tumor Assessments – Clinical 
Clinical examination should include caliper measurement when lesions are superficial. Lesions 
that cannot be measured with calipers should be recorded as non-measurable. Documentation by 
color photography in good light and including a ruler to estimate the size of the lesion is 
required. 


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Note that when lesions can be evaluated by clinical examination and imaging, imaging 
evaluation should be undertaken by CT or MRI as appropriate. 
7.1.3. 
Quality of Life Assessments 
Patient reported outcomes using the FACT-G (Appendix 8) assessment will be performed at 
screening, C1D1, and at the beginning of each cycle (per office visit, prior to drug 
administration) for up to 6 months or end of treatment, whichever comes first.  
7.1.4. 
ECOG Performance Status 
The ECOG performance status will be assessed in accordance with the Schedule of Procedures 
(Appendix 1 Table A1.1 and Table A1.2). The ECOG categories are summarized in Appendix 2. 
7.2. 
Safety Assessments 
Refer to the Schedule of Procedures (Appendix 1 Table A1.1 and Table A1.2) for time points. 
The following safety endpoints will be assessed: Medical history, AEs, vital signs, detailed/brief 
(system-guided) physical examinations, 12-lead ECGs, LVEF (via ECHO or MUGA), and 
laboratory evaluations. 
AEs will be graded according to the NCI CTCAE version 4.0. SAEs will be reported until 
28 days after the last dose of IP(s) 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 the administration of neratinib, it should be promptly reported. More details on AEs 
can be found in Section 12. 
The diary used for recording of IP intake will also be used by patients to document any other 
study treatment. In case of diarrhea, the diary also serves to document the number of loose stools 
per day and use of loperamide/other antidiarrheal treatments taken. 
7.2.1. 
Laboratory Assessments 
Laboratory testing will be performed in accordance with the Schedule of Procedures 
(Appendix 1 Table A1.1 and Table A1.2).  
The institutional laboratory will analyze all hematology, routine blood chemistry, and urine 
samples collected. Samples will be analyzed at a facility meeting Good Laboratory Practice 
(GLP) requirements as evidenced by current accreditation by an independent testing 
organization.  
Laboratory assessments are not required on C1D1 if previously obtained within 72 hours prior to 
C1D1 as part of screening, with no clinically significant findings. 
The following laboratory parameters will be determined, as summarized in Table 18. 
 
 


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Table 18: 
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  
Alanine transaminase (ALT) 
Aspartate transaminase (AST) 
Blood urea nitrogen (BUN) 
Calcium 
Chloride  
Serum Creatinine 
Glucose (non-fasting) 
Lactate dehydrogenase (LDH) 
Magnesium 
Phosphorus 
Potassium  
Serum total cholesterol (non-fasting) 
Sodium  
Total bilirubin 
Total protein  
Urinalysis (dipstick or laboratory 
analysis; microscopic 
examination if abnormal): 
Blood 
Protein 
Glucose 
Serum or urine pregnancy test: 
In women of child-bearing capacity (at screening and repeated only if 
performed outside 72 hours of C1D1). 
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/or 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 12.1.2. For 
all laboratory values that are outside of the laboratory’s reference range, the Investigator (or 
designee) must record CS (clinically significant) or NCS (not clinically significant) on the 
laboratory sheet. 
7.2.2. 
Vital Signs 
The following vital signs will be assessed in accordance with the Schedule of Procedures 
(Appendix 1 Table A1.1 and Table A1.2): 
• Blood pressure (systolic and diastolic; mmHg) 
• Resting heart rate (beats per minute) 
• Respiration rate (breaths per minute). 
• Body temperature (°C) 
• Weight (kg) 
• Height, cm (Screening only) 


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7.2.3. 
Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Procedures 
(Appendix 1 Table A1.1 and Table A1.2).  
The detailed/brief (system-guided) physical examination will evaluate any clinically significant 
abnormalities; including worsening of medical history conditions. 
7.2.4. 
Electrocardiograms 
Single standard 12-lead digital ECGs will be performed in accordance with the Schedule of 
Procedures (Appendix 1 Table A1.1 and Table A1.2).  
• For the baseline assessment, ECG will be performed within 14 days prior to C1D1 for 
all cohorts. Patients will have ECGs performed only at baseline and at end of 
treatment.  
The ECG 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. Each ECG will be reviewed by the Investigator or delegate 
who will document this review by his/her initials and date. The Investigator (or delegate) will 
record CS (clinically significant) or NCS (not clinically significant) on each non-normal ECG. 
7.2.5. 
Left Ventricular Ejection Fraction (LVEF) 
The MUGA scan or ECHO scan to determine LVEF will be performed in accordance with the 
Schedule of Procedures (Appendix 1 Table A1.1 and Table A1.2). 
• The Screening MUGA/ECHO scans to determine LVEF will be performed as routine 
procedures within 28 days before C1D1.  
• For any cohort treated with trastuzumab (Table 2 and Table 3): following Screening, 
MUGA/ECHO scans will be performed every 12 weeks (+/- 7 days) and at end of 
treatment.  
• For all other cohorts not receiving trastuzumab (Table 4 and Table 5): MUGA/ECHO 
scans will be performed at screening and at end of treatment.  
It is strongly recommended to use the same method of cardiac evaluation (ECHO or MUGA) at 
each time point for each patient.  
7.2.6. 
Archival and Fresh Tumor Tissue, Whole Blood (for Germline DNA), and 
Plasma Collection 
Biospecimen collections will be performed in accordance with the Schedule of Procedures 
(Appendix 1 Table A1.1 and Table A1.2). All specimens should be processed, packaged and 
shipped according to the Laboratory Manual.  
Archival and/or Fresh Tumor Tissue: 
All efforts will be made to collect archival and/or fresh pretreatment (screening) tumor 
tissues (except for breast cancer and NSCLC cohorts where collection of a pretreatment 


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biopsy is mandatory), and, if possible, upon disease progression for analysis as outlined in 
the Exploratory Objectives of the protocol.   
Whole Blood for Germline DNA:  
Blood will be obtained during the study (preferably acquired during screening, at the same time 
as hematology, serum chemistry, and plasma samples are taken). 
Plasma for Biomarker Analysis of cfDNA:  
Serial plasma samples for subsequent exploratory biomarker analyses will be collected from each 
patient during the 3 phases of the study: 
1. Pretreatment (preferably acquired during screening, or at the latest on C1D1 but before 
the patient takes their first neratinib monotherapy or combination therapy),  
2. On-treatment and  
3. Post-treatment (coordinated with EOT).  
It is expected that these banked plasma specimens will subsequently be used for cfDNA 
mutational analysis to investigate mechanisms of primary and/or acquired resistance to neratinib 
therapy. 
7.3. 
Protocol Deviations 
Protocol deviations should be reported to the Sponsor (or designee) as they occur or are 
discovered. 
7.4. 
Patient Diary 
A Patient Diary will be provided by the Investigator for the patient to record daily intake of 
neratinib for every cycle, loperamide (and/or other antidiarrheal medication) only for the first 
two cycles of treatment and the frequency of diarrhea.  


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8. 
STUDY CONDUCT 
Schedule of Procedures is provided in (Appendix 1 Table A1.1 and Table A1.2).  
In addition to the procedures listed in this section, 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.  
8.1. 
Informed Consent 
Before any study procedures are performed, obtain informed consent, as required by the 
IRBs/ECs and regulatory authorities. 
8.2. 
Screening All Cohorts 
Screening activities are to be conducted within 14 days prior to C1D1, except for CT, PET/CT or 
MRI disease assessment (within 28 days prior to C1D1), ECHO/MUGA (within 28 days prior to 
C1D1), a serum or urine pregnancy test (at screening, and to be repeated if performed outside 72 
hours of C1D1). In breast cancer and NSCLC patients, fresh tumor biopsy should be obtained 
within 28 days prior to C1D1 and for all other cohorts, archival and/or fresh pretreatment tumor 
tissue should be obtained during screening or within the first cycle of treatment. 
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 
smoking history (only for NSCLC patients), relevant surgical procedures, or 
symptoms experienced during the previous 30 days and those ongoing at the time 
of screening, and any medical conditions that require medication. Identify start of 
current medical conditions by at least a year. 
− 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 6. 
• Demography: date of birth, sex, race (Asian, Black or African American, White, 
Other).  
• Physical examination. Refer to Section 7.2.3. 
• Vital signs, including height and weight. Refer to Section 7.2.2. 
• ECG. Refer to Section 7.2.4. 


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• ECHO or MUGA (to obtain LVEF). Refer to Section 7.2.5.  
• Laboratory tests (hematology and serum chemistry, urine test by dipstick or 
laboratory analysis, urine or serum pregnancy in women of child-bearing capacity [at 
screening and repeated on C1D1 prior to treatment if performed >72 hours prior to 
C1D1]). Refer to Section 7.2.1.  
• Archival and/or fresh tumor tissue sample and whole blood collection from all 
patients for centralized ERBB mutation and amplification. Refer to Section 7.2.6. 
• Baseline pretreatment plasma sample for exploratory biomarker analysis. Refer to 
Section 7.2.6. 
• Whole blood DNA sample for exploratory biomarker analysis. Refer to Section 7.2.6. 
• Quality of Life Assessments. Refer to Section 7.1.3. 
• ECOG performance status. Refer to Section 7.1.4. 
• Radiographic tumor assessment within 28 days prior to C1D1. Refer to Section 7.1.1. 
The C1D1 physical examination, ECOG performance status, and laboratory tests may be omitted 
if the screening values were obtained within 72 hours prior to initiation of treatment. 
8.2.1. 
Active Treatment Stage 
For patients enrolled to a neratinib containing cohort, neratinib will be self-administered by 
patients daily. For study cohorts where neratinib will be administered in combination with 
another therapy, combination treatment will consist of neratinib plus trastuzumab, and neratinib 
plus fulvestrant plus trastuzumab at dose regimens and cycle lengths described in Section 5, and 
in accordance with the Schedule of Procedures provided in (Appendix 1 Table A1.1 and Table 
A1.2).  
In the study cohorts where single agent fulvestrant or fulvestrant plus trastuzumab will be 
administered at dose regimens and cycle lengths described in Section 5, and in accordance with 
the Schedule of Procedures provided in (Appendix 1 Table A1.1 and Table A1.2). 
The following will be performed in accordance with the Schedule of Procedures provided in 
(Appendix 1 Table A1.1 and Table A1.2): 
• Physical examination. Refer to Section 7.2.3. 
• Vital signs and weight. Refer to Section 7.2.2. 
• Laboratory tests. Refer to Section 7.2.1. 
• ECOG performance status. Refer to Section 7.1.4.  
• Radiographic tumor assessment. Refer to Section 7.1.1. 
• Plasma sample for exploratory biomarker analyses. Refer to Section 7.2.6. 
• Treatment compliance assessment. Refer to Section 7.4. 
• Review compliance with loperamide antidiarrheal therapy. Refer to Section 6.1. 
• AE assessment. Refer to Section 12.  


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• Concomitant medication assessment. Refer to Section 6.  
• Dispense and collect IP. Refer to Section 5.4. 
• ECG. Refer to Section 7.2.4.  
• ECHO or MUGA (to obtain LVEF). Refer to Section 7.2.5.  
• Health Outcomes Assessment. Refer to Section 7.1.3.  
8.2.2. 
End of Treatment Visit for All Cohorts 
After the end of treatment (EOT), the following assessments should be scheduled 28 days 
(+14 days) after the last dose of IP(s), in accordance with the Schedule of Procedures in (see 
Table A1.1 and Table A1.2). If the patient is unable or unwilling to undergo any assessment, the 
last assessment on record will be used as end of treatment assessment. 
• Physical examination. Refer to Section 7.2.3. 
• Vital signs, including weight. Refer to Section 7.2.2.  
• ECG. Refer to Section 7.2.4. ECHO or MUGA (obtain LVEF). Refer to 
Section 7.2.5.  
• Laboratory tests (hematology, chemistry). Refer to Section 7.2.1.  
• Plasma sample for exploratory biomarker analyses. Refer to Section 7.2.6. 
• Radiographic tumor and response assessment should be collected for patients 
discontinuing treatment for any reason other than radiological disease progression. 
Refer to Section 7.1.1. 
• AE assessment. Refer to Section 12.  
• Concomitant medication assessment. Refer to Section 6. 
• Treatment compliance assessment. Refer to Section 5.4. 
• Optional tumor biopsy. Refer to Section 7.2.6 . 
Patients will enter the Follow-up Stage after these EOT assessments.  
8.3. 
Long-term Follow-up for All Cohorts 
After the end of treatment, patients who do not withdraw consent will enter the long-term 
Follow-up Stage. 
These patients will be followed for PFS and survival status during the long-term follow-up 
phase. The following will be performed in accordance with the Schedule of Procedures 
(Appendix 1 Table A1.1 and Table A1.2): 
• Continue to monitor AEs until the 28th day after the last dose of IP(s).  
• Anti-cancer medications taken since last contact. 


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• For patients who discontinued treatment for any reason other than disease 
progression, collect radiographic tumor and response assessments until documented 
disease progression, death or withdraw of consent. Refer to Section 7.1.1.  
• After disease progression, follow patients via clinic visits, email or phone calls every 
12 weeks (±14 days) after each patient’s last dose of treatment. Patients who received 
trastuzumab will continue cardiac monitoring with ECHO or MUGA scanning every 
6 months up to 24 months after the last dose of trastuzumab. 
• If a patient withdraws from the follow-up portion of the study, the primary reason for 
discontinuation should be documented (see Section 9.3).  
8.4. 
End of Study 
The EOS will occur when all patients have been followed for OS or death, withdrawal of 
consent, or are lost to follow-up. The Sponsor reserves the right to terminate the study early for 
any reason and offer patients receiving treatment benefit the option to continue to receive 
neratinib via a separate treatment extension study or an expanded access protocol. 


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9. 
PATIENT WITHDRAWAL AND REPLACEMENT 
9.1. 
Investigational Product Discontinuation 
Patients must be discontinued from the investigational products (but may remain in the study 
for long term follow up, if appropriate), under the following circumstances listed in this section 
and in Section 5.2, unless otherwise agreed with the Medical Monitor: 
• If the patient requires more than 2 dose reductions of IP (see Section 5.2). 
• If the IP is withheld due to a neratinib-related AE 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 progression. Patients who, in the opinion of the Investigator, are continuing 
to benefit from neratinib despite disease progression may continue to receive 
neratinib if approved in advance by the Sponsor. Patients who are initially enrolled to 
a non-neratinib containing arm may remain on study and receive neratinib, fulvestrant 
and trastuzumab at the time that the local investigator determines the patient has 
unequivocal evidence of disease progression as documented by imaging, clinical 
examination, or disease related symptoms before the first scan post-treatment.  
• Pregnancy (see Section 12.4).  
• Investigator request. 
• Patient request (ie, withdrawal of consent for treatment). 
Withdrawal due to AE should be distinguished from withdrawal due to other causes and recorded 
on the appropriate AE case report form (CRF) page.  
In the case of the following events, the patient should discontinue treatment, but should be asked 
to remain on study for response assessment as well as PFS if the event leading to discontinuation 
of treatment occurs prior to the first post-baseline tumor assessment, or for response assessment, 
PFS, and OS if the event occurs after the first tumor evaluation:  
• Adverse events/toxicity  
• Symptomatic deterioration  
• Major protocol violation  
• Patient request  
• Investigator request (reasoning required) 
9.2. 
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. 


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• At the patient’s request (withdrawal of consent for the study). See Section 9.3 for 
withdrawal procedures. 
• Individual patient dosing noncompliance. 
• Lost to follow-up (defined as receiving no response 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 10.  
A patient may also be withdrawn from investigational product/study by the Sponsor, 
Regulatory Authorities, or Independent Ethics Committees (IECs)/Institutional Review Boards 
(IRBs).  
9.3. 
Procedures for Investigational Product Discontinuation/Study Withdrawal 
When a patient is withdrawn from the study, the Investigator will notify the Sponsor promptly. 
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 IP or the study for any 
reason, the Investigator must make every effort to perform the evaluations described for the EOT 
visit (performed 28 days [+14 days] after the last dose of study drug, as appropriate), and 
Follow-Up Visits as described in (Appendix 1 Table A1.1 and Table A1.2). If a patient 
discontinues due to an AE, he/she should be strongly encouraged to undergo the EOT assessment 
and continue to be under medical supervision until symptoms/signs cease or the condition 
becomes stable. 
If a patient withdraws consent but agrees to undergo a final examination, this will be documented 
on the Investigator’s copy of the ICF, which will be countersigned and dated by the patient. If a 
patient withdraws consent due to an AE, the reason for discontinuation should be identified as 
‘Due to AE.’ 
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 withdraw consent.  
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 9.1), or at Investigator discretion. Upon confirmed disease progression, or 
discontinuation of IP for any other reason, all further treatment for the patient’s cancer will be at 
the Investigator’s discretion, and all patients will remain in follow-up for PFS and survival, 
unless consent has been withdrawn. 


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10. 
PREMATURE TERMINATION OF THE STUDY  
The Sponsor may suspend or terminate the study or any part of the study at any time for any 
reason. The IP will be available to patients who continue to receive clinical benefit following the 
EOS as described in Section 8.4. 
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 of the IP, IP containers, and other study materials to the Sponsor or have them 
destroyed 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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11. 
STATISTICAL METHODS 
The statistical considerations summarized in this section outline the plan for data analysis of this 
study. The Statistical Analysis Plan (SAP) will provide additional detail.  
11.1. 
Sample Size Justification 
11.1.1. 
Sample Size Justification for the Randomized HR+ and with Prior CDK4/6i 
Breast Cancer Study Cohort: 
A Simon’s 2-stage optimal design (Simon, 1989) will be used to determine whether there is 
sufficient activity to warrant further development of the therapy and to minimize the number of 
patients exposed to therapy if ineffective. For each treatment arm, using Simon’s 2-stage optimal 
design (with significance level 10% and power of 80%), an ORR (confirmed) of 10% or less per 
RECIST by independent assessment will be considered unacceptable (null hypothesis) whereas an 
ORR (confirmed) of 30% per RECIST v1.1 by independent assessment will merit further study 
(alternative hypothesis). In the first stage, 7 patients are enrolled in each treatment arm. If at least 
1 response is observed in the first stage, the second stage in the treatment arm will be opened. In 
the second stage, 11 additional response evaluable patients will be accrued and randomized for a 
total of 18 patients in the treatment arm. The null hypothesis will be rejected (for each arm 
separately) if at least 4 responses are observed in Stage 2 for each arm. 
Once the Simon’s 2-stage criteria are met, enrollment of the neratinib arm may continue until up 
to 50 patients have been enrolled. A sample size of 50 patients provide a 95% CI of (17.9%, 
44.6%) when the ORR is 30%. 
11.1.2. 
Sample Size Justification for All Other Cohorts: 
A Simon’s 2-stage optimal design (Simon, 1989) will be used to determine whether neratinib 
monotherapy has sufficient activity to warrant further development in the following cohorts: 
cervical, salivary gland, and EGFR exon 18 mutant non-small cell lung cancers. A similar 
Simon’s 2-stage design will be used to determine whether neratinib combination therapy has 
sufficient activity to warrant further development in the following cohorts: HR+ and CDK4/6i 
naïve and TNBC. Early study termination will be permitted if data at the first stage indicate that 
the treatment is ineffective. For each cohort, using Simon’s optimal 2-stage design (with 
significance level 10% and power of 80%), an ORRfirst of 10% or less will be considered 
unacceptable (null hypothesis) whereas an ORRfirst of 30% will merit further study (alternative 
hypothesis). In the first stage, enrollment will continue until 7 patients received at least one dose 
of study treatment and completed the first tumor assessment by the investigator (response 
evaluable). If no responses are observed, the second stage for the cohort must be discontinued. 
Otherwise 11 additional response evaluable patients will be accrued for a total of 18 patients in the 
cohort. The null hypothesis will be rejected (for each cohort separately) if at least 4 responses are 
observed in Stage 2 for each cohort.  
Once the Simon’s 2-stage criteria are met, enrollment to the salivary gland and EGFR exon 18 
mutant NSCLC cohorts may continue until  up to 30 patients and the enrollment into the 
cervical, HR+ and CDK4/6i naïve, and TNBC cohorts may continue until up to 50 patients. A 
sample size of 50 patients provide a 95% CI of (17.9%, 44.6%) when the ORRfirst is 30%. A new 


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cohort may also be opened separately at any time per Sponsor discretion and follow the Simon’s 
2-stage criteria. Cohorts may close prior to planned enrollment. 
11.2. 
Statistical Analyses 
In general, efficacy and safety analyses in this study are meant to be cohort-specific and will be 
summarized by monotherapy and combination therapy separately. Safety analyses will also be 
summarized across all cohorts where appropriate.  
11.2.1. 
Populations for Analysis 
For the purpose of patient disposition, the intent-to-treat (ITT) population is defined as all 
patients who are enrolled into the study.  
The primary analysis population is defined as all patients who received at least 1 dose of study 
treatment. This population will be used for all efficacy and safety analyses, if not otherwise 
specified. 
11.2.2. 
Primary Endpoint 
The primary endpoint for the randomized hormone receptor positive (HR+), HER2 negative 
metastatic breast cancer and metastatic cervical cancer cohorts is the confirmed objective 
response rate (ORR) by independent central review according to Response Evaluation Criteria in 
Solid Tumors (RECIST) v1.1. For all other cohorts, the primary endpoint is the first objective 
response rate (ORRfirst) by investigator at the first post-baseline tumor assessment. The 
confirmed ORR and the ORRfirst will be estimated and the associated 2-sided 95% Clopper-
Pearson confidence intervals will be determined. The ORR is defined as the proportion of 
patients who achieve CR or PR, per RECIST version 1.1 and confirmed by repeat tumor 
assessment using the same criteria performed no less than 4 weeks after the initial response. The 
ORRfirst is defined as the proportion of patients who achieve CR or PR, per RECIST version 1.1 
or other defined response criteria, as their best overall response at the first tumor assessment. 
11.2.3. 
Secondary Endpoints 
For the randomized HR+, HER2 negative metastatic breast cancer and metastatic cervical cancer 
cohorts: 
• Confirmed ORR, per RECIST version 1.1, by investigator  
• Duration of response (DOR), per RECIST version 1.1, by both independent central 
review and investigator 
• Clinical benefit rate (CBR), per RECIST version 1.1, by both independent central review 
and investigator 
• Progression-free survival (PFS), per RECIST version 1.1, by both independent central 
review and investigator 
• For the metastatic cervical cancer cohort only, overall survival (OS)  
For all other cohorts: 
• Confirmed ORR, per RECIST version 1.1 or other defined response criteria, by 
investigator 


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• DOR, per RECIST version 1.1 or other defined response criteria, by investigator 
• CBR, per RECIST version 1.1 or other defined response criteria, by investigator 
• PFS, per RECIST version 1.1 or other defined response criteria, by investigator 
• OS 
For all cohorts: 
• Safety and tolerability of study treatments 
• Patient Reported Outcomes (PRO) 
For either independent central review or investigator’s assessment, the ORR is defined as the 
proportion of patients who achieve CR or PR as their best overall response. Complete or partial 
responses must be confirmed by repeat tumor assessment using same criteria performed no less 
than 4 weeks after the response are initially met. The confirmed ORR will be estimated and its 
associated 2-sided 95% Clopper-Pearson confidence intervals will be determined. 
The DOR is defined as the time response criteria were met until progression or death. Median 
DOR will be estimated via Kaplan-Meier with its associated 2-sided 95% confidence intervals. 
The clinical benefit rate (CBR) is defined as CR+PR +SD ≥16 weeks (≥24 weeks for the breast 
cancer patients). The CBR will be estimated, and its associated 2-sided 95% Clopper-Pearson 
confidence intervals will be determined.  
The PFS is defined as the interval from C1D1 until the first date on which recurrence, 
progression, or death due to any cause, is documented, censored at the last assessable evaluation 
or the last evaluation before the initiation of new anticancer therapy, if applicable. Median PFS 
will be estimated via Kaplan-Meier with its associated 2-sided 95% confidence intervals.  
Patient reported outcomes will be evaluated using the FACT-G questionnaire. The assessments 
will be summarized and plotted over time. Changes from baseline will be provided with both 
point estimates and confidence intervals. 
11.2.4. 
Exploratory Endpoints 
Archival tumor tissue will be collected from all patients for centralized ERBB mutation profiling 
using next generation sequencing and/or other molecular techniques. Pre-, on-, and post-
treatment plasma-derived cfDNA will also be collected for exploratory biomarker analysis. 
Optional biopsies (all cohorts except for all breast cancer patients and NSCLC patients where a 
fresh pretreatment tumor biopsy is mandatory) will be collected following disease progression 
and treatment discontinuation. The tissue may be subject to next-generation sequencing, gene 
expression profiling, immunohistochemistry and other assays to identify potential resistance 
mechanisms to neratinib treatment. 
No formal statistical analysis is planned for these exploratory objectives. 
11.2.5. 
Adverse Events, Serious Adverse Events, and Deaths 
All AEs and SAEs will be reported until 28 days after the last dose of IP(s) and will be followed 
until resolution or until the condition stabilizes. AEs and SAEs will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) version 16 or later and tabulated by system 
organ class (SOC) and preferred term. All AEs will be graded by the Investigator according to 


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the NCI CTCAE version 4.0. All tabulations will be sorted by descending frequency of SOC and 
preferred term in the total column unless otherwise noted. 
Cause of death and the time of death (dichotomized as within 28 days of last dose versus more 
than 28 days after last dose) will be summarized via frequencies and percentages. Patient death 
listings will include all death data available including the date of death, cause of death, and any 
AEs resulting in death.  
11.2.6. 
Laboratory Results 
Laboratory test results will be collected pretreatment (baseline) and until 28 days (+14 days) 
after the last dose of study treatment. Standard reference ranges will be used for missing or 
discrepant normal ranges. 
Laboratory data will be summarized in tables using descriptive statistics for baseline and each 
cycle/visit. Descriptive statistics will be calculated on both the actual score and the change from 
baseline score. Additionally, clinically significant abnormalities in laboratory results will be 
summarized for the post-baseline cycles/visits using frequencies and percentages. Shifts in 
normal/abnormal status between baseline and subsequent visits will be summarized as well. 


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12. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
All observed or volunteered AEs regardless of treatment group or causal relationship to the IPs 
will be recorded on the AE page(s) of the CRF. 
12.1. 
Definitions 
12.1.1. 
Adverse Events 
An AE is any untoward medical occurrence that occurs 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 IP, 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 12.1.3) 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 an AE. 
TEAEs are those events that occur or worsen on or after first dose of IP and up to 28 days after 
the last dose of IP.  
12.1.2. 
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 as 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. 
12.1.3. 
Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose (ICH E2A and E6 R1): 
• 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.  
12.1.4. 
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 pretreatment 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 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. 
12.1.5. 
Suspected Unexpected Serious Adverse Reaction 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are events which are serious as per 
the above criteria (see Section 12.1.3 Serious Adverse Events), the nature or severity of which is 
not consistent with the applicable product information (Neratinib IB) and are judged by the 
Investigator or by the Sponsor to be related to the IP.  
12.1.6. 
Severity Assessment 
AEs will be graded by the Investigator according to the NCI CTCAE version 4.0 (Publication 
Date: 14-Jun-2010, https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf), 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.  
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. 


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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 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. 
12.1.7. 
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 IP 
caused the AE. An Investigator’s causality assessment is the determination of whether there 
exists a reasonable possibility that the IP 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 IP caused the event, then the event will be handled as “related 
to investigational product” for reporting purposes, as defined by the Sponsor (see Section 12.2 
and Section 12.3). 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, IP or other illness). The relationship of the AE to the study treatment (IP 
or other concomitant medications) will be assessed following the definitions below: 
• ‘No’ (unrelated): Any event that does not follow a reasonable temporal sequence 
from administration of the IP 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 the IP AND follows a known response pattern to the suspected IP 
AND recurs with re-challenge, AND/OR is improved by stopping the IP 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. 
12.1.8. 
Special Reporting Situations 
Safety events of interest due to the Sponsor’s IP that may require expedited reporting and/or 
safety evaluation include, but are not limited to: 
• Overdose of the IP. 
• Suspected abuse/misuse of the IP. 
• Inadvertent or accidental exposure to the IP. 


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• 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 the IP 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 related as 
required (see Section 12.3). 
12.2. 
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 signs the  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 IP, through 28 calendar days after the last administration of the IP.  
For all AEs with causal relationship to the IP, 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 the IP, 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. 
12.3. 
Reporting Serious Adverse Events 
All SAEs, irrespective of relationship to the IP, 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.  
Should an Investigator be made aware of any SAEs occurring any time after the reporting period 
that may be causally related to the administration of neratinib, 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. 


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• The event can be attributed to agents other than the IP 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). 
12.4. 
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 IPs 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 IP, or the female becomes or is 
found to be pregnant after discontinuing and/or being directly exposed to the IP 
(maternal exposure) within 28 days after last dose of or exposure to study drug. 
See Section 9.1 for action to be taken with IP. 
• A male partner of a pregnant female has been exposed to the IP, 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 IP or exposure as defined above, the Investigator must submit 
this information on an EIU form to the Sponsor (or its designated representative) promptly. In 
addition, the Investigator must submit information regarding environmental exposure to an IP 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 an 
induced 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 
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. 


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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 neonatal death as related to 
exposure to IP. 
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. 
12.5. 
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 IEC/IRB that approved the protocol unless otherwise 
required and documented by the IEC/IRB. 


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13. 
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. 
13.1. 
Data Collection, Processing, and Monitoring 
13.1.1. 
Case Report Forms and Source Documentation 
All data captured for the study is planned to be electronic. However, if necessary, data captured 
may be performed using paper Case Report Forms (CRFs). The Investigator agrees to enter into 
the electronic data capture (EDC) system all data associated with a patient’s study-related visit 
within 5 working days of that visit. 
CRFs 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 CRFs which have been 
designed to record all observations and other data pertinent to the clinical investigation. Each 
CRF should be filled out completely by the Investigator or delegate as stated in the Site 
Delegation List.  
If paper CRFs are used, then all CRFs should be completed in a neat legible manner to ensure 
accurate interpretation of the data; a black ball-point pen should be used to ensure the clarity of 
reproduced copies of all CRFs. Incorrect entries should be crossed with a single line. Corrections 
must be made adjacent to the item to be altered, initialed and dated with the reason for the 
correction if necessary, by an authorized (Investigator/study team designee) person. Overwriting 
of this information or use of liquid correcting fluid is not allowed. 
The data should be reviewed, signed and dated by the Investigator for accuracy and 
completeness. Once the site monitor has verified the contents of the completed CRF 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  
within 5 days of receipt. After all the data issues are resolved, these CRFs may be locked to 
prevent any further data changes. 
13.1.2. 
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 FDA, the European Medicines Agency 
(EMA), other national authorities, eg, the United Kingdom Medicines and Healthcare products 
Regulatory Agency (MHRA), the German Federal Institute for Drugs and Medical Devices 
(BfArM), and local health authorities, the Sponsor and representatives, and the IRB/EC 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 
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Source data to be reviewed during this study will include, but is not restricted to patient’s 
medical file, patient’s diary (if applicable), and original laboratory test, histology, and pathology 
reports. All key data must be recorded in the patient’s hospital notes. 
Auditors, IEC/IRB 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 IEC/IRB 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. 
13.1.3. 
Data Quality Assurance 
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 (21CFR50, 54, 56, 
and 312), European Union (EU) Clinical Studies Directive (Directive 2001/20/EC), and 
applicable regional regulatory requirements. 
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 Sponsor representative to ensure that any problems 
detected in the course of these inspection visits, including delays in completing CRFs, are 
resolved. 
13.1.4. 
Data Processing 
All data will be entered by site personnel into the electronic data capture system/CRF (as 
detailed in Section 13.1.1).  
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 (WHO Drug), which employs the Anatomical Therapeutic Chemical (ATC) 
classification system. Medical history and AEs will be coded using the MedDRA terminology. 
The versions of the coding dictionaries will be provided in the Clinical Study Report. 
13.1.5. 
Retention of Data and Study Records 
As described in the ICH GCP Guidelines, ‘essential documents’, including CRFs, source 
documents, ICFs, laboratory test results, and drug inventory records, should be retained by the 
Investigator until at least 2 years after the last approval of a marketing application in an ICH 
region and until there are no pending or contemplated marketing applications in an ICH region or 


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at least 2 years have elapsed since the formal discontinuation of clinical development of the IP. 
These documents should be retained for a longer period, however, if required by the applicable 
regulatory requirements or by an 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. 
13.2. 
Ethical Aspects 
13.2.1. 
Good Clinical Practice and Ethical Conduct of the Study 
This protocol accords with the principles of the Declaration of Helsinki as set forth at the 18th 
World Medicines Association (Declaration of Helsinki, 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. 
13.2.2. 
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, 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 the 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 IEC/IRB 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 (US only) or Data Protection Consent (Europe only) prior to 
any study-related procedures or change in treatment.  
If a patient is not physically or mentally competent to understand and to give their informed 
consent to participate in the study (eg, is blind or illiterate), a legally acceptable representative or 


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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 
IEC/IRB and signed by all patients subsequently enrolled in the study as well as those currently 
enrolled in the study. 
13.3. 
Other Study Administration Aspects 
13.3.1. 
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. 
13.3.2. 
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 patients within the agreed recruitment period. 
The Investigator will maintain a list of appropriately qualified persons to whom the Investigator 
has delegated significant study-related tasks. An up-to-date copy of the curriculum vitae for the 
Investigator and sub-Investigator(s) will be provided to the Sponsor (or its representative) before 
starting the study. 
If the patient has a primary physician, the Investigator should, with the patient’s consent, inform 
the primary physician of the patient’s participation in the study. 
Agreement with the final clinical study report will be documented by the signed and dated 
signature of the principal or coordinating Investigator in compliance with ICH E3. 


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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 stages 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 all written materials provided to the study patients to the 
IRB/IEC for review; these must be approved before the study is initiated or use. 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 appraised of the progress of the study 
and of any changes made to the protocol as deemed appropriate, and at least once per year. The 
Investigator must also keep the IRB/IEC informed of any serious and significant AEs. 
13.3.3. 
Patient Confidentiality 
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 (US sites only) or Data Protection Consent (European sites only) is to be 
obtained from each patient prior to enrollment into the study, and/or from the patient 's legally 
authorized representative in accordance with the applicable privacy requirements [eg, the Health 
Insurance Portability and Accountability Act of 1996 Standards for Privacy of Individually 
Identifiable Health Information (“HIPAA”), European Union Data Protection Directive 
95/46/EC (“EU Directive”) and any other state and country privacy requirements]. If the patient 
is under the legal age of consent, the Authorization (US sites only) or Data Protection form 


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(European sites only) must be signed by the legally authorized representative in accordance with 
the applicable privacy requirements and other state and country privacy requirements. 
13.3.4. 
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. 
13.3.5. 
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 
proprietary information and commercial interests. 
In all publications, the study is to be identified as PUMA-NER-5201. 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. 
SIGNATURE PAGES 


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Declaration of Sponsor or Responsible Medical Officer 
Title: An Open-Label, Phase 2 Basket Study of Neratinib in Patients With Solid Tumors With 
Somatic Activating HER Mutations  
Study Number: PUMA-NER-5201 
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. 
__
___________________ 
_____________________ 
Name 
Date 
 
__
________________________________ 
Title 
 
10-Feb-2021 | 12:43 PST


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Declaration of Principal Investigator 
Title: An Open-Label, Phase 2 Basket Study of Neratinib in Patients With Solid Tumors With 
Somatic Activating HER Mutations  
Study Number: PUMA-NER-5201 
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 
Date 
 
_____________________________________ 
______________________________ 
Title 
Institution (block letters) 
 
 
_____________________________________ 
______________________________ 
Address 
Phone number 


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16. 
APPENDICES  


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APPENDIX 1 
SCHEDULE OF PROCEDURES  
 


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Table A1.1. 
Schedule of Study Procedures for Cohorts Receiving Trastuzumab Combination Therapy 
Event 
Screening 
Treatment 
Follow-upb 
Visit 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
EOTa 
Study Week 
 
 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
W13 
Cycle Day 
Within 28 
days of C1D1 
Within 14 
days of C1D1 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
D15 
D1 
D8 
D15 
 D1 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, cancer, and medication historyc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd/vital signsd 
 
X 
Xe 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Electrocardiogram 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
ECHO/MUGAf 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
X 
 
Urine testg/ Pregnancy testg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyh / Serum chemistry panelh 
 
X 
Xi 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
Plasma collection for cfDNA biomarker 
analysisj  
 
Xj 
 
 
 
 
 
 
 
 
 
Xj 
 
 
 
Xj 
 
Whole blood sample for germline DNAk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG status 
 
X 
Xe 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Neratinibl 
 
 
X 
 
 
Trastuzumabl 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
Fulvestrantl 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Tumor evaluationm 
Xm 
 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
Xm 
Xm 
MD/RN Phone calln 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
Mandatory fresh pretreatment tumor 
biopsy for all breast cancer patients  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Archival and/or fresh pretreatment 
metastatic tumor tissue sample for all 
patients 
Xp 
 
 
 
 
 
 
 
 
 
 
 
 
Optional on-treatment or end-of-
treatment fresh core tumor biopsyq 
 
 
 
 
 
 
 
 
 
 
Xq 
 
 
 
 
Xq 
 
Loperamide antidiarrheal treatmentr 
 
 
Administered orally daily  
Administered orally as needed (not to exceed 16 mg per day)  
 
 
Patient Diarys 
 
 
X 
 
Concomitant therapy 
Collected continuously throughout study period 
 
Adverse eventst 
Collected continuously throughout study period 
 
Patient Reported Outcomesu 
Xu 
 
Xu 
 
 
Xu 
 
 
Xu 
 
 
Xu 
 
 
Xu 
Xu 
 


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Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; C1D1 = Cycle 1 Day 1; cfDNA = cell-fee DNA; CT = computerized 
tomography; D = Day; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FFPE = formalin-fixed paraffin embedded; Hb = hemoglobin;  Hct = hematocrit; 
ICF = informed consent form; IP = Investigational Product; LDH = lactate dehydrogenase; MD = medical doctor; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition scan; PD = progressive 
disease; PET = positron emission tomography;  RECIST = Response Evaluation Criteria in Solid Tumors; RBC = red blood cells; RN = registered nurse; W = week; WBC = white blood cell  
a. EOT follow-up assessments will be conducted 28 days (+14 days) after the last administration of IP(s). AEs must be followed for 28 days after the last administration of IP(s). 
b. Follow-up visits will occur every 3 cycles (9 weeks ±7 days) for patients discontinuing treatment for any reason other than disease progression until objective disease progression is reported per RECIST v 1.1 (or 
other response criteria). After disease progression, all patients will be followed every 12 weeks for survival and anti-cancer medication taken will be recorded.  
c. Collect chronic medical condition and medical history of significance (including smoking history only for lung cancer patients), or symptoms experienced during the previous 30 days and those ongoing at the time 
of screening, and any medical conditions that require medication. Identify start of current medical conditions by at least providing the year of onset.  
d. Physical examination may be delegated and performed by a properly trained nurse practitioner, physician’s assistant, or equivalent. Full physical examination at screening, C1D1, and thereafter should be a 
detailed/brief (system-guided) physical examination to evaluate any clinically significant abnormalities; including worsening of medical history conditions.  Vital signs include pulse, blood pressure, temperature 
(in Celsius) and respiration rate taken before dosing. Also includes height (screening only) and weight.  
e. Physical examination / ECOG status does not need to be repeated if performed within 72 hours prior to C1D1.  
f. Patients treated with neratinib in combination with trastuzumab will have ECHO/MUGAs performed at baseline, at the beginning of Week 13, every 4 cycles (12 weeks ± 7 days) thereafter, at EOT, and every 6 
months up to 24 months after the last dose of trastuzumb.  
g. Laboratory urinalysis or by urine dipstick (blood, protein, glucose, and microscopic examination, if abnormal).  Urine or serum pregnancy test only for women of child-bearing potential (at screening, and to be 
repeated only if performed outside 72 hours of C1D1).  
h. Hematology panel: Hct, Hb, platelet count, RBC count, and WBC count with differential. Serum chemistry: albumin, alkaline phosphatase, ALT, AST, BUN, calcium, chloride, serum creatinine, glucose (non-
fasting), LDH, magnesium, phosphorous, potassium, serum cholesterol (non-fasting), total bilirubin, total protein, and sodium. Following C1, laboratory tests may take place ± 2 days before Day 1. 
i. Laboratory assessments are not required on C1D1 if previously obtained within 72 hours prior to C1D1 as part of screening, with no clinically significant findings.  
j. Plasma collection for cfDNA biomarker analysis at screening (if collected on C1D1, it has to be done prior to the first IP dose), at the beginning of Week 10 (ORRfirst), and every 3 cycles (9 weeks ± 7 days) 
thereafter, and during the EOT visit. 
k. Whole blood sample for research (single collection) obtained during study, preferably during screening or within the first cycle of therapy. 
l. Neratinib, trastuzumab, and fulvestrant administration performed as described in Section 5.1. Following C1, fulvestrant administration may take place ± 2 days.  
m. Tumor assessment at screening should occur within 4 weeks of C1D1, as appropriate. Post-treatment disease assessment by CT or PET/CT scan or MRI of the chest, abdomen and pelvis, as appropriate, will be 
conducted at the beginning of Week 10 (ORRfirst), every 3 cycles (9 weeks ± 7 days) thereafter until 1 year and annually (once per year). Following one year  on therapy, scans may move to every  4 cycles for 
trastuzumab-containing regimens. Following two years on therapy, scans may move to every 5 cycles for trastuzumab-containing regimens. The scans must be obtained and reviewed prior to start of the next 
cycle. CT or PET/CT or MRI should be done only at EOT if not done within the previous 4 weeks, or if required to confirm an objective response.  Overall response will be scored by independent assessment and 
by the Investigator per RECIST v1.1 using the algorithms defined in the protocol. Tumor assessments should be continued every 3 cycles (9 weeks ± 7 days) for any patients ending therapy for any reason other 
than radiological PD. Patients with a history of brain metastases or those symptomatic for brain metastases will have a brain CT or MRI at baseline. For patients who enrolled prior to Amendment 6, the same 
method of measurement (eg PET/CT) and same method of disease assessment (eg metabolic response by PET Response Criteria) should continue through final assessments.  
n. Phone call to patient 1 day, 2 days, and 3 days after the first dose of neratinib (C1D1) to check on diarrhea symptoms and patient compliance with anti-diarrheal therapy.  
o. AEs, SAEs, and clinically significant abnormal laboratory results should be followed for 28 days after the last dose of IP(s); this information may be collected at the EOT visit or via phone call.  Follow patients via 
phone call every 12 weeks (±14 days) after disease progression to monitor survival.  
p. Archival tissue sample obtained during screening or within the first cycle of therapy.  In cases where a patient is enrolled based on a documented HER mutation derived from a cfDNA specimen (ie, liquid biopsy), 
a mandatory archival FFPE or fresh-tumor biopsy should be submitted for retrospective central confirmation of the mutation.  
q. Optional fresh core tumor biopsy from all patients upon progression of disease.  
r. Loperamide antidiarrheal treatment should be dispensed with the initial supply of neratinib. All patients taking neratinib will maintain a patient diary for the study to record each dose of neratinib taken and while 
receiving antidiarrheal prophylaxis with loperamide taken for the first two cycles of treatment. 
s. Patient Diary will be provided by the Investigator for the patient to record daily study medication intake for every cycle, and frequency and management of diarrhea in the first 2 cycles.  


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t. Symptoms should be assessed from signing of ICF and during any protocol visit that includes a physical examination. AEs should be followed for 28 days after last administration of IP(s). 
u. 
FACT-G will be performed at Screening, C1D1 and at the beginning of each cycle for up to 6 months or EOT, whichever comes first.   
 


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Table A1.2. 
Schedule of Study Procedures for Cohorts Not Receiving Trastuzumab 
Event 
Screening 
Treatment 
Follow-upb 
Visit 
 
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
EOTa 
Study Week 
 
 
W1 
W2 
W3 
W4 
W5 
W6 
W7 
W8 
W9 
W10 
W11 
W12 
W13 
Cycle Day 
Within 28 
days of C1D1 
Within 14 
days of C1D1 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
D8 
D15 
D22 
D1 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical, cancer, and medication historyc 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examinationd/vital signsd 
 
X 
Xe 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Electrocardiogramf 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Xf 
X 
 
ECHO/MUGA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Urine testg/ Pregnancy testg 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hematologyh / Serum chemistry panelh 
 
X 
Xi 
 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
Plasma collection for cfDNA biomarker 
analysisj 
 
Xj 
 
 
 
 
 
 
 
 
Xj 
 
 
 
 
Xj 
 
Whole blood sample for germline DNAk 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ECOG status 
 
X 
Xe 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Neratinibl 
 
 
X 
 
 
Fulvestrantl 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
 
X 
 
 
Tumor evaluationm 
Xm 
 
 
 
 
 
 
 
 
 
Xm 
 
 
 
 
Xm 
Xm 
MD/RN Phone calln 
 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xo 
Mandatory fresh pretreatment tumor 
biopsy for all breast cancer and NSCLC 
patients 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Most recent metastatic tumor tissue 
sample for all patients 
Xp 
 
 
 
 
 
 
 
 
 
 
 
Optional on-treatment or end-of-
treatment fresh core tumor biopsyq 
 
 
 
 
 
 
 
 
 
 
Xq 
 
 
 
 
Xq 
 
Loperamide antidiarrheal treatmentr 
 
 
Administered orally daily 
Administered orally as needed (not to 
exceed 16 mg per day) 
 
 
Patient Diarys 
 
 
X 
 
 
Concomitant therapy 
Collected continuously throughout study period 
 
Adverse eventst 
Collected continuously throughout study period 
 
Patient Reported Outcomesu 
Xu 
 
Xu 
 
 
 
Xu 
 
 
 
Xu 
 
 
 
Xu 
Xu 
 
Abbreviations: AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BUN = blood urea nitrogen; C1D1 = Cycle 1 Day 1; cfDNA = cell-fee DNA; CT = computerized 
tomography; D = Day; ECHO = echocardiogram; ECOG = Eastern Cooperative Oncology Group; EOT = end of treatment; FFPE = formalin-fixed paraffin embedded; Hb = hemoglobin;  Hct = hematocrit; 


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ICF = informed consent form; IP = Investigational Product; LDH = lactate dehydrogenase; MD = medical doctor; MRI = magnetic resonance imaging; MUGA = multiple-gated acquisition scan; 
NSCLC = non-small cell lung cancer; PD = progressive disease; PET = positron emission tomography; RECIST = Response Evaluation Criteria in Solid Tumors; RBC = red blood cells; RN = registered nurse; 
W = week; WBC = white blood cell  
a. End of treatment (EOT) follow-up assessments will be conducted 28 days (+14 days) after last administration of IP(s). AEs must be followed for 28 days after last administration of IP(s).  
b. Follow-up visits will occur every 2 cycles (8 weeks ± 7 days) for patients discontinuing treatment for any reason other than disease progression until objective disease progression is reported per RECIST v 1.1 (or 
other response criteria). After disease progression, all patients will be followed every 12 weeks for survival and anticancer medication taken will be collected. 
c. Collect chronic medical condition and medical history of significance (including smoking history only for lung cancer patients), or symptoms experienced during the previous 30 days and those ongoing at the time 
of screening, and any medical conditions that require medication. Identify start of current medical conditions by at least providing the year of onset.  
d. Physical examination may be delegated and performed by a properly trained nurse practitioner, physician’s assistant, or equivalent. Full physical examination at screening, C1D1 and thereafter should be a 
detailed/brief (system-guided) physical examination to evaluate any clinically significant abnormalities; including worsening of medical history conditions.  Vital signs include pulse, blood pressure, temperature 
(in Celsius) and respiration rate taken before dosing. Also includes height (screening only) and weight.  
e. Physical examination / ECOG status does not need to be repeated if performed within 72 hours prior to C1D1.  
f. All neratinib monotherapy cohorts will have ECGs performed at baseline and at end of treatment only.  
g. Laboratory urinalysis or by urine dipstick (blood, protein, glucose, and microscopic examination, if abnormal).  Urine or serum pregnancy test only for women of child-bearing potential (at screening, and to be 
repeated only if performed outside 72 hours of C1D1).  
h. Hematology panel: Hct, Hb, platelet count, RBC count, and WBC count with differential.  Serum chemistry: albumin, alkaline phosphatase, ALT, AST, BUN, calcium, chloride, serum creatinine, glucose (non-
fasting), LDH, magnesium, phosphorous, potassium, serum cholesterol (non-fasting), total bilirubin, total protein, and sodium. Following C1, laboratory tests may take place ± 2 days before Day 1. 
i. Laboratory assessments are not required on C1D1 if previously obtained within 72 hours prior to C1D1 as part of screening, with no clinically significant findings.  
j. Plasma collection for cfDNA biomarker analysis at screening (if collected on C1D1, it has to be done prior to the first IP dose), at the beginning of Week 9 (ORRfirst), and every 2 cycles (8 weeks ± 7 days) 
thereafter, and during the EOT visit.  
k. Whole blood sample for research (single collection) obtained during study, preferably during screening or within the first cycle of therapy.  
l. Neratinib and fulvestrant administration performed as described in Section 5.1. 
m. Tumor assessment at screening should occur within 4 weeks of C1D1, as appropriate. Post-treatment disease assessment by CT or PET/CT scan or MRI of the chest, abdomen and pelvis, as appropriate, will be 
conducted at the beginning of Week 9 (ORRfirst), and every 2 cycles (8 weeks ± 7 days) until 1 year, and annually (once per year). Following one year  on therapy, scans may move to every 3 cycles for non-
trastuzumab containing regimens. Following two years  on therapy, scans may move to every 4 cycles for non-trastuzumab containing regimens. The scans must be obtained and reviewed prior to start of the next 
cycle. CT or PET/CT or MRI should be done only at EOT if not done within the previous 4 weeks, or if required to confirm an objective response. Overall response will be scored by independent assessment and 
by the Investigator according to RECIST v1.1 using the algorithms defined in the protocol.  Tumor assessments should be continued every 2 cycles (8 weeks ± 7 days) for any patients ending therapy for any reason 
other than radiological PD. For patients who enrolled prior to Amendment 6, the same method of measurement (eg PET/CT) and same method of disease assessment (eg metabolic response by PET Response 
Criteria) should continue through final assessments. 
n. Phone call to patient 1 day, 2 days, and 3 days after the first dose of neratinib (C1D1) to check on diarrhea symptoms and patient compliance with anti-diarrheal therapy.  
o. AEs, SAEs, and clinically significant abnormal laboratory results should be followed for 28 days after the last dose of IP(s); this information may be collected at the EOT visit or via phone call. Follow patients via 
phone call every 12 weeks (±14 days) after disease progression to monitor survival.  
p. Archival tissue sample obtained during screening or within the first cycle of therapy.  In cases where a patient is enrolled based on a documented HER mutation derived from a cfDNA specimen (ie, liquid biopsy), 
a mandatory archival FFPE or fresh-tumor biopsy should be submitted for retrospective central confirmation of the mutation.  
q. Optional fresh core tumor biopsy from all patients upon progression of disease.  
r. Loperamide antidiarrheal treatment should be dispensed with the initial supply of neratinib. All patients taking neratinib will maintain a patient diary for the study to record each dose of neratinib taken and while 
receiving antidiarrheal prophylaxis with loperamide taken for the first two cycles of treatment. 
s. Patient Diary will be provided by the Investigator for the patient to record daily study medication intake for every cycle, and frequency and management of diarrhea in the first 2 cycles.  
t. Symptoms should be assessed from signing of ICF and during any protocol visit that includes a physical examination. AEs should be followed for 28 days after last administration of IP(s).  
u. FACT-G will be performed at Screening, C1D1 and at the beginning of each cycle for up to 6 months or EOT, whichever comes first.  


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


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APPENDIX 3 
INHIBITORS AND INDUCERS OF THE CYTOCHROME 
P450 ISOENZYMES 
CYP3A4 Inducers 
Carbamazepine 
Macrolide Antibiotics 
Rifabutin 
Efavirenz 
Phenobarbital 
Rifampin 
Glucocorticoids 
Phenylbutazone 
Rifapentine 
       Dexamethasone 
Phenytoin 
Sulfinpyrazone 
       Prednisone 
Primidone 
 
CYP3A4 Inhibitors 
Amprenavir 
 Grapefruit Juice 
 Propranolol 
Anastrozole 
 Indinavir 
 Quinine 
Cimetidine 
 Itraconazole 
 Quinidine 
Clarithromycin 
 Ketoconazole 
 Ranitidine 
Clotrimazole 
 Mibefradil 
 Ritonavir 
Danazol 
 Miconazole 
 Saquinavir 
Delavirdine 
 Mirtazapine (weak) 
 Sertraline 
Diethyldithiocarbamate 
 Nefazodone 
 Sildenafil (weak) 
Diltiazem 
 Nelfinavir 
 Troglitazone 
Erythromycin 
 Nevirapine 
 Troleandomycin 
Fluconazole 
 Norfloxacin 
 Zafirlukast 
Fluoxetine 
 Norfluoxetine 
 
Fluvoxamine 
 Paroxetine 
 
CYP3A5-7 Inducers 
Phenobarbital 
Primidone 
Rifampin 
Phenytoin 
 
 
CYP3A5-7 Inhibitors 
Clotrimazole 
Metronidazole 
Troleandomycin 
Ketoconazole 
Miconazole 
 
 
 
 


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APPENDIX 3. 
INHIBITORS AND INDUCERS OF THE CYTOCHROME P460 
ISOENZYMES (CONTINUED) 
CYP2D6 Substrate 
Carvedilol 
 Maprotiline 
Selegiline 
Chloroquine (possible) 
 Methamphetamine 
Sertraline 
Chlorpromazine 
 Metoprolol 
Sparteine 
Citalopram 
 Mexiletine (major) 
Tamoxifen 
Clozapine 
 Mirtazapine 
Thioridazine 
Codeine 
 Morphine 
Timolol 
Cyclobenzaprine 
 Olanzapine 
Tolterodine (major) 
Debrisoquin 
 Ondansetron 
Tramadol 
Delavirdine 
 Oxaminiquine 
Trazodone 
Dexfenfluramine 
 Oxycodone 
TCAs (hydroxylation) 
Dextromethorphan 
 Paroxetine 
       Amitriptyline 
Dolasetron 
 Penbutolol 
       Clomipramine 
Donepezil 
 Pentazocine 
       Desipramine 
Encainide 
 Perphenazine 
       Doxepin 
Flecainide 
 Phenformin 
       Imipramine 
Fluoxetine 
 Primaquine (possible) 
       Nortriptyline 
Fluphenazine 
 Propafenone 
Trimipramine 
Halofantrine 
 Propoxyphene 
Venlafaxine 
Haloperidol 
 Propranolol (minor) 
Ziprasidone 
Hydrocodone 
 Risperidone 
Zolpidem 
Hydroxyamphetamine 
 Ritonavir 
 
Labetalol 
 Ropivacaine 
 
Source: Tatro DS, Drug Interaction Facts: The Authority on Drug Interactions. Wolters Kluwer Health, 2012.  


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APPENDIX 4 
SUBSTRATES AND INHIBITORS OF P-
GLYCOPROTEIN (P-GP) 
P-glycoprotein Substrates 
Amiodarone (eg, Cordarone) 
Fluphenazine (eg, Prolixin) 
Progesterone (eg, Prometrium) 
Chlorpromazine (eg, Thorazine) 
Hydrocortisone (eg, Cortef) 
Promethazine (eg, Phenergan) 
Clarithromycin (eg, Biaxin) 
Indinavir (Crixivan 
Quinidine 
Cyclosporine (eg, Neoral) 
Itraconazole (eg, Sporanox) 
Reserpine 
Dactinomycin (Cosmegen) 
Ketoconazole (eg, Nizoral) 
Ritonavir (Norvir) 
Daunorubicin (eg, Cerubidine) 
Lidocaine (eg, Xylocaine) 
Saquinavir (eg, Fortovase) 
Dexamethasone (eg, Decadron) 
Loperamide (eg, Imodium) 
Sirolimus (Rapamune) 
Digoxin (eg, Lanoxin) 
Lovastatin (eg, Mevacor) 
Tacrolimus (Prograf) 
Diltiazem (eg, Cardizem) 
Mifepristone (Mifeprex) 
Tamoxifen (eg, Nolvadex) 
Doxorubicin (eg, Adriamycin) 
Mitoxantrone (Novantrone) 
Teniposide (Vumon) 
Erythromycin (eg, Ery-Tab) 
Nelfinavir (Viracept) 
Testosterone Delatestryl) 
Estradiol (eg, Estrace) 
Nicardapine (eg, Cardene) 
Trifluoperazine 
Etoposide (eg, Vepesid) 
Nifedipine (eg, Procardia) 
Verapamil (eg, Calan) 
Felodipine (Plendil) 
Ondansetron (Zofran) 
Vinblastine (eg, Velban) 
Fexofenadine (Allegra) 
Paclitaxel (eg, Taxol) 
Vincristine (eg, Vincasar PFS) 
P-glycoprotein Inhibitors 
Amiodarone (eg, Cordarone) 
Indinavir (Crixivan) 
Quinidine 
Atorvastatin (Lipitor) 
Itraconazole (eg, Sporanox) 
Reserpine 
Chlorpromazine (eg, Thorazine) 
Ketoconazole (eg, Nizoral) 
Ritonavir (Norvir) 
Clarithromycin (eg, Biaxin) 
Lidocaine (eg, Xylocaine) 
Saquinavir (eg, Fortovase) 
Cyclosporine (eg, Neoral) 
Mifepristone (Mifeprex) 
Tacrolimus (Prograf) 
Diltiazem (eg, Cardizem) 
Nelfinavir (Viracept) 
Tamoxifen (eg, Nolvadex) 
Erythromycin (eg, Ery-Tab) 
Nicardipine (eg, Cardene) 
Testosterone (Delatestryl) 
Felodipine (Plendil) 
Nifedipine (eg, Procardia) 
Trifluoperazine 
Fluphenazine (eg, Prolixin) 
Progesterone (eg, Prometrium) 
Verapamil (eg, Calan) 
Hydrocortisone (eg, Cortef) 
Propranolol (eg, Inderal) 
 
Source: Tatro DS, Drug Interaction Facts: The Authority on Drug Interactions. Wolters Kluwer Health, 2012.  
 
 


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APPENDIX 5 
DRUGS ASSOCIATED WITH RISK OF QT/QTC 
PROLONGATION LEADING TO TORSADE DE 
POINTES 
Drugs Reported to Prolong QT Interval 
Analgesics 
Celecoxib (Celebrex) 
Methadone (eg, Dolophine, Methadose) 
Anesthetic agents 
Enflurane (eg, Ethrane) 
Halothane 
Isoflurane (eg, Forane) 
 
Antiarrhythmic agents 
Class IA 
Class III 
Disopyramide (eg, Norpace)* 
Amiodarone (eg, Cordarone)*b 
Procainamide (eg, Procanbid)* 
Bretylium* 
Quinidine* 
Dofetilide (Tikosyn)*b 
Class IC 
Ibutilide (Corvert)*b 
Flecainide (eg, Tambocor)*a 
Sotalol (eg, Betapace)*b 
Propafenone (eg, Rythmol)*b 
 
Anticonvulsants 
Felbamate (Felbatol)* 
Fosphenytoin (Cerebyx) 
Antiemetics 
Dolasetron (Anzemet)b 
Droperidol (eg, Inapsine)*b 
Ondansetron (Zofran) 
Antihistamines 
Desloratadine (Clarinex)b (overdose) 
Fexofenadine (Allegra) 
Diphenhydramine (eg, Benadryl) 
Hydroxyzine (Atarax) 
Anti-infectives 
Amantadine (eg, Symmetrel)* 
Macrolides and related antibiotics 
Antimalarials 
Azithromycin (eg, Zithromax) 
Mefloquine (eg, Lariam)b 
Clarithromycin (eg, Biaxin)*b 
Quinine* 
Erythromycin (eg, Ery-Tab, EES)*b 
Antivirals 
Telithromycin (Ketek)b 
Efavirenz (Sustiva)* 
Troleandomycin 
Azole antifungal agents 
Pentamidine (eg, Pentam 300, Nebupent)* 
Fluconazole (eg, Diflucan)*b 
Quinolones 
Itraconazole (eg, Sporanox) 
Gatifloxacin (eg, Tequin)*b 
Ketoconazole (eg, Nizoral) 
Levofloxacin (eg, Levaquin)*a, b 
Voriconazole (Vfend)b 
Moxifloxacin (eg, Avelox)b 
Chloroquine (eg, Aralen)* 
Ofloxacin (eg, Floxin)*b 
Clindamycin (eg, Cleocin) 
Sparfloxacin (Zagam)b 
Foscarnet (Foscavir) 
Trimethoprim/sulfamethoxazole (eg, Bactrim)* 
Antineoplastics 
Arsenic trioxide (Trixenox)*b 
Doxorubicin (eg, Adriamycin) 
Tamoxifen (eg, Nolvadex) 
Bronchodilators 
Albuterol (eg, Proventil)b 
Salmeterol (Serevent)b 
Formoterol (Foradil)b 
Terbutaline (eg, Brethine)b 
Isoproterenol (eg, Isuprel) 
 


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Drugs Reported to Prolong QT Interval 
Calcium channel blockers 
Isradipine (DynaCirc) 
Nicardipine (eg, Cardene) 
Contrast media 
Ionic contrast media* 
Non-ionic contrast media: Iohexol (Omnipaque) 
Corticosteroids 
Prednisolone (eg, Prelone) 
Prednisone (eg, Deltasone)* 
Diuretics 
Furosemide (eg, Lasix) 
Indapamide (eg, Lozol) 
Gastrointestinal agents 
Cisapride (Propulsid)*b  
Famotidine (eg, Pepcid)* 
Immunosuppressants 
Tacrolimus (Protopic)*b (postmarketing) 
Miscellaneous 
Levomethadyl 
Papaverine (eg, Pavaden three times daily [TID])* 
Moexipril/Hydrochlorothiazide (Uniretic) 
Probucol (Lorelco)* 
Octreotide (Sandostatin)b 
Vasopressin (eg, Pitressin)* 
Oxytocin (eg, Pitocin; IV bolus) 
 
Psychotropics 
Droperidol (eg, Inapsine)* 
Primozide (Orap)*b  
Trazodone (eg, Desyrel) 
Haloperidol (eg, Haldol)* 
Quetiapine (Seroquel)b 
Tricyclic antidepressants 
Lithium (eg, Eskalith)* 
Risperidone (Risperdal)b (overdose) 
Amitriptyline* 
Maprotiline* 
Serotonin Reuptake Inhibitors 
(SRIs) 
Clomipramine 
(eg, Anafranil) 
Phenothiazines 
Citalopram (eg, Celexa)* 
Desipramine 
(eg, Norpramin)* 
Chlorpromazine 
(eg, Thorazine)* 
Fluoxetine (eg, Prozac)*a 
Doxepin (eg, Sinequan)* 
Fluphenazine 
(eg, Prolixin)* 
Paroxetine  
(eg, Paxil)* 
Imipramine (eg, Tofranil)* 
Perphenazine 
Sertraline (Zoloft)*a, b 
(postmarketing) 
Nortriptyline 
(eg, Pamelor) 
Thioridazine (Mellaril)*b 
Venlafaxine (Effexor)b 
(postmarketing) 
 
Trifluopherazine 
 
Serotonin 5-HT1 agonists 
Naratriptan (Amerge) 
Sumatriptan (Imitrex)b 
Zolmitriptan (Zomig)b 
Skeletal muscle relaxants 
Tizanidine (eg, Zanaflex)b (animals) 
*  Drugs for which Torsades de Pointes has also been reported. 
a  Association unclear 
b  QT, QTc and/or Torsades de Pointes association listed in FDA approved product labeling 
Source: Tatro DS, Drug Interaction Facts: The Authority on Drug Interactions. Wolters Kluwer Health, 2012.  
 
 


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APPENDIX 6 
RECIST V1.1 CRITERIA 
Patient Eligibility 
Only patients with measurable disease at baseline should be included in this study. Changes in 
only the largest diameter (unidimensional measurement) of the tumor lesions are used in the 
RECIST v1.1 criterion.  
Note: Lesions are either measurable or nonmeasurable using the criteria provided below. The 
term “evaluable” in reference to measurability provides neither additional meaning nor accuracy 
and will not be used. 
Measurable Disease 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in the 
plane of measurement is to be recorded) with a minimum size of: 
• 10 mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10 mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 20 mm by chest X-ray. 
Nonmeasurable Disease 
• Small lesions (longest diameter <10 mm or pathological lymph nodes with ≥10 to 
<15 mm short axis).  
• Truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial 
effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
Target Lesions 
When more than one measurable lesion is present at baseline all lesions up to a maximum of five 
lesions total (and a maximum of two lesions per organ) representative of all involved organs 
should be identified as target lesions and will be recorded and measured at baseline (this means 
in instances where patients have only one or two organ sites involved a maximum of two and 
four lesions respectively will be recorded). Target lesions should be selected on the basis of their 
size (lesions with the longest diameter), be representative of all involved organs, but in addition 
should be those that lend themselves to reproducible repeated measurements. It may be the case 
that, on occasion, the largest lesion does not lend itself to reproducible measurement in which 
circumstance the next largest lesion which can be measured reproducibly should be selected. 
Lymph nodes merit special mention since they are normal anatomical structures which may be 
visible by imaging even if not involved by tumor. Pathological nodes which are defined as 
measurable and may be identified as target lesions must meet the criterion of a short axis of 
≥15 mm by CT scan. Only the short axis of these nodes will contribute to the baseline sum. The 
short axis of the node is the diameter normally used by radiologists to judge if a node is involved 
by solid tumor. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained (for CT scan this is almost always the axial plane; for MRI the plane of 
acquisition may be axial, sagittal or coronal). The smaller of these measures is the short axis. For 


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example, an abdominal node which is reported as being 20 mm x 30 mm has a short axis of 
20 mm and qualifies as a malignant, measurable node. In this example, 20 mm should be 
recorded as the node measurement. All other pathological nodes (those with short axis ≥10 mm 
but <15 mm) should be considered nontarget lesions. Nodes that have a short axis <10 mm are 
considered non-pathological and should not be recorded or followed. A sum of the diameters 
(longest for non-nodal lesions, short axis for nodal lesions) for all target lesions will be 
calculated and reported as the baseline sum diameters. If lymph nodes are to be included in the 
sum, then as noted above, only the short axis is added into the sum. The baseline sum diameters 
will be used as reference to further characterize any objective tumor regression in the measurable 
dimension of the disease. 
Nontarget Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
nontarget lesions and should also be recorded at baseline. Measurements are not required, and 
these lesions should be followed as ‘present’, ‘absent’, or in rare cases ‘unequivocal progression’ 
(more details to follow). In addition, it is possible to record multiple nontarget lesions involving 
the same organ as a single item on the case record form (eg, ‘multiple enlarged pelvic lymph 
nodes’ or ‘multiple liver metastases’). 
Guidelines for Evaluation of Measurable Disease 
All measurements should be recorded in metric notation, using calipers if clinically assessed. All 
baseline evaluations should be performed as close as possible to the treatment start and never 
more than 28 days before the beginning of the treatment. 
Method of assessment 
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up. Imaging based evaluation should 
always be done rather than clinical examination unless the lesion(s) being followed cannot be 
imaged but are assessable by clinical exam. 
Clinical lesions: Clinical lesions will only be considered measurable when they are superficial 
and ≥10 mm diameter as assessed using calipers (eg, skin nodules). For the case of skin lesions, 
documentation by color photography including a ruler to estimate the size of the lesion is 
suggested. As noted above, when lesions can be evaluated by both clinical exam and imaging, 
imaging evaluation should be undertaken since it is more objective and may also be reviewed at 
the end of the study. 
Chest X-ray: Chest CT is preferred over chest X-ray, particularly when progression is an 
important endpoint, since CT is more sensitive than X-ray, particularly in identifying new 
lesions. However, lesions on chest X-ray may be considered measurable if they are clearly 
defined and surrounded by aerated lung.  
CT, MRI: CT is the best currently available and reproducible method to measure lesions selected 
for response assessment. This guideline has defined measurability of lesions on CT scan based 
on the assumption that CT slice thickness is 5 mm or less. When CT scans have slice thickness 
greater than 5 mm, the minimum size for a measurable lesion should be twice the slice thickness. 
MRI is also acceptable in certain situations (eg, for body scans).  


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Ultrasound: Ultrasound is not useful in assessment of lesion size and should not be used as a 
method of measurement. Ultrasound examinations cannot be reproduced in their entirety for 
independent review at a later date and, because they are operator dependent, it cannot be 
guaranteed that the same technique and measurements will be taken from one assessment to the 
next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT or 
MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of 
CT in selected instances. 
Endoscopy, laparoscopy: The utilization of these techniques for objective tumor evaluation is not 
advised. However, they can be useful to confirm complete pathological response when biopsies 
are obtained or to determine relapse in studies where recurrence following CR or surgical 
resection is an endpoint. 
Tumor markers: Tumor markers alone cannot be used to assess objective tumor response. If 
markers are initially above the upper normal limit, however, they must normalize for a patient to 
be considered in CR. Because tumor markers are disease specific, instructions for their 
measurement should be incorporated into protocols on a disease specific basis.  In addition, the 
Gynecologic Cancer Intergroup has developed CA125 progression criteria which are to be 
integrated with objective tumor assessment for use in first-line studies in ovarian cancer. 
Cytology, histology: These techniques can be used to differentiate between PR and CR in rare 
cases if required by protocol (for example, residual lesions in tumor types such as germ cell 
tumors, where known residual benign tumors can remain). When effusions are known to be a 
potential adverse effect of treatment (eg, with certain taxane compounds or angiogenesis 
inhibitors), the cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment can be considered if the measurable tumor has met criteria for response 
or SD in order to differentiate between response (or SD) and PD. 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine objective tumor response 
for target lesions. 
Complete Response (CR): Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or nontarget) must have reduction in short axis to <10 mm. 
Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the baseline sum if that is the 
smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: the appearance of one or more new lesions is also 
considered progression). 
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on study.  
Evaluation of nontarget lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of nontarget lesions. 


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While some nontarget lesions may actually be measurable, they need not be measured and 
instead should be assessed only qualitatively at the time points specified in the protocol. 
Complete Response (CR): Disappearance of all nontarget lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD (stable disease): Persistence of one or more nontarget lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
Progressive Disease (PD): Unequivocal progression of existing nontarget lesions. (Note: the 
appearance of one or more new lesions is also considered progression).  
Table A6.1. 
Evaluation Criteria  
Target Lesions 
Nontarget Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR: complete response; NE: not evaluated; PD: progressive disease; PR: partial response; SD: stable 
disease. 
Note: Patients with a global deterioration of health status requiring discontinuation of the IP 
(defined as neratinib monotherapy or neratinib combination per indication) without objective 
evidence of disease progression at that time should be classified as having “symptomatic 
deterioration.” Every effort should be made to document the objective progression, even after 
discontinuation of the IP. In some circumstances, it may be difficult to distinguish residual 
disease from normal tissue. When the evaluation of CR depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the CR status. 
Confirmatory Measurement/Duration of Response 
Confirmation 
In nonrandomized studies where response is the primary endpoint, confirmation of PR and CR is 
required to ensure responses identified are not the result of measurement error. This will also 
permit appropriate interpretation of results in the context of historical data where response has 
traditionally required confirmation in such studies. However, in all other circumstances, ie, in 
randomized studies (phase 2 or 3) or studies where SD or progression are the primary endpoints, 
confirmation of response is not required since it will not add value to the interpretation of study 
results. However, elimination of the requirement for response confirmation may increase the 
importance of central review to protect against bias, in particular in studies which are not 


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blinded. In the case of SD, measurements must have met the SD criteria at least once after study 
entry at a minimum interval (not less than 6 weeks) that is defined in the study protocol. 
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for 
CR/PR (whichever is first recorded) until the first date that recurrent or PD is objectively 
documented (taking as reference for PD the smallest measurements recorded on study). The 
duration of overall CR is measured from the time measurement criteria are first met for CR until 
the first date that recurrent disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomized studies, from date of 
randomization) until the criteria for progression are met, taking as reference the smallest sum on 
study (if the baseline sum is the smallest, this is the reference for calculation of PD). The clinical 
relevance of the duration of SD varies in different studies and diseases. If the proportion of 
patients achieving SD for a minimum period of time is an endpoint of importance in a particular 
study, the protocol should specify the minimal time interval required between two measurements 
for determination of SD. Note: The DOR and SD as well as the PFS are influenced by the 
frequency of follow-up after baseline evaluation. It is not in the scope of this guideline to define 
a standard follow-up frequency. The frequency should take into account many parameters 
including disease types and stages, treatment periodicity and standard practice. However, these 
limitations of the precision of the measured endpoint should be taken into account if comparisons 
between studies are to be made.  
Optimal duration of treatment with hormone therapy 
Treatment should be administered until there is unequivocal evidence of disease progression as 
documented by imaging, clinical examination, or disease-related symptoms. Tumor markers or 
circulating tumor cells should not be used as the sole criteria for determining progression.  
Assessment of progression may be challenging because of the combination of difficulty in 
interpreting imaging and the indolent nature of HR+ disease in some patients. Treatment should 
focus on patient outcomes and symptoms. Tumor flare reactions (increase in tumor-related 
symptoms) can occur, particularly with tamoxifen and estradiol; were observed shortly after 
beginning a new endocrine treatment; and can be confused with disease progression. Treatment-
related toxicity may be a reason to change therapy Patient outcomes were not improved by 
changing therapy based solely on tumor markers or circulating tumor cells.  
Sources: Boellaard, et al, 2010; Brucher et al, 2001; Costelloe et al 2009; Costelloe, et al; 2010; Dose Schwarz et al, 
2005; Gayed et al, 2004; Hawkins et al 2009; Hellwig et al, 2004; Mac Manus et al, 2003; Rugo, et al; 2016; 
Shankar, et al; 2006; Smith et al, 2000; Stroobants et al, 2003; Swisher et al, 2004; Van den Abbeele et al, 2008; 
Wahl, et al; 2009; Weber et al, 2006; Wieder et al, 2004; Young, et al; 1999 


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APPENDIX 7 
SPECIFIC GUIDANCE ON EGFR AND ERBB2 
MUTATIONS  
In the context of this study, the word mutation refers to an alteration of somatic, tumor-
associated genomic DNA sequence that alters the protein coding region in a nonconserved 
manner, and may range from single base point mutations to larger regions of inserted, repeated 
or deleted genomic DNA sequence. 
A list of known activating or potentially activating somatic mutations in ERBB2 is provided in 
Table A7.1 and in EGFR exon 18 in Table A.7.2. The mutations in this list have been 
characterized in the scientific literature (PubMed) and/or identified in two or more cases as 
detailed in publicly available databases (COSMIC, cBioPortal for Cancer Genomics). 
In cases where a patient is enrolled based on a documented ERBB mutation derived from a 
cfDNA specimen (ie, liquid biopsy), a mandatory archival FFPE or fresh-tumor biopsy should be 
submitted for retrospective central confirmation of the mutation. 
Table A7.1. 
Eligible ERBB2 Mutations 
1 Letter Amino Acid 
Nomenclature 
3 Letter Amino Acid 
Nomenclature 
Other Common Nomenclature 
G309A
Gly309Ala
G309E
Gly309Glu
S310F
Ser310Phe
S310Y
Ser310Tyr
S653C
Ser635Cys
V659E
Val659Glu
G660D
Gly660Asp
V697L
Val697Leu
T733I
Thr733Ile
L755S
Leu755Ser
L755P
Leu755Pro
L755_T759del
Leu755_Thr759del
∆LRENT 
I767M
Ile767Met
D769Y
Asp769Tyr
D769H
Asp769His
D769N
Asp769Asn
Y772_A775dup
Tyr772_Ala755dup
A775_G776insYVMA
G776C
Gly776Cys
G776V
Gly776Val
G776VinsC/VGC/other
Gly776insCys/other
Other exon 20 insertions 
V777L
Val777Leu
G778_P780dup
Gly778_Pro780dup
P780_Y781insGSP
L841V
Leu841Val
V842I
Val842Ile
L869R
Leu869Arg
L866M
Leu869Met
H878Y
His878Tyr
R896C
Arg896Cys


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Table A7.2. 
Eligible EGFR exon 18 Mutations 
EGFR exon 18 
E709X 
E709 indel 
G719X 
G719 indel 
 


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APPENDIX 8 
PATIENT-REPORTED HEALTH OUTCOMES 
ASSESSMENT (FACT-G): 
 


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SAP_001.pdf: 
 
 Oﬃcial Title  
AN OPEN-LABEL, PHASE 2 BASKET STUDY OF NERATINIB IN 
PATIENTS WITH SOLID TUMORS WITH SOMATIC ACTIVATING 
HER MUTATIONS  
 
NCT Number 
NCT01953926 
 
Date  
13-DEC-2022  
 
 
 
 


 
This document contains confidential information of Puma Biotechnology, Inc. This document must not be disclosed to 
anyone other than the study staff and members of the Independent Ethics Committee/ Institutional Review Board. The 
information in this document cannot be used for any purpose other than the evaluation or conduct of the clinical 
investigation without the prior written consent of Puma Biotechnology Inc.  
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
AN OPEN-LABEL, PHASE 2 BASKET STUDY OF NERATINIB IN 
PATIENTS WITH SOLID TUMORS WITH SOMATIC ACTIVATING 
HER MUTATIONS  
 
Study Protocol No. 
PUMA-NER-5201 
Disease Condition 
Solid tumors harboring somatic activating HER mutations 
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 
V1.0 
13-DEC-2022 
 
 
 
 
 


Statistical Analysis Plan 
 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................4 
1. 
PURPOSE OF THE ANALYSIS .................................................................................6 
2. 
PROTOCOL SUMMARY ............................................................................................7 
2.1. 
Study Objectives ...........................................................................................................7 
2.2. 
Overall Study Design and Plan .....................................................................................8 
2.2.1. 
Study Design .................................................................................................................8 
2.2.2. 
Investigational Product, Dose, and Administration: ...................................................14 
3. 
SAMPLE SIZE DETERMINATION .........................................................................15 
3.1. 
Sample Size Justification for the Randomized HR+ Breast Cancer Study 
Cohort: ........................................................................................................................15 
3.2. 
Sample Size Justification for All Other Cohorts: .......................................................15 
4. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ..............................17 
4.1. 
Date Imputations .........................................................................................................17 
4.1.1. 
Missing/Partial Dates in Adverse Events ...................................................................17 
4.1.2. 
Missing/Partial Dates in Concomitant Therapies .......................................................18 
4.1.3. 
Missing/Partial Dates in Subsequent Therapies .........................................................18 
5. 
ANALYSIS POPULATIONS ....................................................................................20 
6. 
STUDY PATIENTS ...................................................................................................21 
6.1. 
Disposition of Patients ................................................................................................21 
6.2. 
Protocol Deviations ....................................................................................................21 
7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .....................22 
7.1. 
Demographic and baseline characteristics ..................................................................22 
7.2. 
Medical History ..........................................................................................................23 
7.3. 
Prior and Concomitant Medications ...........................................................................23 
8. 
MEASUREMENTS OF TREATMENT COMPLIANCE .........................................24 
9. 
EFFICACY EVALUATION ......................................................................................25 
9.1. 
Definitions of Efficacy Endpoints ..............................................................................26 
9.1.1. 
Objective Response Rate at the First Tumor Assessment (ORRfirst) ..........................26 
9.1.2. 
Overall Response Rate (ORR) ....................................................................................26 
9.1.3. 
Clinical Benefit Rate (CBR) .......................................................................................26 
9.1.4. 
Progression-Free Survival (PFS) ................................................................................26 


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9.1.5. 
Duration of Response (DOR) .....................................................................................28 
9.2. 
Analysis Methods .......................................................................................................28 
9.3. 
Examination of Subgroups .........................................................................................29 
10. 
SAFETY EVALUATION ..........................................................................................30 
10.1. 
Overview of Safety Analysis Methods .......................................................................30 
10.2. 
Extent of Exposure .....................................................................................................30 
10.3. 
Adverse Events, Serious Adverse Events, and Deaths ...............................................30 
10.4. 
Clinical Laboratory Evaluation ...................................................................................31 
10.5. 
Hepatotoxicity .............................................................................................................32 
10.6. 
Vital Signs, Physical Findings, and Other Observations Related to Safety ...............32 
10.6.1. 
Vital Signs ..................................................................................................................32 
10.6.2. 
Physical Examinations ................................................................................................33 
10.6.3. 
Left Ventricular Ejection Fraction (LVEF) ................................................................34 
11. 
OTHER ASSESSMENTS ..........................................................................................35 
11.1. 
ECOG Performance Status .........................................................................................35 
11.2. 
Patient Reported Outcomes: FACT-G ........................................................................35 
12. 
INTERIM ANALYSES AND DATA MONITORING .............................................37 
13. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .....................38 
13.1. 
Overall Survival ..........................................................................................................38 
13.2. 
Database Lock ............................................................................................................38 
14. 
REFERENCES ...........................................................................................................39 
 
LIST OF TABLES 
Table 1:  Two-sided Clopper-Pearson 95% CI for ORR ...............................................................15 
Table 2:  Efficacy Variables and Analysis Methods ......................................................................25 
Table 3:  Handling of Missing Response Assessment and Censoring for Progression-Free 
Survival Primary Analysis ..........................................................................................27 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ATC 
Anatomical Therapeutic Chemical [Classification System] 
CB 
clinical benefit 
CBR 
clinical benefit rate 
CR 
complete response 
CRF 
case report form 
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
duration of response 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
ECG 
electrocardiogram 
ERBB2 
human epidermal growth factor receptor 2 
EOS 
end of study 
EOT 
end of treatment 
GLP 
good laboratory practice 
HER2 
human epidermal growth factor receptor 2 
HER3 
human epidermal growth factor receptor 3 
IDMC 
independent data monitoring committee 
ITT 
intent to treat 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
mPERCIST 
modified PERCIST 
MUGA 
multiple-gated acquisition scan 
ORR 
overall objective response rate 
ORRfirst 
objective response rate at the first tumor assessment 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PR 
partial response 


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Abbreviation 
Definition 
PT 
preferred term 
PERCIST 
PERCIST 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
WHODrug 
World Health Organization Drug Reference List 


Statistical Analysis Plan 
 
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1. 
PURPOSE OF THE ANALYSIS 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of the strategy and 
statistical methodology to be used for analysis of data for the 5201 study.  This study is sponsored by 
Puma Biotechnology, Inc. The purpose of the SAP is to ensure the credibility of the study findings by pre-
specifying the statistical approaches to the analysis of study data prior to database lock.  This analysis 
plan is meant to supplement the study protocol.  Any deviations from this plan will be described in the 
Clinical Study Report (CSR). 


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2. 
PROTOCOL SUMMARY 
2.1. 
Study Objectives 
 
The objectives of this study, applicable to each cohort, are: 
For the randomized hormone receptor positive (HR+), HER2 negative metastatic breast 
cancer: 
Primary: 
• To determine the confirmed objective response rate (ORR) by independent central 
review according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 
Secondary: 
• To determine the confirmed ORR by investigator 
• To determine the duration of response (DOR) by both independent central review and 
investigator 
• To determine the clinical benefit rate (CBR) by both independent central review and 
investigator 
• To determine the progression-free survival (PFS) by both independent central review 
and investigator 
For the metastatic cervical cancer cohort: 
Primary: 
• To determine the confirmed ORR by independent central review according to RECIST 
v1.1 
Secondary: 
• To determine the confirmed ORR by investigator 
• To determine the DOR by both independent central review and investigator 
• To determine the CBR by both independent central review and investigator 
• To determine the PFS by both independent central review and investigator 
• To determine overall survival (OS) 
For all other cohorts: 
Primary: 
• To determine the first objective response rate (ORRfirst) by investigator at the first post-
baseline tumor assessment 
Secondary: 
• To determine the confirmed ORR by investigator 


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• To determine the DOR by investigator 
• To determine the CBR by investigator 
• To determine the PFS by investigator 
• To determine OS 
Safety Objectives: 
For all cohorts, including the randomized HR+, HER2 negative metastatic breast cancer and 
metastatic cervical cancer cohorts: 
• To assess the safety profile and tolerability of study treatments 
• To assess Patient Reported Outcomes (PRO) 
Exploratory Objectives: 
• To collect and retrospectively evaluate somatic mutations or gene aberrations using 
next-generation sequencing (NGS) in the most recent pretreatment tumor biopsy or 
fresh tumor tissue biopsies at a central laboratory. 
• To explore genetic modifiers of sensitivity and/or resistance to neratinib using molecular 
profiling techniques in pretreatment archival and/or fresh tumor specimens and paired 
normal whole blood. 
• To evaluate cell-free DNA (cfDNA) from plasma specimens collected at 
baseline/screening, during the course of treatment, and upon disease progression to 
identify HER mutations and other gene aberrations and to assess any potential 
associations with neratinib sensitivity and/or primary/acquired resistance to 
neratinib or neratinib-containing therapy. 
• To evaluate potential genes or protein biomarkers that may be reported to confer 
neratinib sensitivity and/or primary/acquired resistance to neratinib or neratinib-
containing therapy from optional fresh core tumor biopsies during time of treatment 
and/or at the time of treatment discontinuation or disease progression. 
2.2. 
Overall Study Design and Plan 
2.2.1. 
Study Design 
 
This is an open-label, multicenter, multinational, Phase 2 study exploring the efficacy and safety 
of neratinib as monotherapy or in combination with other therapies in patients with HER (EGFR, 
HER2) mutation-positive solid tumors. Patients with tumors harboring somatic mutations in 
HER will be identified through previously documented mutation testing performed prior to 
screening. The presence of human HER mutations (EGFR, HER2) will be retrospectively 


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confirmed by central testing via next generation sequencing (NGS). The study has a basket 
design and includes several cohorts, either defined by an actionable somatic mutation or by 
actionable mutation and tumor histology (for example HER2 mutant cervical cancer). In the 
course of the study, enrollment in certain cohorts can be completed and enrollment in new 
cohorts initiated to test the anticancer effect of neratinib in other histologies, specific 
molecular abnormalities, and/or in combination with other drugs. 
Patients with HER2 mutant, HER2 negative breast cancer will be divided into different 
treatment cohorts on the basis of HR status: HR negative (Triple Negative Breast Cancer [TNBC]) 
and HR+. 
• Patients in the HR negative cohort (TNBC) will receive neratinib in combination with 
trastuzumab. 
• Patients in the HR+, HER2 negative, HER2 mutant positive cohort with RECIST 
measurable tumors and who have been previously been treated with CDK4/6 inhibitors 
(CDK4/6i) will be randomized to receive single agent fulvestrant, fulvestrant in 
combination with trastuzumab, or neratinib in combination with trastuzumab and 
fulvestrant with a randomization ratio of 1:1:1. Randomization will be stratified by the 
number of lines of prior therapy for metastatic disease (≤ 2 and >2 lines) and by prior 
fulvestrant therapy.  
The randomized HR-positive (HR +), HER2 negative, HER2 mutant metastatic breast 
cancer cohort is designed to investigate the individual contribution of neratinib and/or 
trastuzumab to fulvestrant via Simon’s 2 stage optimal design. The decision to carry over 
on enrollment of each arm in the cohort will be based on stage I and II analysis of 
Simon’s 2 stage in consultation with the Independent Data Monitoring Committee 
(IDMC). 
o Patients in the HR+ cohort who receive single agent fulvestrant or fulvestrant 
plus trastuzumab will be eligible for triplet therapy (neratinib, fulvestrant, 
trastuzumab) upon progression. Efficacy will be determined based on response 
to initial regimen only. 
• Patients in the HR+ cohort who have not received prior CDK4/6i therapy (e.g. CDK4/6i 
naive) will receive neratinib in combination with trastuzumab and fulvestrant as part of 
an open label cohort. 
The trial will consist of a screening period, a treatment period, and a follow-up period after the 
study therapy is discontinued for any reason. An end of treatment (EOT) assessment is 


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performed 28 days (+14 days) after the last dose of investigational product(s) and adverse 
events are collected 28 days after the last dose of investigational product(s). 
Neratinib will be administered orally with food once daily (recommended to be taken in the 
morning), on a continuous basis. Dose delays and modifications will be handled as per 
instructions in the package insert. All patients taking neratinib will maintain a patient diary for 
the study to record each dose of neratinib taken and while receiving antidiarrheal prophylaxis 
with loperamide taken for the first two cycles of treatment. For cohorts receiving combination 
treatment that includes trastuzumab, post-treatment radiographic evaluation of their disease 
will be conducted every 3 cycles. For all other cohorts, post-treatment disease assessment will 
be conducted every 2 cycles. Treatment should be administered until there is unequivocal 
evidence of disease progression as documented by imaging, clinical examination, or disease-
related symptoms. Tumor markers or circulating tumor cells should not be used as the sole 
criteria for determining progression. At the time of decision regarding disease progression, 
radiological exam should be performed. Patients will continue study treatment until disease 
progression, unacceptable toxicity, patient withdrawal of consent, or death. Patients who 
develop disease progression, but in the opinion of the Investigator would still benefit from 
continuing study, may continue per-protocol therapy if approved by the Sponsor. Survival 
follow-up will be every 12 weeks after treatment discontinuation. Enrollment will continue as 
dictated by the Simon’s 2-stage design in all the histology and mutation specific cohorts and/or 
up to 30 patients per cohort in multi-cancer, mutation specific NOS cohorts. Enrollment in the 
randomized breast cancer, non-randomized breast cancer and cervical cancer cohorts will also 
continue as dictated by the Simon’s 2-stage design up to 50 patients per cohort. 
 
 


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Tumor Cohorts Open to Enrollment in Amendment 7   
Randomized Breast Cancer Cohort 
Tumor 
Cohort 
Mutation 
Randomized Treatment 
Sample Size (# 
subjects) 
Breast  
HR Positive 
(with prior 
CDK4/6i) 
HER2 
mutant 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; 
once every 28 days thereafter  
Or 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; 
once every 28 days thereafter  
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV 
every 3 weeks 
Or 
• 
Neratinib: 240 mg daily 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; 
once every 28 days thereafter  
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV 
every 3 weeks  
 
 
Up to 18 
 
 
 
Up to 18 
 
 
 
 
 
Up to 50 
Non-randomized Breast Cancer Cohorts 
Tumor 
Cohort 
Mutation 
Assigned Treatment 
Cohort Sample 
Size (# subjects) 
Breast 
HR Positive 
(CDK4/6i 
naïve) 
HER2 
mutant 
• 
Neratinib: 240 mg daily 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; 
once every 28 days thereafter  
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV 
every 3 weeks 
Up to 50 
Breast  
TNBC (HR 
Negative)  
HER2 
mutant 
• Neratinib: 240 mg daily 
• Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV 
every 3 weeks  
Up to 50 
Cervical Cancer Cohort 
Tumor 
Cohort 
Mutation 
Assigned Treatment 
Cohort Sample 
Size (# subjects) 
Cervical 
HER2 
mutant 
• Neratinib: 240 mg daily 
50 
Cohorts Not Receiving Trastuzumab  


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Tumor Cohort 
Mutation 
Assigned Treatment 
Salivary Gland 
HER2 mutant 
• Neratinib: 240 mg daily 
Non-small Cell Lung 
EGFR exon 18 
mutations 
• Neratinib: 240 mg daily 
Tumor Cohorts Closed to Enrollment in Amendment 7 
The following cohorts were closed to enrollment in Amendment 7: solid tumors (NOS) HER2 mutant 
monotherapy and bladder/urinary HER2 mutant combination therapy of neratinib + paclitaxel.  
 
Tumor Cohorts Open to Enrollment in Amendment 6  
Randomized Breast Cancer Cohort 
Tumor Cohort Mutation 
Randomized Treatment 
Sample Size (# 
patients) 
Breast  
HR Positive 
(with prior 
CDK4/6i) 
HER2 
mutant 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; 
once every 28 days thereafter  
Or 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; 
once every 28 days thereafter  
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV 
every 3 weeks 
Or 
• 
Neratinib: 240 mg daily 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; 
once every 28 days thereafter  
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV 
every 3 weeks  
Up to 18 
Up to 18 
Up to 50 
 
 
 


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Non-randomized Breast Cancer Cohorts 
Tumor Cohort Mutation 
Assigned Treatment 
Cohort Sample Size 
(# patients) 
Breast 
HR Positive 
(CDK4/6i 
naive) 
HER2 
mutant 
• 
Neratinib: 240 mg daily 
• 
Fulvestrant: 500 mg on Study Day 1, 15, and 29; 
once every 28 days thereafter  
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV 
every 3 weeks 
Up to 50 
Breast  
TNBC (HR 
Negative)  
HER2 
mutant 
• 
Neratinib: 240 mg daily 
• 
Trastuzumab: 8 mg/kg IV followed by 6 mg/kg IV 
every 3 weeks  
Up to 50 
 
Cervical Cancer Cohort 
Tumor Cohort 
Mutation 
Assigned Treatment 
Cohort Sample Size (# 
patients) 
Cervical 
HER2 mutant 
• 
Neratinib: 240 mg daily 
50 
 
Cohorts Not Receiving Trastuzumab  
Tumor Cohort 
Mutation 
Assigned Treatment 
Salivary Gland 
HER2 mutant 
• 
Neratinib: 240 mg daily 
Lung 
EGFR exon 18 
mutations 
• 
Neratinib: 240 mg daily 
Bladder/ Urinary 
Tract  
HER2 mutant 
• 
Neratinib: 240 mg daily 
• 
Paclitaxel: 80 mg/m2 IV on Days 1, 8, and 15 of every 4-
week cycle 
Solid tumors (NOS) 
HER2 mutant 
• 
Neratinib: 240 mg daily 
 
Tumor Cohorts Closed to Enrollment in Amendment 6 
The following cohorts were closed to enrollment in Amendment 6: colorectal cancer 
combination therapy with neratinib + trastuzumab, lung cancer HER2 mutant combination 
therapy with neratinib+ trastuzumab, gastroesophageal cancer monotherapy, biliary cancer 
monotherapy, ovarian cancer monotherapy, and solid tumor (NOS) HER4 mutant.  
If a tumor has more than one qualifying mutation, the patient will be assigned to the 
appropriate tumor-specified cohort if one exists upon consultation with the Investigator and 
Sponsor. 


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Tumor Cohorts Closed to Enrollment in Other Amendments 
Refer to the protocol for cohorts open or closed in prior amendments. 
 
2.2.2. 
Investigational Product, Dose, and Administration:  
• 
Neratinib: Patients will receive six 40-mg tablets (total daily dose 240 mg) administered orally, 
once daily with food (recommended to be taken in the morning), continuously. 
• 
Fulvestrant: Patients will receive 500 mg total dose administered as two 5 mL injections, by 
intramuscular injection, one in each buttock on Days 1, 15, and 29; then once every 4 weeks 
thereafter; see fulvestrant package insert and Schedule of Procedures. 
• 
Trastuzumab: Patients will receive an initial dose of 8 mg/kg of trastuzumab intravenously (IV) 
administered on Cycle 1 Day 1 (C1D1), followed by 6 mg/kg IV once every 3 weeks thereafter; 
see Herceptin (trastuzumab) package insert and Schedule of Procedures. 
• 
Paclitaxel: Patients in the bladder/urinary tract cancer cohort treated with combination therapy 
will receive 80 mg/m2 administered IV on Days 1, 8, and 15 of every 4-week cycle. 


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3. 
SAMPLE SIZE DETERMINATION 
 
3.1. 
Sample Size Justification for the Randomized HR+ Breast Cancer Study 
Cohort: 
A Simon’s 2-stage optimal design (Simon, 1989) will be used to determine whether there is 
sufficient activity to warrant further development of the therapy and to minimize the number of 
patients exposed to therapy if ineffective. For each treatment arm, using Simon’s 2-stage optimal 
design (with significance level 10% and power of 80%), an ORR (confirmed) of 10% or less per 
RECIST by independent assessment will be considered unacceptable (null hypothesis) whereas 
an ORR (confirmed) of 30% per RECIST by independent assessment will merit further study 
(alternative hypothesis). In the first stage, 7 patients are enrolled in each treatment arm. If at least 
1 response is observed in the first stage, the second stage will be opened. In the second stage, 11 
additional response evaluable patients will be accrued and randomized for a total of 18 patients 
in the treatment arm. The null hypothesis will be rejected (for each arm separately) if at least 4 
responses are observed in Stage 2 for each arm. 
Once the Simon’s 2-stage criteria are met, enrollment of the neratinib arm may continue until up 
to 50 patients have been enrolled. 
Prior to protocol amendment 6, there were approximately 10 HR+, HER2- patients in the N+F+T 
cohort that received prior CDK4/6i therapy; therefore, data can be pooled with the data from 50 
patients randomized in N+F+T arm in protocol amendment 6. The 2-sided Clopper-Pearson 95% 
CIs for the possible ORRs are summarized in the following table for total of 60 patients: 
 
Table 1:  Two-sided Clopper-Pearson 95% CI for ORR 
ORR 
95% CI 
25% 
(14.7%, 37.9%) 
30% 
(18.8%, 43.2%) 
35% 
(23.1%, 48.4%) 
40% 
(27.6%, 53.5%) 
45% 
(32.1%, 58.4%) 
50% 
(36.8%, 63.2%) 
 
3.2. 
Sample Size Justification for All Other Cohorts: 
A Simon’s 2-stage optimal design (Simon, 1989) will be used to determine whether neratinib 
monotherapy has sufficient activity to warrant further development in the following cohorts: 
cervical, salivary gland, NOS, and lung cancers. A similar Simon’s 2-stage design will be used to 
determine whether neratinib combination therapy has sufficient activity to warrant further 
development in the following cohorts: HR+ and CDK4/6i naive, TNBC, and bladder/urinary 
tract cancers. Early study termination will be permitted if data at the first stage indicate that the 


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treatment is ineffective. For each cohort, using Simon’s optimal 2-stage design (with significance 
level 10% and power of 80%), an ORRfirst of 10% or less will be considered unacceptable (null 
hypothesis) whereas an ORRfirst of 30% will merit further study (alternative hypothesis). In the 
first stage, enrollment will continue until 7 patients received at least one dose of study treatment 
and completed the first tumor assessment by the investigator (response evaluable). If no 
responses are observed, the second stage for the cohort must be discontinued. Otherwise, 11 
additional response evaluable patients will be accrued for a total of 18 patients in the cohort. The 
null hypothesis will be rejected (for each cohort separately) if at least 4 responses are observed in 
Stage 2 for each cohort. 
Enrollment to the salivary gland, lung (EGFR exon 18), bladder/urinary tract and HER2-mutant 
NOS cohort may enroll up to 30 patients. 
Once the Simon’s 2-stage criteria are met, enrollment into these cohorts may continue until up to 
50 patients have been enrolled. A new cohort may also be opened separately at any time per 
Sponsor discretion and follow the Simon’s 2-stage criteria. Cohorts may close prior to planned 
enrollment. 


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4. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
In general, efficacy analyses in this study are meant to be cohort-specific analyses.  Safety analyses will 
be summarized across all monotherapy and combination therapy where appropriate. For patients who 
develop disease progression and start combination therapy, the safety on combination therapy will be 
summarized separately starting from the start time of combination therapy. 
Categorical variables will be summarized using counts and percentages.  Percentages will be displayed to 
1 place after the decimal point (xx.x), with the exception of 100%, which will be displayed without 
additional decimal places, and with the exception of 0%, which will not be displayed.  Continuous 
variables will be summarized using number of patients, mean, median, standard deviation, and 
interquartile range (25th – 75th percentile), minimum, and maximum.   
In general, the baseline value will be considered the last measurement observed prior to taking the first 
dose of study treatment.  In the case more than one measurement on the same day is available for a 
patient/assessment, the average will be considered as baseline. 
SAS statistical software, version 9.4 or later, will be used for all analyses.   
If departures from these general conventions are present in the specific evaluations section of this SAP, 
then those conventions will take precedence over these general conventions.  
4.1. 
Date Imputations 
4.1.1. 
Missing/Partial Dates in Adverse Events 
 
Adverse events with start dates that are completely or partially missing will be analyzed as follows: 
1. If the start date has a month and year but the day is missing, the event will be considered 
treatment emergent if the month and year of the start date of the event are:  
a. On or after the month and year of the date of the first dose of study drug  
2. If the start date has a year, but the day and month are missing, the event will be considered 
treatment emergent if the year of the start date of the event is: 
a. On or after the year of the date of the first dose of study drug and  
b. On or before the year of the date of the last dose of study drug plus 28 days 
3. If the start date of an event is completely missing then the event is assumed to be treatment 
emergent. 


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4.1.2. 
Missing/Partial Dates in Concomitant Therapies 
 
Concomitant therapies with start dates that are completely or partially missing will be analyzed as 
follows: 
1. If the start date has a month and year but the day is missing, the event will be considered 
concomitant if the month and year of the start date of the event are:  
o On or after the month and year of the date of the first dose of study drug and  
o On or before the month and year of the date of the last dose of study drug plus 28 days 
2. If the start date has a year, but the day and month are missing, the event will be considered 
concomitant if the year of the start date of the event is: 
o On or after the year of the date of the first dose of study drug  
3. If the start date of an event is completely missing then the event is assumed to be concomitant.  
When the start date is complete and is before the first dose, and the concomitant medication is not 
ongoing but the end date is missing completely or partially, a similar algorithm should be used to assess 
whether the end date is before the last dose of study drug plus 28 days to be included. 
4.1.3. 
Missing/Partial Dates in Subsequent Therapies 
 
Subsequent therapies with start dates that are completely or partially missing will be analyzed as 
follows: 
1. When the month and year are present and the day is missing:  
a. If the onset month and year are the same as the month and the year of last dose of study 
drug, the day of the last dose + 1 will be imputed.   
b. If the onset month and year are not the same as the month and year of the last dose of 
study drug, the first day of the month will be imputed.  
2. When only a year is present:  
a. If the onset year is the same as the year of the last dose of study drug, the date of the last 
dose + 1 will be imputed.   
b. If the onset year is not the same as the year of the last dose of study drug, the first day of 
the year will be imputed.  


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3. If no components of the onset date are present the date of the last dose + 1 will be imputed.  
 


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5. 
ANALYSIS POPULATIONS 
For the purposes of patient disposition, intent-to-treat population (ITT) is defined as all patients who are 
enrolled into the study.  The safety population are all patients who received at least one dose of study 
drug.    
The Primary Analysis Population is defined as all patients who received at least 1 dose of study 
treatment. This population will be used for all efficacy and safety analysis, if not otherwise specified. 
 


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6. 
STUDY PATIENTS 
6.1. 
Disposition of Patients 
 
The number and percentage of patients entering and completing the study will be presented.  Reasons 
for withdrawal of treatment and study will also be summarized by treatment group. 
6.2. 
Protocol Deviations 
 
Protocol deviations will be classified and monitored regularly during the duration of the study.  Among 
other reasons, failure to meet any of the protocol inclusion or exclusion criteria will be considered a 
protocol deviation. All protocol deviations will be listed and summarized by type.  


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7. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data, medical history, and concomitant medication will be summarized by means of 
descriptive statistics or frequency tables. For categorical variables, the number and percentage of 
patients in each category will be presented.  For continuous variables, summaries will include the 
number of patients with data, mean, median, standard deviation, minimum, and maximum.   All 
summaries will be based on the safety population. 
7.1. 
Demographic and baseline characteristics 
 
The following demographic and baseline variables will be summarized by treatment group:  
• 
age (years) 
• 
age group (<65 years, ≥ 65 years)  
• 
sex 
• 
race and ethnicity (per CRF) 
• 
height (cm) 
• 
weight (kg) 
• 
body mass index (BMI) 
Body mass index (BMI) will be calculated as: 𝐵𝑀𝐼(
𝑘𝑔
𝑚2) =
𝑊𝑒𝑖𝑔ℎ𝑡 (𝑘𝑔)
(𝐻𝑒𝑖𝑔ℎ𝑡(𝑐𝑚)∗0.01)2 


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7.2. 
Medical History 
 
Medical history data including: chronic conditions, relevant surgical procedures, symptoms experienced 
during the previous 30 days, symptoms ongoing at the time of screening, any medical conditions that 
require medication and cancer history will be collected at screening, within 14 days prior to Cycle 1/ 
Day1 in accordance with the Schedule of Procedures included in the protocol. 
Cancer history variables include date of first diagnosis, nodal status, histology, tumor stage at diagnosis, 
previous chemotherapy/biotherapy/ immunotherapy, previous adjuvant therapy, previous radiation, 
and prior cancer related surgical therapies. 
Medical history and cancer history data will be summarized and listed; tabulations will be by treatment 
group.  
7.3. 
Prior and Concomitant Medications 
 
Concomitant medications will be defined as medications documented on the Concomitant Medications 
CRF.  Concomitant medications will be coded using the World Health Organization (WHODrug) 
dictionary, v2022-09, and summarized in a table and a data listing. 


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8. 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Patient dose, exposure, and duration of neratinib will be tabulated.  Exposure to other study drugs will 
be listed. 
Duration:  number of days from the first dose of study drug to the last dose of study drug 
Cumulative actual dose (cumdose) :  total dose taken, in mg. 
Dose intensity (DI):  the cumulative dose divided by the duration, or 
 𝐷𝐼=
𝑐𝑢𝑚𝑑𝑜𝑠𝑒
𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛  
Relative dose intensity (RDI) is the cumulative dose divided by the expected dose, which is 240 
mg*duration, or 
𝑅𝐷𝐼=
𝑐𝑢𝑚𝑑𝑜𝑠𝑒
240∗𝑑𝑢𝑟𝑎𝑡𝑖𝑜𝑛∗100% . 
 


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9. 
EFFICACY EVALUATION 
For cohorts receiving combination treatment that includes trastuzumab, post-treatment disease 
assessment by CT or magnetic resonance imaging (MRI) will be conducted at the beginning of Week 10 
(ORRfirst), and every 3 cycles (± 7 days) thereafter (see Schedule of Procedures, Appendix 1 Table A1.1). 
For all other cohorts not receiving trastuzumab, post-treatment disease assessment will be conducted at 
the beginning of Week 9 (ORRfirst), and every 2 cycles (± 7 days) thereafter (see Schedule of Procedures, 
Appendix 1 Table A1.2). Complete or partial response (CR or PR) must be confirmed with a repeat scan 
performed no sooner than 4 weeks after the criteria for response are first met. In cases where the 
subject discontinues treatment for reasons other than progressive disease (e.g., adverse event, patient 
choice, noncompliance, etc.) and the response is either CR or PR, then a confirmation scan is required no 
sooner than 4 weeks after the criteria of response is met. Radiological response is assessed by RECIST 
v1.1. Following one year on therapy, scans may move to every 4 cycles for trastuzumab-containing 
regimens and every 3 cycles for non-trastuzumab containing regimens. Following two years on therapy, 
scans may move to every 5 cycles for trastuzumab-containing regimens and every 4 cycles for non-
trastuzumab-containing regimens.  Tumor assessments will be performed by the study investigators for 
all patients, and by the independent central review for the patients in the HR+, HER2- cohort of patients 
who received a prior CDK4/6 inhibitor, the randomized HR+, HER2- mBC cohort,  and mCC cohorts. 
Table 2 gives an overview of the efficacy variables and the analysis methods that will be implemented.  
Table 2:  Efficacy Variables and Analysis Methods 
Efficacy Variables 
Analysis Methods 
Objective Response Rate at the first tumor 
assessment (ORRfirst) 
Estimate with associated 2-sided Clopper-
Pearson 95% confidence intervals 
Confirmed Overall Objective Response Rate 
(ORR) 
Estimate with associated 2-sided Clopper-
Pearson 95% confidence intervals 
Clinical Benefit Rate (CBR) 
Estimate with associated 2-sided Clopper-
Pearson 95% confidence intervals 
Progression-Free Survival (PFS) 
Median PFS estimated via Kaplan-Meier with 
associated 2-sided 95% confidence intervals 
Overall Survival (OS) a 
Median OS estimated via Kaplan-Meier with 
associated 2-sided 95% confidence intervals 


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Duration of Response (DOR) 
Median DOR estimated via Kaplan-Meier with 
associated 2-sided 95% confidence intervals 
aLong-term follow up was discontinued January 4, 2022 and patients will not be followed for OS.  This analysis 
will not be conducted. 
9.1. 
Definitions of Efficacy Endpoints 
9.1.1. 
Objective Response Rate at the First Tumor Assessment (ORRfirst) 
ORRfirst is defined as the proportion of patients who achieve complete responses (CR) or partial 
responses (PR), per RECIST (v1.1) or other defined response criteria at the first scheduled tumor 
assessment. 
9.1.2. 
Overall Response Rate (ORR) 
 
ORR is defined as the proportion of patients who achieve confirmed complete responses (CR) or partial 
responses (PR), per RECIST (v1.1) or other defined response criteria, as their best overall response. 
Complete or partial responses are confirmed with repeat tumor evaluation using same criteria after 4 
weeks.  
9.1.3. 
Clinical Benefit Rate (CBR) 
 
The CBR is defined as the proportion of patients who achieve overall tumor response (CR or PR) or SD 
for at least 16 weeks (at least 24 weeks for the breast cancer cohorts). To allow for visits occurring 
earlier than scheduled, 105 days and 161 days define 16 weeks and 24 weeks, respectively. 
9.1.4. 
Progression-Free Survival (PFS) 
 
Progression-free survival (PFS) is defined as the time interval from the date of C1D1 until the first date 
on which recurrence, progression or death due to any cause is documented, censored at the last 
assessable evaluation, or at the initiation of new anticancer therapy. It is not necessary to confirm 
disease progression.  
PFS is censored on the date of the last tumor assessment on study for patients who did not have PD and 
who did not die while on study or who started a new anti-cancer therapy prior to documented PD. 
Additionally, patients lacking an evaluation of tumor response after enrollment have their PFS time 
censored on the date of enrollment with duration of 1 day.  Finally, those patients who have not 


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progressed by the time of database lock will have their PFS time censored at the time of their last 
assessment.  The table describes the various censoring mechanisms for the various cohorts. 
Table 3:  Handling of Missing Response Assessment and Censoring for Progression-Free 
Survival Primary Analysis 
Situation 
Date of Progression or 
Censoring 
Outcome 
No baseline and/or no post 
baseline assessment 
1. Randomization for the 
randomized cohorts. 
2. Treatment start date for 
other cohorts. 
Censored 
Disease progression 
documented between 
scheduled visits  
Date of disease progression 
PFS event 
No documented disease 
progression or death 
Date of last adequate 
assessment 
Censored 
Progressive disease or death 
immediately after more than 
one consecutively missed tumor 
assessment visit 
Date of last adequate 
assessment 
Censored (see note below) 
Alternate antineoplastic therapy 
started prior to disease 
progression  
Date of last adequate 
assessment prior to the start of 
subsequent antineoplastic 
therapy 
Censored 
Death before first assessment 
Date of death 
PFS event 
Death between adequate 
assessment visits 
Date of death 
PFS event 
 
Note: Two consecutive missed tumor assessments are defined by the following criteria: 


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• 
For all patients enrolled before amendment 6, or if the latter assessment occurs during year 1 
(day ≤ 365) and the patient is enrolled under amendment 6:  
o For patients receiving trastuzumab, the number of days between the 2 visits is greater 
than 133 days 
o For patients not receiving trastuzumab, the number of days between the 2 visits is 
greater than 119 days  
• 
For patients enrolled under amendment 6 or 7 
o if the latter assessment occurs between day 365 and 730, the number of days between 
the 2 visits is greater than 175 days 
o if the latter assessment occurs after 730, the number of days between the 2 visits is 
greater than  231 days 
9.1.5. 
Duration of Response (DOR) 
 
Duration of response is measured from the time at which measurement criteria are first met for CR or 
PR (whichever status is recorded first) until the first date of recurrence or progressive disease (PD) or 
death is objectively documented.  Censoring rules are similar to those described in section 9.1.4.   
9.2. 
Analysis Methods 
 
Estimates of ORRfirst , ORR and CBR will be determined and their associated 2-sided Clopper-Pearson 95% 
confidence intervals will be derived for each cohort. Patients who drop out prior to the first tumor 
assessment will be considered non-responders. 
Kaplan-Meier methods will be used to estimate PFS and DOR. Median PFS and DOR will be derived from 
the resulting product limit estimator. The associated 2-sided 95% confidence intervals for median PFS 
and median DOR will be determined via methods outlined by Brookmeyer and Crowley (1982).   
Summary tables, by specific tumor type, of the efficacy data will be generated. 
In various cohorts, tumor data were collected for patients in accordance with RECIST, (modified) 
PERCIST, or both.  For those patients whose assessments were made with RECIST, then RECIST criteria 
were used to define the efficacy endpoints.  For those patients whose assessments were made with 


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(modified) PERCIST only then the PERCIST assessments were the criteria for response, progression, and 
benefit. 
9.3. 
Examination of Subgroups 
 
Analyses of subgroups are not currently planned for this study, excepting that efficacy analyses will be 
generated by cohorts. 


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10. 
SAFETY EVALUATION 
10.1. 
Overview of Safety Analysis Methods 
 
All safety analysis will be performed for all patients in the Primary Analysis Population. The following 
assessments will be used to evaluate the safety of neratinib:  
• 
Adverse events (AEs) 
• 
Vital sign measurements 
• 
Physical examination findings 
• 
Electrocardiogram (ECG)  
• 
LVEF results from multiple-gated acquisition (MUGA) scan or echocardiogram (ECHO) 
• 
Laboratory assessments.  
All safety endpoints will be summarized by treatment, and all treated patients when appropriate.   
10.2. 
Extent of Exposure 
 
Extent of exposure to neratinib will be summarized by total dose, dose intensity, and duration of 
therapy for each treatment group.  Refer to section 8 for the definitions. 
10.3. 
Adverse Events, Serious Adverse Events, and Deaths 
 
Adverse events and serious adverse events will be coded using MedDRA v. 25.1 and tabulated by system 
organ class (SOC) and preferred term (PT).  All AEs will be graded by the Investigator according to the 
NCI CTCAE v.4.0. Summaries will in general focus on treatment emergent adverse events (TEAEs).  A 
TEAE is any adverse event that occurs or worsens on or after first dose of investigational product and up 
to 28 days after the last dose. 
Patient incidence of all TEAEs, SAEs, treatment related TEAEs, treatment related SAEs, TEAEs leading to 
IP changes, grade 3 or 4 TEAEs, and fatal AEs will be tabulated by SOC and PT, for each treatment group.  


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Patients on neratinib monotherapy may have, upon disease progression, begun taking another drug in 
combination with neratinib.  Similarly, patients randomized to F or F+T may have crossed over to receive 
N+F+T. To address these situations, adverse events are summarized three ways:  
1. A summary of adverse events that occurred only during the time before combination therapy or 
crossover.  The treatment groups in the table will be the treatment group with which the patient 
started in the first period, which will be noted as PERIOD 1.   
2. For those patients who crossed over to a different therapy, a summary of adverse events that 
started after the crossover.  This will consist of the patients on neratinib monotherapy who 
crossed over to combination therapy, and the F, and F+T patients who crossed over to N+F+T, 
and will be presented by the treatment group in the second period, which will be noted as 
PERIOD 2.  
3. A summary of adverse events that occurred anytime during the study. 
a. For neratinib monotherapy patients the patients first treatment group received 
b. For F and F+T patients, events before crossover will be attributed to period 1, and 
events after crossover will be attributed to period 2. 
For each treatment group, AEs, Serious Adverse Events (SAEs) and Treatment Emergent Adverse Events 
(TEAEs) will be listed in by patient listings sorted by patient ID and study day; SAEs will be flagged. All AE 
listings will include study day,  PT, reported term, dose,  AE onset date, AE resolution date, outcome,  
relationship to drug, action taken, and severity.   
Patient deaths are recorded on the End of Study CRF page. Cause of death and the time of death 
(dichotomized as within 28 days of last dose vs. more than 28 days after last dose) will be summarized 
via frequencies and percentages. Patient death listings will include all death data available including the 
date of death, cause of death, and any AEs resulting in death.  
10.4. 
Clinical Laboratory Evaluation 
 
Blood samples for clinical chemistry and hematology will be collected during screening, on day 1 of each 
treatment cycle (with the exception of cycle 1/day 1 if screening occurred within 72 hours of cycle 1/day 
1), and at the treatment discontinuation visit. Samples for pregnancy testing and urinalysis will be 
collected at screening, and directly before study drug administration. 


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Descriptive statistics will be calculated on both the actual value and the change from baseline value at 
the minimum, maximum, and last value for each patient and lab test. 
The institutional laboratory will analyze all hematology, routine blood chemistry, and urine samples 
collected.  
10.5. 
Hepatotoxicity 
 
Abnormalities in liver function tests will be summarized. Patient incidence of the following will 
be provided: 
• 
3x-, 5x-, 10x-, and 20xULN elevations of AST, ALT, and either ALT or AST.  
• 
Any elevations of bilirubin; elevated TBL to >2xULN.  
• 
Any elevations of ALP >1.5xULN.  
• 
Elevation of AT (>3xULN) accompanied by elevated bilirubin (>2xULN).  
In addition, a listing of potential Hy’s Law cases will be provided.  Potential hepatotoxicity is 
identified by the Hy’s Law (FDA Guidance for Industry Drug Induced Liver Injury: Pre-marketing 
Clinical Evaluation, July 2009) as: ALT or AST >3.0 ULN; TBL>2.0 ULN, ALP<2.0 ULN; and no other 
confounding factors including preexisting or acute liver disease.   
10.6. 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
10.6.1. 
Vital Signs 
 
Vital signs, including systolic and diastolic blood pressure, pulse, and body temperature, as well as 
weight will be collected during screening, on day 1 of each treatment cycle, and at the treatment 
discontinuation visit. 
Descriptive statistics will be calculated on both the actual value and the change from baseline value for 
the minimum, maximum, and last observation. 
 
 


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10.6.2. 
Physical Examinations 
 
Physical examination data will be collected during screening, on day 1 of each treatment cycle and at the 
treatment discontinuation visit. 
A full physical exam will be performed at Screening. Detailed/brief (system-guided) physical 
examinations will be done at subsequent time points to evaluate any clinically significant abnormalities, 
including worsening of conditions included in the patient’s medical history. 
Physical examination results will be listed with vital signs.  Height will be collected at screening.  
Electrocardiograms 
Single standard 12 lead digital ECGs will be performed during screening, and every 8 weeks after that, 
and at treatment discontinuation, if not done within the previous 8 weeks. 
The ECG (measured after resting in a supine position for 5 minutes) will include heart rate, PR, QRS, QT 
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. 
An additional correction formula included but considered secondary is QTcF. This additional corrected 
QT interval is defined as: 
• 
QTcF is the length of the QT interval corrected for heart rate by Fridericia’s formula:  
𝑄𝑇𝑐𝐹= 𝑄𝑇
√𝑅𝑅
3
 
 
where RR is the interval from the onset of one QRS complex to the onset of the next QRS complex, 
measured in seconds, often derived from the heart rate (HR) as 60/HR (here QT is measured in 
milliseconds). 
All ECG parameters and their change from baseline will be summarized at the final, minimum, and 
maximum study time points in period 1(before crossover) for each treatment group using descriptive 
statistics. 
All ECG values will be listed by patient for each cohort.   


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10.6.3. 
Left Ventricular Ejection Fraction (LVEF) 
 
MUGA scan or ECHO  to determine LVEF will be performed during screening and repeated every 8 weeks 
after that, and at treatment discontinuation, if not done within the previous 8 weeks.   
MUGA scans or ECHO scans to determine LVEF will be performed as part of the screening procedures 
within 28 days of Cycle 1/Day 1.  
The mean LVEF and mean LVEF change from baseline will be summarized at the last and minimum 
values in period 1 by treatment arm and overall using descriptive statistics.     
All MUGA and ECHO values will be listed by patient for each treatment group. 


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11. 
OTHER ASSESSMENTS 
11.1. 
ECOG Performance Status 
 
Eastern Cooperative Oncology Group (ECOG) performance status will be assessed at screening, on day 1 
of each treatment cycle, and at the treatment discontinuation visit. ECOG categories are also 
summarized in the study protocol. 
Screening ECOG performance status may be accepted as the Baseline status if the assessment was 
performed within 72 hours of initiation of investigational product and there were no clinically significant 
findings. 
ECOG status will be included in the baseline and demographic variables. The number and percentage of 
patients in each ECOG category will be presented for each treatment group, by nominal visit, and 
minimum and maximum values. 
11.2. 
Patient Reported Outcomes: FACT-G 
 
Patient Reported Outcomes will be evaluated using the FACT-G instrument.  Data for each of the 4 
subscales and the total score will be summarized and plotted over time for the following treatment 
groups: 
a. Hormone receptor positive (HR+), HER2 negative breast cancer patients receiving N+F+T 
(randomized and open label) 
b. Hormone receptor positive (HR+), HER2 negative breast cancer patients receiving F+T 
(until crossover to N+F+T) 
c. Hormone receptor positive (HR+), HER2 negative breast cancer patients receiving F 
(until crossover to N+F+T) 
d. Lung EGFR exon 18 mutation patients receiving N. 
Summaries will be created through cycle 6 by nominal visit; the baseline score is the latter of the score 
at Screening of C1D1, and will be represented as C1D1.  All patients with FACT-G scores in the respective 
treatment group will be summarized regardless of any baseline or post-baseline visits. 


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FACT-G was collected for patients in other cohorts, but the number of patients is small and a summary is 
not meaningful.  Accordingly, these assessments for these patients, and those above, will be provided in 
the listings. 


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12. 
INTERIM ANALYSES AND DATA MONITORING 
Interim analyses may be performed at the completion of each stage for cohorts with a Simon's 2-stage 
design and for other cohorts as necessary. An IDMC will be established to regularly review accumulating 
safety data and efficacy data throughout the study. 


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13. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
13.1. 
Overall Survival 
Long-term follow up was discontinued on January 4, 2022.  Accordingly, analysis of overall 
survival will not be conducted. 
13.2. 
Database Lock 
The database will be locked in December 2022, with not all patients off treatment. The analyses 
will be conducted with the data available in the database; analyses of the data post database 
lock will be described in an amended SAP. 
   


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14.
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