Clinical trial NCT01808573
Conditions: HER2+ Metastatic Breast Cancer (MBC)
Keywords: Neratinib Nerlynx
Sponsor: Puma Biotechnology, Inc.
Start date: 2013-03-29; Completion date: 2019-12-09
Enrollment: 621 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, multi-center, multinational, open-label, active-controlled, parallel design study of the combination of neratinib plus capecitabine versus the combination of lapatinib plus capecitabine in HER2+ MBC patients who have received two or more prior HER2 directed regimens in the metastatic setting.

Detailed description:
This is a randomized, multi-center, multinational, open-label, active-controlled, parallel design study of the combination of neratinib plus capecitabine versus the combination of lapatinib plus capecitabine in HER2+ MBC patients who have received two or more prior HER2 directed regimens in the metastatic setting. Patients will be randomized in a 1:1 ratio to one of the following treatment arms:

* Arm A: neratinib (240 mg once daily) + capecitabine (1500 mg/m\^2 daily, 750 mg/m\^2 twice daily \[BID\])
* Arm B: lapatinib (1250 mg once daily) + capecitabine (2000 mg/m\^2 daily, 1000 mg/m\^2 BID)

Patients will receive either neratinib plus capecitabine combination or lapatinib plus capecitabine combination until the occurrence of death, disease progression, unacceptable toxicity, or other specified withdrawal criterion.

Arms: arm 1: neratinib 240 mg orally, once daily with food, continuously in 21 day cycles, and capecitabine 1500 mg/m\^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle. arm 2: lapatinib 1250 mg orally, once daily, continuously in 21 day cycles, and capecitabine 2000 mg/m\^2 daily in 2 evenly divided doses, orally with water within 30 minutes after a meal, taken on days 1 to 14 of each 21 day cycle.
Interventions: intervention 1: neratinib intervention 2: capecitabine intervention 3: lapatinib
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
A STUDY OF NERATINIB PLUS CAPECITABINE VERSUS 
LAPATINIB PLUS CAPECITABINE IN PATIENTS WITH HER2+ 
METASTATIC BREAST CANCER WHO HAVE RECEIVED TWO 
OR MORE PRIOR HER2-DIRECTED REGIMENS IN THE 
METASTATIC SETTING (NALA) 
 
 
NCT01808573 
 
Study Protocol 
 
Amendment 3      13-FEB-2014 


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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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PROTOCOL SYNOPSIS 
Title: A Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients With HER2+ 
Metastatic Breast Cancer Who Have Received Two or More Prior HER2-Directed Regimens in the Metastatic 
Setting (NALA)  
Condition or Disease: Human epidermal growth factor receptor 2 positive (HER2+) metastatic breast cancer 
(MBC) 
Phase of Development 
3 
Approximate Values 
Number of Patients 
600 
Duration of Patient Participation 
28 Months 
Number of Centers 
200 
Duration of Study 
50 Months 
Objectives: 
Primary: The co-primary objectives of this study are  
 
to compare independently adjudicated progression-free survival (PFS) following treatment with neratinib plus 
capecitabine versus lapatinib plus capecitabine in patients with HER2-positive (HER2+) MBC who have 
received two or more prior HER2-directed regimens in the metastatic setting. 
 
to compare overall survival (OS) following treatment with neratinib plus capecitabine versus lapatinib plus 
capecitabine in this population. 
Secondary: The secondary objectives of this study are to compare between the two treatment groups:  
 
Investigator-assessed PFS. 
 
Objective response rate (ORR), duration of response (DOR) and clinical benefit (CBR) (complete response 
[CR] or partial response [PR] or stable disease [SD] ≥24 weeks).  
 
Time to intervention for symptomatic metastatic central nervous system (CNS) disease. 
 
Safety (adverse events [AEs], serious adverse events [SAEs]). 
 
Health outcomes assessments. 
Exploratory: 
The exploratory objective of this study is: 
 
To assess the population pharmacokinetics (PK) of neratinib when administered in combination with 
capecitabine. 
Study Design: 
This is a randomized, multi-center, multinational, open-label, active-controlled, parallel design study of the 
combination of neratinib plus capecitabine versus the combination of lapatinib plus capecitabine in HER2+ MBC 
patients who have received two or more prior HER2-directed regimens in the metastatic setting. Patients will be 
randomized in a 1:1 ratio to one of the following treatment arms: 
 
Arm A: neratinib (240 mg once daily) + capecitabine (1500 mg/m2 daily, 750 mg/m2 twice daily [BID]) 
 
Arm B: lapatinib (1250 mg once daily) + capecitabine (2000 mg/m2 daily, 1000 mg/m2 BID) 
Patients will receive either neratinib plus capecitabine combination or lapatinib plus capecitabine combination until 
the occurrence of death, disease progression, unacceptable toxicity, or other specified withdrawal criterion.  
Patient randomization will be stratified according to: 
 
The number of previous HER2-directed regimens in the metastatic setting (N = 2 or N ≥3). 


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 
Geographic region (North America vs. Europe, including Israel vs. Rest of World). 
 
Visceral vs. non-visceral-only disease.  
 
Estrogen receptor + (ER+) and/or progesterone receptor (PR+) (i.e., hormone receptor +) versus ER- and 
PR- (i.e., hormone receptor -). 
Patients are anticipated to participate in the study for an average of 28 months. This includes approximately 
0.5 months for screening, an estimated average of 9.5 months for the active treatment phase, and an estimated 
average of 18 months for the long-term follow-up phase. Treatment is to be given for as long as tolerated and while 
there is no disease progression. Patients who permanently discontinue treatment will enter the long-term follow-up 
phase until death or withdrawal of consent. 
Investigational Product, Dose and Administration:  
Neratinib + Capecitabine Combination: 
 
Neratinib dosing: six 40 mg tablets (total daily dose 240 mg) orally, once daily with food, preferably in the 
morning, continuously in 21-day cycles, with no rest between cycles. 
 
Capecitabine dosing: 150 mg or 500 mg tablets (total dose of 1500 mg/m2 daily in 2 approximately evenly 
divided doses), orally with water within 30 minutes after a meal. Doses are to be taken daily for Days 1 to 14 
of a 21-day cycle. 
Lapatinib + Capecitabine Combination: 
 
Lapatinib dosing: five 250 mg tablets (total dose 1250 mg) orally, once daily, 1 hour before or after breakfast, 
continuously in 21-day cycles, with no rest between cycles. 
 
Capecitabine dosing: 150 mg or 500 mg tablets (total dose of 2000 mg/m2 daily, in 2 approximately evenly 
divided doses), orally with water within 30 minutes after a meal. Doses are to be taken daily for Days 1 to 14 
of a 21-day cycle. 
Study Population:  
Inclusion Criteria 
1. Aged ≥18 years at signing of informed consent. 
2. Histologically confirmed MBC, current stage IV. 
3. Documented HER2 overexpression or gene-amplified tumor (immunohistochemistry [IHC] 3+ or IHC 2+ with 
confirmatory fluorescence in situ hybridization [FISH]+). (Note: Patients who are IHC 0 or 1+ are not eligible 
to participate in the study). Tumor samples will be evaluated for HER2 expression by IHC (HercepTest™) and 
if required for gene amplification by FISH analysis (IQFISH pharmDx™). 
4. Prior treatment with at least two (2) HER2-directed regimens for metastatic breast cancer. A new regimen is 
defined as a modification in a planned course of therapy to include other treatment agents (alone or in 
combination) as a result of disease progression, relapse, or toxicity. A new regimen also starts when a planned 
period of observation off therapy is interrupted by a need for additional treatment for the disease. 
5. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors version 1.1 
(RECIST v1.1).  
6. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan (MUGA) or 
echocardiogram (ECHO). 
7. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1. 
8. Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women of reproductive 
capacity (those who are biologically capable of having children) and for women less than 12 months after 
menopause. 


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9. Women of childbearing potential must agree and commit to the use of a highly effective method of 
contraception, as determined to be acceptable by the Investigator, from the time of informed consent until 28 
days after the last dose of the investigational products. Men must agree and commit to use a barrier method of 
contraception while on treatment and for 3 months after last dose of investigational products. 
10. Provide written, informed consent to participate in the study and follow the study procedures. 
Exclusion Criteria 
1. Received previous therapy with capecitabine, neratinib, lapatinib, or any other HER2-directed tyrosine kinase 
inhibitor.  
2. 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. 
3. Any major surgery ≤28 days prior to the initiation of investigational products, or received anti-cancer therapy 
(including chemotherapy, biological therapy, hormonal therapy, investigational agents, or other anti-cancer 
therapy) administered ≤21 days prior to the initiation of investigational products.  
4. Received radiation therapy ≤14 days prior to initiation of investigational products. 
5. Symptomatic or unstable brain metastases. (Note: Asymptomatic patients with metastatic brain disease who 
have been on a stable dose of corticosteroids for treatment of brain metastases for at least 14 days prior to 
randomization are eligible to participate in the study).  
6. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure (New York Heart 
Association functional classification of ≥2), unstable angina, myocardial infarction within 12 months of 
enrollment, or ventricular arrhythmia. 
7. QTc interval >0.450 seconds or known history of QTc prolongation or Torsades de Pointes. 
8. Screening laboratory assessments outside the following limits:  
Laboratory endpoint 
Required limit for exclusion 
Absolute neutrophil count (ANC)  
<1500/µL (<1.5 x 109/L) 
Platelet count  
<100,000/µL (<100 x 109/L) 
Hemoglobin (Hb) 
<8 g/dL (transfusions allowed) 
Transfusions must be at least 14 days prior to randomization. 
Total bilirubin  
>1.5 x institutional upper limit of normal (ULN) 
Aspartate aminotransferase (AST) and/or 
Alanine aminotransferase (ALT)  
>3 x institutional ULN (>5 x ULN if liver metastases are present) 
Creatinine clearance  
<50 mL/min (as calculated by Cockroft and Gault formulaa or 
Modification of Diet in Renal Disease [MDRD] formulab  
a Cockcroft and Gault, 1976 
b Levey et al., 1999 
9. Active infection or unexplained fever >38.5°C (>101.3°F).  
10. Other malignancy within the past 3 years with the exception of a) adequately treated basal cell carcinoma, 
squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the cervix or vulva; c) prostate cancer of 
Gleason Score 6 or less with stable prostate-specific antigen levels; or d) cancer considered cured by surgical 
resection or unlikely to impact survival during the duration of the study, such as localized transitional cell 
carcinoma of the bladder, or benign tumors of the adrenal or pancreas.  
11. Currently breast-feeding. 


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12. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn’s disease, 
malabsorption, or Grade ≥2 (National Cancer Institute [NCI] Common Terminology Criteria for Adverse 
Events Version 4.0 [CTCAE v.4.0] diarrhea of any etiology at screening). 
13. Active infection with hepatitis B or hepatitis C virus. 
14. Known dihydropyrimidine dehydrogenase deficiency. 
15. Known hypersensitivity to 5-fluorouracil or to any component of the investigational products or compounds of 
similar chemical composition. 
16. Unable or unwilling to swallow tablets. 
17. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric illness/social situations that 
would, in the Investigator’s judgment, make the patient inappropriate for this study. 
Efficacy Assessments: 
There are 2 co-primary endpoints: independently adjudicated PFS and OS. All patients randomized will be 
evaluated.  
 
PFS is defined as disease progression (radiographic or other appropriate modality) or death due to any cause. 
o 
Efficacy assessment for PFS will be assessed by a blinded, independent, central review of tumor 
assessments for all patients at screening, and then after every 6 weeks from first dose of investigational 
product, regardless of treatment schedule modification (e.g., dose delay), until documented disease 
progression or death due to any cause. Progressive disease (PD) will be independently-assessed using 
RECIST v1.1. 
 
Overall survival, defined as the time from randomization to death due to any cause. 
o 
Survival data will be collected throughout the active treatment phase and during the long-term follow-up 
phase. Survival follow-up after patient discontinuation of investigational product will be conducted 
approximately every 12 weeks to assess for survival until patient death or withdrawal of consent. 
The secondary endpoints include:  
 
Comparison of clinically relevant improvements in breast cancer patients with respect to radiographic 
changes or changes in other appropriate modalities, including (see footnote*): 
o 
“Investigator-assessed” PFS, assessed by tumor assessments that will occur for all patients at screening, 
and then after every 6 weeks from first dose of investigational product, regardless of treatment schedule 
modification (e.g., dose delay), until documented disease progression or death due to any cause; 
o 
Objective response rate, defined as the proportion of patients demonstrating either a CR or PR during the 
study; 
o 
Duration of response is measured from the time at which response criteria were met for CR or PR 
(whichever status was recorded first) until the first date of recurrence or PD or death; 
o 
Clinical benefit rate, defined as the proportion of patients who achieved overall tumor response (CR or 
PR) or SD for at least 24 weeks. 
 
Time to intervention for symptomatic metastatic CNS disease, defined as date of initiation of intervention or 
therapy for symptomatic CNS disease determined by the investigator to be due to CNS metastasis. This may 
include brain, leptomeningeal and epidural metastases including epidural spinal cord compression arising 
from tumor growth in the epidural space. 
 
* All of the secondary efficacy endpoints including CR, PR, and SD will be assessed by the investigator and by the independent 
review committee utilizing RECIST v1.1. 


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Safety Assessments: 
Patients receiving at least 1 dose of investigational product will be evaluable for safety. Safety will be assessed 
based on medical history, vital sign measurements, physical examination findings, electrocardiogram (ECG) results, 
MUGA or ECHO and laboratory assessments. Adverse events will be graded according to the NCI CTCAE v.4.0. 
AEs and SAEs 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 SAE occurring any time 
after the reporting period, it must be promptly reported.  
Other Assessments: 
Pharmacokinetics:  
A population PK study with sparse sampling will be included in the study to assess the variability of neratinib 
concentration when administered in combination with capecitabine among individuals in the target patient 
population. At selected study centers, PK samples will be collected from approximately 100 patients in the neratinib 
plus capecitabine arm (Arm A) at Cycle 1, on Days 1 and 15. 
Health Outcomes Assessment: 
The following health outcomes assessments will be completed by patients: 
 
European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC 
QLQ-C30), version 3 
 
EORTC QLQ-BR23 (breast cancer-specific questionnaire) 
 
The EuroQol (EQ-5D-5L) multi-dimensional health status questionnaire 
Health outcomes assessments will be performed at screening, every 6 weeks during the active treatment period and 
at treatment discontinuation. 
Criteria for Patient Withdrawal: 
A patient must be discontinued from investigational product(s) (IP) in the following circumstances: 
 
if more than 2 dose reductions are required (Appendix 2) 
 
if IP is withheld >28 days due to AE 
 
disease progression 
 
initiation of alternative anti-cancer therapy, including chemotherapy, radiotherapy, and cancer-related surgery 
 
pregnancy 
 
investigator or patient request 
A patient may withdraw from the entire study, including follow-up, at any time at the discretion of the investigator, 
at the patient’s request, if the patient is lost to follow-up, or if the study is terminated prematurely. 
Statistical Methods: 
The co-primary endpoints are OS and independently adjudicated PFS, which will be determined by disease 
progression (disease progression demonstrated by radiographic imaging or other appropriate modality) or death 
due to any cause. Tumor evaluations for PD will be performed by a central review vendor.  
Secondary efficacy endpoints include Investigator-assessed PFS, ORR, DOR, and CBR (CR, PR or 
SD ≥24 weeks). Other secondary endpoints include time to intervention for symptomatic CNS disease, AEs and 
SAEs, and health outcomes assessments. 
Sample Size: 
The co-primary endpoints will be analyzed using an overall Type I error rate of 0.01 for PFS and 0.04 for OS. 
To detect a hazard ratio (control versus treatment) of 0.70 with approximately 85% power, 419 PFS events 
(PD/deaths) are required to be observed; this assumes a median (intent-to-treat [ITT]) PFS of 8.0 months (34.7 


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weeks) for the experimental arm (neratinib plus capecitabine) and 5.6 months (24.3 weeks) for the control arm 
(lapatinib plus capecitabine). It is expected that the 419th event will be observed at approximately 26 months 
after the first subject is enrolled. At this time, an interim analysis on OS will also be performed. For the OS 
endpoint, a group sequential method will be employed to maintain the overall Type I error rate at 0.04. 
Specifically, O’Brien-Fleming boundaries will be calculated to create appropriate critical values to which the 
log rank statistic will be compared. To detect a hazard ratio (control versus treatment) of 0.725 with 
approximately 85% power, 378 events (deaths) are required to be observed; this assumes a median ITT OS of 
30.3 months for the experimental arm (neratinib plus capecitabine) and 22.0 months for the control arm 
(lapatinib plus capecitabine). Approximately 600 patients will be enrolled and randomized equally between the 
two treatment arms.  
Patients will be stratified according to whether they are hormone receptor positive or negative, the number of 
previous HER2-directed regimens in the metastatic setting (N = 2 or N ≥3), their geographic region (North 
America vs. Europe, including Israel vs. Rest of World), and disease category (visceral vs. non-visceral only). 
Statistical Analysis: 
The primary efficacy analysis will be performed on the ITT population defined as all patients randomized into 
the study. Patients receiving at least one dose of investigational product will be evaluable for safety. 
Efficacy 
When 419 PFS events have occurred the primary PFS analysis will be performed. The median time to PFS and 
corresponding two-sided 95% confidence intervals will be calculated using the product limit estimator and 
displayed using a Kaplan-Meier graph, by treatment group. A log-rank test stratified by hormone receptor 
status, number of prior HER2-directed regimens in the metastatic setting, visceral disease, and geographic 
region will be used to test the null hypothesis of no difference in the time to PFS between the two treatment 
groups at the alpha level of 0.01. When 378 deaths have occurred, the primary OS analysis (final analysis) will 
be performed, using similar methods. A log-rank test controlling for hormone receptor status, number of prior 
HER2-directed regimens in the metastatic setting, visceral disease, and geographic region strata will be used to 
test the null hypothesis of no difference in the hazard between the two treatment groups at the alpha level of 
0.038. 
The treatment difference in the secondary efficacy endpoints of ORR and CBR will be analyzed using a 
Cochran-Mantel-Haenzel (CMH) Chi-square test, stratified by the hormone receptor status, number of prior 
HER2-directed regimens in the metastatic setting, geographic region, and disease category (visceral vs. 
non-visceral only). The treatment difference in the secondary efficacy endpoints of DOR, and Investigator-
assessed PFS will be analyzed using a product limit estimate of the median time to event.  Differences between 
treatment groups will be examined using a log rank test statistic stratified by hormone receptor status, prior 
HER2-directed regimens in the metastatic setting, geographic region, and disease category (visceral vs. non 
visceral only) similar to the analysis for the primary endpoint. All time-to-event endpoints, including time to 
intervention for symptomatic CNS disease, will be displayed using Kaplan-Meier survival plots. Health 
outcomes assessments (EORTC QLQ-C30, EORTC QLQ-BR23 and EQ-5D-5L) will be analyzed using a 
random effects mixed model with treatment, time, number of prior HER2-directed regimens in the metastatic 
setting (binary), geographic region, site of metastases, and the treatment by time interaction.   
Subjects who discontinue therapy early will be censored at their last available time point. Sensitivity analyses 
will be performed to investigate the impact of differential dropout between the 2 treatment groups on the 
treatment effect estimate. 
Safety 
All safety endpoints will be summarized by treatment group and visit when appropriate. Adverse events and 


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serious adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) coding 
system v.15 or later, and they will be tabulated by organ system and preferred term. All AEs will be graded 
according to the NCI CTCAE v.4.0. Differences in the incidence of the most common AEs and SAEs between 
the two treatment groups will be investigated using a CMH chi-square test, stratified on hormone receptor 
status, number of prior HER2-directed regimens in the metastatic setting, geographic region, and disease 
category (visceral vs. non-visceral only).  
Interim Analysis: 
No interim PFS or OS analysis for early stopping is planned. An interim analysis of OS will be conducted at the 
time of the final PFS analysis (at the alpha level of 0.002 at the interim analysis and 0.038 for the final analysis).  
Final Analysis:  
A final PFS analysis will be conducted when 419 PFS events have occurred. 
A final OS analysis will be conducted when 378 deaths have occurred. 
An analysis of all efficacy and safety endpoints will occur after the long-term follow-up phase has been completed. 
Study Design Diagram / Schedule of Procedures: 
A diagram of the study design is provided below in Figure 1. A schedule of procedures is included in Appendix 1. 
Figure 1. Study Schema of PUMA-NER-1301 
 
End of treatment is defined as documented disease progression, unacceptable toxicity or withdrawal of consent. 
 
 
PFS: progression-free survival; OS: overall survival.  
             
       
                                
            
                    
              
                 
          
 
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TABLE OF CONTENTS 
1 
LIST OF ABBREVIATIONS ............................................................................. 16 
2 
INTRODUCTION................................................................................................ 19 
2.1 
Background .................................................................................................... 19 
2.1.1 
General Therapeutic Area .................................................................... 19 
2.2 
Current Therapies ......................................................................................... 19 
2.2.1 
The Epidermal Growth Factor Receptor Family (ErbB Receptors) .... 19 
2.2.2 
Cancer Therapies Targeting HER Receptors ....................................... 20 
2.2.2.1 
Trastuzumab ................................................................................... 20 
2.2.2.2 
Pertuzumab [Perjeta™] .................................................................. 20 
2.2.2.3 
Pertuzumab in Combination with Trastuzumab ............................ 21 
2.2.2.4 
Ado-trastuzumab Emtansine (T-DM1[Kadcyla™]) ...................... 21 
2.2.2.5 
Lapatinib ........................................................................................ 22 
2.2.2.6 
Lapatinib in Combination with Capecitabine ................................ 22 
2.2.3 
Neratinib .............................................................................................. 23 
2.2.3.1 
Preclinical Data ............................................................................. 23 
2.2.3.2 
Neratinib Phase 1 and Pharmacokinetic Data .............................. 23 
2.2.3.3 
Neratinib Single-Agent Activity in Patients with HER2+ Breast 
Cancer ............................................................................................ 24 
2.2.3.4 
Neratinib in Combination with Capecitabine ................................ 25 
2.3 
Study Rationale .............................................................................................. 26 
3 
STUDY OBJECTIVES ........................................................................................ 27 
3.1 
Primary Objective .......................................................................................... 27 
3.2 
Secondary Objectives..................................................................................... 27 
3.3 
Exploratory Objective ................................................................................... 27 
4 
OVERALL DESIGN AND PLAN OF THE STUDY ....................................... 28 
4.1 
Study Design ................................................................................................... 28 
4.2 
Randomization and Blinding ........................................................................ 29 
4.2.1 
Randomization Scheme ....................................................................... 29 
4.2.2 
Enrollment and Randomization of Patients to Treatment .................... 29 
4.2.3 
Blinding and Breaking the Blind ......................................................... 30 
5 
STUDY POPULATION ...................................................................................... 30 
5.1 
Inclusion Criteria ........................................................................................... 30 


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5.2 
Exclusion Criteria .......................................................................................... 31 
6 
INVESTIGATIONAL PRODUCTS AND ADMINISTRATION ................... 33 
6.1 
Investigational Product Administration ...................................................... 33 
6.1.1 
Neratinib Plus Capecitabine ................................................................. 33 
6.1.2 
Lapatinib Plus Capecitabine ................................................................ 33 
6.1.3 
Dose Adjustment .................................................................................. 34 
6.2 
Packaging, Labeling and Storage ................................................................. 36 
6.3 
Drug Accountability....................................................................................... 37 
7 
CONCOMITANT TREATMENT ..................................................................... 38 
7.1 
Required Concomitant Treatment ............................................................... 38 
7.1.1 
Loperamide Antidiarrheal Therapy...................................................... 38 
7.2 
Permitted Concomitant Treatment .............................................................. 41 
7.3 
Prohibited Concomitant Treatment ............................................................. 41 
7.4 
Potential for Drug-Drug Interactions .......................................................... 41 
8 
EFFICACY AND SAFETY ASSESSMENTS ................................................... 44 
8.1 
Efficacy Assessment ....................................................................................... 44 
8.1.1 
Clinical Endpoints and Definitions ...................................................... 44 
8.1.2 
Tumor Assessments ............................................................................. 45 
8.1.2.1 
General Information ...................................................................... 45 
8.1.2.2 
Computerized Tomography and Magnetic Resonance Imaging .... 46 
8.1.2.3 
Caliper measurement by clinical examination when lesions are 
superficial ...................................................................................... 47 
8.2 
Safety Assessment .......................................................................................... 47 
8.2.1 
Laboratory Assessments ...................................................................... 47 
8.2.1.1 
Immunohistochemistry and Fluorescence In Situ Hybridization 
Testing of HER2 and ER/PR Status ............................................... 49 
8.2.2 
Vital Signs ............................................................................................ 50 
8.2.3 
Physical Examinations ......................................................................... 50 
8.2.4 
Electrocardiograms .............................................................................. 50 
8.2.5 
Left Ventricular Ejection Fraction (LVEF) ......................................... 50 
8.3 
Other Assessments ......................................................................................... 51 
8.3.1 
Pharmacokinetics ................................................................................. 51 
8.3.2 
Health Outcomes Assessments ............................................................ 51 
8.3.3 
ECOG Performance Status .................................................................. 51 
8.4 
Protocol Deviations ........................................................................................ 51 


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8.5 
Patient Diary................................................................................................... 51 
9 
STUDY CONDUCT ............................................................................................. 52 
9.1 
Screening/Baseline ......................................................................................... 52 
9.2 
Active Treatment Phase ................................................................................ 53 
9.3 
Treatment Discontinuation Visit .................................................................. 54 
9.4 
Safety Follow-up Contact .............................................................................. 55 
9.5 
Long-term Follow-up Phase .......................................................................... 55 
9.6 
End of Study ................................................................................................... 56 
10 
PATIENT WITHDRAWAL AND REPLACEMENT ..................................... 57 
10.1 
Investigational Product Discontinuation ..................................................... 57 
10.2 
Withdrawal from the Study .......................................................................... 57 
10.3 
Procedures for Patient Withdrawal ............................................................. 58 
10.4 
Patient Replacement ...................................................................................... 58 
11 
PREMATURE TERMINATION OF THE STUDY ......................................... 59 
12 
STATISTICAL METHODS ............................................................................... 60 
12.1 
General Considerations ................................................................................. 60 
12.2 
Study Patients ................................................................................................. 60 
12.2.1 
Disposition of Patients ......................................................................... 60 
12.2.2 
Demographics, Medical History, Baseline Characteristics, and 
Concomitant Medications .................................................................... 60 
12.2.3 
Treatment Compliance ......................................................................... 60 
12.3 
Efficacy Analyses ........................................................................................... 61 
12.3.1 
Primary Efficacy Analysis ................................................................... 61 
12.3.1.1 
Statistical Methods ......................................................................... 61 
12.3.2 
Secondary Efficacy Analyses .............................................................. 62 
12.3.2.1 
Statistical Methods ......................................................................... 62 
12.4 
Safety Analyses ............................................................................................... 63 
12.4.1 
Investigational Product Exposure ........................................................ 63 
12.4.2 
Adverse Events .................................................................................... 63 
12.4.3 
Laboratory Results ............................................................................... 63 
12.5 
Other Analyses ............................................................................................... 64 
12.5.1 
PK analysis........................................................................................... 64 
12.5.2 
Health Outcomes Assessments ............................................................ 64 
12.6 
Interim Analyses ............................................................................................ 64 
12.7 
Determination of Sample Size ....................................................................... 65 


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SAFETY DATA COLLECTION, RECORDING AND REPORTING.......... 66 
13.1 
Definitions ....................................................................................................... 66 
13.1.1 
Adverse Events .................................................................................... 66 
13.1.2 
Abnormal Laboratory Results .............................................................. 66 
13.1.3 
Serious Adverse Events ....................................................................... 67 
13.1.4 
Hospitalization ..................................................................................... 68 
13.1.5 
Suspected Unexpected Serious Adverse Reaction ............................... 69 
13.1.6 
Severity Assessment ............................................................................ 69 
13.1.7 
Causality Assessment........................................................................... 69 
13.1.8 
Special Reporting Situations ................................................................ 70 
13.2 
Reporting Adverse Events ............................................................................. 71 
13.3 
Reporting Serious Adverse Events ............................................................... 71 
13.4 
Pregnancy ....................................................................................................... 72 
13.5 
Sponsor Reporting Requirements to Health Authorities and IRB/IEC ... 73 
14 
ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS ........................... 74 
14.1 
Data Collection, Processing and Monitoring ............................................... 74 
14.1.1 
Case Report Forms and Source Documentation .................................. 74 
14.1.2 
Study Monitoring and Access to Source Documentation .................... 74 
14.1.3 
Data Monitoring Committee ................................................................ 75 
14.1.4 
Data Quality Assurance ....................................................................... 75 
14.1.5 
Data Processing .................................................................................... 76 
14.1.6 
Retention of Data and Study Records .................................................. 76 
14.2 
Ethical Aspects ............................................................................................... 76 
14.2.1 
Good Clinical Practice and Ethical Conduct of the Study ................... 76 
14.2.2 
Informed Consent................................................................................. 77 
14.3 
Other Study Administration Aspects ........................................................... 78 
14.3.1 
Protocol Approval and Protocol Amendment ...................................... 78 
14.3.2 
Investigator Responsibilities ................................................................ 78 
14.3.3 
Patient Confidentiality ......................................................................... 79 
14.3.4 
Financial Disclosure............................................................................. 80 
14.3.5 
Publication Policy ................................................................................ 80 
15 
REFERENCE LIST ............................................................................................. 81 
16 
SIGNATURE PAGES ......................................................................................... 87 
17 
APPENDICES ...................................................................................................... 90 


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LIST OF TABLES 
Table 1. Efficacy of Lapatinib + Capecitabine ............................................................... 23 
Table 2. Dose Reduction Levels for Neratinib-Related Toxicity .................................... 34 
Table 3. Dose Reduction Levels for Capecitabine-Related Toxicity (When Administered in 
Combination with Neratinib) ............................................................................ 35 
Table 4. Dose Reduction Levels for Lapatinib-Related Toxicity ................................... 35 
Table 5. Dose Reduction Levels for Capecitabine-Related Toxicity (When Administered in 
Combination with Lapatinib) ............................................................................ 36 
Table 6. Laboratory Assessments .................................................................................... 48 
 
LIST OF FIGURES 
Figure 1. Study Schema of PUMA-NER-1301 .................................................................. 9 
 
LIST OF APPENDICES 
Appendix 1 ......................................................................................................................... 91 
Appendix 2 ......................................................................................................................... 95 
Appendix 3 ....................................................................................................................... 109 
Appendix 4 ....................................................................................................................... 110 
Appendix 5 ....................................................................................................................... 111 
Appendix 6 ....................................................................................................................... 112 
Appendix 7 ....................................................................................................................... 114 
Appendix 8 ....................................................................................................................... 120 
Appendix 9 ....................................................................................................................... 122 
Appendix 10 ..................................................................................................................... 125 
 
LIST OF TABLES IN APPENDICES 
Table A1. 1 
Schedule of Procedures ........................................................................ 91 
 
Table A2. 1 
General Toxicities Requiring Dose Adjustment of Neratinib and 
Capecitabine ...................................................................................................... 95 
Table A2. 2 
Gastrointestinal Toxicities Requiring Dose Adjustment of Neratinib and 
Capecitabine ...................................................................................................... 96 
Table A2. 3 
Pulmonary Toxicities Requiring Dose Adjustment of Neratinib ......... 97 
Table A2. 4 
Liver Function Test Abnormalities Requiring Dose Adjustment of 
Neratinib and Capecitabine ............................................................................... 98 
Table A2. 5 
Left Ventricular Ejection Fraction (LVEF) Results Requiring Dose 
Adjustment of Neratinib ................................................................................... 99 
Table A2. 6 
Hematologic Abnormalities Requiring Dose Adjustment of Capecitabine 
(When Administered in Combination with Neratinib) ................................... 100 
Table A2. 7 
Hand-and-Foot Syndrome (Palmar-Plantar Erythrodysesthesia Syndrome) 
Requiring Dose Adjustment of Neratinib and Capecitabine........................... 101 


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Table A2. 8 
General Toxicities Requiring Dose Adjustment of Lapatinib and 
Capecitabine .................................................................................................... 102 
Table A2. 9 
Gastrointestinal Toxicities Requiring Dose Adjustment of Lapatinib and 
Capecitabine .................................................................................................... 103 
Table A2. 10 
Pulmonary Toxicities Requiring Dose Adjustment of Lapatinib ...... 104 
Table A2. 11 
Liver Function Test Abnormality Requiring Dose Adjustment of 
Lapatinib and Capecitabine ............................................................................. 105 
Table A2. 12 
Left Ventricular Ejection Fraction (LVEF) Results Requiring Dose 
Adjustment of Lapatinib when Administered in Combination with Capecitabine
 
106 
Table A2. 13 
Hematologic Abnormalities Requiring Dose Adjustment of Capecitabine 
(When Administered in Combination with Lapatinib) ................................... 107 
Table A2. 14 
Hand-and-Foot Syndrome (Palmar-Plantar Erythrodysesthesia Syndrome) 
Requiring Dose Adjustment of Capecitabine (When Administered in Combination 
with Lapatinib) ................................................................................................ 108 
 


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1 
LIST OF ABBREVIATIONS 
5-FU 
5-fluorouracil 
ADL 
activities of daily living 
AE 
adverse event 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
aPTT 
activated partial thromboplastin time 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
BID 
twice daily 
BUN 
blood urea nitrogen 
CBR 
clinical benefit rate 
CFR 
Code of Federal Regulations 
Cmax 
maximum plasma concentration 
CMH 
Cochran-Mantel-Haenzel 
CNS 
central nervous system 
CR 
complete response 
CRF 
case report form 
CRO 
contract research organization 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
Data Monitoring Committee 
DM1 
Emtansine 
DOR 
duration of response 
EC 
Ethics Committee 
ECD 
extracellular domain 
ECHO 
echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
epidermal growth factor receptor (also known as HER1) 
EIU 
Exposure-In-Utero 
ECG 
electrocardiogram, electrocardiography 
ErbB 
epidermal growth factor family of trans-membrane receptors (also known as HER) 
EMA 
European Medicines Agency 
EORTC  
European Organisation for Research and Treatment of Cancer Quality of Life  
EOS 
end of study 
ER 
estrogen receptor 
EU 
European Union 
FDA 
Food and Drug Administration 
FISH 
fluorescence in situ hybridization 
hCG 
human chorionic gonadotropin 
GCP 
Good Clinical Practice 
Hct 
hematocrit 
HER 
human epidermal growth factor receptor 
HER2+ 
human epidermal growth factor receptor 2 positive 


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Hb 
hemoglobin 
HIPAA 
Health Insurance Protection and Portability Act 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IM 
intramuscular 
INR 
international normalized ratio 
IP 
investigational product 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
IV 
intravenous(ly) 
LD 
longest diameter 
LDH 
lactate dehydrogenase 
LLN 
lower limit of normal 
LVEF 
left ventricular ejection fraction 
MBC 
metastatic breast cancer 
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple-gated acquisition scan 
NCI 
National Cancer Institute 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
P-gp 
P-glycoprotein 
PI3K 
phosphoinositide-3 kinase 
PK 
pharmacokinetic 
PPE 
palmar-plantar erythrodysesthesia syndrome 
PR 
partial response, progesterone receptor 
QLQ 
Quality of Life Questionnaire 
RBC 
red blood cell 
RDW 
red blood cell distribution width 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RoW 
rest of world 
SAD 
short axis diameter 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SC 
subcutaneous(ly) 
SD 
stable disease 
SLD 
sum longest diameter 


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SPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SUSAR 
suspected unexpected serious adverse reaction 
TD 
treatment discontinuation 
T-DM1 
trastuzumab emtansine 
TdP 
Torsade de Pointes 
TEAE 
treatment-emergent adverse event 
TID 
three times daily 
TTP 
time to tumor progression 
ULN 
upper limit of normal 
US 
United States (of America) 
WBC 
white blood cell 
WHODrug 
World Health Organization Drug Reference List 


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2 
INTRODUCTION 
2.1 
Background 
2.1.1 General Therapeutic Area 
Approximately 15-20% (Ahn et al., 2012; Saini et al, 2011) of women with breast cancer have 
human epidermal growth factor receptor 2 positive (HER2+) cancer, which is associated with 
aggressive disease and poor prognosis (Slamon et al, 1987). The human epidermal growth factor 
receptor 2 (HER2)/neu gene is a member of the family of EGFR/ErbB genes: amplification or 
overexpression is associated with an aggressive disease biology, including enhanced cell 
proliferation and reduced progression-free survival (PFS), and overall survival (OS) (Slamon et 
al, 1987; Zhang et al, 2007; Badache and Goncalves 2006; Slamon et al., 1989). Compared with 
female breast cancer, male breast cancer cases are more often hormonal receptor (estrogen 
receptor/progesterone receptor) positive and HER2 negative, but treatment of male breast cancer 
patients follows the same indications as female postmenopausal breast cancer with surgery, 
systemic therapy and radiotherapy (Ottini et al., 2010). 
2.2 
Current Therapies 
2.2.1 The Epidermal Growth Factor Receptor Family (ErbB Receptors) 
Members of the epidermal growth factor family of trans-membrane receptors (ErbB family) are 
potent mediators of normal cell growth and development and are expressed in various tissues of 
epithelial, mesenchymal and neuronal origin (Baselga and Swain, 2009). The ErbB family 
consists of four closely related type 1 trans-membrane tyrosine kinase receptors: epidermal 
growth factor receptor (EGFR; also known as ErbB1 and HER1), ErbB2 (HER2), ErbB3 
(HER3), and ErbB4 (HER4).  
Aberrant expression of HER1, HER2 and HER3 are linked to development of many epithelial 
cancers including colorectal, gastric, breast and head and neck cancers. These 
membrane-spanning proteins receive extracellular signals from small peptide ligand molecules, 
including epidermal growth factor-like molecules, transforming growth factor-α and neuregulins. 
Under normal physiological conditions, activation of the HER receptors is controlled by the 
spatial and temporal expression of their ligands (Yarden and Sliwkowski, 2001). Ligand binding 
triggers intracellular signaling through a complex and tightly controlled array of signaling 
pathways that together drive and regulate many cellular functions, including cell proliferation 
and organ development and repair. Binding of ligands to extracellular parts of HER1, HER3 and 
HER4 will result in dimerization and initiates a series of signaling cascades that includes 


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mitogen-activated protein kinase, phosphoinositide-3kinase (PI3K), Akt, and mammalian target 
of rapamycin (Garrett and Arteaga, 2011).  
Each receptor comprises an extracellular domain (ECD) at which ligand binding occurs: an 
alpha-helical trans-membrane segment and an intracellular protein tyrosine kinase domain 
(Olayioye et al., 2000). Receptor dimerization is an essential requirement for signaling activity of 
these receptors and can occur between two different HER receptors (hetero-dimerization) or 
between two molecules of the same receptor (homo-dimerization) (Olayioye et al., 2000; 
Ferguson et al., 2003). HER homodimers weakly perpetuate signals compared with heterodimers 
(Yarden and Sliwkowski, 2001). As the natural ligand for HER2 has not been identified, the 
receptor is presumed to exert its effects via formation of heterodimers with other HER family 
members, and is thought to be the preferred dimerization partner for the other receptors (Rosen et 
al., 2010). In fact, heterodimer formation with HER2 has been shown to increase the affinity of 
ligand binding to the dimerization partner (Graus-Porta et al., 1997). Dimerization of HER3, 
which lacks intrinsic kinase activity, with HER2 induces phosphorylation of HER3, which then 
activates the PI3K and Akt pathways (Graus-Porta et al., 1997).  
2.2.2 Cancer Therapies Targeting HER Receptors 
2.2.2.1 Trastuzumab  
Trastuzumab, the first agent approved for treatment of HER2+ breast cancer, is a monoclonal 
antibody that binds to the juxtamembrane portion of the HER2/neu receptor, resulting in 
inhibition of tumor proliferation (Goldenberg 1999). Possible mechanisms by which trastuzumab 
might decrease signaling include prevention of HER2-receptor dimerization, increased 
endocytotic destruction of the receptor, inhibition of shedding the extra-cellular domain, and 
immune activation (Valabrega et al., 2007). Preclinical models suggest that trastuzumab recruits 
immune effector cells that are responsible for antibody-dependent cytotoxicity (Weiner and 
Adams, 2000). Trastuzumab was first approved for use in the treatment of HER2-amplified 
breast cancer in the US in 1998. 
2.2.2.2 Pertuzumab [Perjeta™]  
Pertuzumab (Perjeta) is a monoclonal antibody that binds HER2 at a different epitope of the 
HER2 extracellular domain (subdomain II) than that at which trastuzumab binds (Baselga et al., 
2012) and prevents HER2 from dimerizing with other ligand-activated HER receptors, most 
notably HER3 (Baselga and Swain, 2009; Agus et al., 2002). The HER2-HER3 heterodimer is 
considered to be the most potent signaling pair (Agus et al., 2002), driving cell proliferation in 
HER2+ cancer (Lee-Hoeflich et al., 2008; Hsieh and Moasser, 2007). In recent studies, the 
addition of pertuzumab to combination therapy has led to improvements in PFS in patients with 


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HER2+ metastatic breast cancer (MBC) and higher response rates in the preoperative setting 
(Murphy and Morris, 2012). 
2.2.2.3 Pertuzumab in Combination with Trastuzumab 
Although treatment with trastuzumab in addition to chemotherapy (as compared with 
chemotherapy alone) significantly improves PFS and OS among patients with HER2+ MBC, in 
most patients, the disease progresses (Nahta and Esteva 2007). Because pertuzumab and 
trastuzumab bind to different HER2 epitopes and have complementary mechanisms of action, the 
combination of these two agents, provide a more comprehensive blockade of HER2 signaling 
and result in greater antitumor activity than either agent alone in HER2+ tumor models (Lee-
Hoeflich et al., 2008; Scheuer et al., 2009). In Phase 2 studies, a pertuzumab-trastuzumab 
regimen showed activity in patients with HER2+ MBC (Baselga et al. 2010; Portera et al., 2008) 
and in patients with early breast cancer (Gianni et al., 2010).  
The Clinical Evaluation of Pertuzumab and Trastuzumab (CLEOPATRA) study assessed the 
efficacy and safety of pertuzumab plus trastuzumab plus docetaxel, as compared with placebo 
plus trastuzumab plus docetaxel (control group), as first-line treatment for patients with HER2+ 
MBC who had not received chemotherapy or biologic therapy for their metastatic disease 
(Baselga et al., 2012). Based on an interim analysis (on 43% of the total number of events 
planned for the final analysis), treatment with pertuzumab plus trastuzumab plus docetaxel 
compared with the control group resulted in a significant reduction in the risk of progression or 
death and an increase of 6.1 months in median PFS (Baselga et al., 2012). The median PFS in the 
control group (12.4 months) was similar to that among HER2+ MBC patients in two other 
randomized studies, who were treated with the combination of trastuzumab and docetaxel 
(11.7 months (Marty et al., 2005) and 11.1 months (Valero et al., 2011). CLEOPATRA findings 
suggest that targeting HER2+ tumors with two anti-HER2 monoclonal antibodies that have 
complementary mechanisms of action results in a more comprehensive blockade of HER2 and 
highlights the clinical importance of preventing the ligand-dependent formation of HER2 dimers 
in order to silence HER2 signaling to the greatest extent possible (Baselga and Swain, 2009; 
Yarden and Sliwkowski, 2001). 
Pertuzumab received approval in the US in 2012 for use in combination with trastuzumab and 
docetaxel for the treatment of patients with HER2+ MBC who have not received prior 
anti-HER2 therapy or chemotherapy for metastatic disease.  
2.2.2.4 Ado-trastuzumab Emtansine (T-DM1[Kadcyla™]) 
Ado-trastuzumab emtansine (T-DM1 [Kadcyla]) is an antibody-drug conjugate that combines 
HER2-targeted delivery of the potent antimicrotubule agent emtansine (DM1), a derivative of the 
antimicrotubule agent maytansine, with the antitumor activity of trastuzumab (Lewis Phillips et 


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al., 2008; Remillard et al., 1975; Cassady et al., 2004; Widdison et al., 2006; Junttila et al., 
2011). In T-DM1, trastuzumab and DM1 are covalently linked via a stable thioether linker 
(N-maleimidomethyl) cyclohexane-1-carboxylate, which is thought to limit the exposure of 
normal tissue to DM1 (Krop et al., 2010; Burris et al., 2011). Antitumor activity was established 
in a proof-of-concept Phase 2 study of single-agent T-DM1 in patients with HER2+ MBC, who 
had progressed while receiving HER2-directed therapy (Burris et al., 2011). Furthermore, in a 
single-arm Phase 2 study, T-DM1 demonstrated efficacy in patients with HER2+ MBC who 
previously received all standard HER2-directed therapies (trastuzumab, lapatinib, an 
anthracycline, a taxane, and capecitabine) (Krop et al., 2012).  
Primary results from the EMILIA study (a Phase 3, randomized, multicenter study of T-DM1 
compared with lapatinib plus capecitabine in patients with HER2+ locally advanced or MBC, 
previously treated with a trastuzumab-based regimen and a taxane) showed a significant and 
clinically meaningful improvement with T-DM1 in PFS compared with lapatinib plus 
capecitabine (Blackwell et al., 2012). Other end points supported T-DM1 as an active and well-
tolerated novel therapy for HER2+ advanced breast cancer. T-DM1 is approved in the US for 
patients with HER2-positive MBC who have previously received trastuzumab and a taxane 
separately or in combination. 
2.2.2.5 Lapatinib 
Another HER2-targeted agent is lapatinib, an oral, selective, reversible, small molecule tyrosine 
kinase inhibitor that targets the tyrosine kinase domains of both HER1 and HER2 (Rusnak et al., 
2011; Gomez et al., 2008). In vitro studies confirmed that lapatinib inhibits growth (Rusnak et 
al., 2011; Xia et al., 2002) and can lead to cell arrest or apoptosis (Rusnak et al., 2001; Xia et al., 
2002; Konecny et al., 2006) in human tumor cells overexpressing HER1 or HER2. Furthermore, 
lapatinib treatment has been shown to inhibit the growth of HER2-overexpressing human breast 
cancer cells that do not respond to trastuzumab after long-term conditioning (Konecny et al., 
2006). Investigations of lapatinib monotherapy conducted in highly refractory MBC patients 
showed modest cytoreduction and disease stabilization in a trastuzumab-refractory setting 
(Blackwell et al., 2005). 
2.2.2.6 Lapatinib in Combination with Capecitabine  
Lapatinib was first approved in the US in 2007 for use in combination with capecitabine for the 
treatment of patients with advanced or MBC whose tumors overexpress HER2 and who have 
received prior therapy including an anthracycline, a taxane and trastuzumab. 
The efficacy of lapatinib in combination with capecitabine is summarized in Table 1. 
Information from both the US Package Insert (independently-assessed) and European Summary 


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of Product Characteristics (SPC) (Investigator-assessed) are included to provide a broader 
regional perspective. 
Table 1. 
Efficacy of Lapatinib + Capecitabine 
Products 
ORR (%) 
Median TTP 
(weeks) 
Median OS 
(weeks) 
Lapatinib + Capecitabine 
23.7a 
27.1a 
23.9b 
75.0a 
74.0b 
Abbreviations: ORR: objective response rate, OS: overall survival; TPP: time to tumor progression. 
a Tykerb® (lapatinib) tablets [US package insert]  
b Tyverb® 250 mg film-coated tablets (SPC)  
 
2.2.3 Neratinib 
2.2.3.1 Preclinical Data 
Neratinib is an orally available small molecule that inhibits HER1, HER2 and HER4 at the 
intracellular tyrosine kinase domains, a mechanism of action that is different from trastuzumab 
as well as lapatinib. Neratinib reduces HER1 and HER2 autophosphorylation, downstream 
signaling, and the growth of HER1 and HER2 dependent cell lines. Neratinib most likely inhibits 
kinase activity through irreversible binding at a targeted cysteine residue in the adenosine 
triphosphate binding pocket of the receptor. Preclinical data suggest that neratinib will have 
antitumor activity in HER1 and/or HER2-expressing carcinoma cell lines, with cellular 
IC50 <100 nM (Rabindran et al., 2004). 
Neratinib may have advantages over other HER2 inhibitors, due to its ability to inhibit both 
HER1 and HER2, and to inhibit irreversibly. Breast cancer cells may become resistant to 
trastuzumab on the basis of ECD truncated HER2 receptor, which can no longer be recognized 
by the antibody (Xia et al., 2004), or because of co-activation of HER1 signaling (Rampaul et al., 
2005; Zaczek et al., 2005). However, since neratinib acts on the intracellular tyrosine kinase 
domain, such cells are likely to maintain sensitivity to neratinib (Mosesson and Yarden, 2004). 
In vivo, neratinib is active in HER2 and HER1-dependent tumor xenograft models, when 
administered orally on a once daily schedule. Overall, neratinib is less potent against 
HER1-dependent tumors than HER2-dependent tumors in vivo, although it has equivalent 
activity against the two kinases in vitro. 
Further pre-clinical information on neratinib is provided in the current Investigator's Brochure. 
2.2.3.2 Neratinib Phase 1 and Pharmacokinetic Data 
Further information on the Phase 1 and PK data for neratinib is provided in the current 
Investigator's Brochure. 


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2.2.3.3  Neratinib Single-Agent Activity in Patients with HER2+ Breast Cancer 
Both the ability of neratinib to concurrently block signal transduction through the three active 
tyrosine kinase HER receptors and its irreversible binding and prolonged inhibition of these 
growth-promoting pathways provide the opportunity to further improve the clinical benefit of 
this therapeutic approach in HER2+ MBC patients. Early clinical data have demonstrated the 
activity of neratinib in patients who have already failed other small molecule or antibody-
based anti-HER receptor therapies, suggesting the ability of this agent to overcome drug 
resistance in this refractory patient population. 
In the single-agent, first in human, Phase 1 study (3144A1-102-US) of neratinib in solid tumor, a 
32% objective response rate (ORR) was observed among patients with trastuzumab refractory 
HER2 overexpressing disease (Wong et al., 2009). Specifically, 8 of 25 patients had partial 
response (PR). Among the responders, 2 PRs occurred at neratinib doses of 120 or 180 mg per 
day, which was below the recommended monotherapy dose. All of these responders had prior 
trastuzumab therapy, notably 6 patients had received at least four trastuzumab-based therapies. 
Additionally, all had received prior anthracycline and gemcitabine, and the majority (7/8) had 
received prior taxane therapy. Six patients had also received prior capecitabine therapy and 3 had 
received prior 5% fluorouracil treatment. This activity in trastuzumab-resistant breast cancers in 
the Phase 1 setting compares favorably to the response rates reported in two Phase 2 studies of 
the reversible dual kinase inhibitor, lapatinib, in a similar patient population (Blackwell et al, 
2005). 
An open-label, multicenter, Phase 2 study evaluated the efficacy and safety of neratinib 240 mg 
daily, in patients with and without prior trastuzumab treatment, who had advanced HER2+ breast 
cancer. The primary end point, the 16-week PFS rates, was 59% and 78% in prior 
trastuzumab-treated patients and trastuzumab-naïve cohorts, respectively (Burstein et al., 2010). 
The ORR was 24% and 56%, respectively, and the median PFS times were 22.3 and 39.6 weeks, 
respectively. Mean steady-state trough concentrations for the 240 mg daily dose exceeded 
concentrations needed to inhibit autophosphorylation of HER2 in preclinical models (Rabindran 
et al., 2004).  
The most common adverse events (AE) were diarrhea, nausea, vomiting, and fatigue. Diarrhea 
was the most frequent Grade 3 to 4 AE, occurring in 30% of patients with prior trastuzumab 
treatment and in 13% of trastuzumab-naïve patients, which resulted in dose reductions of 29% 
and 4% of patients, respectively. However, treatment discontinuation (TD) occurred in only one 
patient due to diarrhea (Grade 2). No neratinib-related Grade 3 or 4 cardiotoxicity was reported.  
Additional information regarding previous clinical studies of neratinib for treatment of HER2+ 
breast cancer is provided in the current Investigator’s Brochure. 


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2.2.3.4 Neratinib in Combination with Capecitabine  
In a Phase 1/2 clinical study (3144A1-2206-WW) investigating the combination of neratinib plus 
capecitabine, the maximum tolerated dose (MTD) of neratinib 240 mg was established in 
combination with capecitabine 1500 mg/m2 in patients with solid tumors. Subsequent 
investigation of this dose regimen in patients with HER2+ advanced breast cancer demonstrated 
that this combination treatment was clinically active and has a manageable toxicity profile. 
In the study, clinical responses at the MTD were observed in 63% of patients (64% of those with 
no prior lapatinib exposure and 57% of those with prior lapatinib), while median durations of 
response were 46 and 48 weeks, respectively. This is a slightly higher response rate and similar 
duration of response (DOR) to that observed in previous neratinib monotherapy studies, but in a 
full study population previously treated with trastuzumab (Burstein et al., 2010; Wong et al., 
2009); an ORR of 29% with neratinib monotherapy has also been reported (Martin et al., 2011). 
In this study, all patients progressed to previous trastuzumab-based therapy, and median PFS 
with neratinib plus capecitabine was 40 weeks in the lapatinib-naive cohort and 36 weeks in the 
lapatinib-treated cohort. These results compare favorably with those previously observed in the 
monotherapy study for patients who received prior trastuzumab (22 weeks) (Geyer et al., 2006). 
The results of this study suggest that the combination of neratinib plus capecitabine may have 
superior efficacy in patients with prior therapy with anti HER2-targeted therapies.  
The results of this Phase 1/2 study also compare favorably with results obtained from the 
combination of lapatinib plus capecitabine in an indirect comparison. In a Phase 3 study, ORR 
(44.2%), clinical benefit rate (CBR) (57.7%), and PFS (6.34 months) with lapatinib plus 
capecitabine were lower than was observed with neratinib plus capecitabine in the Phase 
1/2 study (Xu et al., 2011).  
The combination of neratinib plus capecitabine was associated with an acceptable safety and 
tolerability profile in the Phase 1/2 study. Diarrhea was the most common Grade 3/4 AE in the 
study (reported by 23% of patients), although only 4 patients discontinued treatment due to the 
event (6%), which is similar to previous experience in neratinib monotherapy studies (Burstein et 
al., 2010; Wong et al., 2009). Diarrhea typically occurred within a few days of neratinib 
initiation (median, 2 days) and was most often managed by a dose delay or reduction. Across 
previous neratinib studies, diarrhea typically occurred within 2-8.5 days of neratinib initiation 
and was generally managed with dose adjustments or antidiarrheal medications (Burstein et al., 
2010; Wong et al., 2009).  
The most frequent toxicities reported with capecitabine monotherapy are palmar-plantar 
erythrodysesthesia syndrome (PPE) and gastrointestinal events. While the incidence of PPE (all 
grades, 47%) in this study was similar to the range reported in capecitabine monotherapy studies 
(37% to 60%), the incidence of diarrhea was higher (all grades, 88% compared with 5% to 58% 


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reported in monotherapy studies) (Burstein et al., 2010; Wong et al., 2009), as may be expected 
from the combination of two drugs that are associated with gastrointestinal effects. Overall, no 
unexpected toxicity was observed in patients receiving neratinib plus capecitabine, and few 
patients discontinued treatment due to toxicity. 
Further details can be found in the current Investigator's Brochure which contains comprehensive 
information on the investigational product. 
2.3 
Study Rationale 
The use of taxanes, anthracyclines, and trastuzumab early in the treatment of HER2+ MBC has 
become standard practice. In patients whose HER2 disease recurs after adjuvant/neoadjuvant 
trastuzumab therapy and in patients who initially present with advanced metastatic HER2 
disease, treatment with trastuzumab in combination with a chemotherapy regimen is usually 
prescribed. Almost all patients receiving trastuzumab alone or in combination with other drugs 
for HER2 overexpressing MBC ultimately progress. The clinical benefit of continuing 
trastuzumab after progression in the first-line metastatic setting has not been definitively 
established in prospective clinical studies. It is hypothesized that sensitivity to trastuzumab may 
be retained and that the combination of trastuzumab plus another chemotherapy agent may be 
preferable to chemotherapy alone in the second-line setting (Pusztai and Esteva 2006; 
vonMinckwitz et al., 2009). This may explain the widespread acceptance and use of trastuzumab 
plus a different cytotoxic agent in the second-line setting (Love, 2004).  
After multiple treatment regimens with trastuzumab and possibly lapatinib, it is hypothesized 
that the tumor may no longer be sensitive to the existing HER2 agents. Consequently, the 
continuing development of new anti-HER2 strategies is needed, particularly for patients whose 
disease has progressed on prior regimens. 
The current multicenter, multinational, randomized, controlled clinical study is designed to 
compare OS and independently-assessed PFS following treatment with neratinib plus 
capecitabine versus lapatinib plus capecitabine in patients with HER2+ MBC who have received 
two or more prior HER2-directed regimens in the metastatic setting.  
Further information on the benefits and risks of neratinib in this patient population is provided in 
the current Investigator's Brochure.  


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3 
STUDY OBJECTIVES 
3.1 
Primary Objective 
The co-primary objectives of this study are: 
 to compare independently adjudicated PFS following treatment with neratinib plus 
capecitabine versus lapatinib plus capecitabine in patients with HER2+ MBC who have 
received two or more prior HER2-directed regimens in the metastatic setting. 
 to compare OS following treatment with neratinib plus capecitabine versus lapatinib plus 
capecitabine in this population. 
3.2 
Secondary Objectives 
The secondary objectives of this study are to compare between the two treatment groups:  
 Investigator-assessed PFS. 
 Objective response rate (ORR), duration of response (DOR) and clinical benefit rate (CBR) 
(complete response [CR] or partial response [PR] or stable disease [SD] ≥24 weeks).  
 Time to intervention for symptomatic metastatic central nervous system (CNS) disease. 
 Safety (AEs, serious adverse events [SAEs]).  
 Health outcomes assessments. 
3.3 
Exploratory Objective 
The exploratory objective of this study is:  
 To assess the population PK of neratinib when administered in combination with 
capecitabine. 


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4 
OVERALL DESIGN AND PLAN OF THE STUDY 
4.1 
Study Design 
This is a randomized, multi-center, multinational, open-label, active-controlled, parallel design 
study of the combination of neratinib plus capecitabine versus the combination of lapatinib plus 
capecitabine in HER2+ MBC patients, who have received two or more prior HER2-directed 
regimens in the metastatic setting.  
Patients will be randomized in a 1:1 ratio to one of two treatment arms: 
 Arm A: neratinib (240 mg once daily) + capecitabine (1500 mg/m2 orally daily, 750 mg/m2 
twice daily [BID]) 
 Arm B: lapatinib (1250 mg once daily) + capecitabine (2000 mg/m2 orally daily, 1000 mg/m2 
BID) 
Following a 21-day screening period (Section 9.1), eligible patients will be randomized to 
Arm A or Arm B. Baseline assessments will be performed prior to randomization. Following 
randomization, patients will participate in the active treatment phase, consisting of 21-day 
treatment cycles (Section 9.2). Investigational products will be administered orally by patients as 
described in Section 6.1. Neratinib and lapatinib are to be taken continuously, in 21-day cycles, 
with no rest between cycles. Capecitabine will be taken on Days 1 to 14 of each 21-day cycle. 
Clinic visits during the active treatment phase are planned on Days 1, 8, and 15 of Cycle 1 and 
on Day 1 of each subsequent cycle. Assessments required throughout the study are summarized 
in the Schedule of Procedures (Appendix 1) and a diagram of the study schema is provided in 
Figure 1.  
Patients may be discontinued from investigational product(s) or from the study, as described in 
Sections 10.1, 10.2 and 11.  
The co-primary endpoints are independently adjudicated PFS and OS. The secondary endpoints 
are investigator-assessed PFS, ORR, DOR, CBR (CR, PR or SD ≥24 weeks), health outcomes 
assessments, time to intervention for symptomatic metastatic CNS disease, AEs and SAEs 
(graded according to the National Cancer Institute [NCI] Common Terminology Criteria for 
Adverse Events Version 4.0 [CTCAE v.4.0]). An interim analysis of OS will be performed at the 
time of final PFS analysis (Section 12.6).  
Approximately 600 patients will be enrolled at approximately 200 centers in North America, 
Europe including Israel, and the Rest of World (RoW). See Section 12.7 for a discussion of 
sample size. 


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Patients are anticipated to participate in the study for an average of 28 months. This includes 
approximately 0.5 months for screening, an estimated average of 9.5 months for the active 
treatment phase, and an estimated average of 18 months for the long-term follow-up phase. 
Patients who permanently discontinue treatment will enter the long-term follow-up phase 
(Section 9.5 until death or withdrawal of consent (Section 10.2). 
The approximate duration of the study is 50 months, which is the time estimated to reach the 
required 378 OS events. The end of study (EOS) will occur as of the date of the last visit of the 
last patient undergoing the study. In the event that the EOS is declared earlier (e.g., OS primary 
endpoint is met), patients who continue to receive clinical benefit from neratinib plus 
capecitabine will be offered the opportunity to continue to receive this combination via a 
treatment extension study or expanded access protocol. Patients who continue to derive clinical 
benefit from lapatinib plus capecitabine will be provided the opportunity to receive these 
marketed therapies as well. 
4.2 
Randomization and Blinding 
4.2.1 Randomization Scheme 
Randomization will be managed and maintained centrally through an automated Interactive 
Voice Response System/Interactive Web Response System. Patients will be randomized in a 
1:1 ratio to one of the two treatment arms. 
Randomization will be stratified according to: 
 The number of previous HER2-directed regimens in the metastatic setting (N = 2 or 
N ≥3). 
 Geographic region (North America vs. Europe, including Israel vs. RoW) 
 Visceral vs. non-visceral only disease  
 Estrogen receptor+ (ER+) and/or progesterone receptor (PR+) (i.e., hormone receptor +) 
versus ER- and PR- (i.e., hormone receptor -). 
4.2.2 Enrollment and Randomization of Patients to Treatment 
Once eligibility is confirmed, patients will be randomized to a treatment group according to the 
randomization schedule. All patients must commence treatment with investigational products no 
later than 14 days after randomization. Patients who do not meet the eligibility criteria will not 
be randomized in the study, but may be rescreened up to two times at the Investigator’s 
discretion.  


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4.2.3 Blinding and Breaking the Blind 
This is an open-label study. 
5 
STUDY POPULATION 
5.1 
Inclusion Criteria 
Each patient will be entered into this study only if she/he meets all of the following criteria: 
1. Aged ≥18 years at signing of informed consent. 
2. Histologically confirmed MBC, current stage IV. 
3. Documented HER2 overexpression or gene-amplified tumor (immunohistochemistry 
[IHC] 3+; or IHC 2+ with confirmatory fluorescence in situ hybridization [FISH]+). (Note: 
Patients who are IHC 0 or 1+ are not eligible to participate in the study). Tumor samples will 
be evaluated for HER2 expression by IHC (HercepTest™) and if required for gene 
amplification by FISH analysis (IQFISH pharmDx™). 
4. Prior treatment with at least two HER2-directed regimens for metastatic breast cancer. A new 
regimen is defined as a modification in a planned course of therapy to include other treatment 
agents (alone or in combination) as a result of disease progression, relapse, or toxicity 
(Rajkumar et al., 2011). A new regimen also starts when a planned period of observation off 
therapy is interrupted by a need for additional treatment for the disease. 
5. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors 
(RECIST v1.1 (Eisenhauer et al., 2009), see Appendix 7). Specifically, no ascites, pleural or 
pericardial effusions, osteoblastic bone metastases, or carcinomatous lymphangitis of the 
lung as the only lesion are allowed.  
6. Left ventricular ejection fraction (LVEF) ≥50% measured by multiple-gated acquisition scan 
(MUGA) or echocardiogram (ECHO). 
7. Eastern Cooperative Oncology Group (ECOG) status of 0 to 1 (see Appendix 3). 
8. Negative β-human chorionic gonadotropin (hCG) pregnancy test for premenopausal women 
of reproductive capacity (those who are biologically capable of having children) and for 
women less than 12 months after menopause. 
9. Women of childbearing potential must agree and commit to the use of a highly effective 
method of contraception, as determined to be acceptable by the Investigator, from the time of 
informed consent until 28 days after the last dose of the investigational products. Men must 
agree and commit to use a barrier method of contraception while on treatment and for 
3 months after last dose of investigational products. 


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10. Provide written, informed consent to participate in the study and follow the study procedures. 
5.2 
Exclusion Criteria 
A patient will be excluded from this study if she/he meets any of the following criteria: 
1. Received previous therapy with capecitabine, neratinib, lapatinib, or any other 
HER2-directed tyrosine kinase inhibitor.  
2. 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. 
3. Any major surgery ≤28 days prior to the initiation of investigational products, or received 
anti-cancer therapy (including chemotherapy, biological therapy, hormonal therapy, 
investigational agents, or other anti-cancer therapy) administered ≤21 days prior to the 
initiation of investigational products.  
4. Received radiation therapy ≤14 days prior to initiation of investigational products. 
5. Symptomatic or unstable brain metastases. (Note: Asymptomatic patients with metastatic 
brain disease who have been on a stable dose of corticosteroids for treatment of brain 
metastases for at least 14 days prior to randomization are eligible to participate in the study).  
6. Active uncontrolled cardiac disease, including cardiomyopathy, congestive heart failure 
(New York Heart Association functional classification of ≥2), unstable angina, myocardial 
infarction within 12 months of enrollment, or ventricular arrhythmia. 
7. QTc interval >0.450 seconds or known history of QTc prolongation or Torsades de Pointes. 
8. Screening laboratory assessments outside the following limits:  
Laboratory endpoint 
Required limit for exclusion 
Absolute neutrophil count (ANC)  
<1500/µL (<1.5 x 109/L) 
Platelet count  
<100,000/µL (<100 x 109/L) 
Hemoglobin (Hb) 
<8 g/dL (transfusions allowed) 
Transfusions must be at least 14 days prior to randomization. 
Total bilirubin  
>1.5 x institutional upper limit of normal (ULN) 
Aspartate aminotransferase (AST) and/or 
Alanine aminotransferase (ALT)  
>3 x institutional ULN (>5 x ULN if liver metastases are present) 
Creatinine clearance  
<50 mL/min (as calculated by Cockroft and Gault formulaa or 
Modification of Diet in Renal Disease [MDRD] formulab) 
a Cockcroft and Gault, 1976 
b Levey et al., 1999 


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9. Active infection or unexplained fever >38.5°C (101.3°F).  
10. Other malignancy within the past 3 years with the exception of a) adequately treated basal 
cell carcinoma, squamous cell skin cancer, or thyroid cancer; b) carcinoma in situ of the 
cervix or vulva; c) prostate cancer of Gleason Score 6 or less with stable prostate-specific 
antigen levels; or d) cancer considered cured by surgical resection or unlikely to impact 
survival during the duration of the study, such as localized transitional cell carcinoma of the 
bladder, or benign tumors of the adrenal or pancreas.  
11. Currently breast-feeding. 
12. Significant chronic gastrointestinal disorder with diarrhea as a major symptom (e.g., Crohn’s 
disease, malabsorption, or Grade ≥2 (NCI CTCAE v.4.0) diarrhea of any etiology at 
screening). 
13. Active infection with hepatitis B or hepatitis C virus. 
14. Known dihydropyrimidine dehydrogenase deficiency. 
15. Known hypersensitivity to 5-fluorouracil or to any component of the investigational products 
or compounds of similar chemical composition. 
16. Unable or unwilling to swallow tablets. 
17. Evidence of significant medical illness, abnormal laboratory finding, or psychiatric 
illness/social situations that would, in the Investigator’s judgment, make the patient 
inappropriate for this study. 


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6 
INVESTIGATIONAL PRODUCTS AND ADMINISTRATION 
6.1 
Investigational Product Administration 
6.1.1 Neratinib Plus Capecitabine 
Neratinib  
Neratinib investigational product will be supplied as 40 mg film-coated tablets packaged in 
bottles with desiccant.  
Neratinib (240 mg initial dose; provided as six 40 mg tablets) will be self-administered orally by 
patients on a daily basis, starting with Cycle 1/Day 1. Neratinib should be taken with food, in the 
morning.  
Neratinib is to be taken continuously in 21-day cycles, with no rest between cycles. 
Capecitabine 
Capecitabine investigational product is available as 150 mg and 500 mg film-coated tablets.   
Capecitabine (total dose of 1500 mg/m2 daily, in 2 approximately evenly divided doses) will be 
self-administered orally by patients, starting with Cycle 1/Day 1. Doses are to be taken daily on 
Days 1 to 14 of each 21-day cycle. Capecitabine should be taken with water within 30 minutes 
after a meal.  
During treatment with neratinib plus capecitabine, patients should be monitored for conditions 
that may require dose to be held or discontinued, as described in Appendix 2. Careful attention 
should be paid to the onset of diarrhea or hand-foot syndrome in particular, and early dose 
adjustment or prophylactic therapy should be implemented as described in Appendix 2. 
Daily dosing of neratinib plus capecitabine should continue until a criterion for treatment 
withdrawal or study withdrawal is met (see Sections 10.1 and 10.2, respectively).  
6.1.2 Lapatinib Plus Capecitabine 
Lapatinib  
Lapatinib investigational product is available as 250 mg film-coated tablets.  
Lapatinib (1250 mg initial dose; provided as five 250 mg tablets) will be self-administered orally 
by patients on a daily basis, starting with Cycle 1/Day 1. The total daily dose of lapatinib should 
be taken 1 hour before or after breakfast; daily doses should not be divided.  
Lapatinib is to be taken continuously in 21-day cycles, with no rest between cycles. 


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Refer to the lapatinib (Tykerb®) US Package Insert and/or the (Tyverb®) SPC for further 
information on dosing  
Capecitabine 
Capecitabine investigational product is available as 150 mg and 500 mg film-coated tablets. 
Capecitabine (total dose of 2000 mg/m2 daily, in 2 approximately evenly divided doses) will be 
self-administered orally by patients, starting with Cycle 1/Day 1. Doses are to be taken daily on 
Days 1 to 14 of each 21-day cycle. Capecitabine should be taken with water within 30 minutes 
after a meal.  
During treatment with lapatinib plus capecitabine, patients should be monitored for conditions 
that may require dose to be held or discontinued, as described in Appendix 2. Careful attention 
should be paid to the onset of diarrhea or hand-foot syndrome in particular, and early dose 
adjustment or prophylactic therapy should be implemented as described in Appendix 2. 
Daily dosing of lapatinib plus capecitabine should continue until a criterion for treatment 
withdrawal or study withdrawal is met (see Sections 10.1 and 10.2, respectively).  
Refer to the capecitabine (Xeloda®) US Package Insert and/or the SPC for further information on 
dosing. 
6.1.3 Dose Adjustment 
Investigational product dose adjustment and/or discontinuation should be performed according to 
Appendix 2 and Section 10.1.  
Recommended dose reductions for the -1 and -2 dose levels of neratinib are listed in Table 2.  
Table 2. Dose Reduction Levels for Neratinib-Related Toxicity 
Dose Level 
Neratinib 
Starting Dose 
240 mg 
-1 
160 mg 
-2 
120 mg 
 
Recommended dose reductions for the -1 and -2 dose levels of capecitabine in combination with 
neratinib are listed in Table 3.  


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Table 3. Dose Reduction Levels for Capecitabine-Related Toxicity (When Administered 
in Combination with Neratinib) 
Dose Level 
Capecitabine (administered in combination with neratinib) 
Starting Dose 
1500 mg/m2, 750 mg/m2 BID 
-1a 
1100 mg/m2, 550 mg/m2 BID 
-2a 
750 mg/m2, 375 mg/m2 BID 
Abbreviation: BID: twice daily 
a Since capecitabine is provided as 150 mg or 500 mg tablets, it is recommended that the capecitabine dose 
reduction(s) (to 75% [level -1] or 50% [level -2] of the starting dose) is rounded down to the nearest 500 mg or 
multiple of 150 mg for the BID dose. If the patient’s body surface area is >2.0, the standard of care for the study 
center can be utilized for capecitabine mg/m2 dosing. 
 
The recommended dose reduction for the -1 dose level of lapatinib is listed in Table 4. Lapatinib 
doses should be held in patients with an LVEF that is Grade ≥2 and in patients with an LVEF 
that decreases below the institution’s lower limit of normal (LLN; <50% if not specified). 
Lapatinib (in combination with capecitabine) may be restarted at a reduced dose of 1000 mg/day 
after a minimum of 2 weeks, if the LVEF recovers to normal and the patient is asymptomatic. 
Lapatinib doses should be held in patients with Grade ≥2 NCI CTCAE toxicity, until the toxicity 
improves to Grade ≤1; lapatinib may be restarted at 1250 mg/day. If the toxicity recurs, then 
lapatinib (in combination with capecitabine) should be restarted at a reduced dose of 
1000 mg/day. 
Table 4. Dose Reduction Levels for Lapatinib-Related Toxicity 
Dose Level 
Lapatinib 
Starting Dose 
1250 mg 
-1 
1000 mg (750 mg for severe hepatic impairment; see Appendix 2) 
 
Recommended dose reductions for the -1 and -2 dose levels of capecitabine in combination with 
lapatinib are listed in Table 5.  


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Table 5. Dose Reduction Levels for Capecitabine-Related Toxicity (When Administered 
in Combination with Lapatinib) 
Dose Level 
Capecitabine (administered in combination with lapatinib) 
Starting Dose 
2000 mg/m2, 1000 mg/m2 BID 
-1 
1500 mg/m2, 750 mg/m2 BID 
-2 
1000 mg/m2, 500 mg/m2 BID 
Abbreviation: BID: twice daily 
 
If doses of investigational product 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 to be done every 6 weeks, starting from the first dose of investigational product until 
the first planned tumor assessment at 6 weeks (±3 days), and then after every subsequent 
6 weeks (±3 days) of treatment regardless of any changes in dose or occurrence of AEs. Missed 
dose(s) of investigational product (i.e., any dose that is not administered within the protocol-
defined administration window) will not be made up. The dose adjustment guidelines represent 
the minimum set of measures that Investigators must follow. However, additional measures may 
be taken, as necessary, for certain patients per the Investigator’s medical judgment. All dose 
modifications/adjustments should be documented in the patient’s source file. 
Once an investigational product 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 is not 
permitted. 
Patients must discontinue an investigational product if a criterion for investigational product 
withdrawal is met (see Section 10.1 and Appendix 2).  
Once an investigational product has been discontinued, patients who had been receiving 
combination therapy may continue to receive the other investigational product as monotherapy, 
at the Investigator’s discretion. This is applicable to both treatment arms of the study. 
Reintroduction of the discontinued investigational product at a later time during the active 
treatment phase is not permitted. 
Detailed rules for dose adjustments of neratinib, lapatinib, and capecitabine in case of toxicity 
are provided in Appendix 2. 
6.2 
Packaging, Labeling and Storage 
Detailed packaging information for all investigational products is available in a study reference 
manual(s). All investigational products will be labeled according to local regulations. 


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The Sponsor will supply all investigational products (as required), which should be stored at the 
study sites in a secure location with limited access.  
All investigational products should be stored at 25°C (77°F) or below; do not freeze. Excursions 
are permitted to 30°C (86°F). Neratinib should be stored with desiccant. Keep containers closed 
tightly. 
6.3 
Drug Accountability 
The study site must maintain accurate records documenting dates and quantities of 
investigational product received from the Sponsor. On a per patient basis, records must be 
maintained documenting dates and quantities of investigational product dispensed and returned 
at each study visit. Any investigational product accidentally or deliberately destroyed must be 
documented.  
Throughout the study, reconciliation will be made between the amount of investigational product 
supplied, dispensed, returned, and subsequently destroyed or returned to Sponsor. All 
investigational products that were supplied by the Sponsor will be returned to Sponsor or its 
representative, or destroyed at the site in accordance with Sponsor guidelines. 
Individual patient dosing compliance should be reviewed at each study visit by study site staff. If 
patient non-compliance is noted, the patient should be re-instructed regarding proper dosing 
procedures in order to continue in the study. If repeated non-compliance is noted, additional 
steps may be taken, including withdrawal of the patient from the study (see Section 10.2).  


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7 
CONCOMITANT TREATMENT 
All concomitant treatments, therapies and medications will be captured from the signing of the 
ICF until the end of the treatment. This will include the start date, stop date, generic name, route 
of administration, dose and indication for treatment.  
At screening, patients will be asked what medications they have taken during the last 30 days, 
which medications are ongoing at the time of screening, any medical conditions that require 
medication, and all prior cancer therapies. At each subsequent study visit, patients will be asked 
what concomitant medications they are currently taking.  
7.1 
Required Concomitant Treatment 
7.1.1 Loperamide Antidiarrheal Therapy 
Diarrhea is the major dose-limiting toxicity of neratinib with onset typically occurring early in 
the course of treatment (during the first few weeks of treatment). Primary prophylactic use of 
antidiarrheal medication is mandatory for all enrolled patients in the neratinib treatment arm. 
Loperamide is the recommended standard therapy to treat diarrhea in this study. If alternative 
antidiarrheal medication is proposed, this should be discussed with the Medical Monitor and the 
reason documented in the source documents. Second-line antidiarrheal treatments and adjunctive 
therapies (i.e., octreotide [SANDOSTATIN®]) (or equivalent as approved by the Sponsor) are 
also recommended for use when appropriate. 
The Investigator must review with the patient the Patient Instructions for the management of 
diarrhea and the Patient Diary for the patient’s daily recording of investigational product during 
the first 2 cycles, number of stools, and use of loperamide and/or other anti-diarrheals for 
patients in the neratinib treatment arm. Both the patient and the Investigator must sign the patient 
instructions for the management of diarrhea. The Patient Instructions and Patient Diary are to be 
handed to the patient before leaving the site with investigational product on or before Cycle 
1/Day 1, with clear instructions to contact the Investigator in the event of de novo onset or 
persistent Grade ≥2 diarrhea to discuss the appropriate course of treatment. The Investigator 
must also complete and sign the Investigator Checklist on or before Cycle 1/Day 1.  
Documentation of any occurrences of stools or diarrhea must be as precise as possible and 
captured in the Patient Diary. For AE recording, documentation of “Intermittent” events of 
diarrhea is limited to Grade 1. If events of Grade 1 diarrhea are separated by 3 days without any 
diarrhea, then each event must be documented as separate AEs with corresponding start and stop 
dates. 
The entries on the Patient Diary should be reviewed together with the patient for the first 
2 cycles. If the patient has experienced diarrhea since the last visit, details of the daily number of 


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stools provided on the diary help to grade the diarrhea as precisely as possible (per NCI CTCAE 
v.4.0). Also, the daily dose of loperamide (or other anti-diarrheals, if applicable) noted on the 
diary for patients in the neratinib treatment arm will be reviewed and recorded on the CRF. 
Loperamide will be dispensed directly by the site on or before Cycle 1/Day 1 with neratinib. It is 
very important to initiate treatment with loperamide concomitantly with the first dose of 
neratinib to minimize occurrence and severity of diarrhea.  
Prophylactic dosing instructions (Cycle 1) 
 Inform patients that they will experience diarrhea while taking neratinib. 
 Administer loperamide: initial dose of 4 mg (2 tablets/capsules) with the first dose of 
neratinib, followed by 2 mg (1 tablet/capsule) every 4 hours for the first 3 days. After the 
first 3 days, take loperamide 2 mg every 6 to 8 hours until the end of the first 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, 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 intramuscular injection (equivalent medication 
may be used with approval of the Sponsor). 
 The sites must contact the patient by phone at 1 day, 2 days, and 3 days after the first dose 
of neratinib to inquire about any diarrhea. 
(These phone calls are mandatory and must be recorded in the study chart together with 
response from the patient and action taken.) 
 Instruct patients to promptly report diarrhea symptoms. 
 Instruct patient to record the number of stools per day (see Patient Diary, Section 8.5) and 
the dose of anti-diarrheal medication taken each day (for patients in the neratinib treatment 
arm) for the first 2 cycles. 
For new onset uncomplicated Grade 1 or Grade 2 diarrhea (Cycle 2 and beyond) 
Dietetic measures 
 Stop all lactose-containing products. 
 Drink 8 to 10 large glasses of clear liquids per day. 
 Eat frequent small meals. 


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 Recommend low fat regimen enriched with bananas, rice, applesauce and toast until 
resolution of diarrhea. 
Pharmacological Treatment 
 Administer loperamide: initial dose of 4 mg (2 tablets/capsules) with the first bout of 
diarrhea followed by 2 mg (1 tablet/capsule) every 4 hours or after every unformed stool 
(maximum 16 mg a day) and continue loperamide at this frequency until diarrhea free for 
12 hours.  
 For patients with persistent Grade 1 diarrhea on loperamide, Lomotil (diphenoxylate 
hydrochloride and atropine sulfate) 1 tablet (2.5 mg) every 6 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 three times daily (TID); or 
after initial dose of short-acting octreotide, if well tolerated, a single dose of octreotide 
LAR 20 mg intramuscular (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) 
Pharmacological treatment 
 Administer loperamide: initial dose of 4 mg (2 tablets/capsules) with the first bout of 
diarrhea followed by 2 mg (1 tablet/capsule) every 4 hours or after every unformed stool 
(maximum 16 mg a day) and continue loperamide at this frequency until diarrhea free for 
12 hours. Then titrate the amount of loperamide used to keep diarrhea controlled 
(<4 stools/day). 
 Administer octreotide (100-150 µg SC BID or intravenously (IV) (25-50 µg/h) if 
dehydration is severe, with dose escalation up to 500 µg SC TID). 
 Use IV fluids as appropriate. 
 Consider prophylactic antibiotics as needed (e.g., fluoroquinolones) especially if diarrhea is 
persistent beyond 24 hours or there is fever or Grade 3-4 neutropenia. 
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. 


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Patients with significant diarrhea who are unresponsive to medical treatment may require 
treatment interruption or dose reduction.  
7.2 
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 7.3), or drugs with potential for drug-drug 
interactions (Section 7.4), or in the associated Appendices (Appendix 4, Appendix 5, and 
Appendix 6), 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, 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 
investigational product 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 (e.g., granulocyte colony stimulating 
factor or granulocyte macrophage colony stimulating factor) may be implemented per the 
American Society of Clinical Oncology guidelines at the Investigator’s discretion, if 
significant neutropenia or febrile neutropenia/infection is observed. 
7.3 
Prohibited Concomitant Treatment 
The following treatments are prohibited throughout the duration of the active (treatment) phase 
of the study:  
 Any concurrent chemotherapy, radiotherapy (including palliative radiotherapy), surgery 
related to cancer, anticancer immunotherapy, or other anticancer treatments including other 
investigational agents, megestrol and hormonal agents. 
7.4 
Potential for Drug-Drug Interactions 
Patients should avoid agents known to be strong cytochrome P450 (CYP) 3A4 inducers or 
inhibitors (e.g., ketoconazole) for the duration of the active phase of the study. Patients should 
also avoid grapefruit/grapefruit juice and herbal remedies, including St John's Wort. Refer to 


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Appendix 4 for a list of inhibitors and inducers of CYP isoenzymes. If unavoidable, patients 
taking such agents should be monitored closely. 
Concomitant treatment with inducers of CYP3A4 should be avoided due to risk of decreased 
exposure to lapatinib. Concomitant treatment with strong inhibitors of CYP3A4 should be 
avoided due to risk of increased exposure to lapatinib. Coadministration of lapatinib with orally 
administered medicines with narrow therapeutic windows that are substrates of CYP3A4 (e.g., 
cisapride, pimozide and quinidine) and/or substrates of CYP2C8 (e.g., repaglinide) should be 
avoided. 
Clinically significant drug-drug interaction between sorivudine and 5-fluorouracil (5-FU), 
resulting from the inhibition of dihydropyrimidine dehydrogenase by sorivudine, has been 
described. This interaction, which leads to increased fluoropyrimidine toxicity, is potentially 
fatal. Therefore, capecitabine must not be administered concomitantly with sorivudine or its 
chemically related analogues, such as brivudine. There must be at least a 4-week waiting period 
between end of treatment with sorivudine or its chemically related analogues such as brivudine 
and start of capecitabine therapy. Interactions with allopurinol have been observed for 5-FU that 
may result in possible decreased efficacy of 5-FU. Concomitant use of allopurinol with 
capecitabine should be avoided. 
Chronic immunosuppressive therapies should be avoided, including systemic corticosteroids. If 
unavoidable, patients taking such agents should be monitored closely. Steroids given for 
physiological replacement, as anti-emetics, or inhaled as well as short course of oral/topical 
steroids given for allergic reactions or asthma flares, are allowed. 
Patients using drugs known to cause QT/QTc prolongation should be monitored closely with 
serial electrocardiograms (ECG) at the Investigator’s discretion. Refer to Appendix 6 for a 
summary of drugs known to have a risk of causing QT/QTc prolongation, potentially causing 
Torsade de Pointes (TdP). 
Patients taking digoxin, a P-glycoprotein (P-gp) substrate with a narrow therapeutic window, 
should be monitored closely. The digoxin dose should be adjusted as needed, since neratinib and 
lapatinib are inhibitors of P-gp. Co-administration of neratinib or lapatinib with digoxin could 
result in increased digoxin levels and associated digoxin toxicity. Refer to Appendix 5 for a list 
of substrates and inhibitors of P-gp. 
In addition to CYP3A4 and P-gp, lapatinib inhibits CYP2C8 in vitro at clinically relevant 
concentrations.  
Patients taking oral coumarin-derivative anticoagulants (i.e., warfarin and phenprocoumon) 
should be monitored closely and their anticoagulant dose adjusted as needed. 


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Patients taking concomitant capecitabine and phenytoin should be carefully monitored. The 
phenytoin dose may need to be reduced, as some patients receiving both drugs had toxicity 
associated with elevated phenytoin levels.  
The solubility of lapatinib is pH-dependent; thus, concomitant treatment with substances that 
increase gastric pH (e.g., esomeprazole, lansoprazole) should be avoided, as lapatinib solubility 
and absorption may decrease. 


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8 
EFFICACY AND SAFETY ASSESSMENTS 
8.1 
Efficacy Assessment 
8.1.1 Clinical Endpoints and Definitions 
There are 2 co-primary endpoints in this study: independently-adjudicated PFS and OS. All 
patients randomized will be evaluated. 
The secondary efficacy endpoints include Investigator-assessed PFS, ORR, DOR, and CBR (CR, 
PR or SD ≥24 weeks), time to intervention for symptomatic metastatic CNS disease, and health 
outcomes assessments.  
Progression-free Survival 
Progression-free survival is determined programmatically from adjudicated PD, defined as the 
interval from the date of randomization until the first date on which recurrence, progression (per 
RECIST v1.1 [Appendix 7]) 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.  
Overall Survival 
Overall survival is defined as the time from randomization to death due to any cause.  
Objective Response Rate 
The ORR is defined as the proportion of patients demonstrating either a CR or PR per RECIST 
v1.1 (Appendix 7) as their best overall response during the study. It is not necessary to confirm 
response. 
Duration of Response 
The DOR 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 on which recurrence or PD or death is 
objectively documented, taking as a reference for PD the smallest measurements recorded since 
enrollment, per RECIST v1.1 (Appendix 7). The duration of overall complete response is 
measured from the time measurement criteria are first met for CR until the first date that 
recurrent disease is objectively documented. 
Clinical Benefit Rate  
The CBR is defined as the proportion of patients who achieved overall tumor response (CR or 
PR) or SD for at least 24 weeks. Stable disease is measured from enrollment until the criteria for 
disease progression or response are met, per RECIST v1.1 (Appendix 7). 


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Time to Intervention for Symptomatic CNS Disease 
Time to intervention for symptomatic metastatic CNS disease is defined as the date of initiation 
of intervention or therapy for symptomatic CNS disease determined by the investigator to be due 
to CNS metastasis. This may include brain, leptomeningeal and epidural metastases including 
epidural spinal cord compression arising from tumor growth in the epidural space.  
8.1.2 Tumor Assessments  
Tumor assessments will be performed in accordance with the Schedule of Procedures 
(Appendix 1). Computerized tomography (CT), magnetic resonance imaging (MRI) and other 
forms of baseline tumor assessments must be performed within 28 days prior to randomization. 
Tumor assessments will be performed every 6 weeks from the first day of study treatment 
(Cycle 1/Day 1).  
For patients who end therapy for any reason other than radiologically documented progression, 
every effort should be made to perform radiological tumor assessment until radiologic 
progression is documented. 
Tumor scans and other appropriate tumor assessments must be obtained prior to the start of the 
next treatment cycle. Overall response will be determined by the Investigator at each visit 
according to RECIST v1.1 (Appendix 7).  
8.1.2.1 General Information 
All target and non-target sites of disease (see Appendix 7) identified at screening must be 
followed for the duration of the study. Their presence and absence should be noted throughout 
follow-up. Overall response for each patient is based on the combined results of target and 
non-target lesions and the presence or absence of new lesions. 
Tumor-based efficacy endpoints (i.e., PFS and ORR) will be based on tumor assessments, which 
are performed by the Investigators. Response and progression will be evaluated using RECIST 
v1.1 (Appendix 7). 
Tumor assessments will be performed for all patients at 6-week intervals throughout the active 
treatment phase, starting from Cycle 1/Day 1 until documented disease progression, death, or 
withdrawal of consent, regardless of whether the patient is continuing or has discontinued study 
treatment. Additional tumor evaluations will be performed as clinically indicated. Missed tumor 
assessments must be performed as soon as possible. As soon as evaluations for each tumor 
assessment are completed, the Investigator should assess the patient’s overall response (target 
plus non-target lesions) based on criteria and overall response algorithms as defined in RECIST 
v1.1 (Appendix 7). Scans (and/or good color photographs with a ruler for skin lesions) must be 
assessable for all evaluations.  


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The longest diameters (LD) for all non-nodal target lesions and the short axis diameter (SAD) of 
nodal target lesions will be recorded. The LD for all non-nodal target lesions and the SAD of 
nodal target lesions will be added and reported as the baseline sum longest diameter (SLD). Per 
RECIST v1.1, 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 (see 
Appendix 7).  
Patients who discontinue study treatment for reasons other than PD per RECIST will continue to 
be followed up by protocol for scheduled tumor assessments until PD, and long-term for OS (see 
Section 10.3).  
For patients who show a CR on one scan and on a confirmatory scan obtained 6 weeks later, the 
frequency of subsequent scans may be reduced at the discretion of the investigator to no less than 
one scan every 12 weeks.  
The same method of measurement (CT/MRI) and the same technique of assessment should be 
used to characterize each identified and reported lesion from baseline through the final visit. All 
measurements should be taken and recorded in metric notation, using a ruler or calipers. The 
screening CT/MRI must be performed within 28 days prior to randomization, and preferably no 
more than 28 days before the initiation of treatment. As often as possible, lesions should be 
assessed by the same Investigator using the same method of measurement. Physical examination 
may not be the sole method of assessment for a solitary lesion.  
8.1.2.2 Computerized Tomography and Magnetic Resonance Imaging  
Computerized tomography and MRI are the recommended methods to measure target lesions 
selected for response assessment. Conventional CT and MRI should be performed with cuts of 
10 mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. The size of CT/MRI scan interval cuts must not change for 
a patient after screening.  
Computerized tomography scans of the chest, abdomen and/or pelvis should be obtained as 
clinically indicated. Alternatively, CT scans of the chest and separate CT scans of the abdomen 
and/or pelvis may be obtained. Radiographs may be used during the study to follow lesions seen 
on a bone scan and confirmed by radiographs at screening. In cases of CT contrast media allergy 
or renal insufficiency (creatinine >2 mg/dL [176.8 μmol/L]), in which CT scans with contrast 
cannot be done, enhanced MRIs (for pelvis or abdomen) or CT without contrast (for chest) may 
be used instead, but the same method of assessment must be used throughout the course of the 
study. Ultrasound should not be used for the purposes of measuring or evaluating tumors in this 
study. 


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Definitions of measurable disease and measurable lesions, documentation of “target” and 
“non-target” lesions and evaluation of response are summarized in RECIST v1.1 (Appendix 7). 
8.1.2.3 Caliper measurement by clinical examination when lesions are superficial  
Skin lesions that can be measured with calipers as defined in RECIST v1.1 (Appendix 7) or 
documented using color photography (with ruler) can be considered target or non-target lesions. 
Skin lesions which cannot be measured with calipers or documented using color photography 
(with ruler) should be recorded as non-measurable. Otherwise, this clinical measurement should 
be recorded in the CRF. Documentation by color photography in good light and including a ruler 
to estimate the size of the lesion is required, and will be provided to the central review vendor for 
independent evaluation by an oncologist. 
Note that when lesions can be evaluated both clinically and radiographically, the radiologic 
imaging evaluation (by CT or MRI as appropriate) should take precedence. 
8.2 
Safety Assessment 
Refer to the Schedule of Procedures (Appendix 1) for time points. Safety will be assessed with 
the following procedures: medical history, AEs, vital signs, detailed/brief (system-guided) 
physical examinations, 12-lead ECGs, LVEF (ECHO or MUGA), and laboratory evaluations. 
Adverse events will be graded according to the NCI CTCAE v.4.0. Serious adverse events will 
be reported until 28 days after the last dose of the investigational product and will be followed 
until resolution or until condition stabilizes. Should an Investigator be made aware of an SAE 
occurring any time after the reporting period, it must be promptly reported. More details on AEs 
can be found in Section 13. 
The Patient Diary will be used for recording investigational product intake during the first two 
cycles. In the case of diarrhea, it also serves to document the number of stools per day and use of 
loperamide/other antidiarrheal treatments taken.  
8.2.1 Laboratory Assessments 
Laboratory testing will be performed in accordance with the Schedule of Procedures 
(Appendix 1).  
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 
requirements and using methods documented in a methods validation report.  
Screening laboratory results may be accepted as the baseline assessment if they are performed 
within 72 hours before randomization and there are no clinically significant findings.  


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Laboratory assessments are summarized in Table 6. 
Tumor testing for HER2 gene amplification or overexpression will be determined by a central 
laboratory using the methods presented in Section 8.2.1.1. Wherever possible, tumor tissue from 
a metastatic site or at or beyond the time of recurrence should be submitted. If the tissue is not 
available or acceptable, a fresh tumor biopsy may be performed. 
Table 6. Laboratory Assessments 
Hematology: 
Differentials (basophils, eosinophils, lymphocytes, monocytes, neutrophils) 
Hematocrit (Hct) 
Hemoglobin (Hb) 
Mean corpuscular hemoglobin (MCH) 
Mean corpuscular hemoglobin concentration (MCHC) 
Mean corpuscular volume (MCV) 
Platelet count 
Red blood cell (RBC) count  
Red blood cell distribution width (RDW) 
White blood cell (WBC) count, with differential 
Coagulation factors: 
International Normalized Ratio (INR) 
Prothrombin time (PT) 
Activated partial thromboplastin time (aPTT) 
Clinical chemistry: 
Albumin  
Alkaline phosphatase  
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST)  
Bicarbonate 
Blood urea nitrogen (BUN) 
Calcium 
Chloride  
Serum Creatinine 
Glucose  
Lactate dehydrogenase (LDH) 
Magnesium 
Phosphorus 
Potassium  
Sodium  
Total bilirubin 
Total protein  
Urinalysis (dipstick; 
microscopic examination 
if abnormal): 
Blood 
Protein 
Glucose 
Serum pregnancy test: 
In women of child-bearing capacity (screening only) 
Biomarkers: 
HER2 overexpression by IHC and gene amplification by FISH if required for 
confirmation (see Section 8.2.1.1) 
ER and PR expression 


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All laboratory tests that result in clinically important abnormal results that occur during the study 
will be repeated at appropriate intervals, until results return either to baseline or to a level 
deemed acceptable by the Investigator and the Sponsor’s medical monitor (or his/her designated 
representative), or until a diagnosis that provides an explanation is made.  
Criteria for reporting abnormal laboratory values as AEs are summarized in Section 13.1.2. 
The total volume of blood collected from each patient during the course of the study will be 
dependent upon the number of treatment cycles a patient completes. Approximately 17 mL of 
blood will be collected during screening and 15 mL of blood will be collected at subsequent 
visits (plus 6 mL at each of two visits during Cycle 1 if PK samples are collected). 
8.2.1.1 Immunohistochemistry and Fluorescence In Situ Hybridization Testing of HER2 and 
ER/PR Status 
Tumor samples will be evaluated for HER2 expression by IHC (HercepTest™) and if required 
for gene amplification by FISH analysis (IQFISH pharmDx™) as below.  
 If IHC 3+, no further testing required to confirm HER2+ status. 
 If IHC 2+, further testing required by FISH to confirm HER2+ status.  
 If IHC 0 or 1+, sample is considered negative for HER2 status and no further testing will 
be conducted. 
Either primary breast cancer tissue (e.g., from prior surgical resection) or other breast cancer-
containing tissue (e.g., from biopsy or excision of cancer-containing lymph node or metastatic 
lesion) is acceptable for central HER2 testing. Further, breast cancer-containing specimens 
submitted for central HER2 testing may have been obtained at any time in the patient’s breast 
cancer treatment history, including the period before the development of metastatic disease. 
Wherever possible tissue from the time of recurrence or metastasis should be submitted. 
If there is not enough tissue available, and the IHC result is 2+ and there is no FISH result, or the 
IHC and FISH both fail to give a result, the site will be asked to ship another sample for re-
testing.  
Patients may have a fresh tissue biopsy in order to assess eligibility if there is no available tissue 
for central HER2 testing or if the available tissue (regardless of whether from primary lesion or 
metastatic site, and regardless of when it was obtained in their disease course) cannot be 
confirmed to have been fixed with formalin as the fixative.  
ER/PR status will be determined using a pharmDx™ kit. 


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8.2.2 Vital Signs 
The following vital signs will be assessed in accordance with the Schedule of Procedures 
(Appendix 1): 
 Blood pressure (systolic and diastolic; mmHg). 
 Resting heart rate (beats per minute). 
 Body temperature (°C or °F; oral, core [rectal], axillary or tympanic).  
 Weight. 
 Height (screening only). 
Vital signs will be measured after resting in a seated position for 5 minutes.  
8.2.3 Physical Examinations 
Physical examinations will be performed in accordance with the Schedule of Procedures 
(Appendix 1).  
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. 
8.2.4 Electrocardiograms 
Single standard 12-lead digital ECGs will be performed in accordance with the Schedule of 
Procedures (Appendix 1). 
The ECG (measured after resting in a supine position for 5 minutes) will include heart rate, 
rhythm and RR, PR, QRS, and QTc intervals. The ECG will be read and interpreted at the 
investigational site for patient safety monitoring and documentation will be stored with the 
source documents. 
8.2.5 Left Ventricular Ejection Fraction (LVEF) 
Multiple-gated acquisition scan or ECHO scans to determine LVEF will be performed in 
accordance with the Schedule of Procedures (Appendix 1).  
Screening ECHO/MUGA scans must be performed within 28 days prior to randomization. 
It is strongly recommended to use the same method of cardiac evaluation (ECHO or MUGA) at 
each relevant time point for each patient.  


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8.3 
Other Assessments 
8.3.1 Pharmacokinetics 
At selected study centers, PK samples will be collected from approximately 100 patients in the 
neratinib plus capecitabine arm (Arm A) on Days 1 and 15 of Cycle 1, as noted in the Schedule 
of Procedures (Appendix 1). Patients should be instructed to report the exact time that the dose 
of neratinib was taken on the days of PK sample collection. 
8.3.2 Health Outcomes Assessments  
The following health outcomes assessments will be completed by patients, as noted in the 
Schedule of Procedures (Appendix 1): 
 European Organisation for Research and Treatment of Cancer Quality of Life 
Questionnaire-C30 (EORTC QLQ-C30), version 3 (Appendix 8) 
 EORTC QLQ-BR23 (breast cancer-specific questionnaire; Appendix 9) 
 EuroQol (EQ-5D-5L) multi-dimensional health status questionnaire (Appendix 10) 
8.3.3 ECOG Performance Status 
Eastern Cooperative Oncology Group performance status will be assessed in accordance with the 
Schedule of Procedures (Appendix 1). The ECOG categories are summarized in Appendix 3. 
Screening ECOG performance status may be accepted as the baseline status if the assessment 
was performed within 72 hours before randomization and there are no clinically significant 
findings. 
8.4 
Protocol Deviations 
Protocol deviations should be reported to the Sponsor (or designee). 
8.5 
Patient Diary  
The Patient Diary used for recording of investigational product intake during the first 2 cycles. 
The number of stools per day will also be recorded on the Patient Diary for the first 2 cycles. In 
addition, patients in the neratinib treatment arm will record the use of loperamide/other 
antidiarrheal treatment taken along with the dose of neratinib for the first 2 cycles. 


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9 
STUDY CONDUCT 
A Schedule of Procedures is provided in Appendix 1.  
In addition to the procedures listed below, unscheduled clinic visits and procedures should be 
performed at the Investigator’s discretion to assess symptoms and concerns newly reported by 
the patient to rule out or confirm potential recurrence, or for the purpose of assessing the 
patient’s safety. 
9.1 
Screening/Baseline 
Screening activities are to be conducted within 21 days prior to randomization. Baseline 
assessments must be done within 72 hours before randomization. Randomization should occur 
after all baseline assessments have been completed and the site confirms that the patient still 
meets all eligibility requirements.  
The following information and assessments will be performed, collected and/or recorded at 
screening in accordance with the Schedule of Procedures (Appendix 1):  
 Signed ICF for the study. 
 Collect demography: date of birth, sex, race (Asian, Black or African American, White, 
Native Hawaiian or Pacific Islander, American Indian or Alaskan Native, Other), and 
ethnicity (Hispanic or Latino, Non-Hispanic or Non-Latino).  
 Medical history: 
o Record chronic conditions and/or medical history of significance (including the review 
of history of cardiac, pulmonary and gastrointestinal disease), relevant surgical 
procedures and symptoms experienced during the previous 30 days as well as those 
ongoing at the time of screening, and any medical conditions that require medication.  
o 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, predictive and prognostic biomarkers, previous 
chemotherapy/biotherapy/ immunotherapy, previous adjuvant therapy (drug names, 
start and stop dates, reason for TD), previous radiation, and prior cancer-related 
surgical therapies. 
o Other previous and concomitant medication will be documented, as described in 
Section 7. 
 Physical examination. Refer to Section 8.2.3. 


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 Vital signs, height and weight. Refer to Section 8.2.2. 
 ECG. Refer to Section 8.2.4. 
 LVEF (ECHO or MUGA). Refer to Section 8.2.5. 
 ECOG performance status. Refer to Section 8.3.3. 
 Serum pregnancy test. Refer to Section 8.2.1. 
 Laboratory tests (urine dipstick, hematology and serum chemistry panel). Refer to 
Section 8.2.1. 
 Radiographic (or other appropriate modality for) tumor assessment (RECIST v1.1). Refer 
to Section 8.1.2. 
 In addition, following signing of informed consent, tumor tissue must be prepared and sent 
for central laboratory confirmation of HER2 expression and hormone receptor status (Refer 
to Section 8.2.1.1).  
The following assessments will be performed at baseline in accordance with the Schedule of 
Procedures (Appendix 1):  
 Physical examination. Refer to Section 8.2.3. 
 Vital signs, height and weight. Refer to Section 8.2.2. 
 ECOG performance status. Refer to Section 8.3.3. 
 Health outcomes assessments. Refer to Section 8.3.2. 
 Laboratory tests (urine dipstick, hematology and serum chemistry panel). Refer to 
Section 8.2.1. 
9.2 
Active Treatment Phase 
Neratinib (Arm A) or lapatinib (Arm B) will be self-administered by patients once daily during 
each 21-day cycle. Capecitabine will be self-administered by patients BID on Days 1 to 14 of 
each 21-day cycle (Arm A and B). 
The following will be performed during the active treatment phase in accordance with the 
Schedule of Procedures (Appendix 1): 
 Physical examination. Refer to Section 8.2.3. 
 Vital signs and weight. Refer to Section 8.2.2. 


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 ECG. Refer to Section 8.2.4. 
 LVEF. Refer to Section 8.2.5. 
 ECOG performance status. Refer to Section 8.3.3. 
 Health outcomes assessments. Refer to Section 8.3.2. 
 Concomitant medication assessment. Refer to Section 7. 
 Adverse event assessment. Refer to Section 13. 
 Laboratory tests (hematology and serum chemistry panel). Refer to Section 8.2.1. 
 Radiographic (or other appropriate modality for) tumor assessment. Refer to Section 8.1.2. 
 Dispense investigational product. Refer to Sections 6.1. 
 Review the Patient Instructions for the management of diarrhea with the patient and 
dispense antidiarrheal medication. Refer to Section 7.1.1. 
 Review entries in the Patient Diary through Cycle 2. Refer to Section 8.5. 
 Treatment compliance assessment. Refer to Section 6.3. 
 PK sampling. Refer to Section 8.3.1. 
9.3 
Treatment Discontinuation Visit 
The TD visit will be used to perform safety assessments and should be completed within 3 days 
after the last dose of investigational product.  
The following will be performed in accordance with the Schedule of Procedures (Appendix 1): 
 Physical examination. Refer to Section 8.2.3. 
 Vital signs and weight. Refer to Section 8.2.2. 
 ECG. Refer to Section 8.2.4. 
 LVEF. Refer to Section 8.2.5. 
 ECOG performance status. Refer to Section 8.3.3. 
 Health outcomes assessments. Refer to Section 8.3.2. 
 Concomitant medication assessment. Refer to Section 7. 
 Adverse event assessment. Refer to Section 13. 
 Laboratory tests (hematology and serum chemistry panel). Refer to Section 8.2.1. 


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 Treatment compliance assessment. Refer to Section 6.3. 
Patients who remain on study will enter the long-term follow-up phase after the TD visit. 
Adverse events will continue to be monitored until the 28th day after the last dose of 
investigational product.  
If a patient discontinues from the study for a reason other than disease progression or withdrawal 
of consent, he/she will continue CT/MRI assessments every 6 weeks, starting from 
Cycle 1/Day 1. 
9.4 
Safety Follow-up Contact 
Patients will be contacted by phone 28 days (+5 days) after the last dose of investigational 
product to collect AE, cancer therapy (anti-cancer medication, cancer-related radiotherapy, and 
cancer-related surgery), concomitant medication, and survival information. 
9.5 
Long-term Follow-up Phase 
Patients who discontinue study therapy will be followed for survival status during the long-term 
follow-up phase. If a patient discontinued study therapy due to toxicity, tumor assessments will 
continue to be performed at 6-week intervals throughout the long-term follow-up phase, until 
documented disease progression, death, or withdrawal of consent. Patients will also be contacted 
every 12 weeks for survival status and to collect the following data: 
 Anti-cancer medications, including dose and regimen, taken since last contact. 
 Cancer-related radiotherapy administered since last contact. 
 Cancer-related surgeries/procedures performed since last contact. 
The long-term follow-up phase will continue until patient death or withdrawal of consent. 
Survival follow-up will occur via telephone call if the site is unable to confirm status via chart 
review. 
If a patient withdraws from the long-term follow-up phase of the study, attempts should be made 
to contact the patient to determine the reason(s) for discontinuation (see Section 10.3).  
Patients who are no longer continuing with scheduled study visits will be followed for SAEs 
until the patient starts a subsequent cancer therapy (see Section 13.3). 


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9.6 
End of Study  
The EOS will occur as of the date of the last visit of the last patient undergoing the study. In the 
event that the EOS is declared earlier, investigational product(s) will be available to patients who 
continue to receive clinical benefit as described in Section 4.1. 


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10 PATIENT WITHDRAWAL AND REPLACEMENT 
10.1 
Investigational Product Discontinuation 
Withdrawal due to an AE should be distinguished from withdrawal due to other causes and 
recorded on the appropriate AE CRF page.  
If one of the two investigational products given in combination has been discontinued, patients 
may continue to receive the other investigational product as monotherapy, at the Investigator’s 
discretion. This is applicable to both treatment arms of the study. Reintroduction of the 
discontinued investigational product at a later time during the active treatment phase is not 
permitted. 
Patients must be discontinued from investigational product(s) (but may remain in the study, if 
appropriate) under the circumstances listed below and in Appendix 2, unless otherwise agreed 
with the Medical Monitor. 
 If the patient requires more than two dose reductions of the investigational product(s) 
(see Appendix 2). 
 If investigational product(s) is withheld due to an AE for >28 days. 
 Disease progression. 
 Initiation of alternative anti-cancer therapy. Any concurrent chemotherapy, radiotherapy 
(including palliative radiotherapy), surgery related to cancer, anticancer immunotherapy, or 
other anticancer treatments including other investigational agents, megestrol and hormonal 
agents are prohibited (see Section 7.3). 
 Pregnancy (see Section 13.4). 
 Investigator request. 
 Patient request (i.e., withdrawal of consent for treatment). 
10.2 
Withdrawal from the Study 
Patients may withdraw from the entire study, including follow-up, at any time without penalty 
and for any reason without prejudice to his or her future medical care. Study withdrawal may 
occur for the following reasons:  
 At the discretion of the Investigator. 
 At the patient’s request (withdrawal of consent for the study).  


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 Lost to follow-up (defined as three failed attempts to contact by phone, followed by one 
attempt by sending a certified letter). 
 If the entire study is terminated prematurely as described in Section 11. 
A patient may also be withdrawn from investigational product/study by the Sponsor, 
Regulatory Authorities, or Independent Ethics Committees (IEC)/IRBs.  
10.3 
Procedures for Patient Withdrawal 
When a patient is withdrawn from the study, the Investigator will notify the Sponsor. In all cases, 
the reason(s) for premature discontinuation/withdrawal and the primary reason must be recorded 
on the CRF. If a patient is prematurely withdrawn from the investigational product or the study 
for any reason, the Investigator must make every effort to perform the evaluations described for 
the TD visit, the safety follow-up contact 28 days later, and a follow-up visit 12 weeks later. If a 
patient discontinues due to an AE, he/she should continue to be under medical supervision until 
symptoms cease or the condition becomes stable. 
If a patient withdraws consent but agrees to undergo a final examination, this will be documented 
on the CRF and the Investigator’s copy of the ICF, which will be countersigned and dated by the 
patient.  
If a patient is lost to follow-up or voluntarily withdraws from study participation, every effort 
should be made to determine why the patient was lost to follow-up or withdrew consent. This 
information, including the date, should also be recorded on the patient's conclusion of patient 
participation CRF. 
All patients will remain on active study treatment until treatment or study discontinuation, death, 
or withdrawal of consent. Upon confirmed disease progression, or discontinuation of randomly 
assigned investigational product for any other reason, all further anti-cancer treatment will be at 
the Investigator’s discretion. All patients will remain in the long-term follow-up phase for 
survival unless consent has been withdrawn or until death. 
10.4 
Patient Replacement 
Patients will not be replaced.  


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11 PREMATURE TERMINATION OF THE STUDY 
The Sponsor may suspend or terminate the study or part of the study at any time for any reason. 
Investigational product(s) will be available to patients who continue to receive clinical benefit 
following the EOS as described in Section 4.1. 
If the Investigator suspends or terminates the study, the Investigator will promptly inform the 
Sponsor and the IRB/IEC and provide them with a detailed written explanation. The Investigator 
will also return all investigational products, investigational product containers and other study 
materials to the Sponsor or have them destroyed locally according to Sponsor guidelines. Upon 
study completion, the Investigator will provide the Sponsor, IRB/IEC and regulatory agency with 
final reports and summaries as required by regulations. For investigational new drug application 
studies, the Investigator must submit a written report to the Sponsor and the IRB/IEC within 
3 months after the completion or termination of the study.  


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12 STATISTICAL METHODS 
The statistical considerations summarized in this section outline the plan for data analysis of this 
study. Additional details of the analysis will be provided in a Statistical Analysis Plan (SAP), 
which will be finalized prior to unblinding the data. Any deviations from the protocol or 
SAP-specified analyses will be identified in the clinical study report.  
A final PFS analysis will be conducted when 419 PFS events have occurred and a final OS 
analysis will be conducted when 378 deaths have occurred. An interim analysis of OS will be 
conducted at the time of the final PFS analysis.  
12.1 
General Considerations 
The primary efficacy analysis will be performed on the intent to treat (ITT) population, defined 
as all patients randomized into the study. Formal definitions of the analyses populations are 
provided in the SAP. 
12.2 
Study Patients 
12.2.1 Disposition of Patients 
The number and percentage of patients entering and completing each phase of the study will be 
presented, stratified by treatment. Reasons for withdrawal pre- and post-randomization will also 
be summarized. 
12.2.2 Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications 
Demographic data, medical history, baseline characteristics including predictive and prognostic 
biomarkers, concomitant disease, and concomitant medication will be summarized by means of 
descriptive statistics (n, mean, standard deviation, median, minimum and maximum) or 
frequency tables, overall and stratified by treatment.  
12.2.3 Treatment Compliance 
Duration of treatment will be summarized separately for each investigational product by 
treatment group. In addition, the cumulative quantity, dose intensity (quantity per time unit) and 
the relative dose intensity (dose intensity/scheduled dose per time unit) will be summarized. The 
number of patients with dose holds or dose reductions will be tabulated for each investigational 
product by treatment group. 


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12.3 
Efficacy Analyses 
12.3.1 Primary Efficacy Analysis 
The co-primary endpoints are independently adjudicated PFS and OS. PFS is defined as disease 
progression demonstrated by radiographic imaging or other appropriate modality, or death due to 
any cause. Tumor evaluations will be performed by a central review vendor.  
Patients will be stratified at randomization by whether they had 2 or ≥3 prior HER2+ MBC 
regimens in the metastatic setting, their geographic region (North America vs. Europe including 
Israel vs. Rest of World), disease category (visceral vs. non-visceral only), and hormone receptor 
status (ER and/or PR positive vs. ER and PR negative). All efficacy endpoints will be 
summarized by treatment group and visit when appropriate. 
The efficacy assessment in PFS will be assessed by a blinded, independent, central review of 
tumor assessments for all patients at screening, and then after every 6 weeks from first dose of 
investigational product, regardless of treatment schedule modification (e.g., dose delay), until 
documented disease progression or death. PFS will be independently-assessed using 
RECIST v1.1.  
Missed tumor assessments must be performed as soon as possible. Patients who discontinue from 
study treatment for a reason other than radiographically confirmed (or confirmation by other 
appropriate modality) objective disease progression will have radiological tumor assessments 
performed approximately every 6 weeks from the date of the last tumor assessment until 
documented disease progression or death. 
Survival data will be collected throughout the active treatment phase and during the long term 
follow-up phase. Survival follow-up after patient discontinuation of investigational product will 
be conducted approximately every 12 weeks to assess for survival until patient’s death, 
withdrawal of consent, or the EOS.  
12.3.1.1 Statistical Methods 
When 419 PFS events have occurred the primary PFS analysis will be performed. The median 
time to PFS and corresponding two-sided 95% confidence intervals will be calculated using the 
product limit estimator and displayed using a Kaplan-Meier graph, by treatment group. A 
log-rank test controlling for hormone receptor status, number of prior HER2-directed regimens 
in the metastatic setting, visceral disease, and geographic region strata will be used to test the 
null hypothesis of no difference in the time to PFS between the two treatment groups at the alpha 
level of 0.01. Subjects who discontinue therapy early will be censored at their last available time 
point. Sensitivity analyses will be performed to investigate the impact of differential dropout 
between the two treatment groups on the treatment effect estimate.  


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When the PFS analysis is performed, an interim analysis will be performed on the OS endpoint. 
When 378 deaths have occurred, primary OS analysis (final analysis) will be performed. The 
median time to PFS and corresponding two-sided 95% confidence intervals will be calculated 
using the product limit estimator and displayed using a Kaplan-Meier graph, by treatment group. 
A log-rank test controlling for hormone receptor status, number of prior HER2-directed regimens 
in the metastatic setting, visceral disease status, and geographic region strata will be used to test 
the null hypothesis of no difference in the hazard between the two treatment groups at the alpha 
level of 0.002 at the interim analysis and 0.038 for the final analysis.  
12.3.2 Secondary Efficacy Analyses 
The secondary efficacy endpoints include Investigator-assessed PFS, ORR, DOR, and CBR (CR, 
PR or SD ≥24 weeks).  
The secondary efficacy assessments include: 
 The comparison of clinically relevant improvements in breast cancer patients with respect 
to radiographic changes or changes in other appropriate modalities, including ORR, DOR 
and CBR (CR or PR or SD ≥24 weeks). 
 In addition, time to onset of symptomatic metastatic CNS disease and the quality of life 
instruments EORTC QLQ-C30, BR23, and EuroQol EQ-5D-5L will be analyzed. 
12.3.2.1 Statistical Methods 
The treatment difference in the secondary efficacy endpoints of ORR and CBR will be analyzed 
using a Cochran-Mantel-Haenzel (CMH) Chi-square test, stratified by hormone receptor status, 
number of prior HER2-directed regimens in the metastatic setting, geographic region, and 
disease state (visceral vs. non-visceral only). The treatment difference in the secondary efficacy 
endpoints of DOR and PFS from Investigator-assessed PD will be analyzed using a product limit 
estimate of the median time to event. Differences between treatment groups will be examined 
using a log-rank test statistic stratified by hormone receptor status, number of prior HER2-
directed regimens in the metastatic setting, visceral disease status, and geographic region strata 
(similar to the analysis for the primary endpoints). All time-to-event endpoints, including time to 
intervention for symptomatic CNS disease, will be displayed using a Kaplan-Meier survival plot. 
Health outcomes assessments (EORTC QLQ-C30, EORTC QLQ-BR23 and EQ-5D-5L) will be 
analyzed using a random effects mixed model with treatment, time, number of prior HER2-
directed regimens in the metastatic setting (binary), geographic region, disease category, and the 
treatment by time interaction. Endpoints that could be affected by missing values (e.g., health 
outcomes assessments) will be analyzed using a sensitivity analysis to quantify the impact of 
missing values in the results. 


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12.4 
Safety Analyses 
Patients receiving at least 1 dose of investigational product will be evaluable for safety.  
12.4.1 Investigational Product Exposure 
Extent of exposure to each investigational product will be summarized by total dose, number of 
cycles, number of missed doses, number of dose delays, number of dose reductions. 
12.4.2 Adverse Events 
Safety will be assessed based on medical history, vital sign measurements, physical examination 
findings, ECG results, MUGA or ECHO, liver function test results, ECOG performance status, 
and laboratory assessments. Adverse events and SAEs 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 SAE occurring any time after the 
reporting period, it must be promptly reported.  
All safety endpoints will be summarized by treatment group and visit when appropriate. Adverse 
events and SAEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding system v.15 or later and will be tabulated by system organ class (SOC) and 
preferred term. All AEs will be graded according to the NCI CTCAE v.4.0. Differences in the 
incidence of the most common AEs and SAEs between the two treatment groups will be 
investigated using a CMH chi-square test, stratified on hormone receptor status, prior number of 
HER2-directed regimens in the metastatic setting, geographic region, and visceral or non-
visceral only disease.  
A patient who experiences the same AE more than once within a SOC or preferred term category 
will be counted only once, using the worst toxicity grade for that event.  
Serious adverse events and deaths will be provided in a listing.  Treatment-emergent adverse 
events (TEAEs) leading to treatment discontinuation, dose modification, dose hold, and/or delay 
of investigational product will be tabulated by SOC, PT, and treatment group. 
12.4.3 Laboratory Results 
Laboratory test results will be collected pretreatment and on day 1 of each treatment cycle until 
the TD visit. Standard reference ranges will be used for missing or discrepant normal ranges. 
Mean change from baseline in laboratory test values at each visit will be provided. On-study 
laboratory test abnormalities will be summarized. Shifts in laboratory test values will also be 
summarized. 


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12.5 
Other Analyses 
12.5.1 PK analysis 
A population PK study, with sparse sampling at a subset of study sites, will be included in the 
study to assess the variability of neratinib concentrations when administered in combination with 
capecitabine among individuals in the target patient population. Blood samples will be collected 
as specified in Appendix 1, and they will be processed and stored until analysis.  
Concentrations of neratinib will be measured in plasma with a validated assay method. 
NONMEM, a statistical software program that uses non-linear, mixed effects models to 
determine PK parameters (clearance and volume of distribution), the inter- and intra-patient 
variability and the population variability in the parameter estimates will be used for this analysis. 
Random sources of error, intrinsic factors (e.g., age, sex, race, body weight, liver function and 
renal function) and extrinsic factors (e.g., capecitabine, diarrhea frequency, smoking status) will 
be evaluated to identify factors that contribute to the observed variability in the PK parameter 
estimates.  
The concentrations in this study will be used in the development of a structural model, and it will 
include results from other neratinib studies that included intensive sampling. The best model will 
be evaluated by goodness of fit statistics, reduction in the objective function and posterior 
predictive checks. 
A population pharmacokinetic-pharmacodynamic analysis of neratinib efficacy and tolerability 
endpoints will be performed in this patient population. The final PK model will be used to 
generate post-hoc neratinib patient-level plasma PK profiles, from which patient-level neratinib 
area under the curve (AUC) and maximum plasma concentration (Cmax) exposure metrics will be 
estimated. Neratinib dose and estimated AUC and Cmax exposure metrics will then be used to 
complete an exploratory data analysis of potential exposure-response relationships for efficacy 
and safety endpoints. 
12.5.2 Health Outcomes Assessments 
Health outcomes assessments will include the EORTC QLQ-C30, EORTC QLQ-BR23 and the 
EQ-5D-5L. Questionnaires will be completed by patients at time points specified in Appendix 1.  
12.6 
Interim Analyses 
No interim PFS analysis for early stopping is planned. An interim OS analysis will be performed 
at the time of final PFS analysis.  


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The Lan-DeMets alpha spending function approach will be used to adjust the O’Brien-Fleming 
boundary if the timing based on the final PFS analysis does not correspond to the expected 
information time of half of the OS events (DeMets and Gordon Lan 1994; Cook 2003).  
The hazard rate in the control arm for survival will be assessed to determine if the sample size or 
duration of follow-up or both should be adjusted to ensure timely achievement of the required 
378 death events. 
12.7 
Determination of Sample Size 
The co-primary endpoints will be analyzed using an overall Type I error rate of 0.01 for PFS and 
0.04 for OS. To detect a hazard ratio (control versus treatment) of 0.70 with approximately 85% 
power, 419 PFS events (PD/deaths) are required to be observed; this assumes a median (ITT) 
PFS of 8.0 months (34.7 weeks) for the experimental arm (neratinib plus capecitabine) and 
5.6 months (24.3 weeks) for the control arm (lapatinib plus capecitabine). It is expected that the 
419th event will be observed at approximately 26 months after the first patient is enrolled, which 
would correspond to approximately half of the death events needed to be observed. At this time, 
an interim analysis on OS will also be performed. For the OS endpoint, a group sequential 
method will be employed to maintain the overall Type I error rate at 0.04. Specifically, O’Brien-
Fleming boundaries will be calculated to create appropriate critical values to which the log rank 
statistic will be compared.  
Information 
Fraction 
Expected Death Events 
Study 
Month 
Boundary (Reject Ho) 
Significance Level 
50% 
185 
26 
3.066 
0.002 
100% 
378 
50 
2.058 
0.038 
These boundaries are designed to detect a hazard ratio (control versus treatment) of 0.725 with 
approximately 85% power. Overall, 378 events (deaths) are required to be observed; this 
assumes a median (ITT) OS of 30.3 months for the experimental arm (neratinib plus 
capecitabine) and 22.0 months for the control arm (lapatinib plus capecitabine). Approximately 
600 patients will be enrolled and randomized equally between the two treatment arms.  


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13 SAFETY DATA COLLECTION, RECORDING AND REPORTING 
All observed or volunteered AEs regardless of treatment group or causal relationship to 
investigational product will be recorded on the AE page(s) of the CRF. 
13.1 
Definitions 
13.1.1 Adverse Events 
An AE is any untoward medical occurrence that occurs in a patient or clinical investigation 
patient administered a pharmaceutical product, and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavorable and unintended 
sign (including abnormal laboratory finding), symptom, or disease temporally associated with 
the use of an investigational product, whether or not considered related to the medicinal product 
(definition per International Conference on Harmonisation [ICH] E2A and E6 R1). 
All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, must be 
recorded using medical terminology on the AE CRF page. Whenever possible, diagnoses should 
be given when signs and symptoms are due to a common etiology (e.g., 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 on SAEs) requiring immediate notification to the Sponsor or its designated 
representative. For all AEs, sufficient information should be obtained by the Investigator to 
determine the causality of the AE.  
Interventions for pretreatment conditions (e.g., elective cosmetic surgery) or medical procedures 
that were planned before study enrollment are not considered AE. 
TEAEs are those events that occur or worsen on or after first dose of investigational product and 
up to 28 days after the last dose.  
13.1.2 Abnormal Laboratory Results 
The criteria for determining whether an abnormal laboratory test result should be reported as an 
AE are as follows: 
 Test result is associated with accompanying symptoms, and/or, 


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 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 and 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 
Any abnormal test result that is determined to be an error does not require reporting as an AE, 
even if it did meet one of the above criteria except for when the test result leads to any of the 
outcomes included in the definition of a SAE. Clinically significant laboratory results must be 
recorded in the patient’s CRF. 
13.1.3 Serious Adverse Events 
An SAE is defined as any untoward medical occurrence that at any dose (ICH E2A and E6 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. 


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13.1.4 Hospitalization 
Any inpatient hospital admission that includes a minimum of an overnight stay to a healthcare 
facility meets the criteria for ‘hospitalization’. Admission also includes transfer within the 
hospital to an acute/intensive care unit (e.g., 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 (e.g., caregiver relief). 
 Skilled nursing facilities. 
 Nursing homes. 
 Routine emergency room admissions. 
 Same day surgeries (as outpatient /same day/ambulatory procedures). 
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 (e.g., for work-up of persistent 
pre-treatment lab abnormality). 
 Social admission (e.g., patient has no place to sleep). 
 Administrative admission (e.g., for yearly physical examination). 
 Protocol-specified admission during a study (e.g., for a procedure required by the study 
protocol). 
 Optional admission not associated with a precipitating clinical AE (e.g., for elective 
cosmetic surgery). 
 Hospitalization for observation without a medical AE. 
 Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation or the entire protocol and/or for the individual patient. 
 Admission exclusively for the administration of blood products. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should 


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be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE reporting period should be reported as the AE, and the resulting appendectomy 
should be recorded as treatment of the AE. 
13.1.5 Suspected Unexpected Serious Adverse Reaction 
Suspected Unexpected Serious Adverse Reactions (SUSAR) are events which are serious as per 
the above criteria, the nature or severity of which is not consistent with the applicable product 
information (e.g., current Investigator’s Brochure) and are judged by the Investigator or by the 
Sponsor to be related to investigational product. For a non-Sponsored investigational product 
(e.g., a comparator product) with a marketing authorization, the expectedness of an AE will be 
determined by whether or not it is listed in the package insert/SPC. 
13.1.6 Severity Assessment 
Adverse events will be graded by the Investigator according to the NCI CTCAE v.4.03 (Publish 
Date: June 14, 2010, http://ctep.cancer.gov/reporting/ctc.html), according to the following 
general categories: 
Grade 1: 
Mild; asymptomatic or mild symptoms; clinical or diagnostic 
observations only; intervention not indicated.  
Grade 2: 
Moderate; minimal, local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living.  
Grade 3: 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care activities of daily living. 
Grade 4: 
Life-threatening consequences; urgent intervention indicated.  
Grade 5: 
Death related to AE. 
Note the distinction between the severity and the seriousness of an AE. A severe event is not 
necessarily a serious event. For example, a headache may be severe (interferes significantly with 
patient's usual function) but would not be classified as serious unless it meets one of the criteria 
for SAEs, listed above. 
13.1.7 Causality Assessment 
The Investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious); the Investigator must record the causal relationship in the CRF and report such an 
assessment in accordance with the serious adverse reporting requirements, if applicable. A 


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suspected adverse reaction means any AE for which there is a reasonable possibility that the 
investigational product caused the AE. An Investigator’s causality assessment is the 
determination of whether there exists a reasonable possibility that the investigational product 
caused or contributed to an AE; generally the facts (evidence) or arguments to suggest a causal 
relationship should be provided. If the Investigator does not know whether or not the 
investigational product caused the event, then the event will be handled as “related to 
investigational product” for reporting purposes, as defined by the Sponsor (see Section on 
Reporting Requirements). 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 (e.g., investigational product or other illness). The relationship of the AE to 
the study treatment (investigational product, comparator or placebo [as applicable]) will be 
assessed following the definitions below: 
 ‘No’ (unrelated): Any event that does not follow a reasonable temporal sequence from 
administration of investigational product AND is likely to have been produced by the 
patient’s clinical state or other modes of therapy administered to the patient. 
 ‘Yes’ (related): Any reaction that follows a reasonable temporal sequence from 
administration of investigational product AND follows a known response pattern to the 
suspected investigational product AND recurs with re-challenge, AND/OR is improved by 
stopping the investigational product or reducing the dose. 
In addition, if the Investigator determines an AE is associated with study procedures, the 
Investigator must record this causal relationship on the AE CRF page and report such an 
assessment in accordance with the SAE reporting requirements, if applicable. 
13.1.8 Special Reporting Situations 
Safety events of interest on the Sponsor’s investigational product that may require expedited 
reporting and/or safety evaluation include, but are not limited to: 
 Overdose of an investigational product. 
 Suspected abuse/misuse of an investigational product. 
 Inadvertent or accidental exposure to an investigational product. 
 Medication error that may result from the administration or consumption of the wrong 
drug, by the wrong patient, at the wrong time, or at the wrong dosage strength. 
 Suspected transmission via an investigational product of an infectious agent. 


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Special reporting situations should be recorded on the AE CRF page. Any special reporting 
situation that meets the criteria of a SAE should be recorded on the SAE form and reported as 
required (see Section 13.3). 
13.2 
Reporting Adverse Events 
For serious and non-serious AEs, the reporting period to the Sponsor (or its designated 
representative) begins from the time that the patient provides informed consent, which is 
obtained prior to the patient’s participation in the study, i.e., prior to undergoing any 
study-related procedure and/or receiving investigational product, through 28 calendar days after 
the last administration of the investigational product.  
For all AEs with causal relationship to the investigational product, follow-up by the Investigator 
may be required until the event or its sequelae resolve or stabilize at the level acceptable to the 
Investigator, and the Sponsor concurs with that assessment. 
If a patient begins a new anticancer therapy, the AE reporting period for non-serious AEs ends at 
the time the new treatment is started. Death must be reported if it occurs during the SAE 
reporting period after the last dose of investigational product, irrespective of any intervening 
treatment. 
The Sponsor will evaluate any safety information that is spontaneously reported by an 
Investigator beyond the time frame specified in the protocol. 
13.3 
Reporting Serious Adverse Events 
All SAEs, irrespective of relationship to investigational product, must be reported within 
24 hours of discovery or notification of the event to the Sponsor or designated representative 
using the SAE form. The SAE form must be signed by the Investigator. In particular, if the SAE 
is fatal or life-threatening, notification to the Sponsor must be made immediately, irrespective of 
the extent of available AE information. This timeframe also applies to follow-up information on 
previously forwarded SAE reports as well as to the initial and follow-up reporting of exposure 
during pregnancy and exposure via breast feeding cases. For SAE reporting information, please 
refer to the Study Contact List which is provided as a separate document. 
Relevant medical records should be provided to the Sponsor or its designated representative as 
soon as they become available; autopsy reports should be provided for deaths if available.  
Should an Investigator be made aware of an SAE occurring any time after the reporting period, it 
must be promptly reported. 


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All SAEs that have not resolved by the end of the study, or that have not resolved upon 
discontinuation of the patient's participation in the study, must be followed until any of the 
following occurs: 
 The event resolves. 
 The event stabilizes. 
 The event returns to baseline, if a baseline value/status is available. 
 The event can be attributed to agents other than the investigational product or to factors 
unrelated to study conduct. 
 It becomes unlikely that any additional information can be obtained (patient or health care 
practitioner refusal to provide additional information, lost to follow-up after demonstration 
of due diligence with follow-up efforts). 
13.4 
Pregnancy  
All initial reports of pregnancy must be reported to the Sponsor by the investigational staff 
within 24 hours of their knowledge of the event using the appropriate Exposure-In-Utero (EIU) 
form. 
For investigational products and for marketed products used as investigational product in 
neratinib studies, an exposure during pregnancy occurs if: 
 A female becomes, or is found to be, pregnant either while receiving or having been 
directly exposed (e.g., environmental exposure) to the investigational product, or the 
female becomes, or is found to be, pregnant after discontinuing and/or being directly 
exposed to the investigational product (maternal exposure) for 28 days after last dose of or 
exposure to investigational product. 
 A male partner of a pregnant female has been exposed to the investigational product, either 
due to treatment or environmental exposure, within 3 months prior to the time of 
conception and/or is exposed during his partner’s pregnancy (paternal exposure). 
If any study patient or study patient’s partner becomes or is found to be pregnant during the 
study patient’s treatment with the investigational product or exposure as defined above, the 
Investigator must submit this information on an EIU form to the Sponsor (or its designated 
representative). In addition, the Investigator must submit information regarding environmental 
exposure to an investigational product in a pregnant woman (e.g., 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 


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awareness of the pregnancy. The information submitted should include the anticipated date of 
delivery (see following information related to 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 (e.g., 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 
(e.g., ectopic pregnancy, spontaneous abortion, intrauterine fetal demise, neonatal death, or 
congenital anomaly [including that in a live born, a terminated fetus, an intrauterine fetal demise, 
or a neonatal death]), the Investigator should follow the procedures for reporting SAEs. 
Additional information about pregnancy outcomes that are classified as SAEs follows:  
 “Spontaneous abortion” includes miscarriage and missed abortion. 
 All neonatal deaths that occur within 1 month of birth should be reported, without regard to 
causality, as SAEs. In addition, infant deaths after 1 month should be reported as SAEs 
when the Investigator assesses the neonatal death as related to exposure to investigational 
product. 
Additional information regarding the exposure during pregnancy may be requested by the 
Investigator. Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required. 
13.5 
Sponsor Reporting Requirements to Health Authorities and IRB/IEC 
The Sponsor assumes responsibility for reporting of AEs including SUSARs according to local 
and international regulations, as appropriate. The Investigator (or the Sponsor where required) 
must report these events to the appropriate IEC/IRB that approved the protocol unless otherwise 
required and documented by the IEC/IRB. 


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14 ETHICAL, LEGAL AND ADMINISTRATIVE ASPECTS 
The Sponsor of this study may delegate some administrative aspects of this study to a duly 
authorized representative including, but not limited to, study initiation, monitoring and 
management of SAE reports. 
14.1 
Data Collection, Processing and Monitoring 
14.1.1 Case Report Forms and Source Documentation 
All data captured for the study is planned to be electronic. However, if necessary, data captured 
may be performed using paper CRFs. 
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/co-worker) person. Overwriting of this 
information or use of liquid correcting fluid is not allowed. 
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. After all the data 
issues are resolved, these CRFs may be locked to prevent any further data changes. At the end of 
the study or prior to the site closeout visit, the Investigator will review and approve the data for 
completeness and accuracy.  
14.1.2 Study Monitoring and Access to Source Documentation 
To ensure compliance with relevant regulations, data generated by this study must be available 
for inspection upon request by representatives of the US Food and Drug Administration (FDA), 
the European Medicines Agency (EMA), other national authorities, and local health authorities, 
the Sponsor and representatives, and the IRB/ Ethics Committee (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. 


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The Sponsor or representative’s monitor is responsible for verifying the CRFs at regular intervals 
throughout the study to verify adherence to the protocol; completeness, accuracy and consistency 
of the data; and adherence to local regulations on the conduct of clinical research. Source data to 
be reviewed and/or 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 
(e.g., patient’s medical file, appointment books, original laboratory test reports, X-rays, etc.) that 
substantiate information in the CRFs. These personnel, bound by professional secrecy, will not 
disclose any personal information or personal drug information. 
14.1.3 Data Monitoring Committee 
A Data Monitoring Committee (DMC) will be convened for this study and will act in an advisory 
capacity to the Sponsor with respect to safeguarding the interests of study subjects, assessing 
interim safety and efficacy data, and for monitoring the overall conduct of the study. The 
membership criteria, meeting schedule, and other details of the DMC are described in the DMC 
Charter.  
14.1.4 Data Quality Assurance 
During and/or after completion of the study, quality assurance auditor (s) named by the Sponsor 
or the regulatory authorities may wish to perform on-site audits. The Investigators will be 
expected to cooperate with any audit and provide assistance and documentation (including 
source data) as requested. 
The Sponsor’s representatives are responsible for contacting and visiting the Investigator for the 
purpose of inspecting the facilities and, upon request, inspecting the various records of the 
clinical study (e.g., CRFs and other pertinent data) provided that patient confidentiality is 
respected. 
The Investigator agrees to cooperate with the monitor to ensure that any problems detected in the 
course of these monitoring visits, including delays in completing CRFs, are resolved. 
In accordance with ICH 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 (e.g., pharmacy, drug storage areas, 
laboratories) and review of study-related records will occur to evaluate the study conduct and 
compliance with the protocol, ICH GCP (ICH E6), US Investigational Drugs (21 Code of 


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Federal Regulations [CFR] 312), EU Clinical Studies Directive (Directive 2001/20/EC), and 
applicable regional regulatory requirements. 
14.1.5 Data Processing 
All data will be entered by site personnel into the CRF provided (as detailed in Section 14.1.1).  
The data management plan will include specifications for data review and data consistency. 
Outstanding query reports will be sent to the study monitors for resolution by site personnel.  
To minimize sources of bias in this open label study, access to treatment information will be 
limited to specific site, CRO and Sponsor personnel. All individuals with access to treatment 
information should not disclose this information to others. 
Previous and concomitant medications will be coded using the World Health Organization Drug 
Reference List (WHODrug), which employs the Anatomical Therapeutic Chemical classification 
system. Medical history and AEs will be coded using MedDRA terminology. The versions of the 
coding dictionaries will be provided in the Clinical Study Report. 
14.1.6 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 
at least 2 years have elapsed since the formal discontinuation of clinical development of the 
investigational product. These documents should be retained for a longer period however if 
required by the applicable regulatory requirements or by agreement with the Sponsor. The 
Investigator should obtain written permission from the Sponsor prior to the destruction of any 
study document. 
These records should be made available at reasonable times for inspection and duplication, if 
required, by a properly authorized representative of the US FDA in accordance with 21 CFR 
§312.68 or other National Regulatory Authorities. 
14.2 
Ethical Aspects 
14.2.1 Good Clinical Practice and Ethical Conduct of the Study 
This protocol accords with the principles of the Declaration of Helsinki (World Medical 
Association Declaration of Helsinki) as set forth at the 18th World Medicines Association 
(Helsinki 1964) and amendments thereto. The most current amended version will be in effect. 


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The procedures set out in this study protocol are also designed to ensure that the Sponsor and 
Investigator abide by the principles of the GCP guidelines of the ICH and in keeping with local 
legal requirements. 
14.2.2 Informed Consent 
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, i.e., the objectives, potential benefits and risk, 
inconveniences and the patient’s rights and responsibilities. If applicable, the information will be 
provided in a certified translation of the local language.  
A signed, IRB/IEC approved, ICF must be obtained from patient before any study specific 
procedures can occur. Confirmation of the patient’s informed consent and the informed consent 
process must also be documented in the patient’s medical record. Signed ICFs must remain in 
each patient’s study file and must be available for verification by study monitors at any time. A 
copy of the fully signed ICFs will be given to the patient. 
If the 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 must 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 (e.g., is blind or illiterate), a legally acceptable representative 
or impartial witness, as applicable, may sign the ICF on behalf of the patient. It remains the 
responsibility of the principal Investigator to assure that the patient is suitable for inclusion in 
this study and will be able to adhere to all study procedures throughout the course of the study. 
The explicit wish of a 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. 


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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. 
14.3 
Other Study Administration Aspects 
14.3.1 Protocol Approval and Protocol Amendment 
The protocol (approved by the Sponsor or its representative) will be submitted to the IRB/IEC 
for review and it must be approved before the study is initiated. Prior to implementing changes in 
the study, the Sponsor will produce a protocol amendment and the IRB/IEC must also approve 
any amendments to the protocol. 
Any change in the study plan requires a protocol amendment. An Investigator must not make any 
changes to the study without IRB/IEC and Sponsor approval except when necessary to eliminate 
apparent immediate hazards to the patients.  
14.3.2 Investigator Responsibilities 
The Investigator undertakes to perform the study in compliance with the protocol, ICH 
Guidelines per GCP and the applicable regulatory requirements.  
It is the Investigator’s responsibility to ensure that adequate time and appropriate resources are 
available at the investigational site prior to commitment to participate in this study. The 
Investigator should also be able to demonstrate a potential for recruiting the required number of 
suitable patient within the agreed recruitment period. 
The Investigator will maintain a list of appropriately qualified persons to whom the Investigator 
has delegated significant study-related tasks. An up-to-date copy of the curriculum vitae for the 
Investigator and sub-Investigator(s) will be provided to the Sponsor (or its representative) before 
starting the study. 
If the patient has a primary physician, the Investigator should, with the patient’s consent, inform 
the primary physician of the patient’s participation in the study. 
Agreement with the final clinical study report will be documented by the signed and dated 
signature of the principal or coordinating Investigator in compliance with ICH E3. 
The Investigator must adhere to the protocol as detailed in this document. The Investigator will 
be responsible for enrolling only those patients who have met protocol eligibility criteria. The 
Investigators will be required to sign an Investigator agreement to confirm acceptance and 
willingness to comply with the study protocol. 


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It is the Investigator’s responsibility to communicate with their local IRB/IEC to ensure accurate 
and timely information is provided at all phases during the study. In particular, the appropriate 
approvals must be in place prior to recruitment, notification of any SAEs during the study must 
take place and the IRB/IEC must be informed of study completion. 
It is the responsibility of the Investigator to submit this protocol, the final approved informed 
consent document (approved by the Sponsor or its representative), relevant supporting 
information, and all types of patient recruitment or advertisement information (approved by the 
Sponsor or its representative) 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. 
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 a year. The 
Investigator must also keep the IRB/IEC informed of any serious and significant AEs. 
14.3.3 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 (United States [US] sites only) or Data Protection Consent (EU sites only) 
is to be obtained from each patient prior to enrollment into the study, and/or from the patient's 
legally authorized representative in accordance with the applicable privacy requirements 
(e.g., Health Insurance Protection and Portability Act [HIPAA]), European Union Data Protection 
Directive 95/46/EC (“EU Directive”) and any other state and country privacy requirements).  


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14.3.4 Financial Disclosure 
The Investigator will be required to disclose any financial arrangement whereby the value of the 
compensation for conducting the study could be influenced by the outcome of the study; any 
significant payments of other sorts from the Sponsor, such as a grant to fund ongoing research, 
compensation in the form of equipment, retainer for ongoing consultation, or honoraria; any 
proprietary interest in neratinib; any significant equity interest in the Sponsor, as defined in the 
US CFR (21 CFR 54.2(b)). 
In consideration of participation in the study, the Sponsor will pay the Investigator, study site or 
nominated payee the sums set out in the payment schedule attached to the Investigator 
Agreement. 
14.3.5 Publication Policy 
The Sponsor encourages publication of results derived from the clinical research it sponsors, 
regardless of outcome. Publications include papers in peer reviewed medical journals, abstract 
submission with a poster or oral presentation at a scientific meeting, or making results public by 
some other means. The Sponsor will retain the right to review all material prior to presentation or 
submission for publication and neither institution(s) nor Study Co-chairs/Principal 
Investigator(s) are permitted to publish/present the results of the study, in part or in their entirety 
without the written authorization of the Sponsor. The review is aimed at protecting the Sponsor’s 
pre-existing propriety information and commercial interests. 
First Publication 
The results of the entire multicenter study shall be presented in a first publication upon 
completion of the entire multicenter study (data lock), with authorship being determined by the 
Sponsor using the criteria defined by the International Committee of Medical Journal Editors. At 
least two Sponsor representatives will also be included as coauthors on the first publication of 
the results of the entire multicenter study to allow recognition of the Sponsor’s involvement in 
the design and execution of the study. 
Subsequent Publications 
Results from data subsets should not be published in advance of the first publication, and must 
make reference to it. Publications must normally include at least two Sponsor authors to allow 
recognition of the Sponsor’s involvement. In all publications, the study is to be identified as 
PUMA-NER-1301 (NALA), or some other Sponsor-approved and published name.  


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Declaration of Sponsor or Responsible Medical Officer 
Title: A Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients 
With HER2+ Metastatic Breast Cancer Who Have Received Two or More Prior HER2-Directed 
Regimens in the Metastatic Setting (NALA) 
Study Number: PUMA-NER-1301 
I have read and approve this protocol. My signature, in conjunction with the signature of the 
Investigator, confirms the agreement of both parties that the clinical study will be conducted in 
accordance with the protocol and all applicable laws, regulations and guidelines, including, but 
not limited to, the International Conference on Harmonisation (ICH) Guideline for Good Clinical 
Practice (GCP), the United States Code of Federal Regulations (CFR), the Directives of the 
European Union, the ethical principles that have their origins in the Declaration of Helsinki and 
applicable privacy laws. 
 
 
_____________________________________ 
Signature 
 
_____________________________________ 
_____________________ 
Name 
Date 
 
_____________________________________ 
Title 
 
 
 


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Declaration of Principal Investigator 
Title: A Study of Neratinib Plus Capecitabine Versus Lapatinib Plus Capecitabine in Patients 
With HER2+ Metastatic Breast Cancer Who Have Received Two or More Prior HER2-Directed 
Regimens in the Metastatic Setting (NALA) 
Study Number: PUMA-NER-1301 
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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Appendix 1 
Table A1. 1 
Schedule of Procedures 
Assessment Time Point 
Study Event 
Screeninga 
Baseline 
Cycle 1 
(21-Day Cycle) 
Cycle 2+ 
Treatment 
Discontinuation 
Safety Follow-
up Contact 
Long-Term 
Follow-up 
Study Days 
Within 
21 Days Before 
Randomization 
Within 72 
Hours Before 
Randomization 
Day 1 
Day 8 
(±1 day) 
Day 15 
(±1 day) 
Day 1 
(±2 days) 
0-3 Days After 
Last Dose 
28 Days After 
Last Dose  
(+5 days) 
Every 12 
Weeks Post 
TD 
(±7 days) 
Procedures 
Informed Consentb  
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Medical, Cancer and 
Medication Historyc 
X 
 
 
 
 
 
 
 
 
Physical Examinationd  
X 
Xe 
 
 
 
X 
X 
 
 
Vital Signs, height and 
weightf 
X 
Xe 
 
X 
X 
X 
X 
 
 
ECGg 
X 
 
 
 
 
Xg 
Xg 
 
 
ECHO/MUGAh 
X 
 
 
 
 
Xh 
X 
 
 
ECOG Status 
X 
Xe 
 
 
 
X 
X 
 
 
Heath Outcomes 
Assessmentsi 
 
Xe 
 
 
 
Xi 
X 
 
 
Concomitant Therapy 
 
Collected continuously throughout study period, including each visit 
X 
 
Adverse Eventsj 
 
Collected continuously throughout study period, including each visit 
X 
 
Cancer Therapyk 
 
 
 
 
 
 
 
X 
X 
HER2/ER/PR status 
(by central lab)l 
Xl 
 
 
 
 
 
 
 
 
Serum Pregnancy Testm 
X 
 
 
 
 
 
 
 
 


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Assessment Time Point 
Study Event 
Screeninga 
Baseline 
Cycle 1 
(21-Day Cycle) 
Cycle 2+ 
Treatment 
Discontinuation 
Safety Follow-
up Contact 
Long-Term 
Follow-up 
Study Days 
Within 
21 Days Before 
Randomization 
Within 72 
Hours Before 
Randomization 
Day 1 
Day 8 
(±1 day) 
Day 15 
(±1 day) 
Day 1 
(±2 days) 
0-3 Days After 
Last Dose 
28 Days After 
Last Dose  
(+5 days) 
Every 12 
Weeks Post 
TD 
(±7 days) 
Laboratory 
Hematology Paneln 
X 
Xe 
 
 
 
X 
X 
 
 
Serum Chemistry Panelo 
X 
Xe 
 
 
 
X 
X 
 
 
Urine Dipstickp 
X 
Xe 
 
 
 
 
 
 
 
Efficacy Assessments 
CT/MRIa, i, q 
X 
 
 
 
 
Xi 
 
 
 
Survivalr 
 
 
 
 
 
 
 
X 
X 
Drug Administration (1st dose no later than 14 days after randomization) 
Neratinib (Arm A) or 
Lapatinib (Arm B) 
 
 
Days 1 - 21 of each cycle 
 
 
Capecitabine 
 
 
Days 1 - 14 of each cycle 
 
 
Antidiarrheal Treatments  
 
 
Prior to Neratinib administration 
 
 
 
 
Dosing Compliance  
 
 
 
X 
X 
X 
X 
 
 
PK Sampling at Select Study Centers 
PK Samplingt 
 
 
X 
 
X 
 
 
 
 
a. 
Screening activities are to be conducted within 21 days before randomization. Tumor scans (CT and MRI) and ECHO/MUGA must be performed within 
28 days prior to randomization, and preferably no more than 28 days before initiation of treatment. 
Randomization should occur after all baseline assessments have been completed and the site confirms that the patient still meets all eligibility requirements.  
b. 
Informed consent must be obtained before any screening procedures begin. 
c. 
Collect demographic information, relevant medical history, medical conditions or symptoms experienced during the previous 30 days as well as those 
ongoing at the time of screening, any medical conditions that require medication, and all prior cancer therapies. Identify the start of current medical 
conditions by at least the month/year; identify the start of significant preexisting conditions by at least the year.  
d. 
Full physical exam at screening and brief physical exams at all subsequent time points to assess changes from the screening exam. 


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e. 
Baseline physical exam, vital signs, ECOG status, laboratory assessments, and health outcomes assessments must all be done within 72 hours prior to 
randomization. However, if screening laboratory assessments and ECOG status were performed within 72 hours before randomization and there were no 
clinically significant findings, these procedures do not need to be repeated. 
f. 
Vital signs include pulse, blood pressure (after 5 min rest), and temperature (°C or °F; oral, core [rectal], axillary or tympanic); also measure height 
(screening only) and weight.  
g. 
ECGs should be performed at Cycle 3/Day 1, Cycle 6/Day 1 and Day 1 of every 6th subsequent cycle during the active treatment phase. ECG should also be 
performed at Treatment Discontinuation if not done within the previous 12 weeks. Patients using drugs known to cause QT/QTc prolongation should be 
monitored closely with serial ECGs at the Investigator’s discretion. Refer to Appendix 6 for a summary of drugs known to have a risk of causing QT/QTc 
prolongation, potentially causing Torsade de Pointes (TdP). 
h. 
For LVEF during the active treatment phase, MUGA/ECHO should be repeated at Cycle 3/Day 1, Cycle 6/Day 1 and Day 1 of every 6th subsequent cycle. 
MUGA/ECHO should also be performed at Treatment Discontinuation if not done within the previous 12 weeks.  
i. 
Timing for tumor assessments and health outcomes assessments (EORTC QLQ-C30, EORTC QLQ-BR23 and EQ-5D-5L) at the end of every 6 weeks 
(±3 days) is intended to reflect the end of every second cycle of study treatment. However, if cycles move off schedule for any reason, these assessments 
should remain every 6 weeks starting from Cycle 1/Day 1 during the active treatment phase. Tumor assessments will continue every 6 weeks until 
documented disease progression or death, regardless of whether the patient is continuing study treatment or has discontinued study treatment. The scans 
must be obtained and reviewed prior to start of the next cycle. For patients who show a CR on one scan and on a confirmatory scan obtained 6 weeks later, 
the frequency of subsequent scans may be reduced at the discretion of the investigator to no less than one scan every 12 weeks. 
j. 
Serious adverse events (SAEs) must be reported starting at the time of signing informed consent. All AEs including SAEs must be reported from initiation of 
study treatment and must continue to be followed for 28 days after last administration of investigational product.  
k. 
Cancer therapies evaluated at the safety follow-up contact and at the long-term follow-up contact include anti-cancer medications, cancer-related 
radiotherapy and cancer-related surgery/procedures since last contact. 
l. 
Tumor testing for HER2 gene amplification or overexpression will be performed by a central laboratory using HercepTest™ and possibly FISH analysis 
using IQFISH pharmDx™. ER/PR status will be determined using pharmDx™ kit. Either primary breast cancer tissue (e.g., from prior surgical resection) or 
other breast cancer-containing tissue (e.g., from biopsy or excision of cancer-containing lymph node or metastatic lesion) is acceptable for central HER2 
testing (see Section 8.2.1.1).  
m. If a pregnancy test needs to be repeated during screening, a urine pregnancy test will suffice. 
n. 
Hematology panel: differentials (basophils, eosinophils, lymphocytes, monocytes, neutrophils), hematocrit, hemoglobin (Hb), international normalized ratio 
(INR), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), mean corpuscular volume (MCV), platelet count, 
prothrombin time (PT), activated partial thromboplastin time (aPTT), red blood cell count (RBC), red blood cell distribution width (RDW), white blood cell 
count (WBC) with differential. 
o. 
Serum chemistry includes at least the following: albumin, alkaline phosphatase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total 
bilirubin, bicarbonate, blood urea nitrogen (BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase (LDH), magnesium, phosphorous, 
potassium, total protein, and sodium. Creatinine clearance will be calculated by the Cockroft-Gault Formula or Modification of Diet in Renal Disease 
(MDRD) formula (Levey et al., 1999) within 14 days of enrollment. 


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p. 
Urinalysis by dipstick (blood, protein, glucose, and microscopic examination, if abnormal). 
q. 
Post-treatment disease assessment by CT scan or MRI of the chest, abdomen and pelvis will be conducted every 6 weeks (±3 days). Tumor assessments will 
continue every 6 weeks until documented disease progression or death, regardless of whether the patient is continuing or has discontinued study treatment. 
Overall response will be scored by the Investigator according to RECIST v1.1 using the algorithms defined in Appendix 7. For patients who show a CR on 
one scan and on a confirmatory scan obtained 6 weeks later, the frequency of subsequent scans may be reduced at the discretion of the investigator to no less 
than one scan every 12 weeks. 
r. 
Long-term follow-up for survival status will occur via telephone call if the site is unable to confirm via chart review. 
s. 
Antidiarrheal treatment should be dispensed with the initial supply of neratinib. 
t. 
At select study centers only: PK samples should be collected on Cycle 1, Day 1 and Day 15, at 6 hours post-dose (±20 minutes) and 8 hours post-dose 
(±60 minutes). Patients should be instructed to record the exact minute that the dose was taken on these days. PK samples will be taken from approximately 
100 patients on the neratinib arm (Arm A). 
  


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Appendix 2 
Investigational Product Dose Adjustment for Toxicity 
1. DOSE ADJUSTMENT LEVELS 
Recommended dose reductions for the -1 and -2 dose levels of neratinib, lapatinib and 
capecitabine are provided in Section 6.1.3. 
2. TOXICITIES REQUIRING INVESTIGATIONAL PRODUCT DOSE 
ADJUSTMENTS 
NERATINIB PLUS CAPECITABINE 
General Toxicities 
Guidelines for dose adjustments of neratinib and capecitabine for general toxicities due to 
combination of neratinib plus capecitabine are shown in Table A2. 1. 
Table A2. 1 
General Toxicities Requiring Dose Adjustment of Neratinib and 
Capecitabine  
NCI CTCAE v.4.0 
Action 
Grade 2 adverse reaction  
 
1st appearance 
 
 
Hold neratinib and capecitabine until event resolves to Grade ≤1; then 
resume both drugs at the starting dose level.  
 
2nd appearance 
 
 
Hold neratinib and capecitabine until event resolves to Grade ≤1; then 
resume neratinib at 160 mg and capecitabine at 1100 mg/m2 (550 mg/m2 
BID). 
 
3rd appearance 
 
Hold neratinib and capecitabine until event resolves to Grade ≤1; then 
resume neratinib at 120 mg and capecitabine at 750 mg/m2 (375 mg/m2 
BID). 
 
4th appearance 
 
Discontinue neratinib and capecitabine permanently. 
Grade 3 adverse reaction 
 
1st appearance 
 
 
Hold neratinib and capecitabine until event resolves to Grade ≤1; then 
resume neratinib at 160 mg and capecitabine at 1100 mg/m2 (550 mg/m2 
BID). 
 
2nd appearance 
 
 
Hold neratinib and capecitabine until event resolves to Grade ≤1; then 
resume neratinib at 120 mg and capecitabine at 750 mg/m2 (375 mg/m2 
BID). 
 
3rd appearance 
 
Discontinue neratinib and capecitabine permanently. 
Grade 4 adverse reaction 
 
1st appearance 
 
Discontinue neratinib and capecitabine permanently OR if Investigator 
deems it to be in the patient’s best interest to continue, hold neratinib and 
capecitabine until resolved to Grade ≤1; then resume neratinib at 120 mg 
and capecitabine at 750 mg/m2 (375 mg/m2 BID). 
Abbreviations: BID, twice daily; NCI CTCAE v.4.0: National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 4.0.  


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Gastrointestinal Toxicity 
Guidelines for adjusting doses of neratinib and capecitabine in the event of gastrointestinal 
toxicities are shown in Table A2. 2.  
Table A2. 2 
Gastrointestinal Toxicities Requiring Dose Adjustment of Neratinib and 
Capecitabine 
NCI CTCAE v.4.0 
Actions 
Grade 1 Diarrhea: Increase of <4 stools per 
day over baseline; mild increase in 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 and activities of daily living. 
Lasting ≤2 days 
 
Adjust antidiarrheal treatment per the guidelines for 
management of diarrhea at the first onset of diarrhea (refer to 
Section 7.1.1). 
 
Continue neratinib and capecitabine at full doses. 
 
Instruct patient to follow dietetic recommendations in the 
guidelines for management of diarrhea (refer to 
Section 7.1.1). 
 
Fluid intake of ~2 L/day should be maintained to avoid 
dehydration. 
 
Once the event resolved to Grade ≤1 or baseline, start 
loperamide 4 mg with each subsequent neratinib 
administration. 
Persisting and intolerable Grade 2 
Diarrhea: lasting >5 days despite treatment 
with optimal medical therapy, or associated 
with fever, dehydration, or Grade 3-4 
neutropenia. 
OR 
Grade 3 Diarrhea: lasting >2 days despite 
treatment with optimal medical therapy, or 
associated with fever, dehydration, or Grade 
3-4 neutropenia. 
OR 
Any Grade 4 diarrhea: Life-threatening 
consequences: urgent intervention indicated. 
 
Adjust antidiarrheal treatment per the guidelines for 
management of diarrhea at the first onset of diarrhea (refer to 
Section 7.1.1). 
 
Hold neratinib and capecitabine until recovery to Grade ≤1 
or baseline. 
 
Instruct patient to follow dietetic recommendations of the 
guidelines for management of diarrhea. 
 
Fluid intake of ~2 L/day should be maintained by IV, if 
needed. 
 
If recovery occurs: 
o 
≤1 week after withholding treatment, resume same doses 
of neratinib and capecitabine. 
o 
Within 1-3 weeks after withholding treatment, reduce 
neratinib dose to 160 mg and maintain the same dose of 
capecitabine. 
 
If event occurs a second time and the neratinib dose has not 
already been decreased, reduce neratinib dose to 160 mg 
(maintain the same dose of capecitabine). If neratinib dose 
has already been reduced, then reduce the dose of 
capecitabine to 1100 mg/m2 (550 mg/m2 BID)a (maintain 
the same dose of neratinib). 
 
If subsequent events occur, reduce the dose of neratinib or 
capecitabine to the next lower dose level in an alternate 
fashion (i.e., reduce capecitabine to 750 mg/m2 
(375 mg/m2 BID)b if neratinib was previously reduced, or 
reduce neratinib to 120 mg if capecitabine was previously 
reduced). 
 


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NCI CTCAE v.4.0 
Actions 
 
 
Once the event resolved to Grade ≤1 or baseline, start 
loperamide 4 mg with each subsequent neratinib 
administration. 
Abbreviations: BID: twice daily; IV: intravenous; L: liter; NCI CTCAE v.4.0: National Cancer Institute Common 
Terminology Criteria for Adverse Events Version 4.0. 
a Since capecitabine is provided as 150 mg or 500 mg tablets, it is recommended that the capecitabine dose 
reduction(s) is rounded down to the nearest 500 mg or multiple of 150 mg for the BID dose. If the patient’s body 
surface area is >2.0, the standard of care for the study center can be utilized for capecitabine mg/m2 dosing. 
 
Pulmonary Toxicity 
Guidelines for adjusting doses of neratinib in the event of pulmonary toxicity are shown in 
Table A2. 3. Interstitial lung disease, which can sometimes be fatal, has been reported with other 
oral tyrosine kinase inhibitors that target HER1 ± HER2, including lapatinib, gefitinib and 
erlotinib. Rare cases of pneumonitis (0.6%) and lung infiltration (0.4%) have been reported in 
patients treated with neratinib monotherapy, and were considered drug-related. Patients 
receiving neratinib should be monitored for acute onset or worsening of pulmonary symptoms 
such as dyspnea, cough and fever and treated appropriately. 
Table A2. 3 
Pulmonary Toxicities Requiring Dose Adjustment of Neratinib 
NCI CTCAE v.4.0 
Actions 
Grade 2 Pneumonitis/Interstitial Lung Disease: 
Symptomatic; medical intervention indicated; 
limiting instrumental activities of daily living. 
 
Hold neratinib until recovery to Grade ≤1 or baseline. 
 
Reduce neratinib to 160 mg or discontinue neratinib 
per Investigator’s best medical judgment. 
Grade 3 Pneumonitis/Interstitial Lung Disease: 
Severe symptoms; limiting self-care activities of 
daily living; oxygen indicated. 
 
Discontinue neratinib permanently. 
Abbreviations: NCI CTCAE v.4.0: National Cancer Institute Common Terminology Criteria for Adverse Events 
Version 4.0. 
 
Liver Toxicity 
Guidelines for dose adjustment of neratinib and capecitabine in the event of liver toxicity are 
shown in Table A2. 4. 
Abnormal values in ALT concurrent with abnormal elevations in total bilirubin that meet the 
criteria outlined below in the absence of other causes of liver injury are considered potential 
cases of drug-induced liver injury (potential Hy’s Law cases) and should always be considered 
important medical events. 
Patients who experience Grade ≥3 diarrhea requiring IV fluid treatment or any signs or 
symptoms of hepatotoxicity such as worsening of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash or eosinophilia should be evaluated for changes in liver function 
tests. Fractionated bilirubin and PT must also be collected during hepatotoxicity evaluation. 


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Table A2. 4 
Liver Function Test Abnormalities Requiring Dose Adjustment of Neratinib 
and Capecitabine 
NCI CTCAE v.4.0 
Actions 
Grade 3 ALT (>5-20 x ULN) 
or 
Grade 3 bilirubin (>3-10 x ULN) 
 
Hold neratinib and capecitabine until recovery to Grade ≤1 for 
patients with ALT Grade ≤1 at baseline OR Grade ≤2 for patients 
with Grade 2 ALT at baseline. 
 
Evaluate alternative causes. 
 
For patients with ALT Grade ≤1 at baseline: resume at a reduced 
doses of neratinib 160 mg and capecitabine at 1100 mg/m2 
(550 mg/m2 BID)a if recovery to Grade ≤1 occurs within 3 weeks. If 
Grade 3 ALT or bilirubin occurs again despite the above-mentioned 
dose reduction, permanently discontinue neratinib and 
capecitabine. 
 
For patients with Grade 2 ALT at baseline due to liver metastases: 
contact the Sponsor for guidance on appropriate dose adjustments. 
Grade 4 ALT (>20 x ULN) 
or 
Grade 4 Bilirubin (>10 x ULN) 
 
Permanently discontinue neratinib and capecitabine. 
 
Evaluate alternative causes. 
ALT >3 x ULN 
and 
Total bilirubin >2 x ULN 
and 
Alkaline phospatase <2 x ULN 
(potential Hy’s law indicators of 
drug-induced liver damage) 
 
Hold neratinib and capecitabine. 
The patient should return to the investigational site and be evaluated 
as soon as possible, preferably within 48 hours from awareness of 
the abnormal results. This evaluation should include laboratory tests, 
detailed history and physical assessment and for oncology studies, 
the possibility of hepatic neoplasm (primary or secondary) should be 
considered. In addition to repeating AST and ALT, laboratory tests 
should include albumin, total bilirubin, direct bilirubin, PT and 
alkaline phosphatase. A detailed history, including relevant 
information, such as review of ethanol, concomitant medications, 
recreational drug and supplement consumption, family history, 
sexual history, travel history, history of contact with a jaundiced 
patient, surgery, blood transfusion, history of liver or allergic 
disease, and work exposure, should be collected. Further testing for 
acute hepatitis A, B, or C infection and liver imaging (e.g., biliary 
tract) may be warranted. All cases confirmed on repeat testing as 
meeting the criteria mentioned above (i.e., ALT >3 x ULN 
associated with bilirubin >2 x ULN and alkaline phosphatase 
<2 x ULN), with no other cause for liver function test abnormalities 
identified at the time should be considered potential Hy’s Law cases, 
irrespective of availability of all the results of the investigations 
performed to determine etiology of the abnormal liver function tests. 
Such potential Hy’s Law cases should be reported as SAEs. 
 
Contact the Sponsor immediately to discuss next steps, including 
evaluation of alternative causes, and management of investigational 
product. 
 
These events must be reported as SAEs. 
Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; BID: twice daily; PT: prothrombin 
time; SAE: serious adverse event; ULN: upper limit of normal. 
NOTE: During evaluation of hepatotoxicity, bilirubin must be fractionated, PT must be measured, and liver imaging 
should be considered. 
a Since capecitabine is provided as 150 mg or 500 mg tablets, it is recommended that the capecitabine dose 
reduction(s) is rounded down to the nearest 500 mg or multiple of 150 mg for the BID dose. If the patient’s body 
surface area is >2.0, the standard of care for the study center can be utilized for capecitabine mg/m2 dosing. 


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Left Ventricular Ejection Fraction Toxicity 
Guidelines for dose adjustments of neratinib in the event of abnormalities in LVEF are shown in 
Table A2. 5. LVEF assessments will be performed according to the Schedule of Procedures 
(Appendix 1). It is strongly recommended to use the same method of cardiac evaluation (ECHO 
or MUGA) at each time point for each patient. 
Table A2. 5 
Left Ventricular Ejection Fraction (LVEF) Results Requiring Dose 
Adjustment of Neratinib  
Event on day of scheduled treatment 
Actions 
Asymptomatic absolute decline of LVEF ≥15% 
from baseline OR absolute decline of LVEF ≥10% 
and below the lower limit of normal of 50% 
A) If LVEF is below 40%: Hold neratinib and seek 
cardiology input OR continue neratinib with great 
caution.  
Initiate monthly monitoring of LVEF 
 
If while monitoring monthly, LVEF remains <40%: 
reconsider neratinib only if appropriate and after 
cardiology consult. 
 
If while monitoring monthly, LVEF increases to ≥40%: 
continue neratinib, monitor LVEF every 12 weeks and 
consider cardiac support with input from cardiologist. 
 
B) If LVEF is between 40% to 50%: continue neratinib 
with caution and surveillance. 
Initiate monthly monitoring of LVEF  
 
If while monitoring monthly, LVEF falls to <40%: 
Follow bullet point A instructions described above. 
 
If while monitoring monthly, LVEF remains ≥40%: 
continue neratinib, monitor LVEF every 12 weeks and 
consider cardiac support with input from cardiology. 
Symptomatic cardiac failure 
 
Neratinib should be discontinued. 
Abbreviations: LVEF: left ventricular ejection fraction 
 
If a patient has a second episode of asymptomatic decline in LVEF that meets either of the above 
criteria, permanently discontinue neratinib, repeat LVEF in 3-4 weeks and consider cardiology 
consult. 
Note that, for AEs other than asymptomatic LVEF decline, if neratinib is held for >28 days, the 
patient should be withdrawn from the active treatment phase of the study (see Section 10.1). In 
case of asymptomatic LVEF decline, patients may resume neratinib within 1 week after LVEF 
recovery is documented as above, even if the timeframe exceeds 3 weeks. If a site does not 
provide normal ranges for ECHO or MUGA, a LLN of 50% should be used. 


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Hematologic Toxicity 
Patients with baseline neutrophil counts of <1.5 x 109/L and/or thrombocyte counts of 
<100 x 109/L should not be treated with capecitabine. If unscheduled laboratory assessments 
during a treatment cycle show Grade 3 or 4 hematologic toxicity, treatment with capecitabine 
should be held. 
Guidelines for dose adjustments of capecitabine for hematologic toxicity due to combination of 
neratinib plus capecitabine are shown in Table A2. 6.  
Table A2. 6 
Hematologic Abnormalities Requiring Dose Adjustment of Capecitabine 
(When Administered in Combination with Neratinib) 
NCI CTCAE v. 4.0 
Action 
Grade 3 
Neutrophil: <1000-500/mm3; <1-0.5 × 109/L 
Platelet: <50,000-25,000/mm3; <50-25× 109/L 
Hemoglobin decreased: <8 g/dL; <4.9 mmol/L; 
<80 g/L; transfusion indicated 
 
Neratinib should be continued at the same dose. 
 
Hold capecitabine until event resolves or decreases to 
Grade 1 or Grade 2 
 
Reduce next capecitabine dose to 1100 mg/m2 
(550 mg/m2 BID). 
 
If the event recurs a 2nd time, hold capecitabine until 
event resolves or decreases to Grade 1 or Grade 2 
 
Reduce next capecitabine dose to 750 mg/m2 
(375 mg/m2 BID) 
 
If the event recurs/persists, discontinue capecitabine 
permanently. 
Grade 4 
Neutrophil: <500/mm3; <0.5 × 109/L 
Platelet: <25,000/mm3; <25 × 109/L 
Hemoglobin decreased: Life-threatening 
consequences; urgent intervention indicated 
 
Neratinib should be continued at the same dose. 
 
Capecitabine should be discontinued permanently OR 
if the Investigator deems it to be in the patient’s best 
interest to continue, hold capecitabine until resolved to 
Grade ≤1 
 
If the Investigator decides to resume capecitabine, 
reduce the dose to 750 mg/m2 (375 mg/m2 BID) 
 
If the event recurs/persist, discontinue capecitabine 
permanently. 
Abbreviations: BID: twice daily; L: liter; NCI CTCAE v.4.0: National Cancer Institute Common Terminology 
Criteria for Adverse Events Version 4.0. 
 


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Hand and Foot Syndrome 
Guidelines for dose adjustments of neratinib and capecitabine for toxicity of Hand and Foot 
syndrome (Palmar-Plantar Erythrodysesthesia syndrome) due to combination of neratinib plus 
capecitabine are shown in Table A2. 7.  
Table A2. 7 
Hand-and-Foot Syndrome (Palmar-Plantar Erythrodysesthesia Syndrome) 
Requiring Dose Adjustment of Neratinib and Capecitabine  
NCI CTCAE v.4.0 
Action 
Grade 1: Minimal skin changes or 
dermatitis (e.g., erythema, edema, or 
hyperkeratosis) without pain 
 
Continue neratinib and capecitabine at starting dose. 
Grade 2: Skin changes, e.g., peeling, 
blisters, edema, or hyperkeratosis, with 
pain; limiting instrumental ADL. 
PI: painful erythema and swelling of the 
hands and/or feet and/or discomfort 
affecting ADL. 
 
Continue neratinib at starting dose level and hold capecitabine 
until recovery or to ≤grade 1, then resume at starting dose. 
 
If the event recurs/persists, continue neratinib at starting dose 
level and reduce capecitabine dose to1100 mg/m2 (550 mg/m2 
BID).  
Grade 3: Severe skin changes, e.g., 
peeling, blisters, edema, or hyperkeratosis, 
with pain; limiting self-care ADL. 
PI: moist desquamation, ulceration, 
blistering or severe pain of the hands 
and/or feet and/or severe discomfort 
limiting self-care ADL. 
 
Continue neratinib at starting dose level and hold capecitabine 
until recovery or to grade ≤1, then reduce dose to1100 mg/m2 
(550 mg/m2 BID).  
 
If the event recurs/persists, continue neratinib at starting dose 
level and reduce capecitabine dose to 750 mg/m2 (375 mg/m2 
BID). 
Abbreviations: ADL, activities of daily living; BID, twice daily; NCI CTCAE v.4.0: National Cancer Institute 
Common Terminology Criteria for Adverse Events Version 4.0.  
 


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LAPATINIB PLUS CAPECITABINE 
General Toxicities 
Guidelines for dose adjustments of lapatinib and capecitabine for general toxicities due to 
combination of lapatinib plus capecitabine are shown in Table A2. 8. 
Table A2. 8 
General Toxicities Requiring Dose Adjustment of Lapatinib and 
Capecitabine  
NCI CTCAE v.4.0 
Action 
Grade 2 adverse reaction  
 
1st appearance 
 
 
Hold lapatinib and capecitabine until event resolves to Grade ≤1; 
then resume lapatinib dose at 1250 mg and capecitabine at the 
starting dose level.  
 
2nd appearance 
 
 
Hold lapatinib and capecitabine until event resolves to Grade ≤1; 
then resume lapatinib dose at 1000 mg and capecitabine dose at 
1500 mg/m2 (750 mg/m2 BID). 
 
3rd appearance 
 
Discontinue lapatinib permanently. 
 
Hold capecitabine until event resolves to Grade ≤1; then resume 
capecitabine at 1000 mg/m2 (500 mg/m2 BID). 
 
4th appearance 
 
Discontinue capecitabine permanently. 
Grade 3 adverse reaction 
 
1st appearance 
 
 
Hold lapatinib and capecitabine until event resolves to Grade ≤1; 
then resume lapatinib dose at 1250 mg and capecitabine dose at 
1500 mg/m2 (750mg/m2 BID). 
 
2nd appearance 
 
 
Hold lapatinib and capecitabine until event resolves to Grade ≤1; 
then resume lapatinib dose at 1000 mg and capecitabine at 
1000 mg/m2 (500 mg/m2 BID). 
 
3rd appearance 
 
Discontinue lapatinib and capecitabine permanently. 
Grade 4 adverse reaction 
1st appearance 
 
Discontinue lapatinib and capecitabine permanently OR if 
Investigator deems it to be in the patient’s best interest to continue, 
hold lapatinib and capecitabine until resolved to Grade ≤1; then 
resume lapatinib at 1000 mg and capecitabine at 1000 mg/m2 
(500 mg/m2 BID). 
Abbreviations: BID, twice daily; NCI CTCAE v.4.0: National Cancer Institute Common Terminology Criteria for 
Adverse Events Version 4.0.  
 


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Gastrointestinal Toxicity 
Guidelines for dose adjustments of lapatinib and capecitabine for gastrointestinal toxicity are 
shown in Table A2. 9. 
Table A2. 9 
Gastrointestinal Toxicities Requiring Dose Adjustment of Lapatinib and 
Capecitabine 
NCI CTCAE v.4.0 
Action 
Grade 1: Increase of <4 stools per 
day over baseline; mild increase in 
ostomy output compared to baseline. 
 
Continue lapatinib and capecitabine at starting dose. 
 
Instruct patient to follow dietetic recommendations provided at the start 
of the study. Fluid intake of ~2L should be maintained to avoid 
dehydration.  
Grade 2: Increase of 4-6 stools per 
day over baseline; moderate increase 
in ostomy output compared to 
baseline. 
 
 
Continue lapatinib and hold capecitabine until recovery to ≤ Grade 1 
or baseline. Consider prophylactic antidiarrheal medications with next 
investigational product administration. 
 
If recovery occurs in ≤1 week of treatment being held, resume 
capecitabine at starting dose. 
 
If event persists/recurs, or if recovery occurs within 1-3 weeks of 
treatment being held, reduce dose of lapatinib to 1000 mg and 
capecitabine to 1500 mg/m2 (750 mg/m2 BID). 
 
Following reoccurrence of Grade 2, adjust next dose of capecitabine to 
1000 mg/m2 (500 mg/m2 BID). 
Grade 1 or 2 with complicating 
features (moderate to severe 
abdominal cramping, nausea or 
vomiting ≥ NCI CTCAE Grade 2, 
decreased performance status, fever, 
sepsis, neutropenia, frank bleeding, 
or dehydration) 
or 
Grade 3: Increase of ≥7 stools per 
day over baseline; incontinence; 
hospitalization indicated; severe 
increase in ostomy output compared 
to baseline, limiting self-care ADL. 
 
Hold lapatinib and capecitabine until recovery to ≤Grade 1 or 
baseline.  
 
May require administration of oral or IV fluids and electrolytes. 
Consider prophylactic antidiarrheal medications with next 
investigational product administration. 
 
If recovery occurs in ≤1 week of treatment being held, resume 
lapatinib and capecitabine at starting dose. 
 
If event persists/recurs, or if recovery occurs within 1-3 weeks of 
treatment being held, reduce lapatinib dose to 1000 mg and 
capecitabine dose to 1500 mg/m2 (750 mg/m2 BID). 
Grade 4: Life-threatening 
consequences; urgent intervention 
indicated. 
 
Discontinue lapatinib permanently. 
 
Hold capecitabine until recovery to ≤ Grade 1 or baseline. Consider 
prophylactic antidiarrheal medications with next investigational 
product administration. 
 
If recovery occurs in ≤1 week of treatment being held, resume 
capecitabine at starting dose. 
 
If event persists/recurs, or if recovery occurs within 1-3 weeks of 
treatment being held, reduce dose of capecitabine to 1500 mg/m2 
(750 mg/m2 BID). 


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NCI CTCAE v.4.0 
Action 
 
Following reoccurrence of Grade 4, discontinue capecitabine 
permanently. 
Abbreviations: ADL: activities of daily living; BID, twice daily; IV: intravenous; NCI CTCAE v.4.0: National 
Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0.  
 
Pulmonary Toxicity 
Guidelines for adjusting doses of lapatinib in the event of pulmonary toxicity are shown in 
Table A2. 10. 
Table A2. 10 Pulmonary Toxicities Requiring Dose Adjustment of Lapatinib  
NCI CTCAE v.4.0 
Action 
Grade 3 Pneumonitis/Interstitial 
Lung Disease: Severe symptoms; 
limiting self-care ADL; oxygen 
indicated. 
Discontinue lapatinib treatment permanently. 
Abbreviations: ADL: activities of daily living; NCI CTCAE v.4.0: National Cancer Institute Common Terminology 
Criteria for Adverse Events Version 4.0. 
 


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Hepatic Toxicity 
Guidelines for adjusting doses of lapatinib and capecitabine in the event of hepatic toxicities 
are shown in Table A2. 11.  
Table A2. 11 Liver Function Test Abnormality Requiring Dose Adjustment of Lapatinib 
and Capecitabine 
NCI CTCAE v.4.0 
Action 
ALT or AST Grade 3: 
>5-20 x ULN; 
>5 x ULN for >2 weeks. 
or 
ALT or AST Grade 4: >20 x ULN 
AND 
Total bilirubin > 2 x ULN 
 
Discontinue lapatinib permanently. 
Grade 3 hyperbilirubinemia 
(>3-10 x ULN) 
 
Discontinue lapatinib permanently. 
 
Hold capecitabine until hyperbilirubinemia resolves or decreases 
to Grade 1 (ULN-1.5 x ULN) or Grade 2 (>1.5 x ULN). 
 
Reduce next capecitabine dose to 1500 mg/m2 (750 mg/m2 BID). 
Grade 4 hyperbilirubinemia 
(>10 x ULN) 
 
Discontinue lapatinib and capecitabine permanently. 
OR 
 
If the Investigator deems it to be in the patient’s best interest to 
continue, hold capecitabine until event has resolved to Grade ≤ 1 
(ULN-1.5 x ULN). 
 
If the Investigator decides to resume capecitabine, reduce 
capecitabine dose to 1000 mg/m2 (500 mg/m2 BID). 
LAPATINIB Dose Adjustment in Subjects with Severe Hepatic Impairment (Child-Pugh Class C) 
Test 
Result 
 
HER2+ MBC: Reduce lapatinib dose to 750 mg. 
 
HR+, HER2+ breast cancer: Reduce lapatinib dose to 1000 mg. 
Total bilirubin 
≥2 mg/dL; 
≥34 µmol/L 
Serum albumin 
≤35 g/L 
PT INR 
≥1.7 
Ascites 
Mild to Severe 
Hepatic 
encephalopathy 
Grade 1-2 
(or suppressed 
with 
medication) 
Grade 3-4 
Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; NCI CTCAE v.4.0: National 
Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0; ULN: upper limit of normal. 
 


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Left Ventricular Ejection Fraction Toxicity 
Guidelines for adjusting dose adjustments of lapatinib when given in combination with 
capecitabine in the event of abnormalities in LVEF are shown in Table A2. 12. 
Table A2. 12 Left Ventricular Ejection Fraction (LVEF) Results Requiring Dose 
Adjustment of Lapatinib when Administered in Combination with Capecitabine  
NCI CTCAE v.4.0 
Action 
LV   <           ’  L LN 
OR 
Grade 2: Resting EF 50-40%; 
10-19% decrease from baseline 
OR 
Grade 3: Resting EF 39-20%; 
>20% decrease from baseline 
OR 
Grade 4: Resting EF <20% 
 Hold lapatinib. 
 If, after a minimum of 2 weeks, the LVEF recovers to normal and 
the patient is asymptomatic, the patient may be restarted at a 
reduced dose of lapatinib 1000 mg with capecitabine. 
Abbreviations: EF: ejection fraction; LLN: lower limit of normal; LVEF: left ventricular ejection fraction; 
NCI CTCAE v.4.0: National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0. 
 


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Hematologic Toxicity 
Patients with baseline neutrophil counts of <1.5 x 109/L and/or thrombocyte counts of 
<100 x 109/L should not be treated with capecitabine. If unscheduled laboratory assessments 
during a treatment cycle show Grade 3 or 4 hematologic toxicity, treatment with capecitabine 
should be held. 
Guidelines for dose adjustments of capecitabine for hematologic toxicity due to combination of 
capecitabine plus lapatinib are shown in Table A2. 13. 
Table A2. 13 Hematologic Abnormalities Requiring Dose Adjustment of Capecitabine 
(When Administered in Combination with Lapatinib) 
NCI CTCAE v.4.0 
Action 
Grade 3 
Neutrophil: <1000-500/mm3; <1-0.5 x 109/L 
Platelet: <50,000-25,000/mm3; <50-25 x 109/L 
Hemoglobin decreased: <8 g/dL; <4.9 mmol/L; 
<80 g/L; transfusion indicated 
 
Hold capecitabine until event resolves or decreases 
to Grade 1 or Grade 2 
 
Reduce next capecitabine dose to 1500 mg/m2 
(750 mg/m2 BID) 
 
If the event recurs a 2nd time, hold capecitabine until 
event resolves or decreases to Grade 1 or Grade 2 
 
Reduce next capecitabine dose to 1000 mg/m2 
(500 mg/m2 BID) 
 
If the event recurs/persists, discontinue capecitabine 
permanently. 
Grade 4 
Neutrophil: <500/mm3; <0.5 x 109/L 
Platelet: <25,000/mm3; <25 x 109/L 
Hemoglobin decreased: Life-threatening 
consequences; urgent intervention indicated 
 
Discontinue permanently OR if the Investigator 
deems it to be in the patient’s best interest to 
continue, hold capecitabine until resolved to 
Grade ≤1. 
 
If the Investigator decides to resume capecitabine, 
reduce dose to 1000 mg/m2 (500 mg/m2 BID) 
 
If the event recurs/persists, discontinue capecitabine 
permanently. 
Abbreviations: BID: twice daily; L: liter; NCI CTCAE v.4.0: National Cancer Institute Common Terminology 
Criteria for Adverse Events Version 4.0. 
 


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Hand and Foot Syndrome 
Guidelines for dose adjustments of capecitabine for toxicity of Hand and Foot Syndrome 
(Palmar-Plantar Erythrodysesthesia Syndrome) due to combination of capecitabine plus lapatinib 
are shown in Table A2. 14.  
Table A2. 14 Hand-and-Foot Syndrome (Palmar-Plantar Erythrodysesthesia Syndrome) 
Requiring Dose Adjustment of Capecitabine (When Administered in Combination with 
Lapatinib) 
NCI CTCAE v.4.0 
Action 
Grade 1: Minimal skin changes or 
dermatitis (e.g., erythema, edema, or 
hyperkeratosis) without pain. 
 Continue capecitabine at starting dose. 
Grade 2: Skin changes, e.g., peeling, 
blisters, edema, or hyperkeratosis, with 
pain; limiting instrumental ADL. 
PI: painful erythema and swelling of the 
hands and/or feet and/or discomfort 
affecting ADL. 
 Hold capecitabine until recovery or to Grade ≤1, 
then resume at starting dose. 
 If the event recurs/persists, reduce capecitabine dose to 1500 mg/m2 
(750 mg/m2 BID). 
Grade 3: Severe skin changes, e.g., 
peeling, blisters, edema, or 
hyperkeratosis, with pain; limiting self-
care ADL. 
PI: moist desquamation, ulceration, 
blistering or severe pain of the hands 
and/or feet and/or severe discomfort 
limiting self-care ADL 
 Hold capecitabine until recovery or to Grade ≤1, 
then reduce to 1500 mg/m2 (750 mg/m2 BID). 
 If the event recurs/persists, reduce capecitabine dose to 1000 mg/m2 
(500 mg/m2 BID). 
Abbreviations: ADL: activities of daily living; BID: twice daily; NCI CTCAE v.4.0: National Cancer Institute 
Common Terminology Criteria for Adverse Events Version 4.0; PI: Package Insert.  


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


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Appendix 4 
Inhibitors and Inducers of the Cytochrome P450 Isoenzymes 
CYP3A4 Inducers 
Carbamazepine 
Phenobarbital 
Rifapentine 
Efavirenz 
Phenylbutazone 
St. John’s Wort 
Glucocorticoids: 
Phenytoin 
Sulfinpyrazone 
Dexamethasone 
Primidone 
 
Prednisone 
Rifabutin 
 
Macrolide antibiotics 
Rifampin 
 
CYP3A4 Inhibitors 
Amprenavir 
Grapefruit juice 
Propranolol 
Anastrozole 
Indinavir 
Quinidine 
Cimetidine 
Itraconazole 
Quinine 
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 
 
CYP2D6 Substrate 
Carvedilol 
Hydrocodone 
Propafenone 
Chloroquine (possible) 
Hydroxyamphetamine 
Propoxyphene 
Chlorpromazine 
Labetalol 
Propranolol (minor) 
Citalopram 
Maprotiline 
Risperidone 
Clozapine 
Methamphetamine 
Ritonavir 
Codeine 
Metoprolol 
Ropivacaine 
Cyclobenzaprine 
Mexiletine (major) 
Selegiline 
Debrisoquin 
Mirtazapine 
Sertraline 
Delavirdine 
Morphine 
Sparteine 
Dexfenfluramine 
Olanzapine 
Tamoxifen 
Dextromethorphan 
Ondansetron 
Thioridazine 
Dolasetron 
Oxaminiquine 
Timolol 
Donepezil 
Oxycodone 
Tolterodine (major) 
Encainide 
Paroxetine 
Tramadol 
Flecainide 
Penbutolol 
Trazodone 
Fluoxetine 
Pentazocine 
Tricyclic antidepressants 
(Amitriptyline, Clomipramine, 
Desipramine, Doxepin, Imipramine, 
Nortriptyline, Trimipramine) 
Fluphenazine 
Perphenazine 
Venlafaxine 
Halofantrine 
Phenformin 
Ziprasidone 
Haloperidol 
Primaquine (possible) 
Zolpidem 
Source: Tatro DS, Drug Interaction Facts: The Authority on Drug Interactions. Wolters Kluwer Health 2012. 
 
 


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


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Appendix 6 
Drugs Associated With Risk of QT/QTc Prolongation Leading to Torsade de Pointes 
Drugs Reported to Prolong QT Interval 
Analgesics 
Celecoxib (Celebrex) 
Methadone (e.g., Dolophine, Methadose) 
Anesthetic agents 
Enflurane (e.g., Ethrane) 
Halothane 
Isoflurane (e.g., Forane) 
 
Antiarrhythmic agents 
Class IA 
Class III 
Disopyramide (e.g., Norpace)* 
Amiodarone (e.g., Cordarone)*b 
Procainamide (e.g., Procanbid)* 
Bretylium* 
Quinidine* 
Dofetilide (Tikosyn)*b 
Class IC 
Ibutilide (Corvert)*b 
Flecainide (e.g., Tambocor)*a 
Sotalol (e.g., Betapace)*b 
Propafenone (e.g., Rythmol)*b 
 
Anticonvulsants 
Felbamate (Felbatol)* 
Fosphenytoin (Cerebyx) 
Antiemetics 
Dolasetron (Anzemet)b 
Droperidol (e.g., Inapsine)*b 
Ondansetron (Zofran) 
Antihistamines 
Desloratadine (Clarinex)b (overdose) 
Fexofenadine (Allegra) 
Diphenhydramine (e.g., Benadryl) 
Hydroxyzine (Atarax) 
Anti-infectives 
Amantadine (e.g., Symmetrel)* 
Macrolides and related antibiotics 
Antimalarials 
Azithromycin (e.g., Zithromax) 
Mefloquine (e.g., Lariam)b 
Clarithromycin (e.g., Biaxin)*b 
Quinine* 
Erythromycin (e.g., Ery-Tab, EES)*b 
Antivirals 
Telithromycin (Ketek)b 
Efavirenz (Sustiva)* 
Troleandomycin 
Azole antifungal agents 
Pentamidine (e.g., Pentam 300, Nebupent)* 
Fluconazole (e.g., Diflucan)*b 
Quinolones 
Itraconazole (e.g., Sporanox) 
Gatifloxacin (e.g., Tequin)*b 
Ketoconazole (e.g., Nizoral) 
Levofloxacin (e.g., Levaquin)*a, b 
Voriconazole (Vfend)b 
Moxifloxacin (e.g., Avelox)b 
Chloroquine (e.g., Aralen)* 
Ofloxacin (e.g., Floxin)*b 
Clindamycin (e.g., Cleocin) 
Sparfloxacin (Zagam)b 
Foscarnet (Foscavir) 
Trimethoprim/sulfamethoxazole (e.g., Bactrim)* 
Antineoplastics 
Arsenic trioxide (Trixenox)*b 
Doxorubicin (e.g., Adriamycin) 
Tamoxifen (e.g., Nolvadex) 
Bronchodilators 
Albuterol (e.g., Proventil)b 
Salmeterol (Serevent)b 
Formoterol (Foradil)b 
Terbutaline (e.g., Brethine)b 
Isoproterenol (e.g., Isuprel) 
 
Calcium channel blockers 
Isradipine (DynaCirc) 
Nicardipine (e.g., Cardene) 


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Drugs Reported to Prolong QT Interval 
Contrast media 
Ionic contrast media* 
Non-ionic contrast media: Iohexol (Omnipaque) 
Corticosteroids 
Prednisolone (e.g., Prelone) 
Prednisone (e.g., Deltasone)* 
Diuretics 
Furosemide (e.g., Lasix) 
Indapamide (e.g., Lozol) 
Gastrointestinal agents 
Cisapride (Propulsid)*b, c 
Famotidine (e.g., Pepcid)* 
Immunosuppressants 
Tacrolimus (Protopic)*b (postmarketing) 
Miscellaneous 
Levomethadyl 
Papaverine (e.g., Pavaden three times daily [TID])* 
Moexipril/Hydrochlorothiazide (Uniretic) 
Probucol (Lorelco)*c 
Octreotide (Sandostatin)b 
Vasopressin (e.g., Pitressin)* 
Oxytocin (e.g., Pitocin; intravenous bolus) 
 
Psychotropics 
Droperidol (e.g., Inapsine)* 
Primozide (Orap)*b, d 
Trazodone (e.g., Desyrel) 
Haloperidol (e.g., Haldol)* 
Quetiapine (Seroquel)b 
Tricyclic antidepressants 
Lithium (e.g., Eskalith)* 
Risperidone (Risperdal)b (overdose) 
Amitriptyline* 
Maprotiline* 
Serotonin Reuptake Inhibitors 
(SRIs) 
Clomipramine 
(e.g., Anafranil) 
Phenothiazines 
Citalopram (e.g., Celexa)* 
Desipramine 
(e.g., Norpramin)* 
Chrlorpromazine 
(e.g., Thorazine)* 
Fluoxetine (e.g., Prozac)*a 
Doxepin (e.g., Sinequan)* 
Fluphenazine 
(e.g., Prolixin)* 
Paroxetine  
(e.g., Paxil)* 
Imipramine 
(e.g., Tofranil)* 
Perphenazine 
Sertraline (Zoloft)*a, b 
(postmarketing) 
Nortriptyline 
(e.g., 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 (e.g., 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-induced Prolongation of the QT Interval and Torsades de Pointes. Drug Interaction Facts. The 
Authority on Drug Interactions. Wolters Kluwer Health 2012. 
 
 


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Appendix 7 
RECIST v1.1 Criteria (Eisenhauer et al., 2009) 
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 criteria.  
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 
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes 
with ≥10 to <15 mm short axis) as well as truly non-measurable lesions. Lesions considered 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. Target and/or non-
target lesions should be selected from organs/sites that have not received local/focal therapy 


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(e.g., radiation therapy or radiofrequency ablation), unless disease progression has subsequently 
been radiologically confirmed after focal/local therapy. 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 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 non-target 
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. 
Non-Target Lesions 
All other lesions (or sites of disease) including pathological lymph nodes should be identified as 
non-target 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 (e.g., ‘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 must be performed within 28 days prior to randomization, and preferably no 
more than 28 days before the initiation of 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 


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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 (e.g., 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 (e.g., for body scans).  
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. Specific 
guidelines for both CA-125 response (in recurrent ovarian cancer) and PSA response (in 
recurrent prostate cancer), have been published. In addition, the Gynecologic Cancer Intergroup 


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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 (e.g., 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 non-target) 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 non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for the 
group of non-target lesions. 
While some non-target 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 non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Non-CR/Non-PD: Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 


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Progressive Disease (PD): Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered progression). 
Target Lesions 
Non-target Lesions 
New Lesions 
Overall Response 
CR 
CR 
No 
CR 
CR 
Non-CR/non-PD 
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 
investigational product 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 investigational product. 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 non-randomized 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, i.e., in 
randomized studies (phase II or III) 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 


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in studies which are not blinded. In the case of SD, measurements must have met the SD criteria 
at least once after study entry at a minimum interval (in general not less than 6–8 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. 
 
 


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Appendix 8 
Health Outcomes Assessment: EORTC QLQ-C30 
 


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Appendix 9 
Health Outcomes Assessment: EORTC QLQ-BR23 


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Appendix 10 
Health Outcomes Assessment: EQ-5D-5L 


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Document Information
Document Name: spa-1301.docx
Document Title: SPA - PUMA-NER-1301
Document Version: 4.0
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Meaning Of Signature: I am approving this document
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Date/Time: 2/13/2014 2:13:32 PM

SAP_001.pdf: 
A STUDY OF NERATINIB PLUS CAPECITABINE VERSUS 
LAPATINIB PLUS CAPECITABINE IN PATIENTS WITH HER2+ 
METASTATIC BREAST CANCER WHO HAVE RECEIVED TWO 
OR MORE PRIOR HER2-DIRECTED REGIMENS IN THE 
METASTATIC SETTING (NALA) 
 
 
NCT01808573 
 
Statistical Analysis Plan v2.1     17 Jan 2018 
 
Statistical Analysis Plan – Supplemental   14 Nov 2018 


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Statistical Analysis Plan 
17 Jan 2018 
PUMA-NER-1301 
v2.1 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................5 
1. 
PURPOSE OF THE ANALYSES ................................................................................7 
2. 
PROTOCOL SUMMARY ............................................................................................8 
2.1. 
Study Objectives ...........................................................................................................8 
2.1.1. 
Primary Objective .........................................................................................................8 
2.1.2. 
Secondary Objectives ...................................................................................................8 
2.1.3. 
Exploratory Objective ...................................................................................................8 
2.2. 
Overall Study Design and Plan .....................................................................................8 
2.3. 
Study Population ...........................................................................................................9 
2.4. 
Treatment Regimens .....................................................................................................9 
2.5. 
Treatment Group Assignments or Randomization .......................................................9 
2.6. 
Sample Size Determination ........................................................................................10 
3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS ..............................11 
4. 
ANALYSIS POPULATIONS ....................................................................................12 
4.1. 
Intent to treat (ITT) Population ...................................................................................12 
4.2. 
Safety Population ........................................................................................................12 
4.3. 
Pharmacokinetics (PK) Population .............................................................................12 
4.4. 
Quality of Life (QoL) Population ...............................................................................12 
5. 
STUDY PATIENTS ...................................................................................................13 
5.1. 
Disposition of Patients ................................................................................................13 
5.2. 
Protocol Deviations ....................................................................................................13 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .....................13 
6.1. 
Demographic and baseline characteristics ..................................................................13 
6.2. 
Medical History ..........................................................................................................13 
6.3. 
Prior and Concomitant Medications ...........................................................................14 
7. 
MEASUREMENTS OF TREATMENT COMPLIANCE .........................................15 
8. 
EFFICACY EVALUATION ......................................................................................16 
8.1. 
Overview of Efficacy Analysis Issues ........................................................................16 
8.1.1. 
Handling of Dropouts or Missing Data ......................................................................16 
8.1.2. 
Multicenter Studies .....................................................................................................16 
8.2. 
Efficacy Variables ......................................................................................................16 
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Statistical Analysis Plan 
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8.2.1. 
Progression Free Survival (PFS) ................................................................................17 
8.2.2. 
Overall Survival (OS) .................................................................................................18 
8.2.3. 
Central Nervous System Disease (CNS) ....................................................................18 
8.2.4. 
Objective Response Rate (ORR) ................................................................................18 
8.2.5. 
Duration of Response (DOR) .....................................................................................19 
8.2.6. 
Clinical Benefit Rate (CBR) .......................................................................................19 
8.3. 
Analysis Methods .......................................................................................................19 
8.3.1. 
Primary Efficacy Analyses .........................................................................................20 
8.3.1.1. 
Sensitivity Analyses ....................................................................................................21 
8.3.2. 
Secondary Efficacy Analyses .....................................................................................21 
8.3.3. 
Other Efficacy Analyses .............................................................................................22 
8.3.3.1. 
Health Outcome Assessments .....................................................................................22 
8.3.3.2. 
Analysis of Health Outcome Assessments .................................................................23 
8.4. 
Examination of Subgroups .........................................................................................23 
8.5. 
Exploratory Biomarker Analysis ................................................................................23 
9. 
SAFETY EVALUATION ..........................................................................................24 
9.1. 
Overview of Safety Analysis Methods .......................................................................24 
9.2. 
Extent of Exposure .....................................................................................................24 
9.3. 
Adverse Events, Serious Adverse Events, and Deaths ...............................................24 
9.4. 
Clinical Laboratory Evaluation ...................................................................................25 
9.5. 
Vital Signs, Physical Findings, and Other Observations Related to Safety ...............25 
9.5.1. 
Vital Signs ..................................................................................................................25 
9.5.2. 
Physical Examinations ................................................................................................26 
9.5.3. 
Electrocardiograms .....................................................................................................26 
9.5.4. 
Left Ventricular Ejection Fraction (LVEF) ................................................................27 
9.5.5. 
Liver Function Test Results ........................................................................................27 
9.5.6. 
ECOG Performance Status .........................................................................................27 
10. 
INTERIM ANALYSES AND DATA MONITORING .............................................28 
11. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL .....................28 
12. 
LIST OF PLANNED TABLES ..................................................................................29 
13. 
LIST OF PLANNED FIGURES ................................................................................32 
14. 
LIST OF PLANNED DATA LISTINGS ...................................................................33 
15. 
REFERENCES ...........................................................................................................35 
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Statistical Analysis Plan 
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LIST OF TABLES 
Table 1: 
Spending Function ......................................................................................................10 
Table 2: 
Efficacy Variables and Analysis Methods ..................................................................16 
 
LIST OF FIGURES 
Figure 1: 
 Testing Schema ..........................................................................................................20 
 
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LIST OF ABBREVIATIONS 
Abbreviation 
Term 
AE 
adverse event 
BID 
twice daily 
BMI 
body mass index 
CB 
clinical benefit 
cm 
centimeters 
CMH 
Cochran-Mantel-Haenzel 
CNS 
Central Nervous System 
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 
EKG 
electrocardiogram 
EORTC QLQ-C30 
European Organization for the Research and Treatment of Cancer Quality 
of Life Questionnaire 
EORTC QLQ-BR23 
European Organization for the Research and Treatment of Cancer Quality 
of Life Questionnaire Breast Cancer Module 
EOS 
end of study 
EQ-5D-5L 
EuroQol questionnaire 
EQ-VAS 
Visual Analog Scale 
HER 
human epidermal growth factor receptor 
HER2+ 
human epidermal growth factor receptor 2 positive 
IDMC 
Independent Data Monitoring Committee 
ITT 
intent to treat 
kg 
kilogram 
LVEF 
left ventricular ejection fraction 
m 
meter 
MBC 
metastatic breast cancer 
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Abbreviation 
Term 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mmHg 
millimeters of mercury 
MUGA 
multiple-gated acquisition scan 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PR 
partial response 
PT 
preferred term 
QoL 
Quality of Life 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SOC 
System Organ Class 
std 
standard deviation 
TEAE 
treatment-emergent adverse event 
WHODrug 
World Health Organization Drug Reference List 
 
 
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1. 
PURPOSE OF THE ANALYSES 
This statistical analysis plan (SAP) provides a comprehensive and detailed description of strategy 
and statistical methodology to be used for analysis of data for the PUMA-NER-1301 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 data base 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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Statistical Analysis Plan 
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2. 
PROTOCOL SUMMARY 
2.1. 
Study Objectives 
2.1.1. 
Primary Objective  
The co-primary objectives of this study are  
• to compare independently adjudicated progression free survival (PFS) following 
treatment with neratinib plus capecitabine versus lapatinib plus capecitabine in 
patients with HER2-positive (HER2+) metastatic breast cancer (MBC) who have 
received two or more prior HER2 directed regimens in the metastatic setting. 
• to compare overall survival (OS) following treatment with neratinib plus capecitabine 
versus lapatinib plus capecitabine in this population. 
2.1.2. 
Secondary Objectives 
The secondary objectives of this study are:  
• Investigator assessed PFS. 
• Objective response rate (ORR), duration of response (DOR) and clinical benefit rate 
(CBR) (complete response [CR] or partial response [PR] or stable disease [SD] ≥24 
weeks).  
• Time to intervention for symptomatic metastatic central nervous system (CNS) 
disease. 
• Safety (adverse events [AEs] and serious adverse events [SAEs]). 
• Health outcomes assessment. 
2.1.3. 
Exploratory Objective 
The exploratory objective of this study is to assess the population pharmacokinetics (PK) of 
neratinib when administered in combination with capecitabine. 
2.2. 
Overall Study Design and Plan 
This is a randomized, multi-center, multinational, open-label active-controlled, parallel design 
study of the combination of neratinib plus capecitabine versus the combination of lapatinib plus 
capecitabine in HER2+MBC patients, who have received two or more prior HER2-directed 
regimens in the metastatic setting.  Patients will be randomized in a 1:1 ratio to either the 
neratinib plus capecitabine or lapatinib plus capecitabine arms. 
Following a 21-day screening period, eligible patients will be randomized to Arm A or Arm B. 
Baseline assessments will be performed prior to randomization and Cycle 1/Day 1 dosing. 
Patients will then participate in the active treatment phase, consisting of 21-day treatment cycles. 
Patients are anticipated to participate in the study for an average of 28 months. This includes 
approximately 0.5 months for screening, an estimated average of 9.5 months for treatment, and 
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an estimated average of 18 months for the long-term follow-up phase. Patients who permanently 
discontinue treatment will enter the long-term follow-up phase until death or withdrawal of 
consent. 
2.3. 
Study Population 
The study population will include all patients that sign and date an approved informed consent 
form and are eligible per the criteria defined in the protocol. A full list of the inclusion and 
exclusion criteria can be found in the PUMA-NER-1301 protocol. 
2.4. 
Treatment Regimens 
Patients in the Neratinib + Capecitabine Combination arm will receive medication as described 
below: 
• Neratinib: six 40 mg tablets (total daily dose 240 mg) orally, once daily with food, 
preferably in the morning, continuously. 
• Capecitabine: 150 mg or 500 mg tablets (total dose of 1500 mg/m2 daily in 2 evenly 
divided doses), orally with water within 30 minutes after a meal. Dose taken daily for 
Days 1 to 14 of a 21-day cycle. 
Patients in the Lapatinib + Capecitabine Combination arm will receive medication as described 
below: 
• Lapatinib: five 250 mg tablets (total dose 1250 mg) orally, once daily, 1 hour before 
or after breakfast, continuously. 
• Capecitabine: 150 mg or 500 mg tablets (total dose of 2000 mg/m2 daily, in 2 evenly 
divided doses), orally with water within 30 minutes after a meal. Dose taken daily for 
Days 1 to 14 of a 21-day cycle. 
2.5. 
Treatment Group Assignments or Randomization 
Patients will be randomized in a 1:1 ratio to one of the following treatment arms: 
• Arm A: neratinib (240 mg) + capecitabine (1,500 mg/m2 daily, 750 mg/m2 BID) 
• Arm B: lapatinib (1250 mg) + capecitabine (2,000 mg/m2 daily, 1000 mg/m2 BID) 
Patient randomization will be stratified according to: 
• Number of previous HER2 directed regimens in the metastatic setting (N= 2 or N ≥3).  
• Geographic region (North America vs. Europe including Russia and Israel vs. Rest of 
the World) 
• Visceral vs. Non-Visceral only disease 
• Estrogen receptor+ (ER+) and/or progesterone receptor (PR+) (i.e., hormone receptor 
+) versus ER- and PR- (i.e., hormone receptor -). 
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2.6. 
Sample Size Determination 
The co-primary endpoints will be analyzed using an overall Type I error rate of 0.01 for PFS and 
0.04 for OS. To detect a hazard ratio (experimental vs. control) of 0.70 with approximately 85% 
power, 419 PFS events (PD/Deaths) are required to be observed; this assumes a median (ITT) 
PFS of 8.0 months (34.7 weeks) for the experimental arm (neratinib plus capecitabine) and 5.6 
months (24.3 weeks) for the control arm (lapatinib plus capecitabine).   
It is expected that the 419th event will be observed at approximately 26 months after the first 
subject is enrolled, which would correspond to approximately half of the death events needed to 
be observed.  At this time, an interim analysis on OS will also be performed.  For the OS 
endpoint, a group sequential method will be employed to maintain the overall Type I error rate at 
0.04.  Specifically, Lan DeMets alpha spending function approximating the O’Brian-Fleming 
boundaries will be calculated to create appropriate critical values to which the log rank statistic 
will be compared (De Mets and Gordon Lan, 1994). If 50% of the deaths are observed at the 
interim OS analysis, the boundary using the Lan-DeMets alpha spending function is shown 
in Table 1 for OS interim analysis.  
Table 1: 
Spending Function 
Information 
Fraction 
Expected Death 
Events 
Study 
Month 
Boundary (Reject 
Ho) 
2-Sided Significance 
Level* 
50% 
185 
26 
3.066 
0.002 
100% 
378 
50 
2.058 
0.039 
* This significance level relates to the 0.04 alpha allocation to OS but will be updated if the entire 0.05 can be 
allocated to OS. 
These boundaries are designed to detect a hazard ratio (experimental vs. control) of 0.725 with 
approximately 85% power.  Overall, 378 OS events (deaths) are required to be observed; this 
assumes a median (intent to treat [ITT]) OS of 30.3 months for the experimental arm (neratinib 
plus capecitabine) and 22.0 months for the control arm (lapatinib plus capecitabine). 
Approximately 600 subjects will be enrolled and randomized equally between the two treatment 
arms. This sample size assumes a 1% drop out rate per 12 months (52 weeks) equally distributed 
between the treatment arms for the PFS endpoint. 
 
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3. 
GENERAL ANALYSIS AND REPORTING CONVENTIONS 
All study variables will be listed. Selected variables will be summarized and, when appropriate, 
analyzed. Data summaries will be presented by treatment group and, when appropriate, visit.   
For all safety and efficacy variables, the number of patients will be provided overall and by visit, 
with the exception of adverse events and concomitant medications, which will not be 
summarized by visit.  
Categorical variables will be summarized using counts and percents. Percents 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, median, standard deviation, minimum, and maximum.   
Mean and median will be reported at 1 more significant digit than the precision of the data; 
standard deviation will be reported at 2 more significant digits than the precision of the data.  
Minimum and maximum will be reported to the same level of precision as the original 
observations.  In general, any calculated values, such as those due to unit conversion, will be 
rounded to the same number of decimal places as the original data.  P-values will be reported to 
3 decimal places, with values less than 0.001 displayed as ‘<0.001.’ 
In general, the baseline value will be considered the last measurement observed prior to taking 
the first dose of study treatment. 
Data will be listed by treatment and patient. In general, listings will be sorted in the order that 
columns are displayed, starting with the first column on the left (treatment).   
SAS statistical software, version 9.1 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.  
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4. 
ANALYSIS POPULATIONS 
Four analysis populations will be used for this study: the Intent to treat (ITT) population, the 
Safety Population, the Pharmacokinetics (PK) population and the Quality of Life population 
(QoL). 
The analysis of the primary and secondary efficacy endpoints will be performed using the ITT 
population. All safety analyses will be performed using the Safety Population. Exploratory 
Pharmacokinetics analyses will be performed using the PK population. Quality of life analyses 
will be performed using the QoL population. 
4.1. 
Intent to treat (ITT) Population 
The intent to treat population is defined as all patients who are randomized into the study. 
Patients will be analyzed in the treatment arm to which they were randomly assigned regardless 
of which treatment they received. 
4.2. 
Safety Population 
The safety population is defined as all patients who received at least one dose of investigational 
product. Patients will be analyzed based on the treatment they had received regardless of the 
treatment to which they were randomized. 
4.3. 
Pharmacokinetics (PK) Population 
The pharmacokinetics population consists of all patients for whom data on concentrations of 
study treatment is available. 
4.4. 
Quality of Life (QoL) Population 
The QoL population consists of all patients in the safety population for whom a baseline and at 
least one post baseline Health Outcomes Assessment (HOA) are available. 
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5. 
STUDY PATIENTS 
5.1. 
Disposition of Patients 
The number and percentage of patients entering and completing each phase of the study will be 
presented, stratified by treatment. Reasons for withdrawal pre- and post-randomization will also 
be summarized. 
5.2. 
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 
and treatment group. 
6. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Descriptive statistics will be provided for all demographic and baseline characteristics based on 
the ITT population.  Demographic data, medical history, concomitant disease, and concomitant 
medication will be summarized by means of descriptive statistics or frequency tables, overall and 
stratified by treatment.  For categorical variables, the number and percentages 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.   
6.1. 
Demographic and baseline characteristics 
The following demographic and baseline variables will be summarized by treatment group: 
• age (years) 
• age group (<65, ≥ 65 years)  
• sex 
• race & ethnicity (per CRF) 
• region 
• 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 
6.2. 
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 
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medical conditions that require medication and cancer history will be collected at screening, 
within 21 days before 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.   
6.3. 
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 and summarized in a table and a data listing. 
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7. 
MEASUREMENTS OF TREATMENT COMPLIANCE 
Duration of treatment will be summarized separately for each study compound by treatment 
group.  In addition, the cumulative quantity, dose intensity (quantity per time unit), and the 
relative dose intensity (dose intensity/scheduled dose per time unit) will be summarized. 
The number of patients with dose holds or dose reductions will be tabulated for each test article 
by treatment group. 
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8. 
EFFICACY EVALUATION 
8.1. 
Overview of Efficacy Analysis Issues 
8.1.1. 
Handling of Dropouts or Missing Data 
Missing assessments for PFS, the number of subjects who drop out prior to PFS or OS, and the 
length of follow up for dropouts will be summarized by treatment group.  Sensitivity analyses 
will be performed to assess the impact of subject dropout or missing assessments on the primary 
efficacy analyses.  
Other endpoints that could be affected by missing values (e.g. health outcome assessments) will 
be analyzed using a sensitivity analysis to quantify the impact of missing values in the results. 
8.1.2. 
Multicenter Studies 
Data from all sites will be pooled for the purpose of analyses. Exploratory analyses by site are 
not an objective of this study and are not currently planned. 
8.2. 
Efficacy Variables 
Table 2 gives an overview of the efficacy variables and the analysis methods that will be used for 
analysis. 
Table 2: 
Efficacy Variables and Analysis Methods 
Endpoint 
Method  
Primary 
 
Progression Free Survival 
(independently adjudicated)   
• 
Kaplan-Meier estimates 
• 
Stratified Log-rank test 
• 
Stratified Cox Proportional Hazards model 
Overall Survival 
• 
Kaplan-Meier estimates  
• 
Stratified Log-rank test 
• 
Stratified Cox Proportional Hazards model 
Secondary 
 
Progression Free Survival 
(investigator assessed) 
• 
Kaplan-Meier estimates 
• 
Stratified Log rank test 
• 
Stratified Cox Proportional Hazards model 
Objective Response Rate 
(independently adjudicated and 
investigator assessed)   
• 
Cochran-Mantel-Haenszel test (CMH) 
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Table 2: 
Efficacy Variables and Analysis Methods (Continued) 
Endpoint 
Method  
Duration of Response 
(independently adjudicated and 
investigator assessed)   
• 
Kaplan-Meier estimates  
Clinical Benefit Rate 
(independently adjudicated and 
investigator assessed)   
• 
Cochran-Mantel-Haenszel test (CMH) 
Time to intervention for 
symptomatic metastatic central 
nervous system disease (CNS) 
(investigator assessed)   
• 
Cumulative incidence function for time to intervention for 
symptomatic CNS 
Health Outcome Assessments 
• 
Random Effects Mixed Model 
These are definitions of the criteria used to determine objective tumor response for target lesions.  
These components make up the endpoints which are defined below, see the protocol for more 
detail.  
Complete Response (CR): Disappearance of all target and non-target lesions. Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm.  All 
lymph nodes must be non-pathological in size (<10 mm short axis). 
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.  PD can also be determined if there is unequivocal 
progression of existing non-target lesions. (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. 
8.2.1. 
Progression Free Survival (PFS) 
Progression free survival (PFS) is defined as the time interval from the date of randomization 
until the first date on which recurrence, progression (per RECIST v1.1), or death due to any 
cause, is documented. It is not necessary to confirm disease progression.  
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All tumor assessments and deaths collected will be used except in the following 2 cases: 
1. If a subject misses 2 or more consecutive assessments immediately prior to the 
documentation of PD or death the subject will be censored at the last assessment prior to 
the missed visits (following the FDA guidance on clinical trial endpoints for the approval 
of cancer drugs and biologics). 
2. For subjects that started a new anti-cancer therapy, all tumor assessments and deaths after 
the start date of new anti-cancer therapy will be excluded from the analysis. 
After taking into account the two conditions listed above, subjects without documented PD or 
death, including those who dropped out, will be censored at their last tumor assessment. Patients 
who did not have any tumor assessments after the screening visit will be censored on the 
randomization date.  
Assessment of PFS will be performed by a blinded, independent, central review of tumor 
assessments for all patients at Screening, and then after every 6 weeks from first dose of 
investigational product, regardless of treatment schedule modification (e.g., dose delay), until 
documented disease progression or death. PFS will be assessed using the Response Evaluation 
Criteria in Solid Tumors (RECIST v1.1). 
8.2.2. 
Overall Survival (OS) 
Overall survival is defined as the time from randomization to death due to any cause, censored at 
the last date known alive on or prior to the data cutoff employed for the analysis.  Patients who 
switch anticancer therapy will continue to be followed for the OS assessment. 
Survival data will be collected throughout the study treatment phase and during post-progression 
follow-up.  Survival follow-up after patient discontinuation of investigational product will be 
conducted approximately 4 weeks after treatment discontinuation and then every 12 weeks to 
assess for survival until subject’s loss to follow-up or death.   
8.2.3. 
Central Nervous System Disease (CNS) 
Time to intervention for symptomatic metastatic central nervous system disease is defined as the 
time from randomization to the first start date of an intervention for symptomatic metastatic CNS 
disease. Subjects that do not have an intervention for symptomatic metastatic CNS and do not die 
will be censored at the last date known alive on or prior to the data cutoff. Deaths are treated as 
competing events. Interventions for symptomatic CNS disease will include anti-cancer 
medication, cancer-related radiation therapy, cancer-related surgery/procedure, or concomitant 
medication/therapy as collected on the CNS CRF.   
8.2.4. 
Objective Response Rate (ORR) 
Objective response rate is defined as the proportion of patients demonstrating an objective 
response during the study. Objective response includes confirmed complete responses (CR) and 
partial responses (PR) as defined in the RECIST criteria included in the study protocol. Tumor 
assessments after the initiation of new anticancer therapy will not be included when determining 
ORR. 
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8.2.5. 
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, taking as a reference for PD the smallest 
measurements recorded since enrollment, per RECIST v1.1. This value is censored at the last 
valid tumor assessment if PD or death has not been documented.  Tumor assessments after the 
initiation of new anticancer therapy will not be included when determining DOR. 
8.2.6. 
Clinical Benefit Rate (CBR) 
Clinical benefit rate is the proportion of patients who achieve overall tumor response (confirmed 
CR or PR) or stable disease (SD) lasting for at least 24 weeks from randomization. Tumor 
assessments after the initiation of new anticancer therapy will not be included when determining 
CBR. 
8.3. 
Analysis Methods 
The significance levels allocated to the co-primary efficacy endpoints are 0.01 for PFS and 0.04 
for OS. However, once the null hypothesis for PFS is rejected at alpha = 0.01 at the time of the 
primary analysis then OS can be tested at the overall significance level of 0.05. The additional 
alpha propagated to the OS endpoint will not be spent at the interim OS analysis (Ye, 2013). The 
interim boundary for OS will remain the same as the boundary using the Lan-DeMets alpha 
spending function with overall alpha=0.04 based on the actual information fraction (number of 
deaths as a proportion of the 378 target number of deaths). The time to CNS intervention will be 
tested after PFS and OS. If PFS is not significant and OS is, then time to CNS will be tested at 
alpha =0.04; if both are significant, then time to CNS will be tested at alpha=0.05. Unless OS is 
significant at the interim analysis, time to CNS intervention will not be tested at the primary PFS 
analysis (interim OS), and will only be tested after OS is significant at the final OS analysis 
(Figure 1). 
Test of all other secondary endpoints are descriptive. 
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Figure 1: 
 Testing Schema 
 
8.3.1. 
Primary Efficacy Analyses 
The co-primary endpoints are OS and independently-assessed PFS. PFS will be determined by 
adjudicated disease progression (disease progression demonstrated by radiographic imaging or 
other appropriate modality), or death due to any cause, described in Section 8.2.1.  Subjects will 
be stratified at randomization by whether they had 2 or ≥3 prior HER2+ MBC regimens in the 
metastatic setting; whether they had visceral disease or non-visceral only; their tumor’s hormone 
receptor status, and their geographic region.   
When 419 centrally assessed PFS events have occurred the primary PFS analysis will be 
performed. The median time to PFS and corresponding two-sided 95% confidence intervals will 
be calculated using the product limit estimator and displayed using a Kaplan-Meier graph, by 
treatment group. A log-rank test controlling for hormone receptor status, number of prior HER2-
directed regimens in the metastatic setting, visceral disease status, and geographic region will be 
used to test the null hypothesis of no difference in the time to PFS between the two treatment 
groups at the alpha level of 0.01. A stratified Cox Proportional hazard model will be used to 
estimate the hazard ratio. PFS events will continue to be captured after the primary PFS analysis 
and a secondary, descriptive, analysis similar to the primary will be performed at the time of the 
primary OS analysis. When the PFS analysis is performed, an interim analysis will be performed 
on the OS endpoint. When 378 deaths have occurred, the primary (final) OS analysis will be 
performed. The median time to OS and corresponding two-sided 95% confidence intervals will 
be calculated using the product limit estimator and displayed using a Kaplan-Meier graph, by 
treatment group. A log-rank test controlling for hormone receptor status, number of prior HER2-
directed regimens in the metastatic setting, visceral disease status, and geographic region strata 
will be used to test the null hypothesis of no difference in the survival between the two treatment 
groups as described in the overview of Section 8.3. 
The co-primary efficacy analyses will be performed on the intent to treat (ITT) population 
defined as all subjects randomized into the study.  Sensitivity analyses will be performed to 
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investigate the impact of dropout between the two treatment groups on the treatment effect 
estimate. 
8.3.1.1. 
Sensitivity Analyses  
The following sensitivity analyses for PFS will be performed:  
1. If there are more than 10% of patients that start a new anti-cancer therapy prior to the 
documentation of a PD, the initiation of the new therapy will be considered as an event 
and the start date for the new anti-cancer therapy will be considered the PFS event date. 
2. Similar to the primary analysis, a sensitivity analysis will be done without stratifying by 
the randomization strata. Identical event and censoring rules will be used as described in 
the primary PFS analysis (Section 8.2.1). 
3. A sensitivity analysis will be performed using all tumor assessments and deaths. This 
means that new anti-cancer therapy will not be used to exclude tumor assessments and 
deaths and tumor assessments will be used even if a subject misses 2 or more visits prior 
to progression being documented. 
4. Similar to the primary analysis, a sensitivity analysis will be done using interval 
censoring estimation to address any potential imbalance in intermittent missing 
assessments. 
For OS, an unadjusted analysis without stratifying by the randomization strata will be performed.  
8.3.2. 
Secondary Efficacy Analyses 
The secondary endpoints of ORR, CBR and duration of response will be assessed using the 
centrally reviewed tumor assessments as well as the investigator tumor assessments. The 
secondary endpoint of time to intervention for symptomatic CNS disease will only use the 
investigator-reported data. 
The treatment difference in the secondary efficacy endpoint of investigator assessed PFS will be 
assessed with the product limit estimate of the median time to event.  Differences between 
treatment groups will be examined using a log rank test statistic stratified by hormone receptor 
status, number of prior HER2-directed regimen in the metastatic setting, visceral disease status, 
and geographic region strata (similar to the analyses for the primary endpoints).  All time-to-
event endpoints including time to intervention for symptomatic CNS disease will be displayed 
using a Kaplan-Meier survival plot.   
For the secondary endpoints of ORR and CBR the subjects included in the analyses are those that 
had measurable disease (per RECIST v1.1) at screening. Any tumor assessments after the start of 
new anti-cancer therapy will not be included in the analyses for these two endpoints. The 
treatment difference in the secondary efficacy endpoints of ORR and CBR will be analyzed 
using a Cochran-Mantel-Haenzel (CMH) Chi-square test, stratified on hormone receptor status, 
number of prior HER2-directed regimens in the metastatic setting, geographic region and disease 
category (visceral vs. non-visceral only).  
Duration of response will be summarized by treatment group for the patients that responded. If 
there are patients that continue to respond, they will be censored at their last tumor assessment 
and a Kaplan-Meier analysis will be done to estimate the duration of response.  
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With the exception of the CNS endpoint, which will be tested only after the null hypothesis is 
rejected for OS; all other secondary endpoints are descriptive analyses and will be done at the 
time of the primary PFS analysis.   
Cumulative incidence of time to intervention for symptomatic CNS is defined as time from 
randomization to the start of therapy for symptomatic CNS. Competing event are deaths prior to 
intervention for symptomatic CNS. Gray’s test (Gray, 1988) stratified for factors used in the 
randomization will assess the equality of cumulative incidence functions between the treatment 
arms. Additionally, the Kaplan Meier method, stratified log-rank test, and Cox proportional 
hazard model will be performed without considering competing events. 
As a sensitivity analysis to the secondary CNS endpoint, the time to progressive central nervous 
system (CNS) lesions will be analyzed using the centrally reviewed tumor assessments as well as 
the investigator tumor assessments. Time to progressive CNS lesions is defined as the time 
interval from the date of randomization until the first date on which a scheduled or unscheduled 
visit documents the appearance of newly diagnosed or progressive CNS lesions, per RECIST 
v1.1. If there is no evidence of CNS progression, the subject will be censored at the last 
assessable evaluation on study or prior to new anti-cancer therapy, if applicable.  Competing 
events include progression at other sites and deaths prior to progressive CNS. Gray’s test 
(Gray, 1988) stratified for factors used in the randomization will assess the equality of 
cumulative incidence functions between the treatment arms.   Additionally, the Kaplan Meier 
method, stratified log-rank test, and Cox proportional hazard model will be performed without 
considering competing events. 
8.3.3. 
Other Efficacy Analyses 
8.3.3.1. 
Health Outcome Assessments 
The following health outcomes endpoints will be assessed at Cycle 1 Day 1 of the study (at any 
time within 24 hours of randomization) and at the end of every 6 weeks (± 3 days) starting from 
Cycle 1 Day1 as indicated in the Schedule of Procedures included in the protocol. 
• European Organization for the Research and Treatment of Cancer Quality of Life 
Questionnaire C-30 (EORTC QLQ-C30), version 3  
•  EORTC QLQ Breast Cancer Module (BR23)  
• The EuroQol (EQ-5D) multi-dimensional health status questionnaire 
8.3.3.1.1. EORTC QLQ C30 and BR23 
The EORTC QLQ-C30 is a questionnaire developed to assess the quality of life of cancer 
patients which includes measures of physical functioning [PF], role functioning [RF], emotional 
functioning [EF], social functioning [SF], global QoL, and fatigue [FA]). It is supplemented by 
the breast cancer module (BR-23) which includes measures of body image, sexual functioning, 
systemic therapy side effects, breast symptoms, and arm symptoms. The complete questionnaire 
includes 53 items; 23 of them are specific of breast cancer. Patients will be asked to indicate the 
extent to which they have experienced symptoms or problems using a 4 point scale as follows: 1, 
is not at all; 2, a little; 3, quite a bit and 4, very much. Patients are also asked to rate their overall 
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health and quality of life during the past week using a 7 point scale where 1 is very poor and 7 is 
excellent.  
Patient responses on the level of severity on the EORTC QLQ C30 and BR23 dimensions will be 
used to derive the corresponding EORTC QLQ C30 and BR23 scores, as per published 
methodology. 
8.3.3.1.2. EQ-5D-5L 
The EuroQol questionnaire (EQ-5D-5L) is a brief, self-administered generic health status 
instrument consisting of two parts. In the first part respondents are asked to describe their current 
health state on 5 dimensions (mobility, self-care, usual activities, pain or discomfort, and anxiety 
or depression) with each dimension having 5 levels of function (1 = no problem, 2 = slight 
problem, 3 = moderate problem, 4 = severe problem, and 5= unable to function/extremely 
affected). The second part is a patient’s self-rating of current health state on a Visual Analog 
Scale (EQ-VAS) with endpoints labeled ‘best imaginable health state’ and ‘worst imaginable 
health state’. The EQ-5D-5L endpoints are the EQ-5D-5L Index which is derived by combining 
one level from each of the 5 dimensions and converting it to a single summary index or health 
utility value (Shaw et al., 2005) and the EQ-VAS score, which ranges from 0 for worst 
imaginable health state to 100 for best imaginable health state. Overall scores for the EQ-5D-5L 
index range from -0.594 to 1, with low scores representing a higher level of dysfunction. 
Patient responses on the level of severity on the 5 EQ-5D-5L dimensions will be used to derive 
the corresponding EQ-5D-5L utility values, as per published methodology. 
8.3.3.2. 
Analysis of Health Outcome Assessments 
Patient-reported health-related quality of life measures (EORTC QLQ-C30 and EQ-5D) will be 
summarized by treatment group and visit. Differences between treatment groups will be 
described using an F test from a random effects mixed model with treatment, time, number of 
prior HER2-directed regimens in the metastatic setting (binary), geographic region, hormone 
receptor status, disease category, and the treatment by time interaction. 
Endpoints that could be affected by missing values (e.g., health outcomes assessments) will be 
analyzed using a sensitivity analysis, including pattern mixture models. Results will be 
summarized by treatment group and visit. 
8.4. 
Examination of Subgroups 
All efficacy variables will be summarized by number of prior HER2-directed regimens in the 
metastatic setting, geographic region, hormone receptor status, and disease category. These 
analyses will be presented using forest plots and tests of interaction will be done. PFS and OS 
will, in addition, be summarized by de novo MBC vs. recurrent MBC. 
8.5. 
Exploratory Biomarker Analysis 
Future exploratory biomarker evaluations may include but are not limited to quantitative 
measures of HER2, gene expression analysis, and genomic analysis including but not limited to 
PIK3CA mutation status.  The role of the immune response including measurement of tumor 
infiltrating lymphocytes (TILS) and levels of immune markers may also be assessed.   
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9. 
SAFETY EVALUATION 
9.1. 
Overview of Safety Analysis Methods 
All safety analysis will be performed for all patients in the Safety population. The following 
assessments will be used to evaluate the safety of neratinib in combination with capecitabine in 
HER2+ metastatic breast cancer (MBC) patients whose disease has progressed following two (2) 
prior HER2+ directed regimens in the metastatic setting:  
• Adverse events (AEs) 
• Medical history 
• Vital sign measurements 
• Physical examination findings 
• Electrocardiogram (EKG)  
• LVEF results from multiple-gated acquisition scan (MUGA) or echocardiogram 
(ECHO) 
• Liver Function Tests results  
• Eastern Cooperative Oncology Group (ECOG) performance status 
• Laboratory assessments  
All safety endpoints will be summarized by treatment group and visit when appropriate.   
9.2. 
Extent of Exposure 
Extent of exposure to each investigational product will be summarized by total dose, number of 
cycles, number of missed doses, number of dose delays and number of dose reductions. 
9.3. 
Adverse Events, Serious Adverse Events, and Deaths 
All AEs and SAEs 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 SAE occurring any time after the reporting period, it must be promptly reported.  
The Patient Diary used for recording of investigational product intake will also be used by 
patients to document any AEs experienced during study treatment. In the case of diarrhea, it also 
serves to document the number of loose stools per day and use of loperamide/other antidiarrheal 
treatments taken. 
AEs and SAEs will be coded using the most current version of MedDRA 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. 
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TEAEs and SAEs will be tabulated by SOC, PT, and treatment group.  All tabulations will be 
sorted by descending frequency of SOC and PT in the total column unless otherwise noted. 
TEAEs will also be summarized according to relationship to study drug and severity. TEAEs of 
toxicity grade 3 or higher will also be summarized. 
Similarly, treatment emergent adverse events leading to treatment discontinuation, dose 
modification, dose hold, and/or delay of investigational product will be tabulated by SOC, PT 
and treatment group.  
Separate summaries and comparisons between treatment groups will be presented for treatment 
emergent diarrhea events leading to treatment discontinuation, dose holds, dose reductions, and 
delay of investigational product. Therapies used to treat diarrhea will also be summarized using 
descriptive statistics and compared between treatment groups.  
SAEs, and TEAEs will be listed in by patient listings sorted by treatment, patient ID and study 
day; SAEs will be flagged. All AE listings will include study day, SOC, PT, reported term, dose, 
Cycle/day, AE onset date, AE resolution date, outcome, duration, relationship to drug, action 
taken, and severity.   
Patient deaths are recorded on the End of Study CRF page. The number and incidence of death 
will be summarized by cause of death overall, treatment arm, and on-study status at time of death 
(within 28 days of last dose vs. more than 28 days after last dose).  Patient death listings will 
include all death data available including date of death, cause of death and any AEs resulting in 
death. 
9.4. 
Clinical Laboratory Evaluation 
Blood samples for clinical chemistry and hematology will be collected during screening, before 
study drug administration, on day 1 of each treatment cycle and at the treatment discontinuation 
visit. Samples for pregnancy test and urinalysis will be collected at screening and before study 
drug administration. 
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. 
The institutional laboratory will analyze all hematology, routine blood chemistry, and urine 
samples collected.  
9.5. 
Vital Signs, Physical Findings, and Other Observations Related to 
Safety 
9.5.1. 
Vital Signs 
Vital signs, including systolic and diastolic blood pressure, pulse, and body temperature, as well 
as weight will be collected during screening and on days 1, 8 and 15 of cycle 1 and on day 1 of 
the following cycles. Height will be collected at screening.  
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Summary tables will include descriptive statistics (number of patients, mean, std, median, min, 
and max) for baseline and each cycle/visit. Descriptive statistics will be calculated on both the 
actual score and the change from baseline score.  Supplemental data will not be included in this 
summary; therefore the latest assessment in the cycle/visit window will be used for the 
evaluation. 
A second summary will focus on the individual patient measures with the intent of identifying 
post-baseline abnormalities defined as clinically significant.  
9.5.2. 
Physical Examinations 
Physical examinations will be collected during screening, before study drug administration, 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.  Changes in weight will be 
summarized across time on study and the frequency of clinically significant changes will be 
tabulated overall and by treatment. 
9.5.3. 
Electrocardiograms 
Single standard 12 lead digital EKGs will be performed during screening, at Cycle 3 Day 1, 
Cycle 6 Day 1, Day 1 of every 6th cycle after that, and on the treatment discontinuation visit if 
not done within the previous 12 weeks. 
The EKG (measured after resting in a supine position for 5 minutes) will include heart rate, 
rhythm, and RR, PR, QRS, QT and QTc intervals. The EKG will be read and interpreted at the 
investigational site for patient safety monitoring, and documentation stored with the source 
documents. 
Additional correction formulas included but considered secondary are QTcF and QTcB. These 
additional corrected QT intervals are defined as: 
• QTcB is the length of the QT interval corrected for heart rate by Bazett’s formula: 
QTcB = QT / (RR)1/2 
• QTcF is the length of the QT interval corrected for heart rate by Fridericia’s formula: 
QTcF = QT / (RR)1/3 
All EKG parameters and their change from baseline will be summarized across study time points 
by treatment arm and overall using descriptive statistics. The frequency of abnormal EKG events 
will be tabulated by treatment arm and overall at each time point. 
All EKG values will be listed by patient.  Change in EKG findings will also be presented in a 
separate by-patient listing.  
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9.5.4. 
Left Ventricular Ejection Fraction (LVEF) 
MUGA scan or ECHO scans to determine LVEF will be performed during screening and 
repeated at Cycle 3 Day 1, Cycle 6 Day 1, Day 1 of every 6th cycle after that,  and at treatment 
discontinuation, if not done within the previous 12 weeks. 
MUGA scans or ECHO scans to determine LVEF will be performed as part of Screening 
procedures within 2 weeks before Cycle 1/Day 1, unless results are already available from within 
4 weeks before Cycle 1/Day 1.  
The mean LVEF and mean LVEF change from baseline will be summarized across study time 
points by treatment arm and overall using descriptive statistics.   
All MUGA and ECHO values will be listed by patient.  Change in MUGA and ECHO findings 
will also be presented in a separate by-patient listing.  
9.5.5. 
Liver Function Test Results 
A listing will be generated for patients potentially meeting Hy’s Law criteria (total bilirubin >= 
(2xULN) and AST or ALT > (3xULN) at any time during the study). Plots or tables of on-
therapy peak total bilirubin vs. peak AST (or ALT) will also be generated to help identify 
potential Hy’s Law cases. 
9.5.6. 
ECOG Performance Status 
ECOG performance status will be assessed at screening, Day 1 of every cycle, and at treatment 
discontinuation in accordance with the Schedule of Procedures in the study protocol. The 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 are no clinically 
significant findings. 
The ECOG status will be included in the baseline and demographic variables. The number and 
percentages of patients in each ECOG category will be presented by treatment and overall. 
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Statistical Analysis Plan 
17 Jan 2018 
PUMA-NER-1301 
v2.1 
10. 
INTERIM ANALYSES AND DATA MONITORING 
No interim PFS analysis is planned. One OS interim analysis is planned at the time of the 
primary PFS analysis. An Independent Data Monitoring Committee will review safety data on an 
ongoing basis throughout the study.   
 
11. 
CHANGES TO THE ANALYSES PLANNED IN THE PROTOCOL 
This section is to be filled out if there are any changes to the analyses prior to finalization of the 
SAP. 
 
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Statistical Analysis Plan 
17 Jan 2018 
PUMA-NER-1301 
v2.1 
12. 
LIST OF PLANNED TABLES 
Grouping 
Title 
Disposition 
Summary of Subject Disposition 
 
Summary of Protocol Deviations 
Demography  
Summary of Demographics and Baseline Characteristics 
Medical History 
Summary of Medical History  
Cancer History 
Summary of Prior Cancer History and Therapies 
 
Summary of Baseline Breast Cancer Disease Burden 
 
Summary of Prior Anticancer Medications 
 
Summary of Prior Anticancer Radiotherapy 
 
Summary of Prior Anticancer Surgical Therapy 
 
Summary of Biomarkers 
Concomitant 
Medications 
Summary of Concomitant Medications 
 
Summary of Non-Pharmacologic Anti-Diarrheal Treatments 
Study Medication 
Summary of test article exposure 
 
Summary of test article dose reduction 
 
Summary of test article dose hold 
Efficacy 
Summary of Progression-Free Survival 
 
Summary of Censoring in Progression-Free Survival 
 
Summary of Objective Response Rate 
 
Summary of Duration of Response 
 
Summary of Censoring in Duration of Response 
 
Summary of Clinical Benefit Rate 
 
Summary of Overall Survival 
 
Summary of Censoring in Overall Survival 
Health Outcomes 
Summary of EORTC QLQ C30 BR23 Observed Results 
 
Summary of EORTC QLQ C30 BR23 Change from baseline 
 
Summary of EORTC QLQ C30 BR23 Mixed Model Between Treatment 
Comparison 
 
Summary of EQ-5D Observed Results 
 
Summary of EQ-5D Change from baseline 
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Statistical Analysis Plan 
17 Jan 2018 
PUMA-NER-1301 
v2.1 
Grouping 
Title 
 
Summary of EQ-5D Mixed Model Between Treatment Comparison 
 
Summary of EQ-VAS Observed Results 
 
Summary of EQ- VAS Change from baseline 
 
Summary of EQ- VAS Mixed Model Between Treatment Comparison 
Safety 
Frequency Table of Treatment Emergent Adverse Events by Body System and 
Preferred Term 
 
Frequency Table of Serious Adverse Events by Body System and Preferred 
Term 
 
Frequency Table of Treatment Emergent Adverse Events Leading to Study 
Discontinuation by Body System and Preferred Term 
 
Frequency Table of Treatment Emergent Adverse Events Leading to Study 
Drug Reduction by Body System and Preferred Term 
 
Frequency Table of Treatment Emergent Adverse Events Leading to Study 
Drug Hold by Body System and Preferred Term 
 
Frequency Table of Treatment Emergent Adverse Events by Body System, 
Preferred Term and Relationship to Study Medication 
 
Frequency Table of Treatment Emergent Adverse Events by Body System, 
Preferred Term and Severity 
 
Frequency Table of Treatment Emergent Adverse Events by Body System and 
Preferred Term (Toxicity Grade 3 or Higher)  
 
Summary of Death 
Diarrhea 
Summary of Time to First Diarrhea Treatment Emergent Adverse Event 
 
Diarrhea Characteristics 
 
Summary of Time to First Diarrhea Treatment Emergent Adverse Event by 
Severity 
 
Summary of Diarrhea Treatment Emergent Adverse Events Leading to 
Treatment Discontinuation 
 
Summary of Diarrhea Treatment Emergent Adverse Events Leading to Dose 
Hold 
 
Summary of Diarrhea Treatment Emergent Adverse Events Leading to Dose 
Reduction 
 
Summary of Anti-diarrheal Medications 
Laboratory 
Mean and Mean Change from Baseline in Numeric Laboratory Data:  
Hematology/ Clinical Chemistry/Urinalysis 
 
Frequency Table of Potentially Clinically Significant Laboratory Data:  
Hematology/ Clinical Chemistry/Urinalysis 
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Statistical Analysis Plan 
17 Jan 2018 
PUMA-NER-1301 
v2.1 
Grouping 
Title 
 
Shift from Baseline in Laboratory Data:  Hematology/ Clinical 
Chemistry/Urinalysis 
Vital Signs 
Mean and Mean Change from Baseline in of Vital Signs Data 
 
Frequency Table of Potentially Clinically Significant Vital Signs Data  
 
Mean and Mean Change from Baseline in ECG Data 
Physical Exam 
Summary of Physical Examination 
ECG 
Frequency Table of Potentially Clinically Significant Values in QTc(F) Interval 
at Post First Dose  
 
Frequency Table of Potentially Clinically Significant Values in QTc(B) 
Interval at Post First Dose 
 
Frequency Table of Potentially Clinically Significant Values in QT Interval at 
Post First Dose 
LVEF 
Mean and Mean Change from baseline in LVEF Data 
 
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Statistical Analysis Plan 
17 Jan 2018 
PUMA-NER-1301 
v2.1 
13. 
LIST OF PLANNED FIGURES 
Grouping 
Title 
Efficacy 
Kaplan-Meier Plot of  Progression Free Survival (centrally assessed) 
 
Kaplan-Meier Plot of Overall Survival 
 
Kaplan-Meier Plot of  Progression Free Survival (locally assessed) 
 
Kaplan-Meier Plot of Duration of Response 
 
Kaplan-Meier Plot of intervention for CNS disease 
 
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Statistical Analysis Plan 
17 Jan 2018 
PUMA-NER-1301 
v2.1 
14. 
LIST OF PLANNED DATA LISTINGS 
Grouping 
Title 
Disposition 
Listing of Screen Failures 
Demography  
Listing of Demographics and Baseline Characteristics 
Medical History 
Listing of Medical History  
Cancer History 
Listing of Prior Cancer History 
 
Listing of Prior Cancer Therapies 
Concomitant Medications 
Listing of Concomitant Medications 
 
Listing of Non-Pharmacologic Anti-Diarrheal Treatments 
Study Medication 
Listing of Test Article Administration 
 
Listing of Subjects with Dose Reduction 
 
Listing of Subjects with Dose Hold 
Efficacy 
Listing of Tumor Data (centrally assessed) 
 
Listings of Tumor Measurements and Assessments 
Health Outcomes 
Listing of EORTC QLQ C30 and BR23 data 
 
Listing of EQ-5D data 
Safety 
Listing of Adverse Events 
 
Listing of Adverse Events with Toxicity Grade 3 or higher 
 
Listing of Treatment Emergent Adverse Events with Toxicity Grade 3 or 
higher 
 
Listing of Drug Related Adverse Events 
 
Listing of Serious Adverse Events 
 
Listing of Adverse Events Leading to Treatment Discontinuation 
 
Listing of Adverse Events Leading to Dose Reduction 
 
Listing of Adverse Events Leading to Dose Hold 
 
Listing of Drug Related Adverse Events 
 
Listing of Deaths 
 
Listing of potential Hy’s law cases 
Diarrhea 
Listing of Treatment Emergent Diarrhea by Severity 
 
Listing of Treatment Emergent Diarrhea Grade 3 or Higher 
 
Listing of Anti-diarrheal Medications 
Laboratory 
Listing of Laboratory Data  
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Statistical Analysis Plan 
17 Jan 2018 
PUMA-NER-1301 
v2.1 
Grouping 
Title 
Vital Signs 
Listing of Vital Signs Data 
 
Frequency Table of Potentially Clinically Significant Vital Signs Data  
Physical Exam 
Listing of Physical Examination Data 
ECG 
Listing of ECG Data 
LVEF 
Listing of LVEF Data 
 
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Statistical Analysis Plan 
17 Jan 2018 
PUMA-NER-1301 
v2.1 
15. 
REFERENCES 
De Mets DL and Gordon Lan KK. Interim analysis: the alpha spending function approach. Stat 
Med. 1994;13(13-14):1341-56. 
Gray RJ. A class of K-sample tests for comparing the cumulative incidence of a competing risk. 
Ann Stat 1988; 16:1140-54. 
Shaw JW, Johnson JA, Coons SJ. US valuation of the EQ-5D health states: development and 
testing of the D1 valuation model. Med Care. 2005;43(3):203-220. 
Ye Y, Li A, Liu L, and Yao B. A group sequential Holm procedure with multiple primary 
endpoints, Stat Med 2013 Mar 30;32(7):1112-24. 
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Neratinib 
 
14-NOV-2018 
Supplemental Statistical Analysis Plan: PUMA-NER1301 
Version 1.0 
 
 
 
 
SUPLEMENTAL STATISTICAL ANALYSIS PLAN 
FOR THE NALA (1301) STUDY 
 
 
 
STUDY DRUG 
Neratinib 
 
 
VERSION 1.0 
DATE OF PLAN 
14-NOV-2018 
 
 
SPONSOR 
Puma Biotechnology, Inc. 
10880 Wilshire Blvd, Suite 2150 
Los Angeles, CA 90024 USA 
Phone: +1 424.248.6500 
Fax: +1 424.248.6501 
 
 
 
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Neratinib 
 
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Supplemental Statistical Analysis Plan: PUMA-NER1301 
Version 1.0 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................4 
1. 
INTRODUCTION ........................................................................................................5 
2. 
ANALYSIS OF QUALITY OF LIFE DATA ..............................................................6 
2.1.1. 
QoL populations ...........................................................................................................7 
2.2. 
QLQ-C30 and BR-23 Scoring ......................................................................................7 
2.2.1. 
EQ-5D-5L Scoring ........................................................................................................7 
2.3. 
Assessments on the same date ......................................................................................8 
2.4. 
Visit Time Window ......................................................................................................8 
2.4.1. 
Visit windows: ..............................................................................................................8 
2.4.2. 
Multiple Assessments within a visit window ...............................................................9 
2.5. 
Statistical Analysis ........................................................................................................9 
2.5.1. 
Descriptive Analysis .....................................................................................................9 
2.5.2. 
Mixed Model Analysis .................................................................................................9 
2.5.3. 
Response Analysis ........................................................................................................9 
2.5.4. 
Time To Deterioration (TTD) Analysis ......................................................................10 
2.5.5. 
Area Under Curve (AUC) analysis .............................................................................10 
2.5.6. 
Completion rate ..........................................................................................................11 
2.5.7. 
Pattern Mixture Model Analysis .................................................................................11 
3. 
ANALYSIS OF THE CNS ENDPOINTS ..................................................................12 
3.1. 
Secondary CNS endpoint ............................................................................................12 
3.2. 
Progressive CNS Endpoint .........................................................................................12 
3.3. 
Statistical Analysis ......................................................................................................12 
3.3.1. 
Sensitivity analysis for the secondary CNS endpoint .................................................12 
3.3.2. 
Time to progressive CNS disease ...............................................................................12 
4. 
SENSITIVITY ANALYSIS FOR OVERALL RESPONSE RATE ..........................13 
5. 
PROGNOSTIC VARIABLES OF INTEREST ..........................................................13 
6. 
ADDITIONAL EXPLORATORY ANALYSIS ........................................................13 
6.1. 
Time to RECIST defined PFS or clinical progression ................................................14 
6.2. 
Time to treatment failure ............................................................................................14 
 
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Neratinib 
 
14-NOV-2018 
Supplemental Statistical Analysis Plan: PUMA-NER1301 
Version 1.0 
LIST OF TABLES 
Table 1: 
Quality of Life Instruments and Scales ........................................................................6 
Table 2: 
List of Planned Tables ................................................................................................15 
Table 3: 
List of Planned Figures ...............................................................................................16 
Table 4: 
List of CNS locations..................................................................................................17 
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Neratinib 
 
14-NOV-2018 
Supplemental Statistical Analysis Plan: PUMA-NER1301 
Version 1.0 
LIST OF ABBREVIATIONS 
Abbreviation 
Term 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AUC 
Area Under the Curve 
BR-23 
European Organization for Research and Treatment-QOL questionnaire breast 
cancer specific module 
CNS 
Central Nervous System 
EOT 
End of treatment 
EQ-5D-5L 
EuroQol Group health status questionnaire 
HOA 
Health Outcomes Assessment 
KM 
Kaplan-Meier 
OS 
Overall Survival 
PFS 
Progression-free Survival 
QLQ-C30 
European Organization for Research and Treatment-QOL questionnaire 
QOL 
Quality of Life 
SAP 
Statistical Analysis Plan 
TTD 
Time to Deterioration 
UK 
United Kingdom 
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Neratinib 
 
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Supplemental Statistical Analysis Plan: PUMA-NER1301 
Version 1.0 
1. 
INTRODUCTION 
This supplemental Statistical Analysis Plan (SAP) is intended to further describe the efficacy 
analysis for the secondary endpoints of Health Outcomes Assessments (HOA) and Central 
Nervous System (CNS) as well as some additional sensitivity analyses.  
For the purposes of this supplemental SAP we will use the term Quality of Life (QoL) to cover 
all the analysis relating to the Health Outcomes Assessments (HOA).  
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Supplemental Statistical Analysis Plan: PUMA-NER1301 
Version 1.0 
2. 
ANALYSIS OF QUALITY OF LIFE DATA  
This section expands on the QoL analysis described in sections 8.3.3.1-8.3.3.2 of the Statistical 
Analysis Plan (SAP) version 2.1. 
In summary, there were three Quality of Life (QoL) instruments used in the NALA study: QLQ-
C30, BR-23, and EQ-5D-5L. There are 26 scales in these instruments and they are presented 
in Table 1  (QLQ-C30: 16 scales, BR-23: 8 scales, VAS and EQ-5D-5L health index score). The 
HOA instruments are administered every 2 cycles (6 weeks) until the end of study drug 
administration.  
Table 1: 
Quality of Life Instruments and Scales 
 
Scale 
Number 
of items 
Score 
Range 
Version 
3.0 
 Item 
Numbers 
Function 
or 
Symptom 
Scales 
 
QLQ-C30 Summary Score 
C30Sum 
13 
0-100 
1-28, 30 
F 
QLQ-C30 
Global Health status/QoL 
 
 
 
 
 
 
Global health status/QoL 
QL2 
2 
0-100 
29, 30 
F 
QLQ-C30 
Functional Scales 
 
 
 
 
 
 
Physical functioning 
PF2 
5 
0-100 
1 to 5 
F 
QLQ-C30 
Role Functioning 
RF2 
2 
0-100 
6,7 
F 
QLQ-C30 
Emotional Functioning 
EF 
4 
0-100 
21 to 24 
F 
QLQ-C30 
Cognitive Functioning 
CF 
2 
0-100 
20, 25 
F 
QLQ-C30 
Social Functioning 
SF 
2 
0-100 
26, 27 
F 
QLQ-C30 
Symptom Scales 
 
 
 
 
 
 
Fatigue 
FA 
3 
0-100 
10, 12, 18 
S 
QLQ-C30 
Nausea and vomiting 
NV 
2 
0-100 
14, 15 
S 
QLQ-C30 
Pain 
PA 
2 
0-100 
9, 19 
S 
QLQ-C30 
Dyspnoea 
DY 
1 
0-100 
8 
S 
QLQ-C30 
Insomnia 
SL 
1 
0-100 
11 
S 
QLQ-C30 
Appetite loss 
AP 
1 
0-100 
13 
S 
QLQ-C30 
Constipation 
CO 
1 
0-100 
16 
S 
QLQ-C30 
Diarrhea 
DI 
1 
0-100 
17 
S 
QLQ-C30 
Financial difficulties 
FI 
1 
0-100 
28 
S 
QLQ-C30 
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Neratinib 
 
14-NOV-2018 
Supplemental Statistical Analysis Plan: PUMA-NER1301 
Version 1.0 
Table 1: 
Quality of Life Instruments and Scales (continued) 
 
2.1.1. 
QoL populations 
In the 1301 SAP version 2.1 the QoL population was defined as a single population across all the 
HOA instruments. After the approval of the SAP it was determined that it would be best to 
define a separate population for each of the subscales. A subject will be included in the 
population for a particular subscale if they are in the safety population and they had a baseline 
assessment for that subscale as well as at least one post baseline assessment (up to last dose day 
+28 days) for the specific subscale. In the analysis dataset there will be a flag for each subscale 
population.  
2.2. 
QLQ-C30 and BR-23 Scoring 
The scoring for QLQ-C30 and BR-23 follows the EORTC QLQ-C30 scoring manual in 
following link: https://www.eortc.be/qol/files/SCManualQLQ-C30.pdf 
2.2.1. 
EQ-5D-5L Scoring 
The EQ-5D-5L consists of 6 items: 5 dimensions (mobility, self-care, usual activity, 
pain/discomfort, and anxiety/depression) and a health state score.  Each of the 5 dimensions has 
5 levels. The combination of 1 level from each of the 5 dimensions (e.g. 12234) will be used to 
obtain the health index score.  
 
Scale 
Number 
of items 
Score 
Range 
Version 
3.0 
 Item 
Numbers 
Function 
or 
Symptom 
Scales 
 
Functional Scales 
 
 
0-100 
 
 
 
Body Image 
BRBI 
4 
0-100 
9-12 
F 
BR23 
Sexual Functioning 
BRSEF 
2 
0-100 
14, 15 
S 
BR23 
Sexual Enjoyment 
BRSEE 
1 
0-100 
16 
S 
BR23 
Future Perspective 
BRFU 
1 
0-100 
13 
F 
BR23 
Symptom Scales/Items 
 
 
0-100 
 
 
 
Systemic therapy side effects 
BRST 
7 
0-100 
1-4, 6, 7, 8 
S 
BR23 
Breast Symptoms 
BRBS 
4 
0-100 
20-23 
S 
BR23 
Arm Symptoms 
BRAS 
3 
0-100 
17, 18, 19 
S 
BR23 
Upset by hair loss 
BRHL 
1 
0-100 
5 
S 
BR23 
 
 
 
 
 
 
 
EQ-5D-5L Health State Summary 
Score 
VAS 
 
-0.595 – 
1.000 
 
F 
EQ-5D-5L 
EQ-5D-5L Index Score 
IndexS 
 
0-100 
 
F 
EQ-5D-5L 
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Neratinib 
 
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Supplemental Statistical Analysis Plan: PUMA-NER1301 
Version 1.0 
To obtain EQ-5D-5L Index score, it is necessary to map to a value set from a particular country 
that has been well established and validated.   The EQ-5D-5L cross-walk value set for United 
Kingdom (UK) will be used in the derivation of health index scores. UK value sets has been used 
by PUMA studies 3004 and 6201 in alignment with wide utilization of EQ-5D results in UK. 
Derivation of the EQ-5D-5L index scores will use the “EQ-5D-5L Crosswalk value sets” link at 
the following location:  
https://euroqol.org/eq-5d-instruments/eq-5d-5l-about/valuation/crosswalk-index-value-
calculator/ 
2.3. 
Assessments on the same date 
Multiple assessments on the same date will be averaged so only one score will be used for any 
subscale for the given date. 
2.4. 
Visit Time Window  
Each QoL assessment is mapped to a scheduled visit. The defined visit windows are non-
overlapping and cover all possible dates from Baseline through the date of last dose of study 
drug administration plus 28 days. 
2.4.1. 
Visit windows: 
• The Baseline assessment will be the closest assessment on or before the date of first 
dose of study drug. 
• The time window for C3D1 will be first dose date+1 through first dose date +62 days. 
• Except Baseline and C3D1, the time window for the rest of visits will be defined as: 
− Start of window: study day of (1+21*(# of cycles)-21))  
− End of visit window: study day of (1+21*(# of cycles) +20)).  
− The target visit day for a scheduled visit is: (1+21*(# of cycles)). 
The visit time window mapping up to cycle 19 can be found below in reference to Day 1 which 
is the first dose date (Day 1). 
Cycle  
Target Day 
Start Day 
End Day 
Baseline 
Day 1 
< Day 1  
Day 1  
Cycle 3 Day 1 
Day 43 
Day 2 
Day 63 
Cycle 5 Day 1 
Day 85 
Day 64 
Day 105 
Cycle 7 Day 1 
Day 127 
Day 106 
Day 147 
Cycle 9 Day 1 
Day 169 
Day 148 
Day 189 
Cycle 11 Day 1 
Day 211 
Day 190 
Day 231 
Cycle 13 Day 1 
Day 253 
Day 232 
Day 273 
Cycle 15 Day 1 
Day 295 
Day 274 
Day 315 
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Supplemental Statistical Analysis Plan: PUMA-NER1301 
Version 1.0 
Cycle  
Target Day 
Start Day 
End Day 
Cycle 17 Day 1 
Day 337 
Day 316 
Day 357 
Cycle 19 Day 1 
Day 379 
Day 358 
Day 399 
2.4.2. 
Multiple Assessments within a visit window 
If a subject has multiple assessments on different dates within a visit window the assessment 
closest to the target visit day will be used for descriptive analysis/plotting, mixed model and 
response analysis by visits where a single value is associated with a visit.  
2.5. 
Statistical Analysis 
2.5.1. 
Descriptive Analysis 
Observed scores and change from baseline will be summarized by treatment group and visit for 
all 26 subscales. Results will be summarized in a table and figure for each subscale. The tables 
will include all time points available in the data and the plots are to include time points through 
cycle 19 (approximately 12.5 months). 
2.5.2. 
Mixed Model Analysis 
A mixed model analysis with an outcome of change from baseline and the covariates including 
baseline score, treatment arm, visit (categorical), treatment arm by time interaction, prior HER2-
directed regimens in the metastatic setting (2 or 3+), hormone receptor status (positive or 
negative),  and disease location (visceral  and non-visceral) will be used to evaluate differences 
between treatment arms. The analysis will use the F test from the repeated measures mixed 
model. Three randomization factors are included in the model to be consistent with the primary 
analysis as documented in a note to file (dated 8-SEP-2018) to the main SAP. 
A reduced mixed model will be used to estimate the change over time by treatment group. These 
results will be summarized in a table and figure for each subscale.  The reduced mixed model 
will only include baseline score, treatment arm, time (categorical), and treatment arm by time 
interaction.  
2.5.3. 
Response Analysis 
A response analysis will be used to evaluate the score change over time with a minimum clinical 
important threshold value.  At each post-baseline assessment, a subject’s score will be classified 
as having a response of improved, stable, or worsened.  A Mantel-Haenszel Chi Square test to 
assess any differences between treatment arms will be done at each visit and the results will be 
summarized in a table. 
We will conduct the response analysis for the following 7 subscales: 
• Global Health 
• C30 summary score, 
• Physical functioning 
• Fatigue 
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Supplemental Statistical Analysis Plan: PUMA-NER1301 
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• Constipation 
• Diarrhea 
• Systemic Therapy Side Effects scale 
For the functional scales and the C30 summary score, an improvement is defined as an increase 
in 10 points or more, worsening is defined as a decrease of 10 points or more, and stable is 
defined as neither improved nor worsened.  
For the symptom scales, an improvement is defined as a decrease of 10 points or more, 
worsening is defined as an increase of 10 points or more, and stable is defined as neither 
improved nor worsened. The results will be summarized in a table for each of the seven scales. 
2.5.4. 
Time To Deterioration (TTD) Analysis  
For TTD analysis, all records (including multiple assessments within a visit window post 
baseline assessment) sorted in chronological order will be used to identify the first event. This 
analysis will be done for the 7 subscales listed in Section 2.5.3 
Time to deterioration is defined as the time from Baseline to: 
1. Function scales: to the first assessment date where a 10 point or more decrease was 
observed for the scale of interest 
2. Symptom scales: to the first assessment date where a 10 point or more increase was 
observed for the scale of interest. 
If subject's score change did not reach the deterioration threshold value they will be censored at 
their last HOA assessment. If a subject dies (occurred on or before last dose date plus 28 days) 
prior to a documented decline in HOA assessment, the subject will be considered to have the 
deterioration event on the death date unless the date of death occurs after 2 missed HOA 
assessments (12 weeks + 3 days), in that case, the subject will be censored at last QOL 
assessment prior to death.  
The log-rank test from a Kaplan-Meier method will be used to assess treatment differences. In 
addition a Cox Proportional Hazards model including treatment arm, prior HER2-directed 
regimens in the metastatic setting (2 or 3+), hormone receptor status (positive or negative), and 
disease location (visceral  and non-visceral) will be used to estimate the hazard ratio. The use of 
three of the four randomization strata is documented in a Note to file dated 6-SEP-2018. 
2.5.5. 
Area Under Curve (AUC) analysis 
Time adjusted AUC will be derived for each of the subscales listed in Section 2.5.3  
The time adjusted AUC is calculated using the trapezoidal rule between adjacent time points 
using the actual assessment study day for each subject by subscale. This method sums up the 
areas cumulated through multiple consecutive time point assessments from baseline assessment 
day to last assessment day. The area between two time points is calculated by taking the average 
subscale score between the 2 time points and multiplied by the duration between the two time 
points.  
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Supplemental Statistical Analysis Plan: PUMA-NER1301 
Version 1.0 
All assessments post baseline will be utilized except when there are multiple assessments on the 
same day, in which case, only the derived average subscale for the day in question will be used. 
Time-adjusted area under the curve = Area under the Curve/(duration from baseline assessment 
to last assessment in days) 
Comparison of AUC by treatment group will be summarized in a table using an ANCOVA 
model to test for treatment difference of AUC. The model will include the baseline subscale 
value and treatment arm.  
2.5.6. 
Completion rate 
A completion analysis will be done to evaluate the magnitude of missing assessments. The 
completion analysis will focus on the following scales.  
1. QLQ-C30 – the C30 summary subscale (required non-missing subscale scores from all 
except financial difficulty, the most conservative scale from C30) 
2. BR-23 - the systemic therapy sides effects subscale 
3. EQ5D-5L - either the VAS or Index Score  
Completion is defined as: 
• Overall:  The actual number of assessments (baseline and all post baseline 
assessments)  / expected number of assessments (from baseline to last assessment thru 
last dose date+28 days)*100%.   
• Calculation for expected number of assessments will be based on treatment duration 
and corresponding cycle of last dose day. If last dose day falls in a day in cycle Y 
which is the completion of an even cycle , the expected number of HOA assessments 
will be the integer part of  (Y/2) + 1; or else If last dose day falls in a cycle Y and Y/2 
does not yield a whole number then , the expected number of HOA assessments will 
be the integer portion of (Y/2)  + 2.  
For example, a subject with the last dose in cycle 4 would be expected to have 3 
assessments (Baseline, cycle 3 and EOT). If there are multiple assessments on the same 
day only one assessment will be counted for that day.  Lastly, if the completion is greater 
than 100%, it will be truncated at 100%. 
• Completion at each scheduled visit:  The number of subjects that completed the scale 
flagged for the scheduled visit divided by the number of subjects under treatment in 
the corresponding cycle.  
The overall completion rate and completion rate by visit will be summarized by treatment group 
for each relevant scale. 
2.5.7. 
Pattern Mixture Model Analysis 
After reviewing findings from the descriptive statistics, the overall completion rate, and the 
scheduled visit specific completion rate analysis if there exists a pattern of missing assessments 
additional sensitivity analysis like pattern mixture model analysis may be added in an ad hoc 
fashion. 
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3. 
 ANALYSIS OF THE CNS ENDPOINTS 
Additional details on the CNS endpoints are provided in this section.  
3.1. 
Secondary CNS endpoint 
The secondary CNS endpoint is time to intervention for symptomatic CNS disease. This is 
defined as the time from the date of randomization to the first date of an intervention for 
symptomatic metastatic CNS disease.  Interventions include medications to control signs or 
symptoms caused by the CNS metastases (ie, high dose steroids in case of cranial hypertension), 
CNS radiotherapy, CNS surgery and cancer treatment specific for CNS metastases.   
3.2. 
Progressive CNS Endpoint 
The alternative CNS endpoint is time to progressive CNS lesions. This is defined as the time 
interval from the date of randomization until the first date on which a scheduled or unscheduled 
tumor assessment documents the appearance of newly diagnosed or progressive CNS lesions, per 
RECIST v1.1. For subjects that have CNS lesions as target lesions, the sum of the longest 
diameter (SLD) of CNS lesions only will be calculated at each tumor assessment and if the 
change from the nadir is greater than 20% this will be considered progressive CNS disease. If the 
subject has nontarget CNS lesions progressive CNS disease will be considered if any of the 
nontarget CNS lesions have a status of unequivocal progression. If the subject had a newly 
diagnosed CNS lesion post-baseline this will be considered progression as well.  
3.3. 
Statistical Analysis 
3.3.1. 
Sensitivity analysis for the secondary CNS endpoint 
1. The Kaplan Meier method, stratified log-rank test, and Cox proportional hazard model 
will be performed without considering competing events. A Kaplan-Meier curve with the 
results of the Cox model will summarize this analysis. 
2. An analysis only looking at time to first dose of radiation for symptomatic CNS will be 
performed. Subjects that do not have a radiation intervention for symptomatic metastatic 
CNS and do not die will be censored at the last date known alive on or prior to the data 
cutoff. Deaths or other treatments for symptomatic CNS are treated as competing events. 
3. A subgroup analysis only including subjects with a prior or current history of CNS 
metastases at the time of randomization will be done for the secondary CNS endpoint .A 
prior history will be defined as location of disease in the brain at screening, prior 
radiation of the brain, and prior surgery in the brain. 
3.3.2. 
Time to progressive CNS disease 
The time to progressive central nervous system (CNS) lesions will be analyzed using the 
centrally reviewed tumor assessments as well as the investigator tumor assessments.  
Time to progressive CNS lesions is defined as the time interval from the date of randomization 
until the first date on which a scheduled or unscheduled visit documents the appearance of newly 
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diagnosed or progressive CNS lesions, per RECIST v1.1. Table 4 lists the CNS locations for the 
derivation of CNS progression based on the central or local tumor assessment data. All 
progressive CNS events will be counted regardless of their timing with regards to progression at 
other sites. Competing events include progression at other sites and deaths prior to the 
observance of progressive CNS. If there is no evidence of CNS progression or a competing 
event, the subject will be censored at the last assessable tumor evaluation on study or prior to 
new anti-cancer therapy, if applicable. Gray’s test (Gray, 1988) stratified for factors used in the 
randomization will assess the equality of cumulative incidence functions between the treatment 
arms.  The cause specific hazard ratio and p-value will also be performed.  Additionally, the 
Kaplan Meier method, stratified log-rank test, and stratified Cox proportional hazard model will 
be performed without considering competing events. For this analysis subjects will be censored 
at the time of PD at a site other than CNS or at their last viable tumor assessment for subjects 
that did not have a PD. For these CNS endpoints the same censoring rules as those specific in the 
main SAP for the PFS analysis will be applied. Events, CNS events or any competing events, 
after the start of a new anti-cancer therapy or after 2 missed assessments will be censored and not 
considered as events. 
4. 
SENSITIVITY ANALYSIS FOR OVERALL RESPONSE RATE 
The SAP indicates that only subjects with measurable disease at baseline will be used in the 
calculation of Overall Response Rate.  As a sensitivity analysis, all subjects will be included in 
the calculation. For subjects that only have non-target lesions at baseline, they can only be 
considered a responder if they achieve CR in all non-target lesions. 
5. 
PROGNOSTIC VARIABLES OF INTEREST 
The following prognostic variables will be investigated for the primary endpoints of PFS and 
OS. 
1. Previous HER2 directed therapies 
a. Trastuzumab only  
b. TDM-1 only 
c. Trastuzumab and Pertuzumab 
d. Trastuzumab and T-DM1 
e. Trastuzumab and Pertuzumab and T-DM1 
2. De Novo and non De Novo disease at diagnosis 
De novo disease at diagnosis is defined as having M stage of M1 or if the date of initial 
diagnosis is equal to or within 45 days of the date of first presentation with distant 
metastatic disease. 
6. 
ADDITIONAL EXPLORATORY ANALYSIS  
The following exploratory analyses for PFS will be performed. 
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6.1. 
Time to RECIST defined PFS or clinical progression 
For this analysis all the definitions stated in the main SAP apply but the definition of PD is 
expanded to include subjects that ended treatment for clinical progression and did not experience 
PD per RECIST. 
6.2. 
Time to treatment failure 
Time to treatment failure is defined as the time from randomization to treatment discontinuation 
for any reason. For those subjects that are still on treatment at the time of the analysis, they will 
be censored on the data cut-off date. 
 
 
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Table 2: 
List of Planned Tables 
Grouping 
Title 
HOA analysis 
 
Descriptive HOA 
Summary of scale scores and change from baseline at each cycle (26 
tables) 
HOA Mixed model 
Summary of model results for each subscale (26 tables) 
HOA reduced mixed model 
Summary of estimated means at each cycle for each subscale (26 tables) 
Response analysis 
Summary of response by subscale (7 tables) 
AUC Analysis 
Summary of ANCOVA model results (1 table) 
Completion analysis 
Summary of overall completion (1 table) 
 
Summary of completion by visit (1 table) 
 
 
CNS Analysis 
 
Time to intervention for 
symptomatic CNS 
Summary of time to intervention for symptomatic CNS 
CNS disease progression 
Summary of CNS Progression-Free Survival – Central Assessment 
 
Summary of CNS Progression-Free Survival – Local Assessment 
CNS disease progression – 
no competing events 
Summary of CNS Progression-Free Survival – Central Assessment 
 
Summary of CNS Progression-Free Survival – Local Assessment 
PFS sensitivity analysis 
Summary of Progression-free survival including EOT for clinical 
progression. 
Sensitivity for ORR 
Summary of ORR and CBR (ITT Population) 
Time to treatment failure 
Summary of time to Treatment Failure 
 
 
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Table 3: 
List of Planned Figures 
Grouping 
Title 
QOL analysis 
 
Descriptive QOL 
Figure of scale scores at each cycle (26 figures) 
 
Figure of change from baseline in each scale (26 figures) 
Estimated means from 
mixed model 
Mixed Model Results by Cycle (Change from Baseline) (26 figures) 
Time to deterioration 
KM curve by treatment group (7 figures) 
 
 
CNS Analysis 
 
Time to intervention for 
symptomatic CNS 
Cumulative hazard curves 
 
KM curve for no competing events 
CNS disease progression – 
with competing risks 
Cumulative hazard curve for CNS Progression-Free Survival – Central 
Assessment 
 
Cumulative hazard curve for CNS Progression-Free Survival – Local 
Assessment 
CNS disease progression – 
no competing events 
KM curve for CNS Progression-Free Survival – Central Assessment 
 
KM curve of CNS Progression-Free Survival – Local Assessment 
Other 
 
KM of time to treatment 
discontinuation 
KM curve of time to treatment discontinuation 
Sensitivity for PFS 
KM curve of time to PFS including clinical progression 
Forest Plot for prognostic 
factors – PFS 
Forest plot including prior treatments and DeNovo Disease for Central PFS  
Forest Plot for prognostic 
factors – PFS 
Forest plot including prior treatments and DeNovo Disease for Local PFS  
Forest Plot for prognostic 
factors – OS 
Forest plot including prior treatments and DeNovo Disease for OS  
 
 
 
 
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Table 4: 
List of CNS locations  
 
Bioclinica (Central review) 
INFORM (Local review) 
CNS Locations 
Basal Ganglia 
Brainstem 
Caudate 
Cerebellum 
CNS (Brain) 
Corpus Callosum 
Dural 
Epidural 
Falx 
Fourth Ventricle 
Frontal Lobe 
Frontoparietal 
Hippocampus 
Lateral Ventricle 
Leptomeningeal 
Occipital Lobe 
Parietal Lobe 
Parietoccipital 
Spinal Cord 
Subdural 
Temporal Lobe 
Temporaloccipital 
Temporalparietal 
Thalamus 
Third Ventricle 
Brain 
CNS 
Retina 
 
 
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