Clinical trial NCT02213042
Conditions: Neoplasms, Breast
Keywords: CLAP016A2206 biomarker Lapatinib Prosigna ErbB2 PAM50 HER2 HER2-overexpressing metastatic breast cancer HER2-enriched Trastuzumab
Sponsor: Novartis Pharmaceuticals
Start date: 2014-10-24; Completion date: 2020-06-04
Enrollment: 42 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This was a multicenter, open-label, Phase II study in subjects with Human epidermal growth factor receptor (HER2)-positive metastatic breast cancer who received at least 2 prior lines of anti-HER2-targeted therapies of which at least one included a Trastuzumab-containing regimen. This study was a post-approval commitment with regulatory authorities. It was designed to evaluate whether treatment with Dual blockade promoted changes to biomarkers associated with immunomodulation.

Detailed description:
This study was designed to address the post-authorization measures as agreed with the Committee for Medicinal Products for Human Use (CHMP). Recruitment of subjects into this study was challenging, and following agreement with the European Medicines Agency (EMA) enrollment into this study was halted after the enrollment of 42 of the 225 planned subjects.

The primary endpoint of the study evaluated changes in expression of biomarkers associated with immunomodulation between a pre-treatment biopsy and the disease progression biopsy. Secondary efficacy endpoints included overall response rate, clinical benefit rate and progression-free survival (PFS), as well as safety/tolerability. All subjects received study treatment until disease progression, death, unacceptable toxicity, or subject withdrawal. In case of disease progression during the treatment period, the subject was followed-up for 30 days for safety evaluation. In case of study treatment discontinuation for any reasons other than disease progression, the subject was followed-up for safety and efficacy assessments until disease progression, new anticancer therapy, death, withdrawal of consent or end of study, whichever came first.

This study supported a better understanding of the rapidly accumulating evidence for the importance of the immune microenvironment in HER2-positive breast cancer and the observed immunomodulation in the neoadjuvant setting could be confirmed in the advanced setting and supported the putative mechanism of action of HER2 dual blockade and its potential function on the tumor microenvironment. No formal comparisons between treatment arms were undertaken.

Arms: arm 1: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required. arm 2: In subjects with HER2-overexpressing MBC with a molecular subtype of HER2 Enriched, Trastuzumab (loading dose of 8 mg/kg followed by the maintenance dose of 6 mg/kg IV q3weekly) along with chemotherapy of the investigator's choice or Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly along with chemotherapy of the investigators choice. Subjects randomized to this arm and hormone receptor positive received an aromatase inhibitor at the discretion of the investigator. arm 3: In subjects with HER2-overexpressing MBC with a molecular subtype of Non- HER2 Enriched (luminal A, luminal B or Basal type), Lapatinib 1000mg once daily orally along with Trastuzumab (loading dose of 8 milligram/ kilogram (mg/kg) followed by the maintenance dose of 6 mg/kg Intravenous (IV) Every 3 weeks (q3weekly)) or Lapatinib 1000 milligram (mg) once daily orally along with Weekly Trastuzumab (loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV weekly. For subjects who were hormone receptor positive, an aromatase inhibitor of the investigator's choice was required.
Interventions: intervention 1: Lapatinib intervention 2: Trastuzumab intervention 3: Aromatase Inhibitors (AIs)
Intervention descriptions: intervention 1: Lapatinib is available as 250-mg orange tablets. Subjects randomized to the Lapatinib plus Trastuzumab arm received 1000 mg per day of Lapatinib, so wre instructed to take 4 x 250 mg tablets per day. Lapatinib was to be taken either 1 hour (or more) before a meal or 1 hour (or more) after a meal intervention 2: Trastuzumab is a sterile, white to pale yellow, preservative-free lyophilized powder for IV administration. Trastuzumab was administered on Day 1 of the start of Lapatinib or in conjunction with the first cycle of chemotherapy, as an 8 mg/kg loading dose. Subsequently, Trastuzumab was administered q3weekly as a 6 mg/kg maintenance dose. At the discretion of the investigator, weekly Trastuzumab could be given in either of the three treatment arms (loading dose 4mg/kg followed by weekly administration of 2mg/kg). intervention 3: Subjects who were hormone receptor-positive were required to receive an aromatase inhibitor as combination treatment; however the choice of the aromatase inhibitor selected for each patient was determined by the patients' investigator. The AIs the Investigator could choose from were anastrozole, exemestane, and letrozole and dosing was per product information.

Protocol documents:
Prot_000.pdf: 
Clinical Development
GW572016 
Protocol EGF117165 / NCT02213042    
An Open-Label, Phase II, Study to Evaluate Biomarkers 
Associated with Response to Subsequent Therapies in 
Subjects with HER2-Positive Metastatic Breast Cancer 
Receiving Treatment with Trastuzumab in Combination 
with Lapatinib or Chemotherapy
Authors
 
Document type
Amended Protocol Version (Clean)
EUDRACT number
2014-001220-30
Version number
03
Development phase
Phase II
Document status
Final
Release date
15-May-2017
Novartis internal 
reference number
CLAP016A2206
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Amendment 3 
Amendment rationale
Subsequent to the acquisition of GlaxoSmithKline (GSK) compound GW572016, the 
purpose of this protocol Amendment 3 is to:
–
Delete or replace references to GlaxoSmithKline or its staff with that of Novartis 
and its authorized agents to align with the change of sponsorship;
–
Make administrative changes to align with Novartis processes and procedures;
As of May 2017:
42 patients have received study treatment in five countries; 
34 patients have completed or discontinued study treatment.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities (HAs).
The changes herein affect the Informed Consent and all sites are required to update and 
submit for approval, a revised Informed Consent that takes into account the change of 
study sponsorship described in the protocol amendment.
Upon approval of this amendment, patients who have already been enrolled in the study 
will sign a new informed consent form indicating Novartis is the new study sponsor and 
continue the appropriate visit schedule.


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Description: This is a multicenter, open-label, Phase II study in subjects with HER2-
positive metastatic breast cancer who received at least 2 prior lines of anti-HER2-targeted 
therapies of which at least one included a trastuzumab-containing regimen.  Eligible 
subjects will have confirmed HER2-positive and hormonal status from a biopsy taken at 
screening (pre-treatment biopsy).
Subjects will have consented to a subsequent biopsy
at disease progression.  Subjects will be assigned to one of two cohorts based on the
molecular subtype of the pre-treatment biopsy by Prosigna.  Eligible subjects with a 
HER2-enriched molecular subtype will be randomized in a 1:1 ratio to 1 of 2 treatment 
arms: trastuzumab in combination with lapatinib (trastuzumab loading dose of 8 mg/kg 
followed by 6-mg/kg infusions every 3 weeks (q3weekly) and 1000 mg of lapatinib once 
daily) or trastuzumab in combination with chemotherapy of the investigator’s choice 
(trastuzumab loading dose of 8 mg/kg followed by 6-mg/kg q3weekly infusions and 
chemotherapy as decided by investigator).  Eligible subjects with breast cancer 
classified as a molecular subtype complementary to the HER2-enriched referred to as 
Non-HER2-enriched (i.e., luminal A, luminal B or basal-like) will be enrolled into an 
additional arm treated with trastuzumab in combination with lapatinib (trastuzumab 
loading dose of 8 mg/kg followed by 6-mg/kg infusions every 3 weeks (q3weekly) and 
1000 mg of lapatinib once daily).
Subjects with hormone receptor positive breast cancer 
assigned to receive treatment with lapatinib and trastuzumab will be required to receive 
concomitant endocrine therapy with an aromatase inhibitor of the investigator’s choice.  
Subjects with hormone receptor-positive disease assigned to the treatment arm of 
trastuzumab in combination with chemotherapy may receive concomitant endocrine 
therapy with an aromatase inhibitor, of the investigator’s choice and at the discretion of 
the investigator.  All subjects will receive study treatment until disease progression, 
death, unacceptable toxicity, subject withdrawal or any other reasons mentioned in 
section 4.2.1.  The primary endpoint is to evaluate the changes in the expression of 
biomarkers associated with immunomodulation between the progression biopsy and the 
pre-treatment biopsy within each arm.  Secondary efficacy endpoints include overall 
response rate; clinical benefit rate; and progression-free survival (PFS) on treatment; as 
well as safety/tolerability. Due to difficulty in enrolling subjects, enrollment was halted 
and the study will be terminated early. No formal comparisons between treatment arms
will be undertaken.
Subject: lapatinib, HER2-overexpressing metastatic breast cancer, trastuzumab, ErbB2, 
HER2, biomarker, PAM50, HER2-enriched, Prosigna


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Revision Chronology:
2013N170247_0
No publishing date 
Amendment No. 0 (original version): 
This version was never dispatched to 
the countries.
2013N170247_01
26-MAR-2014
Amendment No. 01: Global 
amendment: This version was 
amended to remove the third biopsy 
(based on the feedback from the 
countries). This version was the first 
one dispatched to the countries. 
2013N170247_02
23-MAR-2017
Amendment 
No. 
02: 
Global 
amendment: Study EGF117165 is a 
post-approval commitment required by 
the CHMP to evaluate biomarkers of 
drug 
resistance 
in 
patients 
with 
HER2+ metastatic breast cancer whilst 
on treatment with trastuzumab in 
combination with either lapatinib or 
chemotherapy. Recruitment of patients 
into study EGF117165 has been 
difficult. Efforts to boost recruitment 
were undertaken but the prospect to 
significantly improve recruitment is 
poor, thus preventing Novartis from 
meeting the agreed timelines for 
completion.
In addition, the results of this trial will 
likely become obsolete by the time of 
delayed 
completion. 
Therefore, 
Novartis proposes to terminate the 
study and to conduct a final analysis of 
the enrolled patients.
In this context, the updates to the 
protocol are as follows:
The Primary Objective was updated to 
remove the evaluation of changes in 
the expression of biomarkers 
associated with HER family, 
apoptosis, and ABC transporters. The 
Primary Objective now evaluates the
changes in the expression of 


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biomarkers associated with
immunomodulation.
The Secondary Objectives were 
updated to remove OS and PFS on first 
next line and subsequent lines of anti-
cancer therapies. The Patient Reported 
Outcomes (PRO) and Health-Related 
Quality of Life (HRQOL) were also 
removed. 
 
 
 
Section 4.2.3 Subject Completion:
Follow-up time was re-defined as 
follows: A subject will be considered 
to have completed the study if the 
subject presents with disease 
progression, starts a new anti-cancer 
therapy, dies or withdraws from the 
study, or the study ends, whichever 
comes first. In case of disease 
progression during the treatment 
period, the subject will be followed-up 
for 30 days for safety evaluation and 
no further study-specific follow-up 
will be carried out; the subject will be 
considered as having completed the
study. 
In case of study treatment 
discontinuation for any reasons other 
than disease progression, the subject 
will be followed-up for safety and 
efficacy assessments until disease 
progression, new anticancer therapy, 
death, withdrawal of consent or end of 


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study, whichever comes first. 
2013N170247_03
15-May-2017
Amendment 
No. 
03: 
Global 
amendment:
Delete or replace references to GSK or 
its staff with that of Novartis/Novartis 
and its authorized agents.
Make administrative changes to align 
with 
Novartis 
processes 
and 
procedures.


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Sponsor Signatory:
Signature:
Date:
Dr.


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SPONSOR INFORMATION PAGE
Clinical Study Identifier:
EGF117165
Sponsor Contact Information
Novartis Pharma Services AG
In some countries, the clinical trial sponsor may be the local Novartis and its authorized 
agents.  Where applicable, the details of the Sponsor and contact person will be 
provided to the relevant regulatory authority as part of the clinical trial submission.
Sponsor Serious Adverse Events (SAE) Contact Information:
Please refer to the study procedures manual.
For study conduct questions not related to patient safety, the first line of contact should 
be with the designated local country company contact. In the event that the designated 
company contact is not available, please contact the Medical Lead.
Contact Information:
 MD, PhD
Novartis Pharma AG
Postfach CH-4002 Basel
Switzerland
Telephone:
Email: 
Regulatory Agency Identifying Number(s): 
Eudra CT number: 2014-001220-30
IND Number: 61362


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INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

I acknowledge that I am responsible for overall study conduct. 
I agree to 
personally conduct or supervise the described clinical study.

I agree to ensure that all associates, colleagues and employees assisting in the 
conduct of the study are informed about their obligations. 
Mechanisms are in 
place to ensure that site staff receive the appropriate information throughout the 
study.
Investigator Name:  _____________________________
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................15
PROTOCOL SUMMARY...............................................................................................18
1.
INTRODUCTION....................................................................................................23
1.1.
Background ................................................................................................23
1.1.1.
Breast Cancer..............................................................................23
1.1.2.
Role of HER2 Overexpression in Breast Cancer..........................23
1.1.2.1.
Preclinical Evidence for Trastuzumab.........................23
1.1.2.2.
Trastuzumab as First-Line Therapy for 
Metastatic Breast Cancer ...........................................24
1.1.2.3.
Continuation of Trastuzumab Post Progression 
of Disease ..................................................................24
1.1.3.
Role of Lapatinib in the Treatment of Breast Cancer....................25
1.1.3.1.
Preclinical Evidence for Lapatinib...............................25
1.1.3.2.
Lapatinib as Monotherapy ..........................................26
1.1.3.3.
Lapatinib in Combination with Chemotherapy.............26
1.1.3.4.
Lapatinib in combination with aromatase 
inhibitors.....................................................................27
1.1.4.
Role of Dual blockade with Lapatinib and Trastuzumab in 
Treatment of Breast Cancer.........................................................27
1.1.4.1.
Preclinical Mechanism................................................27
1.1.4.2.
Clinical Efficacy of Dual blockade...............................28
1.1.4.2.1.
Phase I Study EGF10023 .......................28
1.1.4.2.2.
Phase III Study EGF104900 –
Dual blockade in Metastatic 
Breast Cancer.........................................29
1.1.4.3.
Dual blockade in the Neoadjuvant Setting ..................32
1.2.
Study Rationale ..........................................................................................34
1.2.1.
Clinical Validity of Dual blockade .................................................34
1.2.2.
HER2-Enriched Population for Study EGF117165.......................34
1.2.3.
Immunomodulation by dual blockade as a putative 
mechanism affecting response to subsequent lines of 
therapy. .......................................................................................36
1.2.4.
Hypothesis...................................................................................37
1.3.
Benefit: Risk Assessment ...........................................................................37
This benefit was demonstrated in a population of subjects 
with previous prolonged exposure to, and progression on, 
multiple cytotoxic chemotherapy and trastuzumab-based 
regimens......................................................................................38
1.3.1.
Risk Assessment .........................................................................38
1.3.2.
Benefit Assessment .....................................................................40
1.3.3.
Overall Benefit: Risk Conclusion..................................................41
2.
OBJECTIVES AND ENDPOINTS...........................................................................42
3.
STUDY DESIGN ....................................................................................................43
3.1.
Discussion of Design ..................................................................................46


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3.1.1.
Use of 3-weekly trastuzumab dosing ...........................................46
3.1.2.
Endocrine and HER2-Directed Therapy for Hormone-
Receptor Positive, HER2-Positive MBC.......................................47
3.1.3.
Biomarkers and the Timing of Tumor Biopsies.............................48
4.
SUBJECT SELECTION AND DISCONTINUATION/ COMPLETION 
CRITERIA ..............................................................................................................50
4.1.
Subject Selection Criteria............................................................................50
4.1.1.
Number of Subjects .....................................................................50
4.1.2.
Inclusion Criteria..........................................................................50
4.1.3.
Exclusion Criteria.........................................................................53
4.2.
Permanent Discontinuation from Study Treatment and Subject 
Completion Criteria.....................................................................................54
4.2.1.
Permanent Discontinuation from Study Treatment.......................54
At the end of the study, every effort will be made to continue provision of 
study treatment outside this study through an alternative setting 
to subjects who in the opinion of the Investigator are still 
deriving clinical benefit...................................................................56
4.2.2.
Subject Withdrawal from Study....................................................56
4.2.3.
Subject Completion......................................................................57
4.3.
Screening/Run-in Failures ..........................................................................58
5.
STUDY TREATMENTS..........................................................................................58
5.1.
Study Treatment and Reference Therapy ...................................................58
5.1.1.
Lapatinib......................................................................................58
5.1.1.1.
Lapatinib Dosage and Administration .........................58
5.1.2.
Trastuzumab................................................................................59
5.1.2.1.
Trastuzumab Dosage and Administration...................60
5.1.3.
Chemotherapy .............................................................................60
5.1.3.1.
Paclitaxel....................................................................60
5.1.3.2.
Docetaxel ...................................................................60
5.1.3.3.
Nab paclitaxel.............................................................60
5.1.3.4.
Capecitabine ..............................................................61
5.1.3.5.
Gemcitabine ...............................................................61
5.1.3.6.
Vinorelbine .................................................................61
5.1.3.7.
Chemotherapy Dosage and Administration ................61
5.1.3.8.
Premedication for Paclitaxel and Docetaxel 
Administration.............................................................62
5.1.4.
Endocrine Therapy with Aromatase Inhibitors..............................62
5.2.
Dose Adjustments.......................................................................................63
5.3.
Handling and Storage of Study Treatment ..................................................63
5.4.
Treatment Assignment................................................................................63
5.5.
Blinding.......................................................................................................64
5.6.
Product Accountability ................................................................................64
5.7.
Treatment Compliance................................................................................64
5.8.
Dose Delays and Modifications...................................................................64
5.8.1.
Lapatinib......................................................................................65
5.8.2.
Trastuzumab................................................................................67
5.8.2.1.
Trastuzumab Dose Recommendations for
Hypersensitivity Reactions..........................................68
5.8.3.
Aromatase Inhibitor (AI) of Investigator choice.............................68
5.8.4.
Criteria for Evaluating Cardiac and Respiratory Events................68


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5.8.5.
Criteria for Evaluating Dermatologic Adverse Events...................70
5.8.6.
Criteria for Evaluating Gastrointestinal Adverse Events ...............71
5.8.6.1.
Nausea and Vomiting .................................................71
5.8.6.2.
Diarrhea .....................................................................71
5.9.
Monitoring, Interruption, and Stopping Criteria for Hepatobiliary 
Events ........................................................................................................72
5.9.1.
Liver Chemistry Stopping and Follow-up Criteria .........................72
5.9.1.1.
Liver Chemistry Stopping Criteria ...............................72
5.9.1.2.
Liver Chemistry Follow-up ..........................................73
5.9.1.3.
Liver Chemistry Monitoring Criteria.............................75
5.9.2.
Restarting Study Treatment .........................................................75
5.9.2.1.
Drug Restart/Rechallenge Following Liver 
Events that are Possibly Related to IP........................75
5.9.2.2.
Drug Restart Following Transient Resolving 
Liver Events Not Related to Study Treatment.............76
6.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .........................76
6.1.
Permitted Medications and Non-Drug Therapies.........................................76
6.2.
Prohibited Medications and Non-Drug Therapies........................................77
6.3.
Treatment after Discontinuation of Study Treatment or Withdrawal 
from/Completion of Study ...........................................................................78
6.4.
Treatment of Study Treatment Overdose....................................................79
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................79
7.1.
Collection of Biopsies and Archival Tumor Tissue.......................................87
7.2.
Critical Baseline Assessments....................................................................87
7.2.1.
Baseline Assessments.................................................................87
7.2.2.
Baseline documentation of target and non-target lesions.............88
7.3.
Efficacy.......................................................................................................88
7.3.1.
Efficacy Endpoints .......................................................................88
7.3.2.
Clinical Efficacy Assessment .......................................................89
7.3.2.1.
Assessment Guidelines ..............................................90
7.3.2.2.
Efficacy Assessment Schedule...................................91
7.3.2.3.
Follow-up Assessments for Subjects 
Permanently Discontinued from Study 
Treatment...................................................................91
7.3.2.4.
Assessment of Subject Completion ............................92
7.3.3.
Guidelines for Evaluation of Disease ...........................................92
7.3.3.1.
Measurable and Non-measurable Definitions .............92
7.3.4.
Response Criteria........................................................................93
7.3.4.1.
Evaluation of Target Lesions ......................................93
7.3.4.2.
Evaluation of non-target lesions..................................94
7.3.4.3.
New lesions................................................................95
7.3.4.4.
Evaluation of overall response....................................95
7.3.4.5.
Evaluation of best overall response............................96
7.4.
Safety .........................................................................................................96
7.4.1.
Safety Endpoints..........................................................................96
7.4.2.
Adverse Events............................................................................97
7.4.2.1.
Definition of an AE......................................................97
7.4.2.2.
Definition of an SAE ...................................................98
7.4.2.3.
Laboratory and Other Safety Assessment 
Abnormalities Reported as AEs and SAEs .................99


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7.4.2.4.
Cardiovascular Events..............................................100
7.4.2.5.
Death Events............................................................100
7.4.2.6.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ..............100
7.4.3.
Time Period and Frequency of Detecting AEs and SAEs...........101
7.4.4.
Method of Detecting AEs and SAEs...........................................101
7.4.5.
Prompt Reporting of SAEs and Other Events ............................101
7.4.6.
Regulatory Reporting Requirements for SAEs ...........................103
7.4.7.
Pregnancy Testing, Prevention and Reporting...........................103
7.4.7.1.
Pregnancy Test and Prevention ...............................103
7.4.7.2.
Pregnancy Reporting................................................104
7.4.8.
Laboratory Assessments ...........................................................104
105
7.6.
Translational Research.............................................................................105
7.6.1.
Tumor Biomarker Analysis.........................................................106
106
8.
DATA MANAGEMENT .........................................................................................107
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS.................................107
9.1.
Hypotheses...............................................................................................107
9.2.
Study Design Considerations....................................................................107
9.2.1.
Sample Size Assumptions .........................................................107
9.2.2.
Sample Size Sensitivity..............................................................107
9.2.3.
Sample Size Re-estimation........................................................107
9.3.
Data Analysis Considerations ...................................................................108
9.3.1.
Analysis Populations..................................................................108
9.3.2.
Analysis Data Sets.....................................................................108
9.3.3.
Treatment Comparisons ............................................................108
9.3.3.1.
Primary Comparisons of Interest ..............................108
9.3.4.
Interim Analysis .........................................................................109
9.3.5.
Key Elements of Analysis Plan ..................................................109
9.3.5.1.
Efficacy Analyses .....................................................110
9.3.5.1.1.
Primary Analysis...................................110
9.3.5.1.2.
Secondary Analyses.............................110
9.3.5.2.
Safety Analyses........................................................111
9.3.5.2.1.
Extent of Exposure ...............................111
9.3.5.2.2.
Adverse Events ....................................111
9.3.5.2.3.
Clinical Laboratory Evaluations.............112
9.3.5.2.4.
Other Safety Measures.........................112
9.3.5.3.
Translational Research Analyses .............................112
112
10. STUDY CONDUCT CONSIDERATIONS .............................................................112
10.1.
Posting of Information on Publicly Available Clinical Trial Registers..........112
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................113
10.3.
Quality Control (Study Monitoring) ............................................................113
10.4.
Quality Assurance.....................................................................................114
10.5.
Study and Site Closure .............................................................................114
10.6.
Records Retention....................................................................................115


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10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication ..................116
11. REFERENCES.....................................................................................................117
12. APPENDICES ......................................................................................................128
128
12.2.
Appendix 2:  Country Specific Requirements ..........................................134
12.3.
Appendix 3:  ECOG Performance Status.................................................135
12.4.
Appendix 4:  Liver Chemistry Monitoring, Interruption Stopping and 
Follow-up Criteria......................................................................................136
12.5.
Appendix 5:  Liver Safety Drug Restart or Rechallenge Guidelines .........137
12.6.
Appendix 6: Asymptomatic Cardiac Event Assessment ............................142
12.7.
Appendix 7: Diarrhea Mangement Guidelines...........................................143
12.8.
Appendix 8:  Dermatological Assessment ...............................................151
12.8.1.
Purpose of Dermatological Monitoring .......................................151
12.8.2.
Evaluation and Grading Guide...................................................151
12.8.2.1.
The Most Commonly Reported Dermatological 
Reactions .................................................................151
12.8.3.
Severe Skin Events ...................................................................154
12.8.4.
Stopping and holding rules ........................................................155
12.8.4.1.
Holding rule ..............................................................155
12.8.4.2.
Re-challenge ............................................................155
12.8.4.3.
Stopping rules ..........................................................155
12.8.5.
Treatment ..................................................................................155
12.9.
Appendix 9:  Cockcroft and Gault Method for Calculated Creatinine 
Clearance .................................................................................................157
12.10. Appendix 10 List of protocol Changes Changes........................................158
12.10.1. Protocol Amendment 1 ..............................................................158
12.10.2. Protocol Amendment 2 ..............................................................158
12.10.3. Protocol Amendment 3 ..............................................................237


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LIST OF ABBREVIATIONS
ABC
Adenosine triphosphate binding cassette
ADCC
Antibody-dependent cellular cytotoxicity
ADL
Activities of daily living
AE
Adverse event
AI
Aromatase inhibitor
ANC
Absolute neutrophil count
ALT
Alanine aminotransferase
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
ATP
Adenosine triphosphate
AV
Atrioventricular
Bcl-2
B-cell lymphoma 2
Bcl-xl
B-cell lymphoma-extra large
Bcl2L11
Bcl-2-like protein 11
-HCG 
beta human chorionic gonadotropin
BIRC5
Baculoviral inhibitor of apoptosis repeat-containing 5
BSA
Body surface area
BTC
-cellulin
CBR
Clinical benefit rate
cfDNA
Circulating free DNA
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence interval
CISH
Chromogenic in situ hybridization
CNS
Central nervous system
CR
Complete response
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
DFS
Disease free survival
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EGF
Epidermal growth factor
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency
EP
Evaluable Population
ER
Estrogen receptor
ERK
Extracellular signal-regulated kinase
ESMO
European Society for Medical Oncology
FDA
Food and Drug Administration
FDR
False discovery rate
FISH
Fluorescence in situ hybridization
FDG-PET
fluorodeoxyglucose-positron emission tomography
FSH
Follicle stimulating hormone


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g/dL
Grams/deciLiter
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HBEGF
Heparin-binding EGF-like growth factor
HER
Human epidermal growth factor receptor
HER2
Human epidermal growth factor receptor 2
HR
Hazard ratio
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology System
ITT
Intent to Treat
IV
Intravenous(ly)
kg
Kilogram
L
Liter
LFT
Liver function test
LLN
Lower limit of normal
LSLV
Last subject last visit
LVEF
Left ventricular ejection fraction
m2
Meter squared
MAPK
Mitogen-activated protein kinase
MBC
Metastatic breast cancer
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MSDS
Material Safety Data Sheet
MUGA
Multigated acquisition
MW
Molecular weight
NA
Not applicable
NCCN
National Comprehensive Cancer Network
NE
Not evaluable
OR
Odds ratio
ORR
Overall response rate
OTR
Optimally tolerated regimen
PAM
Prediction Analysis of Microarray
PAM50
Prediction Analysis of Microarray 50
PBMC
Peripheral blood mononuclear cells
pCR
Pathological complete response
PD
Progressive disease
PD-1
Programmed cell death 1
PDL-1
Programmed cell death 1 ligand 1
PFS
Progression-free survival
PgR
Progesterone receptor
PI3K
Phosphoinositide 3-kinase
PK
Pharmacokinetics
PO
Per os (orally)


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PR
Partial response
q3weekly
Every 3 weeks
QoL
Quality of life
QTcB
QT interval corrected for heart rate (Bazett’s formula)
QTcF
QT interval corrected for heart rate (Fridericia’s formula)
RAP
Reporting and analysis plan
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious adverse event
SD
Stable disease
SISH
Silver in situ hybridization
SPM
Study Procedures Manual
t½
Half life
TDM-1
Trastuzumab emtansine
TGF
Transforming growth factor 
TKI
Tyrosine kinase inhibitor
TNF
Tumor necrosis factor
TTP
Time to progression
ULN
Upper limit of normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
TYKERB/ TYVERB
Abraxane
Arimidex
Aromazine
Femara
Gemzar
Herceptin
InForm
Navelbine
Prosigna
Taxol
Taxotere
Xeloda


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PROTOCOL SUMMARY
Rationale
Overexpression of human epidermal growth factor receptor 2 (HER2), the protein 
product of the ERBB2 gene, occurs in approximately 20 percent of human breast cancers.  
Compared to other types of breast cancer, these cancers are associated with a greater risk 
for disease progression and death [Slamon, 1987; Meric, 2002] as well as resistance to 
chemotherapeutic and hormonal agents, and poorer prognosis [Slamon, 2001; Nicholson, 
1999].
Trastuzumab has been extensively evaluated and represents a clinical breakthrough in 
treating patients with HER2-positive breast cancer.  Trastuzumab in combination with 
chemotherapy is indicated as first-line treatment of patients with HER2-positive 
metastatic breast cancer.  The combination regimen demonstrated a superior clinical 
benefit as compared to that observed with chemotherapy alone.  In addition, 
trastuzumab has been shown to be effective in prolonging survival in women with ErbB2 
amplified breast cancer when used in the adjuvant setting [Piccart-Gebhart, 2005; Perez, 
2005; Romond, 2005; Joensuu, 2006; Smith, 2007; Slamon, 2011].
Progression on a trastuzumab-containing regimen eventually occurs in the metastatic 
setting.  Limited data are available on the efficacy of continuation of trastuzumab in 
combination with chemotherapy compared to chemotherapy alone after progression on a
trastuzumab containing regimen.  
Subjects with HER2-positive metastatic breast cancer (MBC) randomized to capecitabine 
monotherapy or the continuation of trastuzumab in addition to capecitabine had an 
increased median time to progression from 5.6 months to 8.2 months (hazard ratio [HR]: 
0.69; 95% confidence interval [CI]: 0.48 to 0.97) [von Minckwitz, 2009].  As such, 
common clinical practice incorporates the continued use of trastuzumab, usually in 
combination with chemotherapy, following progression of disease on a prior 
trastuzumab-containing regimen [Wong, 2011].  Declining clinical activity, however, is 
to be expected with each subsequent regimen with continued use of trastuzumab past 
progression [Pegram, 2012].  
Trastuzumab conjugated to the cytotoxic microtubule inhibitor mertansine, trastuzumab 
emtansine (T-DM1) has been studied in subjects that have progressed on at least one 
prior trastuzumab-containing regimen.  As the second line treatment of HER2-positive 
MBC, T-DM1 improved progression free survival (PFS) (HR = 0.65; 95% CI 0.55 to 
0.77; p<0.00) as well as overall survival (OS)(HR = 0.68; 95% CI 0.55 to 0.85; p<0.001) 
compared with lapatinib in combination with capecitabine [Verma, 2012].  Compared to 
treatment of physician’s choice, T-DM1 also improved PFS (HR = 0.528, 95% CI, 0.422, 
0.661, p<0.0001) [Wildiers, 2013].
Lapatinib is a reversible, orally bioavailable, small molecule tyrosine kinase quinazoline 
inhibitor that potently inhibits both Epidermal Growth Factor Receptors (EGFR) and 
HER2.  Lapatinib monotherapy demonstrated modest activity in MBC previously 
treated with trastuzumab [Blackwell, 2009].  Lapatinib is approved in combination with 


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capecitabine or trastuzumab in patients with HER2-overexpressing MBC and who have 
progressed on prior trastuzumab.  Lapatinib is also indicated in combination with an 
aromatase inhibitor for the treatment of patients with hormone sensitive metastatic 
disease, not currently intended for chemotherapy [Lapatinib Summary of Product 
Characteristics, 2015].
Dual blockade: Lapatinib in combination with trastuzumab
Resistance to trastuzumab is considered to be a key factor in disease progression and is 
observed in the majority of patients with disease that initially responded to treatment.  
There is a scientific rationale for combining two HER2-targeted agents with non-
overlapping mechanisms of resistance and complementary mechanisms of action.  Each 
drug targets a distinct functional domain of the HER2 receptor: trastuzumab, an IgG1 
monoclonal antibody, binds to domain IV of the extracellular region whereas lapatinib, a 
tyrosine kinase inhibitor (TKI), binds to the adenosine triphosphate (ATP) site in the 
intracellular kinase domain.  Preclinical evidence demonstrates that lapatinib and 
trastuzumab are synergistic in HER2-positive breast cell lines that are sensitive to 
trastuzumab as well as some that have acquired resistance to trastuzumab [Konecny, 
2006].  In addition, it was shown that lapatinib is active in some cell lines that are 
resistant to trastuzumab. As such, the combination of trastuzumab and lapatinib (Dual 
blockade) is promising as the combination more completely inhibits HER2 signalling.
In the neoadjuvant setting, Dual blockade has shown a greater rate of pathological 
complete response (pCR) in combination with chemotherapy or without chemotherapy 
compared with trastuzumab or lapatinib alone.
In the metastatic setting, the combination of Dual blockade was compared with single 
HER2 inhibition with lapatinib monotherapy in subjects with HER2-positive tumors 
previously treated with trastuzumab in study EGF104900.  The majority of subjects 
(81%) had 2 or more prior trastuzumab-containing regimens in the metastatic setting and 
had documented progression (by Response Evaluation Criteria in Solid Tumors 
[RECIST]) on a preceding trastuzumab-based therapy.  
The primary endpoint of EGF104900 was PFS.  The median PFS was longer in the Dual 
blockade arm (12.0 weeks) than in the lapatinib monotherapy arm (8.1 weeks) in the 
intent to treat (ITT) population with Strata (N=291).  The hazard ratio (HR=0.73; 95% 
CI: 0.57 to 0.93; p=0.008) translates to a 27% reduction in risk of disease progression or 
death for subjects receiving Dual blockade therapy [Blackwell, 2010].
In a pre-planned analysis of OS when a total of 75% of the subjects had died, subjects in 
the Dual blockade arm had a longer median OS of 14.0 months compared with 9.5 
months in the lapatinib monotherapy arm.  The HR (HR=0.74; 95% CI: 0.57 to 0.97; 
stratified log rank p=0.026) translates to a 26% reduction in risk of death for subjects 
receiving Dual blockade therapy [Blackwell, 2012]. 
Subgroup analysis results based on the stratification factor of hormone receptor status 
showed that the efficacy of the Dual blockade in terms of OS was increased in subjects 


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with hormone receptor-negative tumors compared to those with hormone receptor-
positive tumors, although the hazard ratios for PFS were similar (0.73).
Based on the final results of EGF104900, the Committee for Medicinal Products for 
Human Use (CHMP) of the European Medicines Agency (EMA) has granted positive 
opinion for the regulatory approval for lapatinib, in combination with trastuzumab in 
HER2 positive metastatic breast cancer. As such, lapatinib plus trastuzumab is indicated 
for the treatment of patients with hormone receptor-negative metastatic breast cancer 
whose tumors overexpress HER2/neu (ErbB2) and who have progressed on prior 
trastuzumab therapy(s) in combination with chemotherapy in the metastatic setting.
The PFS/OS pattern observed in EGF104900, whereby a statistically significant but 
modest PFS gain associated with a larger and clinically meaningful OS benefit for Dual 
blockade, was also seen in another combination of two anti-HER2 agents. In the 
CLEOPATRA study [Baselga, 2012b; Swain, 2013], the median PFS was 12.4 months in 
subjects who received trastuzumab and docetaxel and 18.5 months in subjects who 
received pertuzumab with trastuzumab and docetaxel (HR: 0.65; 95% CI: 0.54 to 0.78; 
p<0.001).  This represents a median improvement in PFS of 6.1 months.  In an update 
of OS data [Swain, 2013], the median OS in subjects who received trastuzumab and 
docetaxel was 37.6 months and the median OS in subjects who received pertuzumab with 
trastuzumab and docetaxel had not been reached.  
This unusual PFS/OS pattern has been observed in two phase III trials of two different 
combinations of anti-HER 2 agents. A potential mechanistic hypothesis to explain the 
unusual PFS/OS pattern is that Dual blockade may exert a “post-treatment effect” on 
subsequent therapies by modulating sensitivity to subsequent chemotherapy(ies) 
regimens.
Protocol EGF117165 is a phase II study evaluating whether treatment with Dual blockade 
promotes changes of biomarkers associated with immunomodulation. 
Primary Objective:

To evaluate changes in the expression of biomarkers associated with 
immunomodulation. 
Secondary Objectives:

To describe overall response rate (ORR), clinical benefit rate (CBR), and PFS on 
study treatment in subjects treated with trastuzumab in combination with lapatinib 
or chemotherapy.

To describe the safety and tolerability of trastuzumab in combination with 
lapatinib and of trastuzumab in combination with chemotherapy.


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Study Design
This is a multicenter, open-label, 3 arm, parallel group, Phase II study in subjects with 
HER2-positive metastatic breast cancer (MBC) who received prior treatment for 
metastatic disease including a trastuzumab-containing regimen.  Subjects will have 
received treatment with at least 2 prior lines of treatment for MBC.  Subjects will be 
required to have documented progression on their prior regimen for the treatment of 
MBC, which must have included trastuzumab and chemotherapy.  During screening, all 
subjects will have a biopsy of their metastatic disease (pre-treatment biopsy).  The 
central laboratory will perform testing on this biopsy to determine HER2 and hormone 
receptor status.  The intrinsic molecular subtype also will be determined centrally from 
this pre-treatment biopsy.  Based on molecular subtype classification, subjects will be 
eligible for one of 2 cohorts: randomized HER2-enriched cohort or non-randomized Non-
HER2-enriched cohort.  Subjects with a HER2-enriched molecular subtype will be 
randomized to treatment with trastuzumab in combination with lapatinib or trastuzumab 
in combination with chemotherapy of the investigator’s choice.  Subjects in the Non-
HER2-enriched cohort will be assigned to treatment with trastuzumab in combination 
with lapatinib.
Subjects enrolled to trastuzumab in combination with lapatinib will receive a trastuzumab 
loading dose of 8 mg/kg followed by 6-mg/kg infusions every 3 weeks (q3weekly) and 
1000 mg PO of lapatinib once daily. Subjects enrolled to trastuzumab in combination 
with chemotherapy of the investigator’s choice will receive a trastuzumab loading dose of 
8 mg/kg followed by 6-mg/kg q3weekly infusions and chemotherapy as decided by 
investigator.  Subjects with hormone receptor-positive tumors from the baseline biopsy 
will be required to have a concomitant aromatase inhibitor with trastuzumab in 
combination with lapatinib however, for those subjects randomized to trastuzumab in
combination with chemotherapy; a concomitant aromatase inhibitor is at the discretion of 
the investigator.  In all treatment arms, weekly trastuzumab (loading dose of 4mg/kg 
followed by week infusions of 2mg/kg) can be administered rather than every 3 weeks if 
preferred.   
At disease progression a biopsy should be taken from the same site as the pre-treatment 
biopsy. The comparison of gene and/or protein expression changes in these paired 
biopsies will be the basis for the primary objective.
All subjects will receive study treatment until disease progression, death, unacceptable 
toxicity, subject withdrawal or any other reasons mentioned in section 4.2.1.  


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Study Assessments
The primary endpoint is to analyze the changes in gene and/or protein expression profile 
within each arm on a prespecified set of biomarkers associated with immunomodulation.  
The HER2-enriched and Non-HER2-enriched cohorts will be analyzed separately.
Biopsies will be taken at screening (pre-treatment biopsy) and at the time of disease 
progression (progression biopsy).  Disease assessments will be performed every 9 weeks 
until 54 weeks then every 24 weeks thereafter.  
 
 
Safety assessments including physical examination, Eastern Cooperative Oncology 
Group (ECOG) performance status, vital signs and weight, adverse event (AE) 
monitoring, and laboratory tests (complete blood count, blood chemistry including liver 
function test) will be done at screening and then every 3 weeks for the duration of study 
treatment.  Additional safety assessments, such as cardiac monitoring, are required for
all subjects every 12 weeks until withdrawal from the study treatment.


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1.
INTRODUCTION
1.1.
Background
1.1.1.
Breast Cancer
Breast cancer is globally one of the most prevalent cancers, as improvements in early 
diagnosis and current advancements in treatment modalities have increased the survival 
rates for these patients.  In the United States, there were approximately 2.6 million 
patients with breast cancer in 2007 [Howlader, 2011].  In Europe, data from 38
population-based cancer registries from 17 European countries (approximately 3 million 
patients diagnosed during 1970-1992) demonstrated that breast cancer accounted for 34% 
of all prevalent cancers in women [Micheli, 2002]. Population-based studies have 
suggested that with the introduction of novel therapeutic agents, women are living longer 
after a diagnosis of advanced cancer [Chia, 2007]. Despite improvements in early 
diagnosis and treatments, almost all patients with metastatic disease, and up to 40% of 
patients receiving adjuvant hormonal therapy, eventually relapse and ultimately die from 
their disease [Ring, 2003].
1.1.2.
Role of HER2 Overexpression in Breast Cancer
Approximately 20% of human breast cancers exhibit gene amplification and/or 
overexpression of the Human epidermal growth factor receptor 2(HER2) receptor 
[Slamon, 1987; Slamon, 1989]. Due to the constant open conformation of extracellular 
domain II and high concentrations of the HER2 receptor on the cell surface, HER2 
receptors homo-dimerize and ligand independent activation of the HER2 intraocular
tyrosine kinase domain occurs [Garrett, 2003].  Activation of the HER2 and downstream 
pathways promotes cellular growth and survival through a variety of partially 
overlapping mechanisms.  
Patients with HER2-overexpressing breast cancers have particularly aggressive disease 
that is associated with a greater risk for disease progression and death [Meric, 2002; 
Sauter, 2009]. HER2 receptor overexpression is associated with poorly differentiated, 
high-grade tumors, lymph node involvement, increased cellular proliferation, and a 
relative resistance to certain types of chemotherapy as well as an increased proclivity for 
central nervous system (CNS) metastases [Burstein 2005, Kallioniemi 1991,Gabos 2006].
Role of Trastuzumab in the Treatment of Breast Cancer
1.1.2.1.
Preclinical Evidence for Trastuzumab
Trastuzumab is a recombinant humanized monoclonal antibody which binds to the 
juxtamembrane extracellular subdomain IV of the HER2 receptor. Although the 
mechanisms by which trastuzumab inhibits HER2-overexpressing tumors are 
incompletely understood, several possible mechanisms have been observed in 
experimental preclinical in vitro and in vivo models, including internalization and 
degradation of HER2, inhibition of the HER2 ectodomain cleavage, modulation of the 
p27-Cdk2 complex formation, and induction of immune-mediated responses via the 
antibody-dependent cellular cytotoxicity (ADCC) function, a mechanism not 


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demonstrated by tyrosine kinase inhibitors [Campone, 2011]. Structural studies using 
recombinant HER2 receptor ectodomains, as well as in vitro experiments with HER2 
monoclonal antibodies that recognize different receptor epitopes, indicate that 
trastuzumab binds in a region not involved in receptor dimerization [Cho, 2003; Agus, 
2002].  Diminished receptor signalling may result from trastuzumab-mediated 
internalization and degradation of the HER2 receptor [Baselga, 2001; Sliwkowski, 1999];
although some researchers have demonstrated that receptor levels are unchanged in 
response to trastuzumab treatment [Austin, 2004]. 
1.1.2.2.
Trastuzumab as First-Line Therapy for Metastatic Breast Cancer
Trastuzumab has been extensively clinically evaluated and has represented a clinical 
breakthrough in treating patients with HER2-positive breast cancer. As a single agent, 
trastuzumab has demonstrated activity in advanced and metastatic breast cancer.
In 
patients who were previously treated with 1 to 2 lines of chemotherapy, response rates 
have ranged from 15% to 20% [Cobleigh, 1999]. In the first-line setting for metastatic 
breast cancer (MBC), a 26% overall response rate (ORR) (95% confidence interval [CI], 
18.2 to 34.4) and median time to disease progression of 3.5 to 3.8 months were observed 
for weekly trastuzumab monotherapy [Vogel, 2002]. 
The above studies with trastuzumab monotherapy gave way to studies that combined 
chemotherapy with trastuzumab. Trastuzumab in combination with chemotherapy 
showed activity as first-line treatment of subjects with HER2-positive MBC. In 
combination with either an anthracycline or taxane as first-line treatment in MBC, the 
addition of trastuzumab increased the ORR, which ranged from 38% to 50%, with the 
highest difference observed in combination with paclitaxel versus paclitaxel alone. The 
survival advantage was greatest in the anthracycline and cyclophosphamide plus 
trastuzumab arm (median 26.8 months) versus anthracycline and cyclophosphamide only
(21.4 months). A survival benefit also was seen in the paclitaxel plus trastuzumab arm 
(median 22.1 months) compared with paclitaxel alone (18.4 months), although this was 
not statistically significant [Slamon 2001]. More recently, trastuzumab in combination 
with pertuzumab and docetaxel for the treatment of first-line MBC extended progression 
free survival (PFS) from 12.4 months to 18.5 months (hazard ratio [HR] = 0.62; 95% CI 
0.51 to 0.95; p<0.001) and trended toward improvement of overall survival (OS)
[Baselga 2012b].  
1.1.2.3.
Continuation of Trastuzumab Post Progression of Disease
While the definition of trastuzumab-refractory and/or -resistant disease has not been 
clearly characterized [Wong, 2011], clinical practice has evolved to continue the use of 
sequential lines of trastuzumab-based therapies despite the lack of robust evidence from 
clinical studies to support this practice [Beslija, 2007]. As such, this approach has been 
acknowledged by national treatment guidelines [NCCN, 2010; Cardoso, 2012]. Several 
clinical questions, however, remain unanswered about the optimal use of trastuzumab in 
MBC following progression of disease. For example, after progression on trastuzumab 
and chemotherapy in the first-line setting in the study of Slamon and colleagues [Slamon, 
2001], a subset of subjects continued with trastuzumab monotherapy. The ORR in these 


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subjects was 9%, substantially lower than the aforementioned 38% to 50% for first-line 
treatment [Tripathy, 2004].
When administered as an antibody-drug conjugate combining trastuzumab with the 
cytotoxic activity of the microtubule inhibitor DM1 (a derivative of maytansine), 
trastuzumab emtansine (T-DM1) as second-line treatment for MBC improved both PFS
(9.6 versus 6.4 months; HR = 0.65; 95% CI 0.55 to 0.77; p<0.001) as well as OS (30.9 
versus 25.1 months; HR = 0.68; 95% CI 0.55 to 0.85; p<0.001) compared with lapatinib 
in combination with capecitabine [Verma, 2012]. In subjects that received a median of 
4 prior regimens for MBC, T-DM1 demonstrated a median PFS of 6.2 months compared 
to 3.3 months for treatment of physician’s choice (HR = 0.528, 95% CI, 0.422, 0.661, 
p<0.0001) [Wildiers, 2013].  Treatment of physician’s choice consisted mainly of 
trastuzumab-containing regimens (80.4% of the subjects had a trastuzumab containing 
regimen).  
The safety and efficacy of trastuzumab also has been investigated with additional 
chemotherapy combinations in several smaller prospective, nonrandomized clinical trials 
and has been successfully combined with various cytotoxic therapies including 
vinorelbine, gemcitabine, and capecitabine, as well as nab-paclitaxel, paclitaxel, and 
docetaxel, with response rates ranging from 8% to 67% and median time to progression 
(TTP) of 3.5 to 9.5 months in the second-line and beyond MBC setting [Pegram, 2012]. 
Despite this treatment paradigm, evidence suggests that with each successive trastuzumab 
regimen in the metastatic setting, the clinical efficacy declines. As noted above, 
trastuzumab in combination with pertuzumab and docetaxel for the treatment of first-line 
MBC resulted in a PFS of 18.5 months [Baselga 2012b] which decreased to 9.6 months 
in second-line MBC as an antibody conjugate with mertansine [Verma, 2012] and further 
decreased to 6.2 months in subjects with at least 2 lines of anti-HER2-directed therapies 
for MBC [Wildiers, 2013]. 
1.1.3.
Role of Lapatinib in the Treatment of Breast Cancer
1.1.3.1.
Preclinical Evidence for Lapatinib
Lapatinib is a reversible, orally bioavailable small molecule tyrosine kinase quinazoline 
inhibitor (molecular weight (MW) 943) that inhibits both Epidermal Growth Factor 
Receptor (EGFR) and HER2. Lapatinib binds in the adenosine triphosphate (ATP) site 
and inhibits the tyrosine kinase activity located in the intracellular domains of HER2 and 
its co-receptor EGFR and the phosphorylation of both HER2 and EGFR are blocked 
[Wood, 2004].  Lapatinib inhibits cell proliferation and induces apoptosis by decreasing 
the downstream Mitogen-activated protein kinase (MAPK)/ Extracellular signal-
regulated kinase (ERK) and the Phosphoinositide 3-kinase (PI3K)/AKT signal 
transduction pathways [Rusnak, 2001; Hegde, 2007].  Preclinical data demonstrated that 
lapatinib retained significant in vitro activity against HER2-positive cell lines selected for 
insensitivity to trastuzumab [Konecny, 2006].
Lapatinib is also effective in cases of 
trastuzumab resistance involving HER2 heterodimers, PTEN loss, or mutations in 
PIK3CA [O’Brien, 2010; Ghosh, 2007].


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1.1.3.2.
Lapatinib as Monotherapy
As first-line treatment for subjects with locally advanced or metastatic ErbB2-
overexpressing breast cancer, single-agent lapatinib has resulted in a partial response
(PR) rate and clinical benefit rate (CBR) (confirmed objective response at any time or 
stable disease for ≥24 weeks) of 24% and 31%, respectively [Gomez, 2006]. 
A Phase II study of single-agent lapatinib in 78 subjects with HER2-positive MBC with 
progressive disease on prior trastuzumab-containing regimens demonstrated a response 
rate of 5% and a CBR (complete response (CR)+PR+ stable disease (SD) ≥ 6 months) of 
9% with a 15-week TTP and an OS of 79 weeks [Blackwell, 2009].  Tested in an even 
more heavily pretreated population (n=140) who had progressed on prior trastuzumab-
containing regimens in addition to progression while receiving anthracyclines, taxanes, 
and capecitabine, response rates ranged between 1.4% to 4.3% by independent and 
investigator assessments, respectively.  Approximately 6% of subjects, most (76%) of 
whom had received 4 or more lines of prior therapy, achieved clinical benefit in addition 
to a modest TTP of 9.1 weeks [Burstein, 2008].  Therefore, lapatinib monotherapy 
demonstrated early evidence of clinical activity in heavily pretreated, HER2-positive 
patients who had progressive disease on trastuzumab as well as cytotoxic therapy.
1.1.3.3.
Lapatinib in Combination with Chemotherapy
EGF100151, a Phase III, randomized, open-label, multicenter study, compared lapatinib 
and capecitabine versus capecitabine in women with refractory advanced or metastatic 
breast cancer who had been treated with anthracyclines, taxanes, and prior trastuzumab 
therapy in the metastatic setting.  Based on a blinded, independently reviewed analysis, 
the median TTP in the combination and single-agent arms, respectively, based on a 
blinded, independently reviewed analysis was 27.1 weeks and 18.1 weeks (HR = 0.57; 
95% CI 0.43 to 0.77; p = 0.0001), with objective response rates (CR + PR) of 24% and 
14%, respectively, by independent review (odds ratio [OR] = 1.9; 95% CI 1.1 to 3.4; 
p = 0.017) and 32% and 17%, respectively, by investigator-reported data (OR = 2.2; 95% 
CI 1.3 to 3.6; p = 0.002) [Geyer, 2006]. More recently, the clinical benefit of the 
lapatinib plus capecitabine regimen in second-line MBC and beyond was also 
demonstrated, with PFS rates of approximately 6 months, in comparison with TDM-1 [, 
2012] and in comparison with trastuzumab in combination with capecitabine [Pivot, 
2012]. Several smaller, nonrandomized studies of lapatinib in combination with other 
chemotherapies (i.e., vinorelbine, docetaxel, paclitaxel) have also demonstrated similar 
clinical efficacy in the setting of progression of disease on trastuzumab-based regimens
[Di Leo, 2008; Cristofanilli, 2006; Jagiello-Gruzfeld 2009; LoRusso, 2008; Rezai, 2011].  
Of note, in an exploratory analysis of study EGF100151, fewer subjects in the lapatinib 
plus capecitabine arm had CNS metastases as a first site of relapse during the study than 
in the capecitabine group.
In this analysis, 4 (2%) subjects in the combination therapy 
group had symptomatic CNS progression as part of their first progression event as 
compared with 13 (6%) patients in the monotherapy group (p = 0.045) [Cameron, 2008]. 
Therefore, a body of evidence is amassing supporting the clinical utility of lapatinib 
following the progression of disease on trastuzumab-based therapies.


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1.1.3.4.
Lapatinib in combination with aromatase inhibitors
Lapatinib has been studied in combination with letrozole for the treatment of advanced or 
metastatic breast cancer in hormone receptor positive (estrogen receptor [ER] positive 
and/or progesterone receptor [PgR] positive) postmenopausal women.
EGF30008 was a randomised, double-blind, controlled trial in subjects with hormone-
sensitive locally advanced or MBC, who had not received prior therapy for their 
metastatic disease.  One thousand two hundred and eighty-six subjects were randomised 
to letrozole 2.5 mg once daily plus lapatinib 1500 mg once daily or letrozole with placebo.  
Randomization was stratified by sites of disease and prior adjuvant anti-estrogen therapy.  
HER2 receptor status was retrospectively determined by central laboratory testing.  Of 
all subjects randomised to treatment, 219 subjects had tumors overexpressing the HER2 
receptor (the ‘HER2-positive population’), which was the pre-specified primary 
population for the analysis of efficacy. There were 952 HER2 negative subjects and a 
total of 115 subjects whose HER2 status was unconfirmed.
In the HER2-positive population, investigator-determined PFS was significantly greater 
with letrozole plus lapatinib compared with letrozole plus placebo (35.4 weeks [24.1;
39.4] versus 13.0 weeks [12.0; 23.7] and a HR= 0.71 [0.53, 0.96])
The benefit of lapatinib plus letrozole on PFS in the HER2-positive population was 
confirmed in a pre-planned Cox regression analysis (HR=0.65 [95 % CI 0.47-0.89]
p=0.008).
In addition to a PFS benefit seen in the HER2-positive subject population, 
combination therapy of lapatinib and letrozole offered an improvement in objective 
response rate compared with letrozole treatment alone (27.9% and 14.8% respectively) 
and in clinical benefit rate (47.7% and 28.7% respectively). At the time of the primary 
PFS analysis, the OS data analyzed included a limited number of events with less than 
half of the HER2-positive subjects having died. The corresponding HR was 0.77 (95% 
CI:  0.52, 1.14) and was not statistically significant.  This study was the basis of the 
approval of lapatinib in combination with an aromatase inhibitor for the treatment of 
patients with hormone sensitive metastatic breast cancer.
1.1.4.
Role of Dual blockade with Lapatinib and Trastuzumab in 
Treatment of Breast Cancer
1.1.4.1.
Preclinical Mechanism
Preclinical data provided the scientific rationale for combining 2 HER2-targeted agents 
with unique and complementary mechanisms of action and potentially non-overlapping 
mechanisms of resistance. Certain mechanisms such as estrogen receptor (ER) 
signaling may attenuate the activity of both trastuzumab and lapatinib in HER2-positive
cells [Wang, 2011]. Other mechanisms of resistance such as activation of the PI3K
pathway [Dave 2011; O’Brien, 2010], levels of EGFR or HER3 [Ritter, 2007; Dua, 2010], 
expression of HER ligands [Ritter, 2007; Dua, 2010], and presence of carboxy terminal 
fragments of HER2 [Scaltriti, 2007; Xia, 2004], however, appear unique to either 
trastuzumab or lapatinib.  


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In addition, Dual blockade may enhance the effects of either single agent.  Whereas 
lapatinib can inhibit the phosphorylation of HER3, likely through inhibiting the activation 
of HER2 dimerized with HER3 [Ritter, 2007], sustained inhibition of HER2 kinase 
activity with lapatinib has been shown to increase HER3 protein and phosphorylation 
levels.  However, combined treatment with trastuzumab inhibited HER3 
phosphorylation after sustained inhibition of HER2 by lapatinib [Garrett, 2011].  In 
other models, lapatinib exposure led to accumulation and stabilization of inactivated 
HER2 at the cell surface, which, in combination with trastuzumab, enhanced ADCC 
[Scaltriti, 2009; Maruyama, 2011]. 
Preclinical evidence has shown that combining these agents is synergistic, enhances anti-
proliferative and apoptotic effects, and circumvents resistance to either agent alone 
[Konecny, 2006; Xia, 2005; O'Donovan, 2011].  Further supporting the complementary 
functions, the lapatinib plus trastuzumab combination achieved better blockade of the 
HER2 pathway and greater tumor inhibition than either agent alone [Rimawi, 2006; 
Rimawi, 2011].
In summary, the preclinical scientific rationale for the combination of lapatinib and 
trastuzumab is supported by the potentially non-overlapping mechanism of resistance, the 
complementary mechanisms of action, and the ability of each agent to enhance the 
activity of the other.  
1.1.4.2.
Clinical Efficacy of Dual blockade
1.1.4.2.1.
Phase I Study EGF10023
The Phase I study in subjects with HER2-positive MBC determined the optimally 
tolerated regimen (OTR) of lapatinib in combination with trastuzumab.  Early evidence 
of efficacy of the combination was observed in this study. This study was conducted in 
2 phases: a dose-escalation phase to determine the OTR, and a pharmacokinetics (PK) 
phase to assess the potential for a drug-drug interaction when these 2 drugs are used in 
combination. All subjects (N=54) in study EGF10023 had HER2-positive MBC at 
study entry; almost half (44%) were ER- and progesterone receptor (PgR)-negative, and 
50 of the subjects had received prior trastuzumab therapy.  Concurrent administration of 
lapatinib (1000 mg) and trastuzumab did not result in significant alterations in the PK of 
either drug.
A total of 50 of the subjects were evaluable for clinical activity.  As best response to 
treatment, CR was documented in 1 subject (1500-mg dose cohort) and PR in 7 subjects 
(2 in the 1250-mg dose cohort, 4 in the 1000-mg dose cohort, and 1 in the 750-mg dose 
cohort) for an ORR of 15%.  Five of the 7 responding subjects required a dose reduction 
to a lower dose level during the course of study treatment.  All subjects had received 
prior trastuzumab-containing regimens (median, 2 regimens [range, 1 to 6]).  Overall, 6 
subjects (11% of the overall population) had SD 6 months.
Dose-limiting toxicities (DLTs) were reported in 1 of 11 subjects enrolled in the lapatinib 
1000-mg dose cohort, in 2 of 10 subjects enrolled in the 1250-mg dose cohort, and in 2 of 
3 subjects enrolled in the 1500-mg dose cohort.  As 2 out of 3 subjects experienced a 
DLT in the 1500-mg dose cohort, the OTR was exceeded at this combination dose 


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regimen.  As a result, the 1000-mg and 1250-mg dose cohorts were considered in the 
determination of the OTR.  Although the adverse event (AE) profiles and rates of DLTs 
were comparable between the 1000-mg and 1250-mg dose cohorts, the tolerability of the 
1000-mg dose cohort was considered by the investigators to be more acceptable based on 
the constitutional symptoms (e.g., fatigue, arthralgia, anorexia, headache) experienced by 
the subjects in the 1250-mg dose cohort. As a result, the OTR was defined as 1000 mg 
lapatinib once daily with weekly trastuzumab (4 mg/kg intravenous [IV] loading dose 
followed by 2 mg/kg IV weekly).
All subjects in all dose cohorts experienced an AE during the study. AEs occurring in 
>20% of subjects in the 1000-mg dose cohort (n=38) were diarrhea (all grades 82%; 
Grade 3 was 13%), nausea (all grades 58%; Grade 3 was 3%), rash (all grades 58%; 
Grade 3 was 3%), fatigue (all grades 53%; Grade 3 was 11%), anorexia (all grades 39%; 
no Grade 3), and pruritis (all grades 24%; no Grade 3). The most common Grade 3 AEs 
were diarrhea (17%), fatigue (11%), and rash (6%).  One of 3 (33%) subjects in the 
1500-mg lapatinib cohort experienced a Grade 4 AE of hypokalemia.  No Grade 5 or 
fatal AEs were reported.
Left ventricular ejection fraction (LVEF) was monitored in this study due to the potential 
for cardiac dysfunction.  One subject in the 1500-mg dose cohort experienced 
asymptomatic reversible LVEF decline to 45% (echocardiogram [ECHO]) from a 
baseline value of 58% (multigated acquisition [MUGA]) and returned to baseline while 
still on therapy.  
Concurrent administration of trastuzumab plus lapatinib was generally well tolerated, 
showed evidence of clinical activity in subjects who had progressed on prior trastuzumab
therapy, and did not result in significant alterations in the PK of either drug.  Therefore, 
these findings supported further exploration of the safety and activity of 1000 mg/day 
lapatinib plus trastuzumab in larger studies of subjects with HER2-positive MBC.
1.1.4.2.2.
Phase III Study EGF104900 – Dual blockade in Metastatic Breast 
Cancer
Study EGF104900 was a randomized, open-label, multicenter, Phase III study designed 
to compare the efficacy and safety of lapatinib in combination with trastuzumab (Dual 
blockade) with that of lapatinib monotherapy in women with Stage IV, HER2-positive 
MBC who had received a prior trastuzumab-containing regimen in the metastatic setting. 
Upon radiologic evidence of disease progression on the lapatinib monotherapy treatment 
arm, subjects were allowed to cross over to receive treatment with Dual blockade.
The primary objective of the study was to compare investigator-assessed PFS in the Dual 
blockade arm with that in the lapatinib monotherapy arm, and secondary endpoints 
included a comparison of OS between the 2 treatment arms.
The eligibility criteria required subjects to have had at least 1 prior trastuzumab-
containing regimen (trastuzumab plus cytotoxic chemotherapy or trastuzumab plus an 
anti-hormonal regimen) in the metastatic setting.  Additionally, they must have had 
trastuzumab as their most recent regimen prior to study entry, with evidence of 
progressive disease on the most recent prior trastuzumab-containing regimen.


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Subjects with either measurable disease or bone-only disease were randomized in a 1:1 
fashion to either Dual blockade with lapatinib (1000 mg per os (orally) (PO) daily) plus 
trastuzumab (4 mg/kg IV load on Day 1 followed by 2 mg/kg weekly) or lapatinib (1500 
mg PO daily) monotherapy. Randomization was stratified according to site of disease 
(visceral versus nonvisceral) and hormone receptor status (ER-negative and PgR-negative 
status versus ER-positive and/or PgR-positive status). 
Study Population
The subject population had previous prolonged exposure to, and progression on, multiple 
cytotoxic chemotherapy- and trastuzumab-based regimens.  The overall population had 
received a median of 6 prior anticancer regimens, 7 prior chemotherapies, and 3 prior 
lines of trastuzumab-containing regimens in the metastatic setting.  Moreover, they must 
have had a trastuzumab-chemotherapy combination as their most recent treatment 
regimen prior to entering the study and must have had disease that progressed on this 
most recent prior trastuzumab-containing regimen.
Efficacy 
PFS was statistically significant in favor of the Dual blockade arm, with an HR of 0.73 
(95% CI 0.57 to 0.93; p = 0.008). The median PFS was longer in subjects who received 
Dual blockade treatment (12.0 weeks) compared with subjects who received 
monotherapy treatment (8.1 weeks) and was confirmed by independent review, with an 
HR of 0.71 (95% CI 0.52 to 0.98; p = 0.027) in favor of the Dual blockade arm.  Median 
PFS by independent evaluation was 16.4 weeks and 11.1 weeks in subjects treated with 
Dual blockade and monotherapy treatment, respectively.  Of note, for the 80% of 
subjects who had progressed on 2 or more lines of trastuzumab-containing regimens in 
the metastatic setting prior to study entry, there was a statistically significant 
improvement in PFS with Dual blockade (investigator-evaluated PFS, HR = 0.76; 95% 
CI 0.58 to 1.00; p = 0.041). Investigator-evaluated ORR was 10.3% in the Dual 
blockade arm and 6.9% in the lapatinib arm (OR=1.5; 95% CI 0.6 to 3.9; p = 0.4647),
and investigator-assessed CBR (defined as a confirmed CR or PR at any time or SD for at 
least 24 weeks) was 24.7% in the combination arm and 12.4% in the monotherapy arm 
(OR = 2.2; 95% CI 1.2 to 4.5; p = 0.01) [Blackwell, 2010].
Final survival analysis, which included 291 subjects per their randomized treatment, 
regardless of crossover status, demonstrated a median OS of 14.0 months for the Dual 
blockade arm and 9.5 months for the monotherapy arm (N=291; HR=0.74; 95% CI 0.57 
to 0.97; stratified log-rank p = 0.026) [Blackwell, 2012].  Additionally, there was a 10% 
improvement in the absolute OS rate at 6 months and a 15% improvement at 12 months 
for subjects who received Dual blockade treatment compared with subjects who received 
monotherapy treatment. 
Data from exploratory analyses in the pivotal study showed an increased overall benefit 
for subjects with hormone receptor negative disease. The efficacy of the Dual blockade in 
terms of OS and ORR was increased in subjects with hormone receptor-negative tumors 
compared to those with hormone receptor-positive tumors, although the hazard ratios for 
PFS were similar (HR = 0.73 for both subgroups).


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Safety 
The most common AEs experienced in this study were diarrhea, nausea, rash, fatigue, 
and vomiting, and these events were similar in frequency between the lapatinib and Dual 
blockade arms with the exception of diarrhea (observed in 62% of subjects in the Dual 
blockade arm and 48% of subjects in the lapatinib monotherapy arm).  Grade 3 or 4 
diarrhea was reported in 8% of subjects in the Dual blockade arm and in 7% in the
lapatinib monotherapy arm.
Non fatal serious adverse events (SAE)s were reported in 27% of subjects in the Dual 
blockade arm compared with 16% of subjects in the lapatinib arm.  Decreased ejection 
fraction was the most frequent SAE (in 5% of subjects of the Dual blockade arm).  No 
other SAEs were reported by more than 3% of subjects.  Most subjects experienced 
SAEs in the Dual blockade arm that were not considered to be treatment-related by the 
investigator (8% versus 3% subjects for the Dual blockade and lapatinib monotherapy
arms, respectively, had SAEs considered related to study treatment).  
Five subjects experienced a fatal SAE.  Two of these cases were due to progressive 
disease and 1 was attributed to aspiration pneumonia (Dual blockade arm), 1 to 
hepatorenal failure (lapatinib arm), and 1 to cardiac insufficiency (Dual blockade arm).  
Per protocol, cardiac function was monitored every 12 weeks, and cardiac toxicity overall 
was low. While the frequency of cardiac events was higher in the Dual blockade
treatment group (7% [n=11]) compared with the lapatinib monotherapy arm (2% [n=3]), 
most of the events were asymptomatic and resolved.
Symptomatic cardiac events 
occurred in 3 subjects randomized to the Dual blockade arm, 1 subject in the lapatinib 
monotherapy arm, and 1 subject in the crossover arm.  Of the 3 subjects in the Dual 
blockade arm, 2 recovered while 1 subject died of cardiac insufficiency in association 
with a suspected pulmonary embolism.  Each of the subjects in the lapatinib 
monotherapy arm and in the crossover arm also recovered.
As lapatinib was present in both arms of the study, and consistent with the safety profile 
for lapatinib, diarrhea was the most common AE experienced in subjects treated with 
either Dual blockade or lapatinib monotherapy. More subjects experienced diarrhea 
with Dual blockade (62%, with 8% of subjects in the arm reporting Grade 3 or 4 events) 
compared with the lapatinib monotherapy arm (48%, with 7% of subjects in the arm 
reporting Grade 3 or 4 events).  Most events resolved without adverse sequelae, and the 
majority (98%) of subjects in the Dual blockade arm were able to continue study drug 
without dose reductions.  Study treatment interruptions due to diarrhea were reported in 
10% of subjects in the Dual blockade arm and in 15% of subjects in the lapatinib 
monotherapy arm, and no subjects randomized to Dual blockade discontinued study drug 
due to diarrhea.
The overall number of hepatobiliary AEs was similar in both arms (11% and 9% 
respectively).  Most hepatobiliary events were asymptomatic transaminase elevations 
that were infrequent and reversible upon treatment discontinuation; overall, there were 
few (4% [n=6] and 3% [n=5] for Dual blockade and lapatinib monotherapy, respectively) 
Grade 3 or 4 hepatobiliary AEs.


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In summary, a statistically significant improvement in PFS and OS with dual blockade 
therapy compared with lapatinib monotherapy was demonstrated in these subjects who 
experienced progressive disease following multiple prior trastuzumab-containing 
regimens.  This is the first study to demonstrate an OS benefit in this unique population 
of heavily pretreated subjects.
Additional subgroup analyses for OS showed that the magnitude of the benefit of Dual 
Blockade in subjects with hormone receptor-negative tumours [HR 0.62
(95% CI 0.42-0.90)] was greater than the benefit in subjects with hormone receptor-
positive tumours [HR 0.84 (95% CI 0.58-1.23); although the hazard ratios for PFS were the 
same in both subgroups.
The results of EGF104900 were the basis for 2013 CHMP positive opinion and 
subsequent granting of marketing authorization from the European Medicines Agency 
(EMA) of dual blockade in the following indication:  “Lapatinib in combination with 
trastuzumab (Dual blockade) for adult patients with hormone receptor-negative 
metastatic breast cancer (MBC), whose tumors overexpress HER2 (ErbB2), that has 
progressed on prior trastuzumab therapy(ies) in combination with chemotherapy.”
1.1.4.3.
Dual blockade in the Neoadjuvant Setting
In the neoadjuvant setting, dual blockade has shown a higher rate of pathological 
complete response (pCR) given with or without concurrent chemotherapy compared with 
trastuzumab or lapatinib treatment. Several Phase II and Phase III clinical trials 
conducted in the neoadjuvant setting that randomized subjects to either dual blockade or 
either of their components have demonstrated the clinical utility of more complete HER2 
receptor blockade utilizing the Dual blockade approach.  
Study EGF106903, also known as the Neo-ALTTO study, was a randomized, open-label, 
multicenter, Phase III, neoadjuvant study enrolling 455 HER2-positive women with 
histologically confirmed invasive breast cancer [Baselga, 2012c]. Subjects newly 
diagnosed with Stages II or III primary breast cancer were randomized (1:1:1) to either a) 
Dual blockade with lapatinib (1000 mg PO daily) plus  trastuzumab (4 mg/kg IV load 
followed by 2 mg/kg weekly) for 6 weeks, followed by lapatinib (750 mg PO daily) plus  
trastuzumab (2 mg/kg IV weekly) plus paclitaxel (80 mg/ meter squared (m2) IV weekly) 
for an additional 12 weeks; b) trastuzumab alone (4 mg/kg IV load followed by 2 mg/kg 
weekly) for 6 weeks, followed by trastuzumab (2 mg/kg IV weekly) plus paclitaxel 
(80 mg/m2 IV weekly) for an additional 12 weeks; or c) lapatinib alone (1500 mg PO 
daily) for 6 weeks, followed by lapatinib (1500 mg PO daily) plus weekly paclitaxel (80 
mg/m2 IV) for an additional 12 weeks.
The proportion of subjects with pCR at surgery (defined as absence of invasive disease in 
the breast [Fisher, 1997; Fisher, 2002] was statistically significantly higher in the Dual 
blockade arm (51.3%) than in the trastuzumab arm (29.5%; p = 0.0001) with an overall 
OR of 2.62 (97.5% CI 1.50 to 4.58; p<0.001). The difference between the lapatinib arm 
(24.7%) and the trastuzumab arm (29.5%) was not statistically significant.  Additionally, 
locoregional pCR (defined as absence of invasive disease in the breast and axilla) was 


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46.9% in the Dual blockade arm compared with 27.6% in the trastuzumab arm and 20.0% 
in the lapatinib arm (binomial p = 0.0007; OR = 2.40; p<0.001). 
Another randomized, open-label, multicenter Phase III study (NSABP B-41) compared 
whether neoadjuvant Dual blockade or lapatinib increased pCR rate compared with
trastuzumab [Robidoux, 2012]. Subjects enrolled in this study were randomized to 
receive doxorubicin (60 mg/m2 q3weekly) in combination with cyclophosphamide (600 
mg/m2 q3weekly) for 4 cycles sequentially, followed by either Dual blockade
(trastuzumab 4 mg/kg IV load followed by 2 mg/kg weekly plus lapatinib 750 mg PO 
daily) for 4 28-day cycles or trastuzumab or lapatinib (1250 mg PO daily), all 3 anti-
HER2 regimens given concurrent with weekly paclitaxel (80 mg/m2 on Days 1,8, and 15 
of a 28-day cycle for 4 cycles). 
pCR was achieved in the breast as well as locoregionally in the breast and axilla in 62% 
versus 52.5% (p = 0. 95) and 60.2% versus 49.4% (p = 0.056) of subjects, respectively, 
treated with Dual blockade compared with trastuzumab.  There was no difference 
between lapatinib or trastuzumab, respectively (53.2% versus 52.5%, p = 0.99 breast 
only; 47.4% versus 49.4%, p = 0.78 breast and axilla).
Several additional smaller randomized, 3-arm translational studies have also been 
conducted as proof-of-principle studies for Dual blockade. Importantly, although not all 
of the Phase III studies achieved statistical significance, there is a consistent increase in 
the magnitude of pCR for treatment with Dual blockade when compared with the 
trastuzumab control. 
Table 1
Overview of Pathologic Complete Response Rates
Lapatinib
Trastuzumab
Lapatinib + Trastuzumab
pCR in breast and nodea, %:
EGF106903 (Neo-ALTTO)
[Baselga 2012c]
20
28
47
LPT109096
45
54
74
CHERLOB
[Guarneri, 2012]
26
25
47
NSABP B41
[Robidoux, 2012]
47
49
60
pCR in breastb, %
EGF106903 (Neo-ALTTO)
[Baselga 2012c]
25
30
51
LPT109096
52
54
74
CALGB 40601
[Carey, 2013]
32
40
51
NSABP B41
[Robidoux, 2012]
53
53
62
a.
Defined as no invasive cancer in the breast and lymph nodes.
b.
Defined as no invasive cancer in the breast or only non-invasive in situ cancer in the breast specimen


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1.2.
Study Rationale
1.2.1.
Clinical Validity of Dual blockade
In the EGF104900 study population with heavily pretreated HER2-positive breast cancer,
treatment with Dual blockade had a clinically meaningful OS benefit of 4.5 months yet a 
modest PFS improvement of approximately 1 month compared with lapatinib 
monotherapy.  In an effort to further understand the apparent disconnect between a more 
modest PFS improvement with a clinically meaningful OS improvement, several 
additional analyses were undertaken to assess factors or biases that theoretically may 
have influenced the OS benefit and could account for this apparent disconnect. Of the 
factors evaluated, none were considered significant as to bias the OS benefit observed in 
EGF104900 thus no bias was identified.  
Similar divergence of PFS and OS durations was reported in the large phase III Cleopatra 
[Baselga 2012a] and PHEREXA [Urruticoechea 2016] trials evaluating dual HER2 
blockade (pertuzumab plus trastuzumab) in HER2-positive MBC. 
Study EGF104900 demonstrated that in the population of HER2-positive subjects, Dual 
blockade can enhance blockade of the HER2 receptor in this heavily trastuzumab 
pretreated population.  This effect driven by Dual blockade was both necessary and 
sufficient to provide a clinically meaningful OS benefit, even in the absence of cytotoxic 
therapy.
1.2.2.
HER2-Enriched Population for Study EGF117165
The application of whole transcriptome profiling to classical breast cancer clinical 
subtypes has unravelled substantial biological complexity.  Gene expression profiles 
revealed inherent structure that clustered breast cancers into 4 distinct, primary breast 
cancer subtypes—luminal A, luminal B, HER2-enriched, and basal-like—and a normal-
like group.  Analyses of breast cancers by intrinsic molecular subtype demonstrated 
significant differences in terms of risk factors, baseline prognoses, and responses to 
systemic therapies [Perou, 2000; Sorlie, 2001; Parker, 2009].
The Prediction Analysis of Microarray (PAM) is a classifier algorithm used to assign 
breast cancers to 1 of the 4 intrinsic molecular subtypes noted above.  The assignment of 
a breast cancer to a molecular subtype is based on the expression of 50 genes that were 
derived from an initial list of 1906 intrinsic genes identified by whole transcriptome 
microarray analyses.  As indicated above, prototypic tumor samples representative of 
classical clinical breast cancer molecular subtypes (i.e., ER-positive or ER-negative 
tumors, HER2-positive or HER2-negative tumors, triple-negative), in addition to tissue 
from normal breast samples, were used in the development of the classifier algorithm and 
refinement of the intrinsic gene signature to a minimized set of 50 (PAM50).  PAM50 
has been developed as an in vitro diagnostic using the Nanostring nCounter analysis 
platform. The commercial name of the PAM50 assay is Prosigna.  The intended in vitro 
diagnostic use of the assay is to assess a breast cancer patient’s risk of distant recurrence 


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at 10 years.  For this purpose, the standardized test has received Food and Drug 
Administration (FDA) 510(k) clearance.
Determination of HER2 status in breast cancer using standard immunohistochemistry 
(IHC)/fluorescence in situ hybridization (FISH)-based methods not only provides 
prognostic information to a patient but also is a standard-of-care requirement for patients 
to receive treatment with HER2-directed agents. Of note, the HER2-enriched subtype 
signature includes 2 genes on the chromosome 17q12-21 amplicon: HER2 and GRB7
[Parker, 2009]. In a comprehensive retrospective molecular analysis of >400 banked 
breast tumors, only 50% of clinically HER2-positive tumors were classified as the HER2-
enriched subtype by PAM50 assay [Cancer Genome Atlas Network, 2012].  
Retrospective analyses have shown that the HER2 enriched subtype correlated with 
enhanced clinical outcome when treated with trastuzumab in the early breast cancer 
setting [Prat 2014, Glück 2012; Gomez Pardo, 2011].  
In the aforementioned CALGB 40601 neoadjuvant study in clinically HER2-positive 
early breast cancer, 33% of the evaluable samples were HER2 enriched compared to 33% 
luminal A, 22% luminal B, 7% basal-like, and 6% normal-like subtypes.  In a 
prospective analysis of pCR rates by breast cancer subtype, HER2-enriched tumors has 
the highest rate of pCR (75%) regardless of anti-HER2 therapy used in combination with 
paclitaxel.  In those found to be HER2 enriched, pCR rate for the Dual blockade arm 
was 89% compared to 40% in Luminal A35% in Luminal B; and 50% in basal-like 
subgroups.  In the setting of a constant chemotherapy backbone across all treatment 
arms, higher pCR rates were observed in the HER2-enriched subtype, supporting the use 
of this assay in defining those subjects whose disease may be more dependent on the 
HER2 pathway and consequently exquisitely sensitive to the effects of HER2-directed 
therapy. 
A prospective clinical trial in the metastatic setting evaluating clinical outcome of anti-
HER2 therapy by PAM50 or Prosigna assigned breast cancer molecular subtype has not 
been reported.  Nevertheless, it has been recognized that subjects with HER2 positive 
disease derive differential benefit from anti-HER2 blockade.  Based on the neoadjuvant 
data discussed above, classification into the HER2 enriched subtype may predict 
enhanced as well as prolonged benefit to anti-HER2 directed therapy. In fact, gene 
expression analyses in primary tumors of a prematurely closed trial of single anti-HER2 
therapy in first line metastatic setting showed that the HER2-enriched subtype identified 
a group of subjects with longer time on protocol compared to the non-HER2-enriched 
subtype [Montemurro 2013].  Additionally, in the heavily pre-treated HER2 population 
as defined in this study, HER2-enriched tumors might represent those strongly driven by 
the HER2 pathway and as such could derive the most benefit from enhanced blockade of 
the HER2 receptor in the absence of chemotherapy.  In order to avoid any real or 
perceived lack of clinical equipoise when randomizing subjects in EGF117165 to a 
trastuzumab chemotherapy combination versus the non-cytotoxic based Dual blockade, 
the randomized portion of EGF117165 will target those subjects with breast cancer that is 
not only HER2 positive by standard clinical definitions, but is also HER2-enriched as 
defined by the Prosigna assay. 


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A prospective clinical trial in the metastatic setting evaluating clinical outcome of anti-
HER2 therapy using the “HER2 enriched” definition has not been reported. Additionally, 
the benefit of dual blockade from the EGF104900 study was seen in the intent-to-treat
(ITT) population which included all HER2 positive subjects as defined by standard 
histopathologic criteria. At this time, there is a lack of knowledge regarding any 
molecular mechanism(s) that might modulate response in a HER2 enriched population 
compared to a standard defined HER2 positive population.  Therefore, this study will 
also enroll standard HER2 positive subjects as defined by standard histopathologic 
criteria with a non-HER2 enriched subtype that will be assigned to treatment with 
lapatinib in combination with trastuzumab. 
1.2.3.
Immunomodulation by dual blockade as a putative mechanism 
affecting response to subsequent lines of therapy.  
Chemotherapies traditionally produce cytotoxic effects that translate into reduction in 
tumor burden, resulting in a significant measurable effect. 
The development of novel 
targeted agents for solid tumors, with mechanisms of action that produce effects that 
differ from those traditionally measured in clinical studies, have been described for 
immunomodulatory and epigenetic-targeted agents [Wolchok, 2009].  These differences 
in on-treatment effects could, in part, explain modest PFS gains while subjects may gain 
a more prolonged benefit from subsequent therapy, which may ultimately translate to an 
OS advantage. 
The EGF104900 study population was heavily pretreated, with a median of 6 prior 
chemotherapeutic agents; as is standard in the treatment of breast cancer, the types of 
agents received were of different mechanistic classes (e.g., taxanes, anthracyclines, and 
alkylating agents). The chemotherapy-free period during which subjects received 
treatment with Dual blockade in EGF104900 may have reversed resistance to 
chemotherapy, thus conferring the disease sensitive to subsequent anticancer therapy.
There is now mounting evidence that a pre-existing immunologic response might 
enhance the effects of conventional cytotoxic chemotherapy and HER2 targeted therapy 
in early HER2+ breast cancer [Denkert 2010, Issa-Nummer 2013, Denkert 2015, 
Ignatiadis 2012, Loi 2013, Loi 2014] and anti-HER2 therapies seem to be able to engage 
the immune system in different ways. For instance, pre-clinical data suggest that 
Lapatinib enhances T-cell and IFN-γ-based immunity and affects the myeloid infiltrate
(i.e. tumor-associated macrophages and monocytes) in tumors [Hannesdóttir 2013, Laoui
2013]. Emerging data from the neoadjuvant setting provide useful insights on molecular 
changes induced by HER2-targeted neoadjuvant treatment and recent studies are 
suggesting that single HER2 targeted agents and Dual blockade of the HER2 receptor 
induce changes in immune markers and the tumor microenvironment [Bianchini 2016, 
Dieci 2015].  The Neosphere trial showed that HER2 targeted agents and dual HER2 
blockade modulate the amount of tumor infiltrating lymphocytes (TIL) - a surrogate 
biomarker of pre-existing host antitumour immunity - and the expression levels of 
selected mRNA immune markers [Bianchini 2016]. The investigators were also able to 
show that these patient-level immune modulations are linked to distant event free survival 
and the differential changes in stromal TILS (sTIL) levels actually seem to carry more 
prognostic information than either pre-or post-treatment sTIL levels.


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Tumors with increased numbers of TIL after treatment may be able to elicit an antitumor 
immune response and may have a particularly strong response to subsequent treatment 
lines, as the immune cells may have been already sensitized against some tumor antigens 
before the onset of chemotherapy and therefore enhance the ability of chemotherapy to 
eliminate cancer cells. Immunomodulation by dual HER2 blockade is a plausible 
mechanism how molecular changes could help to overcome resistance to 
chemotherapeutic agents, eventually leading to increased clinical activity and augmented 
response seen in overall survival.
The primary hypothesis under evaluation in this study is that the chemotherapy-free 
period during which subjects receive treatment with Dual blockade modulates the 
immune microenvironment, which in turn may influence the efficacy of sequential 
treatment. A recent study just revealed a comparable distribution and composition of 
infiltrating lymphocyte subtypes in metastasis when compared to the matched primary 
tumor [Sobottka 2016]. This pattern was found regardless of the anatomical site at which 
the metastasis had occurred, suggesting that primary tumor shapes the infiltrating 
immune cell composition rather than the metastases with their local immunity [Sobottka
2016]. The EGF11765 study will support a better understanding if the rapidly 
accumulating evidence for the importance of the immune microenvironment in HER2-
positive breast cancer and the observed immunomodulation in the neoadjuvant setting 
can be confirmed in the advanced setting and support the putative mechanism of action of 
HER2 dual blockade and its potential function on the tumor microenvironment.
1.2.4.
Hypothesis
It is postulated that treatment with Dual blockade (lapatinib in combination with 
trastuzumab) may cause molecular changes that may sensitize tumors to subsequent post-
study therapies. As discussed above, based on emerging data the focus will be on 
immunomodulation markers. The primary endpoint of the study will be to evaluate 
changes in expression of biomarkers associated with immunomodulation.
This Phase II study will evaluate potential mechanisms related to immunomodulation to 
explore the antitumor activity of dual blockade and gain insight into the observed post-
study treatment effect on survival in EGF104900.  In addition, it will provide a 
descriptive clinical outcome for subjects treated with trastuzumab in combination with 
lapatinib or chemotherapy.  
1.3.
Benefit: Risk Assessment
Dual blockade demonstrated a statistically significant benefit in PFS compared with 
lapatinib monotherapy in study EGF104900, with a median PFS of 12.0 weeks for 
subjects who received dual blockade compared with 8.1 weeks for subjects who received 
lapatinib alone.  This translated into a 28% reduction in the risk of progression or death 
for subjects who received dual blockade relative to subjects treated with lapatinib 
monotherapy.  
The median overall survival (OS) was substantially longer in subjects who received dual 
blockade (14 months) compared with those who received lapatinib monotherapy (9.5 


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months); the hazard ratio was 0.74.  There was a 10% improvement in absolute OS rate 
at 6 months and a 15% improvement at 12 months for subjects who received dual 
blockade compared with subjects who received lapatinib monotherapy. 
Although all subjects benefited from dual blockade, the magnitude of the benefit of dual 
blockade in subjects with hormone receptor-negative tumors was greater than the benefit 
in subjects with hormone receptor-positive tumors.  The median PFS for the hormone 
receptor negative subgroup was 15.3 weeks and the median overall survival for this 
population was 17.2 months.  HER2-positive, hormone-receptor negative tumors 
predominantly have the HER2-enriched molecular subtype. 
This benefit was demonstrated in a population of subjects with previous prolonged 
exposure to, and progression on, multiple cytotoxic chemotherapy and trastuzumab-based 
regimens.  
1.3.1.
Risk Assessment
This section outlines the risk assessment and mitigation strategy for this protocol.
Summaries of findings from both clinical and nonclinical studies conducted with 
lapatinib can be found in the Investigator’s Brochure (IB) and product label.  
Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk 
Mitigation Strategy
Study Treatments
Hepatobiliary 
`events
Lapatinib has been associated with a low 
incidence of hepatotoxicity (<1%).  In 
EGF104900, the overall number of 
hepatobiliary events was similar in both 
arms (11% and 9% respectively), and the 
incidence of Grade 3 or 4 events did not 
increase by the addition of trastuzumab to 
lapatinib [Blackwell 2012].  Additionally, 
most hepatobiliary events were 
asymptomatic transaminase elevations 
that were infrequent and reversible upon 
treatment discontinuation.  Consistent 
with this, in EGF104900 no hepatobiliary 
abnormalities met the criteria for Hy’s Law.
This rate was comparable to the rate 
observed for lapatinib monotherapy (8% 
reported hepatobiliary adverse events 
compared to 3% in the placebo arm) in the 
adjuvant breast cancer setting in 
EGF105485 (TEACH) [Goss 2013].
Certain chemotherapies are also 
associated with a risk for hepatotoxicity.
Liver function will be monitored 
every 3 weeks during 
treatment.
Hepatic SAE definition and 
LFT monitoring/stopping rules 
added to protocols.  These 
instructions are comparable to 
those included in the 
prescribing information.


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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk 
Mitigation Strategy
Study Treatments
Cardiac events 
(decreased LVEF)
HER2 targeted agents are associated with 
decreased LVEFs.  The rate of LVEFs 
was numerically higher in the dual 
blockade arm (6% incidence of LVEF AEs) 
compared to the lapatinib monotherapy 
arm (2% incidence of LVEF AEs) in 
EGF104900.  Most of the cardiac SAEs 
were asymptomatic and reversible events 
of decreased ejection fraction.  The 
frequency of cardiac events was higher in 
the dual blockade treatment group (7%) 
compared with 2% in the lapatinib group in 
EGF104900.  This is consistent with the 
established safety profiles of lapatinib and 
trastuzumab.
Routine monitoring of LVEF 
every 12 weeks.
Cardiac SAE definition and 
monitoring rules added to 
protocols.  Comparable 
instructions included in 
prescribing information.
Diarrhea
Diarrhea is a recognised AE associated 
with tyrosine kinase inhibition.  Diarrhea 
is one of the most commonly reported AEs 
with lapatinib treatment.  More subjects 
experienced diarrhea with Dual blockade
(62%, with 8% of subjects reporting Grade 
3 or 4 events) compared with the lapatinib 
arm (48%, with 7% of subjects reporting 
Grade 3 or 4 events) in EGF104900.  
Diarrhea was generally manageable with 
standard treatments and resolved without 
dose interruption.
Implementation of diarrhea 
management guidelines in the 
protocol.  
Rash
Rash/skin toxicity is a recognized adverse 
event associated with tyrosine kinase 
inhibition and more profoundly with TKi 
that target EGFR. This toxicity is a 
common AE with lapatinib and 
trastuzumab treatment.  The incidence of 
rash did not increase with the addition of 
trastuzumab to lapatinib.  In EGF104900, 
35 subjects (23%) in the Dual blockade
arm and 43 subjects (29%) in the lapatinib 
arm experienced rash.  With the 
exception of one Grade 3 rash event in the 
lapatinib arm, all events of rash were 
Grade 1 or 2 and did not lead to SAEs or 
require withdrawal of a subject from the 
study.
Implementation of rash 
management guidelines in the 
protocol.


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Potential Risk of 
Clinical 
Significance
Data/Rationale for Risk 
Mitigation Strategy
Study Treatments
Nausea/vomiting
Nausea/vomiting are known effects of 
small-molecule tyrosine kinase inhibitors 
and certain types of chemotherapy.  The 
incidence of nausea was 28% for each 
arm in EGF104900.  The incidence of 
nausea and vomiting varies by the type of 
chemotherapy used in combination with 
trastuzumab.
Routine safety assessments 
every 3 weeks will monitor for 
these effects.
Myelosuppression
/Neutropenia
Chemotherapy is associated with 
myelosuppressive effects including 
neutropenia.  Incidence rates vary with 
the combination of different 
chemotherapies with trastuzumab.
There were few cytopenias in EGF104900 
which studied Dual blockade in the 
absence of chemotherapy.
Routine monitoring for 
hematological abnormalities 
will be conducted every 3
weeks
Study Procedures
Biopsy
Complications of a biopsy include pain 
(typically mild), haemorrhage; infection; 
adverse response to anesthesia; 
pneumothorax and/or pleural effusion
Subject may be required to lie 
flat for several hours following 
the procedure to control 
bleeding.  Pain can be 
managed with small amounts 
of narcotics.
Abbreviations: AE, adverse event; ; LFT, liver function test; LVEF, left ventricular ejection fraction; 
SAE, serious adverse event.
1.3.2.
Benefit Assessment
A subject enrolled to trastuzumab in combination with lapatinib will have the potential 
benefit of receiving an active anti-HER2 therapy without the associated toxicities of 
chemotherapy.  Subjects enrolled to trastuzumab in combination with chemotherapy of 
the investigator’s choice will receive treatment with the common clinical practice of 
continuation of trastuzumab in combination with chemotherapy.
Subjects enrolled in the study will contribute to the process of developing new therapies 
in this area of unmet medical need as well as contribute to the understanding of the 
evolution of a tumor as it disseminates from the primary tumor and is treated in the 
metastatic setting with HER2-based therapy including trastuzumab.
In addition, the biopsy of a metastatic site provides potential data to inform the 
investigator on the treatment of the subject’s metastatic disease.  As the HER2 and 
hormone receptor status of a metastatic site may diverge from the primary breast cancer 


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sample, confirmation of HER2 and hormone receptor status is recommended by 
European Society for Medical Oncology (ESMO) guidelines.  Loss of HER2 expression 
would severely limit the efficacy of subsequent anti-HER2 therapies.  Likewise, loss of 
hormone receptor status would make the patient unlikely to benefit from endocrine
therapy with an aromatase inhibitor.
1.3.3.
Overall Benefit: Risk Conclusion
Lapatinib is a tyrosine kinase inhibitor that is indicated in the treatment of MBC.  The 
scientific rationale for combination treatment with lapatinib and trastuzumab is robust.  
Lapatinib in combination with trastuzumab has been shown to prolong PFS and reduce 
the risk of death by 26% in women with HER2-positive breast cancer who have been 
previously treated with trastuzumab and chemotherapy.  
Both hormone receptor-positive and hormone receptor-negative subjects benefited from 
Dual blockade.  However, the benefit of Dual blockade was not limited to the subjects 
with hormone receptor-negative disease in EGF104900 or HER2 enriched in a
neoadjuvant study with Dual blockade [Carey, 2013].  Therefore, a more complete 
blockade of HER2 via the combination of lapatinib and trastuzumab should control this 
disease in the absence of chemotherapy regardless of breast molecular subtype.
Cumulative safety data for lapatinib demonstrate that identified risks include 
hepatobiliary events, cardiac events (decreased LVEF), interstitial lung 
disease/pneumonitis, diarrhea, rash, nausea/vomiting, and neutropenia.  The majority of 
these events are class effects associated with tyrosine kinase inhibitors.  The ICF will
communicate the identified/potential risks associated with the study.  Specific 
monitoring and guidance in the protocol will manage these risks as has been done in 
other studies.  


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2.
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary

To evaluate changes in the expression of 
biomarkers associated with immunomodulation. 

Changes in gene and/or protein expression 
profile within each arm on a prespecified set of 
biomarkers associated with immunomodulation 
between the pre-treatment biopsy and disease 
progression biopsy.  The HER2-enriched and 
Non-HER2-enriched cohorts will be analyzed 
separately.
Secondary

To describe ORR, CBR, and PFS on study 
treatment in subjects treated with trastuzumab in 
combination with lapatinib or chemotherapy.

To explore association between changes in 
biomarkers and PFS.

To describe the safety and tolerability of 
trastuzumab in combination with lapatinib and of 
trastuzumab in combination with chemotherapy.

Investigator-assessed PFS defined as the 
interval of time between randomization and 
disease progression or death due to any cause; 
investigator-assessed ORR defined as
percentage of subjects with a CR or PR; and 
CBR defined as percentage of subjects with a 
CR, PR, or SD for at least 6 months

Describe if a change at disease progression in 
biomarker correlates with PFS.

Summary AE profile for both treatment arms
Abbreviations: AE, adverse event; CBR, clinical benefit rate; CR, complete response; HER, human epidermal 
growth factor receptor; 
 PD, progressive disease; PFS, progression-
free survival;PR, partial response; ORR, overall response rate; SD, stable disease.


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3.
STUDY DESIGN
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns.  Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Table 9), are required for study conduct.
This is a Phase II, 3 arm, open-label study (See Figure 1 for study schema).  The subject 
population is subjects with HER2-positive metastatic breast cancer who received at least 
two prior regimens containing trastuzumab in the metastatic setting.  The last regimen 
must have included trastuzumab plus chemotherapy.   The molecular subtype of a
biopsy of a metastatic site will be centrally determined by the Prosigna assay.  HER2 
and hormone receptor status will be centrally determined.  Subjects with centrally 
determined HER2 positive disease will be allocated to one of two cohorts depending on 
the molecular subtype of their biopsy:  

COHORT 1 - HER2-Enriched contains HER2+ subjects with a HER2-enriched 
molecular subtype.  Subjects with HER2-enriched molecular subtype will be 
randomized 1:1 to either:
o
ARM A - Trastuzumab in combination with lapatinib: lapatinib 1000 
mg PO once daily plus trastuzumab (loading dose of 8 mg/kg) followed by 
the maintenance dose of 6 mg/kg IV q3weekly.  Weekly trastuzumab 
(loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV 
weekly is acceptable at the discretion of the investigator. Subjects with 
hormone receptor (ER and/or PgR)-positive, HER2-positive MBC 
randomized to this arm will be required to be treated with an aromatase 
inhibitor of the investigator’s choice.
o
ARM B - Trastuzumab in combination with chemotherapy: 
trastuzumab (loading dose of 8 mg/kg) followed by maintenance dose of 6 
mg/kg IV q3weekly plus chemotherapy of the investigator’s choice.  
Weekly trastuzumab (loading dose of 4 mg/kg) followed by maintenance 
dose of 2 mg/kg IV weekly is acceptable at the discretion of the 
investigator.  An aromatase inhibitor may be used for hormone receptor-
positive, HER2-positive subjects at the discretion of the investigator.

COHORT 2 - Non-HER2-Enriched contains HER2+ subjects with luminal A, 
luminal B and basal-like molecular subtypes
o
Subjects in the Non-HER2 enriched cohort will be assigned to a third arm:  
ARM C - Trastuzumab in combination with lapatinib: lapatinib 1000 
mg PO once daily plus trastuzumab (loading dose of 8 mg/kg) followed by
the maintenance dose of 6 mg/kg IV q3weeks.  Weekly trastuzumab 
(loading dose of 4 mg/kg) followed by maintenance dose of 2 mg/kg IV 
weekly is acceptable at the discretion of the investigator. Subjects with 
hormone receptor (ER and/or PgR)-positive, HER2-positive MBC 
randomized to this arm will be required to be treated with an aromatase 
inhibitor of the investigator’s choice.


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Figure 1
Study Schema
Biopsies of a metastatic site will be collected at two timepoints: screening (pre-treatment) 
and at disease progression (progression).  The primary objective is to evaluate changes 
in biomarkers associated with immunomodulation, between the pre-treatment biopsy and 
the progression biopsy within each arm.  Radiologic disease assessments will be 
performed every 9 weeks until 54 weeks then every 24 weeks thereafter until disease 
progression, death, or withdrawal from study treatment for any reason (e.g. unacceptable 
toxicity).  
 
Safety assessments including physical examination, Eastern Cooperative Oncology 
Group (ECOG) performance status, vital signs and weight, adverse event (AE) 
monitoring, and laboratory tests (complete blood count, blood chemistry including liver 
function test) will be done at screening and then every 3 weeks for the duration of therapy.  
Additional safety assessments, such as cardiac monitoring, are required for all subjects 
every 12 weeks until discontinuation from the study therapy.
All subjects will receive study treatment until disease progression, death, unacceptable 
toxicity, subject withdrawal of consent or any other reasons mentioned in section 4.2.1.  


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In case of disease progression during the treatment period, the subject will be followed-
up for 30 days for safety evaluation and no further study-specific follow-up will be 
carried out; the subject will be considered as having completed the study. 
Similarly, in case of disease progression after the treatment period (i.e. in subjects who 
discontinued for any reasons other than disease progression) and before the end of the 
study (defined as all subjects having completed the study, i.e. presented with disease 
progression, started new anti-cancer therapy, died or withdrew from the study (whichever 
came first) during the study treatment period or the follow-up period after discontinuation 
due to any reasons other than disease progression), no further study-specific follow-up 
will be carried out; the subject will be considered as having completed the study. 
In case of study treatment discontinuation for any reasons other than disease progression, 
the subject will be followed-up for safety and efficacy assessments until disease 
progression, new anticancer therapy, death, withdrawal of consent or end of study, 
whichever comes first. 
The data cut-off for the primary analysis will be defined at 12 months after the last 
subject enrolled in the study or the last subject progressed/withdrew, whichever is earlier. 
Following the cut-off date for the primary analysis, the study will remain open. Ongoing 
subjects will continue to receive study treatment and be followed as per the schedule of 
assessments, as long as subjects derive benefit from lapatinib. The end of study defined 
as the earliest occurrence of one of the following:
•       All patients have died or discontinued from the study
•       Another clinical study becomes available that can continue to provide lapatinib
in this patient population and all subjects ongoing are eligible to be transferred to that 
clinical study 
•       At the end of the study, every effort will be made to continue provision of study 
treatment outside this study through an alternative setting to subjects who in the opinion 
of the Investigator are still deriving clinical benefit. 
Due to difficulty in enrolling subjects into this trial, future enrolment will be halted and 
the study will be terminated early. 
At the time of stopping the enrollment, the sponsor will notify all the investigators in 
writing. Subjects who have signed consent prior to receipt of the written notification, if
determined eligible for a cohort (HER2-enriched or Non-HER2-enriched) will be 
permitted to continue in the study. 
The term ‘study treatment’ is used throughout the protocol to generally describe the 
combination of products or individual products under evaluation in this protocol.  When 
referring to specific compounds or one combination, the compound names or other 
designation will be used.  
Refer to Section 5.8 for guidelines for adverse events of special interest and dose 
modifications and Section 5.9.1 for liver stopping criteria.
Subject completion is defined in Section 4.


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Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM).  The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety including the biopsy and blood specimen collection procedures.
3.1.
Discussion of Design
This study is a post-approval commitment with regulatory authorities.  It is designed 
with the primary endpoint to evaluate the changes in biomarkers associated with
immunomodulation between the pre-treatment and disease progression biopsy.  
Subjects will undergo a biopsy at screening (pre-treatment biopsy) that will be used to 
determine the breast cancer molecular subtype of the tumor.  HER2 and hormone 
receptor status will be centrally determined on the pre-treatment biopy, tumors that are 
HER2-enriched have features that suggest they are more likely to be dependent on HER2 
signaling and in effect may modulate pathways that differ from tumors that are not 
HER2-enriched.  Therefore, two cohorts will be utilized in this study, a HER2-enriched 
cohort and Non-HER2-enriched cohort. A prospective clinical trial in the metastatic 
setting evaluating clinical outcome of anti-HER2 therapy using the “HER2 enriched” 
definition has not been reported. Additionally, the benefit of dual blockade from the 
EGF104900 study was seen in the ITT population which included all HER2 positive 
subjects as defined by standard histopathologic criteria. At this time, there is a lack of 
knowledge regarding any molecular mechanism(s) that might modulate response in a 
HER2 enriched population compared to a standard defined HER2 positive population.  
Therefore, this study will also enroll a standard HER2 positive population as defined by 
standard histopathologic criteria with non-HER2-enriched subtype that will be assigned 
to treatment with lapatinib in combination with trastuzumab. Both cohorts will be treated 
with dual blockade (trastuzumab in combination with lapatinib). The inclusion of these 
two cohorts was discussed and agreed upon with the scientific advice working party of 
the Committee for Medicinal Products for Human Use (CHMP).  
3.1.1.
Use of 3-weekly trastuzumab dosing
The initial studies leading to the approval of trastuzumab in HER2-positive metastatic 
breast cancer (MBC), utilized a weekly dosing schedule for trastuzumab of 4 mg/kg, 
followed by 2 mg/kg [Vogel, 2002; Cobleigh, 1999, Slamon, 2001].  This was based on 
the hypothesis that trastuzumab had an elimination half-life (t½) of 6 days.  However, 
data have subsequently shown that trastuzumab t½ is closer to 28 days, which led to the 3-
week dosing schedule of 8 mg/kg, followed by 6 mg/kg [Bruno, 2005]. 
The efficacy of the 3-weekly dosing schedule has been clinically validated in several 
studies.  A Phase II study evaluated the safety and efficacy of trastuzumab given every 3 
weeks in combination with paclitaxel as first- or second-line treatment for metastatic 
breast cancer (MBC) [Leyland-Jones, 2003].  In this open-label study of trastuzumab-
naive subjects with HER2-positive MBC, the mean trastuzumab t½ ranged from 18-27 
days, and reached steady-state levels at approximately Cycle 8 (i.e. Week 24). Serum 
trough levels for the 3-week dosing were similar to the regulatory approved monotherapy 
trastuzumab weekly regimen [Cobleigh, 1999], exceeded the minimum targeted trough 


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level of 20 g/mL prior to administration of the second cycle of therapy, and were 
subsequently higher with continued treatment (50.1 g/mL Cycle 4; 72.3 g/mL Cycle 
12). This regimen was thought to be efficacious with a reported objective response rate of 
59%.  This compares favourably with the rate of 41% observed with trastuzumab 
administered weekly with paclitaxel administered every 3 weeks as first-line treatment of 
HER2-positive MBC in a randomized study [Slamon, 2001], and also with a rate of 57% 
observed in a non-randomized Phase II study of weekly trastuzumab in combination with 
weekly paclitaxel [Seidman, 2002].
Similarly, Baselga and colleagues confirmed this finding in a Phase II study of 
trastuzumab monotherapy dosed every 3 weeks given as first-line treatment for HER2-
positive MBC [Baselga, 2005]. The average exposure on the 3 week schedule at any 
given time was comparable with weekly dosing schedules. The mean trough levels 
exceeded 27 g/mL at Cycle 2 and increased to approximately 50 g/mL by Cycle 6.  
The cumulative dose was identical between the 2 scheduling regimens. Additionally, 
efficacy did not seem to be altered, as the study reported 23% response rate for centrally 
confirmed HER2-positive disease, similar to the response rate of 15% observed in the 
weekly trastuzumab monotherapy trial [Cobleigh, 1999].
The trastuzumab Summary of Product Characteristics recommends administration on a 
weekly schedule (4 mg/kg initial loading dose, then 2 mg/kg thereafter) for MBC and 
either a weekly or q3weekly (8 mg/kg initial loading dose, then 6 mg/kg thereafter) 
schedule for early breast cancer [Trastuzumab Summary of Product Characteristics, 
2013].  The q3weekly schedule, however, has been incorporated in many clinical trials 
for MBC. In the adjuvant setting, clinical studies of adjuvant trastuzumab with 
chemotherapy utilized both the weekly and 3-weekly trastuzumab dosing schedules 
[Romond, 2005; Piccart-Gebhart, 2005], and reported no difference between either 
disease free survival DFS or OS. Therefore, dosing scheduling of trastuzumab was 
demonstrated to have no impact on efficacy.  Furthermore, the q3weekly schedule is 
more convenient for subjects, as it reduces the number of infusions received as well as 
the number of visits to the clinic.  
As such, subjects will be allowed to use either the weekly trastuzumab dosing schedule or 
the q3weekly trastuzumab dosing schedule at the discretion of the investigator.
3.1.2.
Endocrine and HER2-Directed Therapy for Hormone-Receptor 
Positive, HER2-Positive MBC
Preclinical and clinical evidence supports that more complete HER-2 blockade occurs 
with the use of both lapatinib in combination with anti-estrogen therapy to avoid escape 
of upregulation of the estrogen receptor.  As a result, endocrine therapy with an 
aromatast inhibitor of the investigator’s choice will be mandated for the lapatinib 
trastuzumab treatment arm. 
The benefit of combining endocrine with an aromatase inhibitor and HER2-targeted 
therapy in the treatment of HER2-positive MBC has been demonstrated in 2 Phase III 
randomized studies.  Lapatinib in combination with letrozole demonstrated a 
statistically significant improvement in investigator-evaluated PFS compared with 


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letrozole plus placebo (HR = 0.71; 95% CI 0.53 to 0.96; stratified log-rank p = 0.019), 
indicating a 29% reduction in risk of disease progression.  Median PFS in this first-line 
setting was 35.4 weeks (95% CI 24.1 to 39.4) compared with 13.0 weeks (95% CI 12.0, 
to 23.7), respectively [Johnston, 2009].
In the Phase III TaNDEM trial, anastrozole was compared with anastrozole plus 
trastuzumab as first-line treatment for postmenopausal women with HER2-positive, 
hormone receptor-positive MBC.  The combination of anastrozole plus trastuzumab 
treatment doubled median PFS from 2.4 months to 4.8 months (approximately 10 weeks 
to 21 weeks; (anastrozole compared with combination treatment, respectively), with a HR 
of 0.63 (95% CI 0.47 to 0.84; log-rank p = 0.0016) [Kaufman, 2009].
Investigators will choose the aromatase inhibitor administered to subjects in the 
trastuzumab-lapatinib combination arm.  Premenopausal subjects with hormone 
receptor-positive disease should receive ovarian ablation/suppression (luteinizing 
hormone-releasing hormone analogue, surgery or ovarian irradiation) in combination 
with an aromatase inhibitor (AI).  Postmenopausal subjects should receive an AI of the 
investigator’s choice.  As in clinical practice, third generation AIs are used 
interchangeably and are perceived to be equivalent by the clinicians.
The drug interaction potential of the AIs has been reviewed in literature [Lonning, 2003]. 
Based on the pharmacokinetics of lapatinib and the AIs the only relevant mechanisms for 
a potential interaction would involve metabolism mediated by CYP3A4. There is no 
evidence that the AIs interact with ABC transporters.  Based on assessment of available 
data, the potential for drug-drug interactions between lapatinib and AI is very low. There 
are no apparent pharmacokinetic considerations related to the combined therapeutic use 
of these agents.
The combination of Dual blockade with aromatase inhibitors and tamoxifen was studied 
in the ALTTO (EGF106708) trial.  As of February 2014, all subjects have completed 
treatment and no pharmacovigilance safety signal has emerged.
3.1.3.
Biomarkers and the Timing of Tumor Biopsies
This study will have tumor biopsies taken at screening (pre-treatment biopsy) and at 
disease progression (progression biopsy) to analyze biomarkers associated with 
immunomodulation potentially connected to an impact on the response to chemotherapy 
(see Section 1.2.3).  The primary endpoint will evaluate changes in these biomarkers 
measured in the progression biopsy compared to the pre-treatment biopsy.  
Analysis of these candidate biomarkers in pre-treatment tumor tissue and at disease 
progression may provide indicative information on immunomodulation, as an effect of 
treatment.
The site of the pre-treatment biopsy and progression biopsy should remain the same if 
possible. CNS and bone biopsies are excluded organs. 


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4.
SUBJECT SELECTION AND DISCONTINUATION/ 
COMPLETION CRITERIA
4.1.
Subject Selection Criteria
4.1.1.
Number of Subjects
Since the initiation of this trial, the enrollment has been poor due to lack of interest by 
investigators and patients. Therefore, future enrolment will be halted and the study will 
be terminated early. Up to 31 Jul 2016, 29 patients have been enrolled.
4.1.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on study treatment that may impact subject eligibility is provided in 
the IB/IB supplement, product label for lapatinib [TYVERB™Package Leaflet, 2015], the 
study procedures manual (SPM), and the product labels for trastuzumab, paclitaxel, 
docetaxel, nab paclitaxel, capecitabine, gemcitabine, and vinorelbine [Herceptin Package 
Insert, 2014; Xeloda Package Insert, 2006; Abraxane Package Insert,2005; Gemzar
Package Insert, 2007; Taxotere Package Insert, 2004;Taxol Package Insert, 2000; 
Navelbine Package Insert, 2002].
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability, or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is essential.
Subjects eligible for enrollment in the study must meet all of the following criteria:
1.
Signed written informed consent
2.
Female 18 years 
3.
Histologically or cytologially confirmed invasive breast cancer with distant 
metastasis
4.
Subjects must have at least one measurable lesion per Response Evaluation Criteria 
in Solid Tumors (RECIST) 1.1 [Eisenhauer, 2009]
Note:  Biopsied lesions should not be used as target lesions.
5.
Documentation of HER2 overexpression or gene amplification, in the invasive 
component of either the primary tumor or metastatic disease site as defined as:

3+ by IHC 
and/or

HER2/neu gene amplification by fluorescence, chromogenic, or silver in situ 
hybridization [FISH, CISH or SISH;6 HER2/neu gene copies per nucleus or a 
FISH, CISH, or SISH test ratio (HER2 gene copies to chromosome 17 signals)
of ≥2.0 OR HER2/chromosome 17 ratio 2.0 with average HER2 copy number 
6 signals/cell nucleus];


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6.
Centrally determined HER2-positive, hormone receptor status, breast molecular 
subtype by PAM50 on the pre-treatment biopsy of metastatic lesion obtained during 
screening
Note:  Biopsied lesions should not be used as target lesions.
7.
Progression on at least 2 lines of anti-HER2-targeted therapies for MBC 
8.
Documented radiological disease progression during the most recent treatment 
regimen for metastatic disease
9.
Most recent treatment regimen for metastatic disease must include trastuzumab and 
chemotherapy. 
Note:  Trastuzumab emtansine (T-DM1) is considered acceptable as prior 
trastuzumab/chemotherapy regimen 
10. Agreement to provide 2 tumor biopsies 
11. Prior treatment with pertuzumab, lapatinib, and/or trastuzumab emtansine is 
allowed; however, the last treatment for MBC must not include trastuzumab in 
combination with pertuzumab.  
12. Subjects with radiographically stable CNS metastases, defined as radiographically 
stable on the previous 2 brain imaging scans, asymptomatic, and off systemic 
steroids and anticonvulsants for at least 1 month are eligible; treatment with 
prophylactic anticonvulsants is permitted unless listed under Prohibited Medications
(Section 6)
13. Discontinuation of all prior chemotherapy, immunotherapy, or biological therapy at 
least 3 weeks prior to the first dose of study treatmentis required.  
Note: Discontinuation of trastuzumab is not necessary.
14. All treatment related toxicities, except alopecia, must have recovered to Grade 1 or 
better (Common Terminology Criteria for Adverse Events (CTCAE); version 4.0) 
prior to administration of the first dose of study treatment.
15. Baseline LVEF ≥50% as measured by ECHO or MUGA and above the testing 
institution’s lower limit of normal
16. QTc <450 msec or QTc <480 msec for patients with bundle branch block. The 
QTc is the QT interval corrected for heart rate according to either Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), or another method, machine or manual 
overread. 
For subject eligibility and withdrawal, QT correction formula QTcB will be used. 
For purposes of this data analysis, Bazett's formula will be used as the primary 
method of calculating the corrected QT interval. The QTc should be based on either 
a single ECG or an average of 3 sequential ECGs obtained within 24 hours of each 
other.
The QTc should be based on single or averaged QTc values of triplicate ECGs 
obtained over a brief recording period. 


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17. Women of childbearing potential must have a negative serum pregnancy test within 
7 days prior to the first dose of study treatment and agree to use effective 
contraception, as defined in Section 7.4.7, during the study and for 30 days 
following the last dose of study treatment.  
18. ECOG performance status of 0 or 1 (Section 12.3)
19. Completion of screening and baseline assessments 
20. Able to swallow and retain orally administered medication and does not have any 
clinically significant gastrointestinal abnormalities that may alter absorption such as 
malabsorption syndrome or major resection of the stomach or bowels.
21. At least 4 weeks must have elapsed since the last surgery and 2 weeks must have 
elapsed since radiotherapy
22. Adequate baseline organ function as defined in Table 2
Table 2
Baseline Laboratory Values
Screening laboratory values should be used to confirm subject eligibility.  Laboratory 
results may be retested if necessary to confirm eligibility.
SYSTEM
LABORATORY VALUES
Hematologic1
  ANC 
1.5 109/L
  Hemoglobin
9.0 g/dL (after transfusion if needed)
  Platelets
100 109/L
Hepatic
  Albumin
2.5 g/dL
  Serum bilirubin
1.25 x ULN2
 AST and ALT
2.5 ULN 
Renal
Calculate creatinine clearance,3
40 mL/min
1.
These values must be independent of growth factor support  and stable for at least one 
week post transfusion.
2.
With the exception of those subjects who have Gilbert’s syndrome; the bilirubin in these 
subjects should be at their baseline
3.
Calculated by the Cockcroft and Gault method. (Refer to Appendix 9 for more details)
Abbreviations:  ANC, absolute neutrophil count; ALT, alanine aminotransferase; AST, 
aspartate aminotransferase; ULN, upper limit of normal.
French subjects: In France, a subject will be eligible for inclusion in this study only if 
either affiliated to or a beneficiary of a social security category.


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4.1.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.
Subjects meeting any of the following criteria must not be enrolled in the study:
1.
Lactating female
Note:  Women with potential to have children must be willing to practice 
acceptable methods of birth control during the study
2.
Bone-only disease and/or disease that cannot be biopsied.
3.
Unstable CNS metastases or leptomeningeal carcinomatosis not considered 
radiographically stable (as defined above in inclusion criterion 12)
Note:  Subjects with radiographically stable central nervous system (CNS) 
metastases are defined as radiographically stable on the previous 2 brain imaging 
studies, asymptomatic, and off systemic steroids and anticonvulsants for at least 1 
month; treatment with prophylactic anticonvulsants is permitted unless listed under 
Prohibited Medications
4.
Any serious and/or unstable pre-existing medical, psychiatric disorder, or other 
conditions including concurrent disease that could interfere with subject’s safety, 
obtaining informed consent, or compliance with the study procedures.  
5.
Serious cardiac illness or medical condition including but not confined to:

Uncontrolled arrhythmias (e.g. ventricular tachycardia, high-grade
atrioventricular (AV)-block, supraventricular arrhythmias which are not 
adequately rate-controlled);

Angina pectoris requiring antianginal medication;

History of congestive heart failure or systolic dysfunction (LVEF <50%);

Documented myocardial infarction <6 months from study entry;

Evidence of transmural infarction on ECG;

Poorly controlled hypertension (e.g. systolic >160mm Hg or diastolic >100mm 
Hg);

Clinically significant valvular heart disease.
6.
Current active hepatic or biliary disease (with exception of subjects with Gilbert’s 
syndrome, asymptomatic gallstones, liver metastases, or stable chronic liver disease 
per investigator assessment)
7.
Any clinically significant gastrointestinal abnormalities that may alter absorption 
such as malabsorption syndrome or major resection of the stomach or bowels as well 
as subjects with ulcerative colitis are also excluded
8.
Any prohibited medication as described in Section 6.2


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9.
Prior treatment with trastuzumab in combination with lapatinib or prior treatment 
with an irreversible inhibitor of the intracellular domain of the HER2 receptor such 
as neratinib
10. Last treatment for metastatic disease including trastuzumab in combination with 
pertuzumab
11. Administration of an investigational drug within 30 days or 5 half-lives, whichever is 
longer, preceding the first dose of study treatment
12. A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to any of the study drugs or their excipients that, in the opinion of 
the investigator or medical lead, contraindicates participation
French subjects must not have participated in any study using an investigational drug 
during the previous 30 days.
4.2.
Permanent Discontinuation from Study Treatment and 
Subject Completion Criteria
4.2.1.
Permanent Discontinuation from Study Treatment
Discontinuation Criteria for patient studies if any of the following criteria are met:

QTc >500msec 

Uncorrected QT >600msec

Change from baseline: QTc > 60 msec*
These criteria should be based on the average QTc value of triplicate ECGs. For 
example, if an ECG demonstrates a prolonged QT interval, obtain two more 
ECGs over a brief period, and then use the averaged QTc values of the three 
ECGs to determine whether the patient should be discontinued from the study.  
*This criterion is optional but should be strongly considered based on local 
regulatory requirements.
For subjects with underlying Bundle Branch Block: 
Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle Branch 
Block
<450msec
>500msec
450-480msec
≥530msec
Subjects will receive study treatment until disease progression, death, withdrawal of 
consent or any other reasons mentioned in this section, including unacceptable adverse 
event (as well as meeting stopping criteria for liver chemistry defined in Section 5.9 or 
for hematologic and other non-hematologic toxicity).  


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Study treatment may be permanently discontinued for any of the following reasons:

deviation(s) from the protocol

request of the subject or proxy

investigator’s discretion

subject is lost to follow-up

study is closed or terminated

Subject’s own request for reasons other than those above
All subjects who may require permanent discontinuation of 1 of the 2 study treatment
products in a given treatment combination must discontinue both study treatment
products in that combination.  
In addition, study treatment will be discontinued if the sponsor discontinues the study due 
to safety reasons.
The primary reason for permanent discontinuation of study treatment must be clearly 
documented in the subject’s medical record and recorded in the electronic case report 
form (eCRF).
All subjects who discontinue from study treatment due to an AE or any other reasons
other than disease progression will have safety and efficacy assessments performed until 
disease progression, new anticancer therapy, death, withdrawal or until the end of study 
(defined as all subjects having completed the study, i.e. presented with disease 
progression, started new anti-cancer therapy, died or withdrew from the study (whichever 
came first) during the study treatment period or the follow-up period after discontinuation 
due to any reasons other than disease progression) as specified in the Time and Events 
table (Table 9) and results documented in the eCRF.
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will 
be recorded as the primary reason for permanent discontinuation on the CRF.  Once a 
subject permanently discontinues study treatment, the subject will not be allowed to be 
retreated.
Subjects with abnormal clinical or laboratory findings that are believed to be treatment-
related will be followed until the condition resolves or until laboratory findings are not 
considered clinically significant.
Refer to details regarding liver chemistry abnormalities and withdrawal as specified in 
Section 5.9.1.
In case of disease progression during the treatment period, the subject will be followed-
up for 30 days for safety evaluation and no further study-specific follow-up will be 
carried out; the subject will be considered as having completed the study. Similarly, in 
case of disease progression after the treatment period (i.e. in subjects who discontinued 


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for any reasons other than disease progression) and before the end of the study (defined 
as all subjects having completed the study, i.e. presented with disease progression, started
new anti-cancer therapy, died or withdrew from the study (whichever came first) during 
the study treatment period or the follow-up period after discontinuation due to any 
reasons other than disease progression), no further study-specific follow-up will be 
carried out; the subject will be considered as having completed the study. 
Following the cut-off date for the primary analysis (defined at 12 months after the last 
subject enrolled in the study or the last subject progressed/withdrew, whichever is earlier), 
the study will remain open. Ongoing subjects will continue to receive study treatment and 
be followed as per the schedule of assessments, as long as subjects derive benefit from 
lapatinib. The end of study defined as the earliest occurrence of one of the following:
•       All patients have died or discontinued from the study
•       Another clinical study becomes available that can continue to provide lapatinib
in this patient population and all subjects ongoing are eligible to be transferred to that 
clinical study 
At the end of the study, every effort will be made to continue provision of study 
treatment outside this study through an alternative setting to subjects who in the opinion 
of the Investigator are still deriving clinical benefit. 
4.2.2.
Subject Withdrawal from Study
A subject may voluntarily discontinue participation in this study at any time.  The 
investigator may also, at his or her discretion, discontinue the subject from participating 
in this study at any time.
Subjects will also be withdrawn from the study if there is a major deviation(s) from the 
protocol that occurred by the investigator or by the subject, without obtaining prior 
consent of Novartis.  
If the subject is prematurely discontinued from participation in the study for any reason, 
the investigator must make every effort to perform the relevant evaluations – please refer 
to Section 7 “Time and Events Schedule” (Table 9) for complete details.  Data are to be 
recorded in the eCRF.  Subjects with abnormal clinical or laboratory findings that are 
believed to be treatment related will be followed until the condition resolves or until 
laboratory findings are not considered clinically significant.
If any of the trial subjects are lost to follow-up prior to subject completion, contact will 
initially be attempted through the trial research nurse and the lead investigator at each 
centre. Where these attempts are unsuccessful, the subject’s doctor should be contacted 
and asked to contact the subject or her/his family and provide follow-up information to 
the recruiting centre. It is only after at least 3 attempts to contact have been unsuccessful, 
that a subject may be declared “Lost to follow-up”. Subjects declared lost to follow-up 
that resume their visits should be followed as per the protocol schedule of assessments.


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4.2.3.
Subject Completion
A subject will be considered to have completed the study if the subject presents with 
disease progression, starts a new anti-cancer therapy, dies or withdraws from the study, or 
the study ends, whichever comes first.  Document the cause of completion in the eCRF.
A subject will be considered to have withdrawn from the study if the subject has not 
experienced disease progression and is lost to follow-up, has withdrawn consent, or has 
withdrawn at the investigator’s discretion.
All subjects will receive study treatment until disease progression, death, unacceptable 
toxicity, subject withdrawal of consent or any other reasons mentioned in section 4.2.1.  
In case of disease progression during the treatment period, the subject will be followed-
up for 30 days for safety evaluation and no further study-specific follow-up will be 
carried out; the subject will be considered as having completed the study. Similarly, in 
case of disease progression after the treatment period (i.e. in subjects who discontinued 
for any reasons other than disease progression) and before the end of the study (defined 
as all subjects having completed the study, i.e. presented with disease progression, started
new anti-cancer therapy, died or withdrew from the study (whichever came first) during 
the study treatment period or the follow-up period after discontinuation due to any 
reasons other than disease progression), no further study-specific follow-up will be 
carried out; the subject will be considered as having completed the study. 
In case of study treatment discontinuation for any reasons other than disease progression, 
the subject will be followed-up for safety and efficacy assessments until disease 
progression, new anticancer therapy, death, withdrawal of consent or end of study, 
whichever comes first. 
Following the cut-off date for the primary analysis (defined at 12 months after the last 
subject enrolled in the study or the last subject progressed/withdrew, whichever is earlier), 
the study will remain open. Ongoing subjects will continue to receive study treatment and 
be followed as per the schedule of assessments, as long as subjects derive benefit from 
lapatinib. The end of study defined as the earliest occurrence of one of the following:
•       All patients have died or discontinued from the study
•       Another clinical study becomes available that can continue to provide lapatinib
in this patient population and all subjects ongoing are eligible to be transferred to that 
clinical study 
At the end of the study, every effort will be made to continue provision of study 
treatment outside this study through an alternative setting to subjects who in the opinion 
of the Investigator are still deriving clinical benefit.
Data collection will continue until a subject has completed or discontinued the study.


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4.3.
Screening/Run-in Failures
A subject is considered to be a screen/baseline failure if the subject signs the informed 
consent form but withdraws before enrolment in treatment arm, or does not meet all 
inclusion and exclusion criteria.  All potential subjects who are screened for enrollment
in this study including screening/baseline failures will be listed on the Subject Screening 
Log/Identification List.  Reasons for exclusion will be recorded for potential subjects 
who do not enter the study.
5.
STUDY TREATMENTS
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design.  Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments. When referring to specific compounds or one combination, the compound 
names or other designation will be used.  
5.1.
Study Treatment and Reference Therapy
5.1.1.
Lapatinib
Commerically packed supplies or non-commerical lapatinib is supplied as 250-mg orange 
tablets that are oval, biconvex, and orange film-coated with 1 side plain and the opposite 
side debossed with FG HLS.  Each tablet contains 405 mg of lapatinib ditosylate 
monohydrate, equivalent to 250 mg lapatinib free base per tablet.  As additional 
formulations of lapatinib become available, equivalent doses of the new formulation can 
be used.  For more information regarding the physical and chemical properties of the 
drug substance and list of excipients, refer to the lapatinib summary of product 
characteristics [Lapatinib Summary of Product Characteristics, 2015].
Lapatinib will be provided to sites by Novartis. The contents of the label will be in 
accordance with all applicable regulatory requirements.
Under normal conditions of handling and administration, study treatmentis not expected 
to pose significant safety risks to site staff. A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available upon request.
Adequate precautions must be taken to avoid direct contact with the investigational 
product. The occupational hazards and recommended handling procedures are provided 
in the MSDS.
5.1.1.1.
Lapatinib Dosage and Administration

Lapatinib will be dispatched to the site only after receipt of required documents in 
accordance with applicable regulatory requirements and Novartis procedures.  
Only subjects enrolled in the study may receive lapatinib, in accordance with all 


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applicable regulatory requirements.  Only the site pharmacist or authorized site 
personnel may supply or administer lapatinib therapy.

Lapatinib will be dispensed to the subject on the first day of treatment, after it has 
been confirmed that the subject meets all eligibility criteria and all baseline and 
screening assessments have been completed and the results reviewed. Subjects 
will receive their re-supply of lapatinib therapy at the time of a scheduled visit.

Study staff will carefully instruct subjects on how to take lapatinib and the correct 
dose to take.  For example, subjects randomized to the lapatinib plus 
trastuzumab arm are to receive 1000 mg per day of lapatinib, so will be instructed 
to take 4 x 250 mg tablets once daily.  Subjects must take lapatinib either 1 hour 
(or more) before a meal or 1 hour (or more) after a meal (for example, 1 hour 
before or 1 hour after breakfast each day).  Lapatinib is taken continuously. A 
record of therapy administered to each subject must be maintained in the source 
documents (see Section 5.7).

Lapatinib dose modification guidelines are outlined in Section 5.2 and should be 
used for the management of treatment-related toxicities.  Subjects should be 
carefully instructed when any dose modifications occur.

NOTE: Lapatinib should NOT be taken with grapefruit or grapefruit juice.  
Grapefruit and grapefruit juice is not permitted for the duration of the study.

If a subject vomits after taking lapatinib, the subject should be instructed not to 
retake the dose.  Subjects should take the next scheduled dose of lapatinib 
therapy.  If vomiting persists then the subject should contact the investigator.  
However, if the tablets are clearly visually found after the vomiting incident then, 
in this circumstance, the dose may be repeated.
5.1.2.
Trastuzumab
Trastuzumab [Herceptin 2014] is a sterile, white to pale yellow, preservative-free 
lyophilized powder for intravenous (IV) administration.  Excipients in each vial 
include:  L-histidine hydrochloride, L-histidine, trehalose, and polysorbate 20, USP.    
Reconstitution with sterile water for injections for 150mg single-dose use vial or 
Bacteriostatic Water for Injection (BWFI), USP, containing 1.1% benzyl alcohol as a 
preservative for 440mg multi-dose vial, yields a solution containing 21mg/mL 
trastuzumab, at approximately pH 6.
Refer to Trastuzumab Product Information [Herceptin 2014] for additional details.
Trastuzumab will be sourced locally from commercial stock. Investigators are 
responsible for ensuring that subjects receive supplies of trastuzumab for the entire 
duration of the study, except in countries where Regulatory Authorities mandate that the 
Sponsor must supply all study treatment(s) required for study participation.  The 
contents of the label will be in accordance with all applicable regulatory requirements.


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5.1.2.1.
Trastuzumab Dosage and Administration
Trastuzumab will be administered on Day 1 of the start of lapatinib or in conjunction 
with the first cycle of chemotherapy, as an 8 mg/kg loading dose.  Subsequently, 
trastuzumab will be administered q3weekly as a 6 mg/kg maintenance dose.  At the 
discretion of the investigator, weekly trastuzumab can be given in either of the three 
treatment arms (loading dose 4mg/kg followed by weekly administration of 2mg/kg). 
Trastuzumab is administered by intravenous infusion and a 3-day window is allowed 
for scheduling for Day 1 of each cycle.  Dose reduction of trastuzumab is not allowed in 
this study.  Specific guidelines in case of dose delay of trastuzumab are outlined in 
Section 5.8.2 and should be used for the management of treatment-related toxicities.
5.1.3.
Chemotherapy
The specific chemotherapy used will be at the discretion of the investigator based on 
previous treatment and subject status at the time of study entry.  
Please note that Trastuzumab emtansine (T-DM1) is not acceptable as a 
trastuzumab/chemotherapy regimen for Arm B.   
Typical chemotherapies used in this setting are described below. However, the 
chemotherapy that could be used is not limited to these chemotherapies and is the choice
of the investigator
5.1.3.1.
Paclitaxel
Paclitaxel Injection is a clear colorless to slightly yellow viscous solution.  It is supplied 
as a non-aqueous solution intended for dilution with a suitable parenteral fluid prior to 
intravenous (IV) infusion.  Each mL of sterile nonpyrogenic solution contains 6 mg 
paclitaxel, 527 mg of purified Cremophor EL (polyoxythylated castor oil) and 49.7% 
(v/v) dehydrated alcohol, USP.  Paclitaxel is generally available in 30 mg (5 mL), 100 
mg (16.7 mL), and 300 mg (50 mL) multidose vials individually packaged in a carton.  
Refer to the product label for information regarding the physical and chemical properties 
of paclitaxel [Taxol Package Insert 2000].
5.1.3.2.
Docetaxel
Docetaxel is supplied as a viscous solution containing 40 mg/mL docetaxel in single-dose 
vials containing 20 mg or 80 mg of docetaxel in 0.5 mL or 2.0 mL polysorbate 80, 
respectively.  The concentrate for infusion (parenteral preparation to be diluted) will be 
accompanied by solvent (13% ethanol in water for injection).  Refer to the product label 
for information regarding the physical and chemical properties of docetaxel [Taxotere
Package Insert, 2004].
5.1.3.3.
Nab paclitaxel
Nab paclitaxel is supplied as a white to yellow, sterile, lyophilized powder for 
reconstitution with 20 mL of 0.9% sodium chloride injection, USP prior to IV solution.  
Each single-use vial contains 100 mg of paclitaxel and approximately 900 mg of human 


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albumin.  Each milliliter (mL) of reconstituted suspension contains 5 mg paclitaxel.  
Nab paclitaxel is free of solvents.  Refer to the product label for information regarding 
the physical and chemical properties of nab paclitaxel [Abraxane Package Insert, 2005].
5.1.3.4.
Capecitabine
Capecitabine is supplied as a biconvex, oblong, light peach and peach colored, film-
coated tablet for oral administration.  Each light peach colored tablet contains 150 mg 
capecitabine and each peach-colored tablet contains 500 mg capecitabine.  Each tablet 
contains inactive ingredients including anhydrous lactose, croscarmellose sodium, 
hydroxpropyl methylcellulose, microcrystalline cellulose, magnesium sterate.  The film 
coating contains hydroxpropyl methylcellulose, talc, titanium dioxide, and synthetic 
yellow and red iron oxides.  Refer to the product label for information regarding the 
physical and chemical properties of capecitabine [Xeloda Package Insert, 2006].
5.1.3.5.
Gemcitabine
Gemcitabine is supplied in a sterile form for IV use only.  Each single-use vial contains 
either 200 mg or 1 g of gemcitabine HCl (expressed as free base) formulated with 
mannitol (200 mg or 1 g, respectively) and sodium acetate (12.5 mg or 62.5 mg, 
respectively) as a sterile lyophilized powder.  Hydrochloric acid and/or sodium 
hydroxide may have been added for pH adjustment.  Reconstituted dilutions yield a 
gemcitabine concentration of 38 mg/mL, which includes accounting for the displacement 
volume of the lyophilized powder.  Reconstituted gemcitabine is a clear, colorless to 
light straw-colorless solution.  Refer to the product label for information regarding the 
physical and chemical properties of gemcitabine [Gemzar Package Insert, 2007].
5.1.3.6.
Vinorelbine
Vinorelbine Injection is a clear, colorless to pale yellow solution in water for injection 
containing 10mg vinorelbine tartrate per mL.  Vinorelbine Injection is supplied in 
single-use, clear glass vials as a sterile, non-pyrogenic aqueous solution with no 
preservatives or other additives present; 10mg/1mL and 50mg/5mL single-use vials are 
available.  All dosing of vinorelbine is expressed as the free base and not the ditartrate 
salt (for example, a 50mg dose = 69mg of the salt).  All vials are labelled in terms of the 
free base.  Refer to the product label for further information regarding the physical and 
chemical properties of vinorelbine [Navelbine Package Insert, 2002].
5.1.3.7.
Chemotherapy Dosage and Administration
The choice of chemotherapy agent will be at the discretion of the treating investigator.  
Refer to Table 3 for details on administration (recommended dose and schedule, route, 
and duration of treatment) of each chemotherapy agent.  A record of the chemotherapy 
agent administered to each subject must be maintained in the source documents (refer to 
Section 5.5 for details on product accountability).


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Table 3
List of Common Chemotherapy Dose and Schedule
Chemotherapy
Recommended Dose
Route
Recommended
Schedule
paclitaxel1
80 mg/m2
IV
Days 1, 8, and 
15 of a 28-day 
cycle
docetaxel1
75 mg/m2
1h IV
Day 1 of a 
21-day cycle
nab paclitaxel
100 mg/m2
30-min IV
Days 1, 8, and 
15 of 28-day 
cycle
capecitabine
2000 mg/m2 as two equal, 
divided doses administered 
12h apart (morning and 
evening)2
PO
Days 1 – 14 of 
a 21-day cycle
gemcitabine
1250 mg/m2
30-min IV
Days 1 and 8 of 
a 21-day cycle
vinorelbine
20 mg/m2
10-min IV
Days 1, 8, and 
15 of a 21-day 
cycle
1.
refer to Section 5.1.3.8 for information on pre-medication for paclitaxel and docetaxel 
administration.
2.
morning and evening doses of capecitabine must be taken with food or within 30 minutes 
after food with approximately 200mL of water.
Abbreviations:  h=hour; IV=intravenous; PO=orally.
5.1.3.8.
Premedication for Paclitaxel and Docetaxel Administration
Investigators may use their discretion (local standard of care) with regard to 
administration of pre-medications for paclitaxel and docetaxel treatment (e.g., oral 
instead of IV pre-medication permitted where available, administering day before and 
day of paclitaxel administration, etc.).  Investigators must document exactly what was 
given, dates, and route of administration on the ‘Concomitant Medications’ eCRF.  
Please note, dexamethasone is a prohibited medication above 1.5 mg (refer to 
Section 6.2).  Additionally, cimetidine, if given in place of ranitidine, is only permitted 
as a pre-medication and should not be given on a continuous basis.
All pre-medications administered prior to paclitaxel and docetaxel infusion will not be 
supplied for this study.  
Additional information will be in the study procedures manual.
5.1.4.
Endocrine Therapy with Aromatase Inhibitors
The endocrine therapy with an aromatase inhibitor is chosen at the discretion of the 
investigator.  All subjects in one of the two arms treated with trastuzumab in 
combination with lapatinib are required to be treated with a concomitant aromatase 


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inhibitor.  The aromatase inhibitor chosen by the investigator at randomization must 
remain the same throughout the study.  Refer to product information for recommended 
doses and instructions regarding dose delays [Aromasin 2008; Arimidex, 2009; Femara
2010].
Endocrine therapy with an aromatase inhibitor will be administered on Day 1 of study 
treatment. Dose reductions for AIs are not permitted.
5.2.
Dose Adjustments
At each clinic visit, subjects will be evaluated for evidence of study drug-related 
(lapatinib, trastuzumab, endocrine therapy or chemotherapy agent) toxicity.  Results of 
laboratory assessments must be reviewed prior to the administration of study treatment.  
5.3.
Handling and Storage of Study Treatment
Lapatinib and trastuzumab must be stored in a secure area under the appropriate physical 
conditions for the product. Sites must maintain a temperature log for lapatinib.  Access 
to and administration of lapatinib will be limited to the investigator and authorized site 
staff.
Lapatinib must be dispensed or administered only to subjects enrolled in the study 
and in accordance with the protocol.
Unused study treatment will be destroyed at site.  
5.4.
Treatment Assignment
Subjects will be assigned to study treatment in accordance with their molecular subtype.  
The HER2-enriched cohort will be randomized to treatment with either combination 
regimen with equal probability.  The Non-HER2-enriched cohort will be assigned to 
treatment with trastuzumab in combination with lapatinib (Dual blockade).
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study.
Upon completion of all the required baseline and screening assessments, eligible subjects 
will be registered into the Interractive Response Technology (IRT) system by the 
investigator or authorized site staff.  To randomize the subject in the HER2 enriched 
cohort, the study staff will enter the subject number into the IRT to obtain a 
randomization number and treatment group assignment.  Study staff must also enter data 
for HER2 Non-enriched subjects.  Subject numbers must be entered into the system and 
although this cohort will not be ‘randomized’ and assigned a treatment group, non-
enriched subjects will receive a ‘randomization’ number.  Confirmation will be received 
at the site on the completion of transaction.  Study-specific instructional worksheets will 
be provided for the use of the IRT.
Subjects in the HER2-enriched cohort will be centrally randomized using a 
randomization schedule generated by the Biostatistical Department, which will assign 
subjects in a 1:1 ratio to either trastuzumab in combination with lapatinib or 


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chemotherapy of the investigator’s choice.  Once a randomization number has been 
assigned it must not be re-assigned even in cases of errors.
5.5.
Blinding
This is an open-labeled study.
5.6.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of study 
treatment dispensed and/or administered to study subjects, the amount returned by study 
subjects, and the amount received from and returned to Novartis, when applicable.  
Product accountability records must be maintained throughout the course of the study.  
Refer to the SPM for further detailed instructions on product accountability.
5.7.
Treatment Compliance
At each visit, an evaluation of subject compliance with taken medication will be 
performed.  The investigator will make every effort to bring non-compliant subjects into 
compliance.
Lapatinib
Compliance with lapatinib will be assessed through querying the subject during the site 
visits and documented in the source documents and eCRF. 
A record of the number of lapatinib tablets dispensed to and taken by each subject must 
be maintained and reconciled with study treatment and compliance records.  Treatment 
start and stop dates, including dates for treatment delays and/or dose reductions will also 
be recorded in the eCRF.  Redispensing of lapatinib is not allowed unless extreme 
circumstances exist (i.e. hurricane; flood; etc) and approval is granted by the medical lead.
Trastuzumab
Trastuzumab will be intravenously administered to subjects at the study site.  
Administration will be documented in the source documents and reported in the eCRF.  
Compliance with trastuzumab treatment will be collected and recorded in source 
documents and in the eCRF on the Trastuzumab Exposure page including dates of 
administration and dates of treatment delays.
5.8.
Dose Delays and Modifications
Study treatment will be administered until disease progression or death or discontinuation 
of study treatment due to unacceptable toxicity or other reasons (i.e. consent withdrawal, 
non-compliance).  At each study visit, subjects will be evaluated for evidence of study 
treatment-related adverse events.  The severity of adverse events will be graded utilizing 
the CTCAE 4.0 [NCI 2009].  Subjects should be carefully instructed on how to take 
study treatment if any dose modifications occur. If a subject permanently discontinues 


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any one of the study treatments, then the subject must be permanently withdrawn from all 
study treatment.  
Recommendations for study treatment delays due to hematologic and chemistry toxicities 
are found in Table 4.  For recommendations for lapatinib administration due to 
lapatinib-related adverse event, refer to Section 5.8.1; recommendations for trastuzumab 
administration due to trastuzumab-related adverse events refer to Section 5.8.2; and for 
recommendations for AI administration please refer to  Section 5.8.3.  Delays for 
chemotherapy should follow normal practice guidelines and package inserts.
Table 4
Study Treatment Delays for Hematology and Chemistry Toxicities
Toxicity

Hematology

ANC is 1.0 109/L

Platelet count is 75.0 109/L

Hemoglobin is 9.0 g/dL

Chemistry

Unresolved Grade 3 or 4 toxicity (except 
liver chemistry)

For liver chemistry stopping and follow-up 
criteria, refer to Section 5.9

Calculated Creatinine 
Clearance1

40 mL/min
1 Calculated by the Cockcroft and Gault Method.
5.8.1.
Lapatinib
A delay in the administration of lapatinib for no more than 2 weeks is allowed for 
resolution of adverse events according to the criteria summarized in Table 5, except in 
the event of left ventricular cardiac dysfunction, interstitial pneumonitis, or hepatoxicity 
(Refer to Section 5.8.4, and Section 5.9 for further details).  If treatment is delayed for 
reasons other than adverse events (i.e., unplanned travel or vacation, or lack of 
transportation to the site) and the subject has insufficient drug supply available, the 
subject should resume the usual dosing schedule once drug supply is available.  
However, if the subject has been off lapatinib for more than 2 weeks, the investigator 
must consult the medical lead prior to resuming therapy.  
For subjects that are receiving lapatinib plust trastuzumab, one dose reduction of 
lapatinib to 750 mg is permitted according to the criteria defined in Table 5.  If a subject 
permanently discontinues lapatinib for any reason, then re-initiation of lapatinib 
treatment is not permitted.  The medical lead must be consulted prior to implementing 
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Table 5
Recommendations for Lapatinib Administration due to Lapatinib-
related Adverse Events
Adverse Event (NCI CTCAE Grade1)
Action to be Taken 
Grade 1 or Grade 2 (excluding Grade 1 or 
Grade 2 diarrhea with complicating features, 
cardiac events, and  hepatobiliary events)
Continue lapatinib* 

If prolonged duration (≥2 weeks) of 
Grade 2 event occurs which affects 
the subject’s QoL, one dose
reduction of lapatinib by 1 tablet 
(250mg) to 750 mg is permitted
*Refer to the Supportive Care Guidelines 
in the SPM for uncomplicated diarrhea and 
skin-related adverse events.
Grade 1 or Grade 2 diarrhea with 
complicating features
Grade 3 or Grade 4  (excluding Grade 3/ 
Grade 4 interstitial pneumonitis, Grade 4 
rash, symptomatic cardiac events, and 
hepatobiliary events)  
Delay lapatinib until resolution to Grade 2
without complicating features*

If the AE recurs and lapatinib dose 
was 1000 mg at time of recurrence, 
dose reduce 1 tablet (250mg) to 750 
mg

If the AE recurs and lapatinib dose 
was 750mg at the time of 
recurrence, either discontinue or 
consult with the medical lead 

If AE does not resolve to Grade 2 
(within 2 weeks from last 
administration), consult with the
medical lead  
*Refer to the Supportive Care Guidelines 
in the SPM for diarrhea and skin-related 
adverse events.
Grade 3 or Grade 4 interstitial pneumonitis2
Grade 4 rash manifested as toxic epidermal 
necrolysis (i.e., Stevens Johnson’s 
Syndrome, etc)
Permanently discontinue lapatinib and 
treat as clinically appropriate
Cardiac Events 
Refer to Section 5.8.4 for criteria on lapatinib 
administration following cardiac events
Hepatobiliary Events (Any Grade)
Refer to Section 5.9 for lapatinib dose 
modification for liver chemistry stopping and 
follow-up criteria
Hematologic Toxicities
Refer to Table 4
1.
Severity Grade of AE according to National Cancer Institute Common Toxicity Criteria for Adverse Events 
(NCI CTCAE) v4.0 NCI 2009
2.
Refer to Section 5.8.4 for treatment recommendations when subjects present with symptoms of interstitial 
pneumonitis or cardiac events.
Abbreviations:  NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; AE, 
adverse event; QoL, quality of life


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5.8.2.
Trastuzumab
Trastuzumab may be delayed or discontinued for adverse events.  
Dose interruption: Trastuzumab may be held for a maximum of 6 weeks.  If the 
trastuzumab-related adverse event does not recover to Grade 2 after 6 weeks, 
discontinue trastuzumab.  If trastuzumab dosing is delayed more than 6 weeks for 
reasons other than trastuzumab-related adverse events, the medical lead must be 
contacted.  
Trastuzumab loading dose: Administration of trastuzumab occurs on a weekly or 21-
day cycle, and may be delayed for up to 7 days for adverse events without the 
requirement of a re-loading dose.  
For the 21 day cycle, a re-loading dose of 8 mg/kg must be used if more than 28 days 
have elapsed from the last administered trastuzumab dose, followed by the usual 
maintenance dose of 6 mg/kg/IV q3-weekly thereafter.  
For the weekly cycle, a re-loading dose of 4 mg/kg must be used if more than 14 days 
have elapsed from the last administered trastuzumab dose, followed by the usual 
maintenance dose of 2 mg/kg/IV weekly thereafter.  
Dose discontinuation: The recommendation to continue, delay or permanently 
discontinue trastuzumab due to adverse events is summarized in Table 6.  If trastuzumab 
treatment is discontinued, then all study treatments in that must be discontinued.
Table 6
Recommendations for Trastuzumab Administration due to 
Trastuzumab-related Adverse Events
Adverse Events (NCI CTCAE Grade1)
Action to be Taken 
Non-hematologic Grade 1 or Grade 2 (excluding 
cardiac events)
Continue trastuzumab
Non-hematologic Grade 3 or Grade 4 (excluding 
cardiac events, interstitial pneumonitis)
Delay trastuzumab until recovery to Grade 2
(maximum hold up to 6 weeks) 
If AE does not resolve to Grade 2 after 6 
weeks, discontinue trastuzumab
Grade 3 or Grade 4 interstitial pneumonitis2
Permanently discontinue trastuzumab and 
treat as clinically appropriate (refer to Section 
5.8.4) 
Hypersensitivity reactions
Refer to Section 5.8.2.1
Cardiac Events 
Refer to Section 5.8.4 for criteria on 
trastuzumab administration following cardiac 
evaluations
Hematologic Toxicities
Refer to Table 4
1.
Severity Grade of AE according to NCI CTCAEv4.0 [NCI 2009] 
2.
Refer to Section 5.8.4 for treatment recommendations when subjects present with symptoms of interstitial 
pneumonitis or cardiac events
Abbreviations:  NCI CTCAE, National Cancer Institute Common Terminology Criteria for Adverse Events; AE, 
adverse event; QoL, quality of life)


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5.8.2.1.
Trastuzumab Dose Recommendations for Hypersensitivity Reactions
Subjects with extensive pulmonary disease e.g. lymphangitis, multiple metastases, 
recurrent pleural effusions, and those with pre-existing respiratory compromise may be at 
increased risk for serious hypersensitivity reactions.
The decision to administer or discontinue trastuzumab in the event a subject presents with 
hypersensitivity reaction is summarized in Table 7.
Table 7
Dose Delay Recommendations for Trastuzumab-related 
Hypersensitivity
Hypersensitivity Reaction
Action
Life threatening reaction (e.g. 
tachypnea, bronchospasm, 
hypotension, hypoxia) 
Permanently discontinue trastuzumab
Severe or moderate reaction 
Slow or stop the trastuzumab infusion
Provide supportive care with oxygen, beta agonists, 
antihistamines or  corticosteroids
Subject may be retreated with trastuzumab
Pre-medication with corticosteroids, antihistamines 
and antipyretics may be used before subsequent 
trastuzumab infusions 
Moderate or mild reaction
Treat with antipyretics and antihistamines 
Re-treat with trastuzumab next dose
5.8.3.
Aromatase Inhibitor (AI) of Investigator choice
There will be no dose reductions for any of the three of the AIs (letrozole, exemestane, or 
anastrozole).  Please hold any of the three AIs for any Grade 3 or 4 drug related 
toxicities.   If the subject experiences any hematologic toxicity, refer to Table 4.  
If a subject is required to stop treatment with the AI for more than 7 days, the medical 
lead must be consulted.  
5.8.4.
Criteria for Evaluating Cardiac and Respiratory Events
Asymptomatic cardiac events:
Subjects who have a ≥20% decrease in left ventricular cardiac ejection fraction relative to 
baseline, and the ejection fraction is below the institution's lower limit of normal, should 
have a repeat evaluation of ejection fraction 1-2 weeks later while still receiving 
trastuzumab and/or lapatinib.  This event must be reported as an SAE (see Section 
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If the repeat ejection fraction evaluation confirms a ≥20% decrease in left ventricular 
cardiac ejection fraction, and the ejection fraction is below the institution's lower limit of 
normal, then study treatment should be temporarily discontinued.
If the left ventricular ejection fraction recovers during the next 3 weeks, after consultation 
and approval of the medical lead, the subject may be restarted on trastuzumab.  Subjects 
receiving lapatinib may be restarted at a reduced dose by 250mg (lapatinib dose of
750mg).  For such subjects, monitoring of left ventricular ejection fraction will then be 
performed 2 weeks and 4 weeks after re-challenge, and then every 4 weeks thereafter.
If repeat ejection fraction evaluation still shows a decrease ≥20% in left ventricular 
ejection fraction relative to baseline, and the value is below the institution's lower limit of 
normal, then the subject should be withdrawn from trastuzumab and/or lapatinib.  
Ejection fraction should continue to be monitored every four weeks for at least 16 weeks 
or until resolution.
Refer to SPM for cardiac safety algorithm detailing asymptomatic cardiac event 
assessment and follow up.
Symptomatic cardiac events:
Subjects with an NCI CTCAE grade 3 or 4 LVEF decrease must be withdrawn from 
study treatment.
Interstitial pneumonitis:
Subjects with an NCI CTCAE Grade 3 or 4 interstitial pneumonitis must be withdrawn
from study treatment and must be reported as an SAE.
QTc Abnormalities
QT/QTc interval Prolongation:
Discontinuation Criteria for patient studies if any of the following criteria are met:

QTc >500msec 

Uncorrected QT >600msec

Change from baseline: QTc > 60 msec*
These criteria should be based on the average QTc value of triplicate ECGs. For 
example, if an ECG demonstrates a prolonged QT interval, obtain two more 
ECGs over a brief period, and then use the averaged QTc values of the three 
ECGs to determine whether the patient should be discontinued from the study.  
*This criterion is optional but should be strongly considered based on local 
regulatory requirements.
For subjects with underlying Bundle Branch Block: 


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Baseline QTc with Bundle Branch Block
Discontinuation QTc with Bundle Branch 
Block
<450msec
>500msec
450-480msec
≥530msec
When any QT/QTc stopping criteria are met, in addition to discontinuation of study 
treatment, do the following: 

Close and adequate ECG monitoring should be performed, confirm with 
additional ECGs that the interpretation is correct (along with manual overreading)

Obtain consultation from cardiologist 

Check and supplement electrolytes (e.g., magnesium, calcium, potassium).

Check and consider to stop co-administration of other medicine(s) known to cause 
QT prolongation

Check and consider other factors that may contribute to QT prolongation, e.g., 
active ischemia, congestive heart failure (CHF), congenital long QT syndrome, 
etc.
5.8.5.
Criteria for Evaluating Dermatologic Adverse Events
Significant skin adverse events (Grade 3 or more) resulting from lapatinib are rare (1-3%).  
Please refer to Section 12.8 for full guidance on evaluation of skin adverse reaction, 
follow-up including lapatinib holding and stopping rules as well as general guidance on 
treatment options.
If any NCI-CTCAE Grade 4 dermatologic event occurs, lapatinib must be permanently 
discontinued.
For NCI-CTCAE Grade 3 dermatological reactions, or a Grade 2 dermatological reaction 
which is not improved after 2 weeks with recommended management strategies, a brief 
(up to 14 days) therapy interruption is recommended; the daily dose of lapatinib should 
then be reinstated.  In some cases, the skin event may improve without the need for 
interrupting therapy with lapatinib.
It is strongly recommended that subjects who develop dermatological reactions receive 
evaluations by a consultant dermatologist for management on the specific side effect.  
A variety of agents can be used to manage skin reactions.  These include mild-to-
moderate strength steroid creams, topical or systemic antibiotics, topical or systemic 
antihistamines and immunomodulators, and hypoallergenic moisturizers and emolliens 
for dry skin.  Please refer to Section 12.8.5 for full guidance on the treatment of skin 
adverse reaction.


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NOTE:  if revisions are made between protocol amendments, the most updated version 
is included in SPM.
5.8.6.
Criteria for Evaluating Gastrointestinal Adverse Events
If GI adverse events are not appropriately managed, they may be associated with the 
development of dehydration. Management of gastrointestinal adverse events is 
discussed in detail in Appendix 7 Section 12.7.
NOTE:  if revisions are made between protocol amendments, the most updated version 
is included in SPM.
5.8.6.1.
Nausea and Vomiting
In subjects who have emesis and are unable to retain lapatinib and/or other oral 
medication, every attempt should be made to obtain control of nausea and vomiting. If 
a subject vomits after administration of study drug, the subject should be instructed not to 
retake the dose. Only if the subject vomits and the pills are visible, should the dose be 
retaken.  Subjects should take the next scheduled dose. If vomiting persists, then the 
subject should contact the investigator.
5.8.6.2.
Diarrhea
Diarrhea can be debilitating, and on rare occasions, it is potentially life-threatening. 
Based on experience with lapatinib alone or in combination with chemotherapy, diarrhea 
should be managed proactively to avoid complications or worsening of the subject’s 
condition. 
Experience thus far suggests that when lapatinib is combined with trastuzumab in the 
absence of concomitant chemotherapy, the rate and severity of diarrhea is similar to 
lapatinib as a monotherapy.  Most diarrhea is uncomplicated CTC Grade 1 or 2.  In 
rare cases, diarrhea can be debilitating, and potentially life-threatening with dehydration, 
renal insufficiency, and electrolyte imbalances.  
Standardized guidelines for treating chemotherapy-induced diarrhea have been developed 
by an American Society of Clinical Oncology (ASCO) and were used to develop specific 
guidelines for lapatinib used as monotherapy or in combination with other treatments.  
Please refer to detailed guidelines which include definitions, management and study 
treatment holding and dose reduction rules in Appendix 7.
NOTE:  if revisions are made between protocol amendments, the most updated version 
is included in SPM.


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5.9.
Monitoring, Interruption, and Stopping Criteria for 
Hepatobiliary Events
5.9.1.
Liver Chemistry Stopping and Follow-up Criteria
5.9.1.1.
Liver Chemistry Stopping Criteria
All subjects who meet liver chemistry criteria requiring permanent discontinuation of 
study treatment must continue to be followed for the study assessments and procedures as 
defined in Section 7 and at the time points indicated in the Time and Events Schedule in 
Table 9
Liver chemistry stopping criteria 1-5 are defined as follows and are presented in a Figure 
in Appendix 4:
1.
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT3xULN and 
INR>1.5, if INR measured)
NOTE: If serum bilirubin fractionation is not immediately available, and if ALT 
3xULN and bilirubin 2xULN discontinue subject from study treatment. Serum 
bilirubin fractionation should be performed if testing is available.  If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury.
2.
ALT 5xULN.
3.
ALT  3xULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
4.
ALT 3xULN persists for 4 weeks
5.
ALT 3xULN and cannot be monitored weekly for 4 weeks
When any of the liver chemistry stopping criteria 1 - 5 is met, do the
following:
Immediately discontinue subject from study treatment 
Report the event within 24 hours of learning its occurrence
Complete the liver event eCRF and SAE data collection tool if the event also meets the 
criteria for an SAE  
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or 
ALT3xULN and INR>1.5, if INR measured; INR measurement is not required 
and the threshold value stated will not apply to subjects receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).


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NOTE: if serum bilirubin fractionation is not immediately available, and if ALT 
3xULN and bilirubin 2xULN discontinue subject from study treatment. 
Serum bilirubin fractionation should be performed if testing is available. If 
testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury
Complete the liver imaging and/or liver biopsy CRFs if these tests are performed
Perform liver event follow up assessments, and monitor the subject until liver chemistries 
resolve, stabilize, or return to baseline values as described below

Withdraw the subject from the study after completion of the liver chemistry 
monitoring as described below (unless further safety follow-up is required or 
approval of drug restart is granted, as described in Section 5.9.2).

Do not restart study treatment unless written approval for drug restart is granted 
(details for restarting study treatment are described in Section 5.9.2), whereupon the 
subject continues in the study after completion of the liver chemistry monitoring 
described in Section 5.9).  
Subjects meeting criterion 5 should be monitored as frequently as possible.
In addition, for subjects meeting liver stopping criterion 1: 
Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (refer to Section 5.9.1), 
and close monitoring
A specialist or hepatology consultation is recommended
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values.
For subjects meeting any of the liver stopping criteria 2 – 5:
Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (refer to Section 5.9.1)
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; 
Subjects meeting criterion 5 should be monitored as frequently as possible.
5.9.1.2.
Liver Chemistry Follow-up
For subjects meeting any of the liver chemistry stopping criteria 1 – 5, make every 
attempt to carry out the liver event follow up assessments described below:
Viral hepatitis serology including:

Hepatitis A IgM antibody

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM) 

Hepatitis C RNA 


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
Cytomegalovirus IgM antibody  

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing)  

Hepatitis E IgM antibody.
Blood sample for pharmacokinetic (PK) analysis, obtained within [insert time interval 
recommended by clinical pharmacokinetics representative] of last dose.  Record the 
date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the CRF.  If the date or time of the last 
dose is unclear, provide the subject’s best approximation.  If the date/time of the 
last dose cannot be approximated OR a PK sample cannot be collected in the time 
period indicated above, do not obtain a PK sample.  Instructions for sample 
handling and shipping are in the SPM. 
Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).
Fractionate bilirubin, if total bilirubin 2xULN.
Obtain complete blood count with differential to assess eosinophilia.
Record the appearance or worsening of clinical symptoms of hepatitis, or hypersensitivity, 
such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash 
or eosinophilia as relevant on the AE form.
Record use of concomitant medications such as acetaminophen, herbal remedies, other 
over the counter medications, or putative hepatotoxins, on the concomitant 
medications form.
Record alcohol use on the liver event alcohol intake form.
The following assessments are required for subjects with ALT 3xULN and bilirubin 
2xULN (>35% direct) but are optional for other abnormal liver chemistries:
Anti-nuclear antibody, anti-smooth muscle antibody, Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total immunoglobulin G (IgG or gamma 
globulins).
Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate 
liver disease.
Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week [James, 2009]. NOTE: not required in China
Only in those with underlying chronic hepatitis B at study entry (identified by positive 
hepatitis B surface antigen):  quantitative hepatitis B DNA and hepatitis delta 
antibody. NOTE:  if hepatitis delta antibody assay cannot be performed, it can be 
replaced with a PCR of hepatitis D RNA virus (where needed [Le Gal, 2005].


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5.9.1.3.
Liver Chemistry Monitoring Criteria
For subjects with ALT 3xULN but <5xULN and bilirubin <2xULN, without hepatitis 
symptoms or rash, and who can be monitored weekly for 4 weeks, the following actions 
should be taken:

Notify the medical lead within 24 hours of learning of the abnormality to discuss 
subject safety

Continue study treatment

Return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline values 

If at any time the subject meets any of the liver chemistry stopping criteria 1 – X, 
proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values. 
Refer to Appendix 4 for algorithm of liver chemistry monitoring, interruption, stopping 
and follow up criteria.
5.9.2.
Restarting Study Treatment
5.9.2.1.
Drug Restart/Rechallenge Following Liver Events that are Possibly 
Related to IP
Approval for drug restart can be considered where:
The subject is receiving compelling benefit, benefit of drug restart exceeds risk, and no 
effective alternative therapy is available.  Ethics Committee or Institutional Review 
Board approval of drug restart/rechallenge must be obtained, as required.   
If the restart/rechallenge is approved in writing, the subject must be provided with a clear 
description of the possible benefits and risks of drug administration, including the 
possibility of recurrent, more severe liver injury or death.  
The subject must also provide signed informed consent specifically for the study 
treatment (ST) restart/rechallenge.  Documentation of informed consent must be 
recorded in the study chart.  
Study drug must be administered at the dose specified.
Subjects approved for restart/rechallenge of IP must return to the clinic twice a week for 
liver chemistry tests until stable, liver chemistries have been demonstrated and then 
laboratory monitoring may resume as per protocol. 


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5.9.2.2.
Drug Restart Following Transient Resolving Liver Events Not Related 
to Study Treatment
Approval for drug restart can be considered where:

Liver chemistries have a clear underlying cause (e.g., biliary obstruction, 
hypotension and liver chemistries have improved to normal or are within 1.5 x 
baseline and ALT <3xULN).  Ethics Committee or Institutional Review Board 
approval of drug restart/rechallenge must be obtained, as required.

If restart of drug is approved in writing, the subject must be provided with a clear 
description of the possible benefits and risks of drug administration, including the 
possibility of recurrent, more severe liver injury or death.  

The subject must also provide signed informed consent specifically for the restart.  
Documentation of informed consent must be recorded in the study chart.  

Study drug must be administered at the dose specified.

Subjects approved for restarting study treatment must return to the clinic once a 
week for liver chemistry tests until stable liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol. If 
protocol defined stopping criteria for liver chemistry elevations are met, study 
drug must be stopped.
Refer to Appendix 5 for additional guidelines on liver safety drug restart and re-challenge.
6.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
6.1.
Permitted Medications and Non-Drug Therapies
All concomitant medications taken during the study will be recorded in the eCRF.  The 
minimum requirement is that drug name and the dates of administration are to be
recorded.
The following will be recorded on the appropriate eCRF pages:

A complete list of prescription and over-the-counter medications (including 
herbal medications) that have been taken within two weeks prior to the first dose 
of investigational therapy.
All treatments related to supportive care during the study, including transfusion of blood 
and blood products, and treatment with antibiotics, antiemetics, antidiarrhea medications, 
and analgesics, as appropriate.  
All other concomitant medications (including over-the-counter medications) taken during 
the study.
NOTE: Lapatinib is likely to increase exposure to concomitantly administered drugs 
which are metabolized by CYP3A4 or CYP2C8.  Lapatinib inhibits CYP3A4 and 
CYP2C8 in vitro at clinically relevant concentrations.  Caution should be exercised 


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and dose reduction of the concomitant substrate drug should be considered when 
dosing lapatinib concurrently with medications with narrow therapeutic windows 
that are substrates of CYP3A4 or CYP2C8.  Refer to Table 8 for a list of CYP3A4 
Inducers and Inhibitors that are prohibited from screening through discontinuation 
from lapatinib. 
Concurrent treatment with bisphosphonates or denosumab is permitted. Prophylactic 
use of bisphosphonates in subjects without bone disease is not permitted, except for the 
treatment of osteoporosis.
Questions regarding concomitant medications should be directed to the medical lead for 
clarification.  
6.2.
Prohibited Medications and Non-Drug Therapies
The following medications are prohibited from the specified time-point before the first 
dose of study treatment until withdrawal from study treatment (refer to Section 4.2 and 
Section 4.1):
Anticancer therapy should not be given until disease progression or withdrawal from 
study treatment.  Subjects who receive concurrent anticancer therapy (i.e., cytotoxic or 
biologic) will not be allowed to continue study treatment;
Concurrent radiation therapy (radiotherapy will ONLY be allowed for palliation of pain 
for bone metastases and for spinal cord decompressions) and surgery for metastatic breast 
cancer, including resection of non-dominant metastases;
Hormonal therapy(ies), other than physiologic replacement;
Any other investigational drug (please refer to Section 4.1);
Because the composition, pharmacokinetics and metabolism of many herbal supplements 
are unknown, the concurrent use of all herbal supplements is strongly discouraged during 
the study;
Lapatinib is a substrate for CYP3A4.  Inducers and inhibitors of CYP3A4 may alter the 
metabolism of lapatinib.  The list of CYP3A4 inducers and inhibitors that are prohibited 
from screening through discontinuation from study is presented in Table 8. Therefore, 
caution should be used when lapatinib is used in conjunction with proton pump inhibitors 
as the concentration of lapatinib may be affected.  


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Table 8
CYP3A4 Inducers and Inhibitors
Drug Class
Specific Agents
Wash-out1
CYP3A4 Inducers
rifamycin antibiotics
rifampicin, rifabutin, rifapentine
2 weeks
anticonvulsants
phenytoin, carbamezepine, barbiturates (e.g., 
phenobarbital)
antiretrovirals
efavirenz, nevirapine, tipranivir, etravirine
glucocortical steroids
(oral only)
cortisone (>50 mg), hydrocortisone (>40 mg), 
prednisone or prednisolone (>10 mg), 
methylprednisolone or triamcinolone (>8 mg), 
betamethasone or dexamethasone (>1.5 mg)2
other
St. John’s Wort, modafinil
CYP3A4 Inhibitors
antibiotics
clarithromycin, erythromycin, troleandomycin, 
flucloxacillin
1 week
antifungals
itraconazole, ketoconazole, fluconazole (>150 mg daily), 
voriconazole
antiretrovirals
delaviridine, nelfinavir, amprenavir, ritonavir, indinavir, 
saquinavir, lopinavir, atazanavir
calcium channel blockers
verapamil, diltiazem
antidepressants
nefazodone, fluvoxamine
gastrointestinal agents3
cimetidine
fruit/fruit juices
grapefruit, star fruit, and papaw
other
amiodarone
6 months
Miscellaneous
antacids
Mylanta, Maalox, Tums, Rennies
1 hour before and 
after dosing
herbal supplements4
ginkgo biloba, kava, grape seed, valerian, ginseng, 
echinacea, evening primrose oil
2 weeks
1.
Time period between last dose of listed drug and first dose of lapatinib, required to avoid drug-drug interaction 
potential for toxicity (inhibitors) or loss of efficacy (inducers) that could make the subject  unevaluable.  
Clinically appropriate substitution of drugs not on the list is recommended.
2.
A standard 3-5 day course of dexamethasone at a dose following the institutions standard of care for the 
prevention and/or treatment of platinum-induced nausea and vomiting is allowed.  Glucocortical steroid oral dose 
equivalents (in parentheses) to dexamethasone 1.5 mg (or less) given daily are allowed.  Intravenous dosing 
should be considered if clinically appropriate.
3.
Emetogenic chemotherapy may require 3-4 daily doses of aprepitant.  CYP3A4 inhibition by oral (not IV) 
aprepitant may require a concurrent dose reduction of 1-2 lapatinib tablets.
4.
This list is not all-inclusive; therefore, for herbal supplements not listed, please contact the medical lead or Clinical 
Scientist.
NOTE: If future changes are made to the list of prohibited medications, formal documentation will be created and 
stored with the study file.  Any changes will be communicated to the investigative sites in the form of a letter and 
revised version included in SPM.
6.3.
Treatment after Discontinuation of Study Treatment or 
Withdrawal from/Completion of Study
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the subject’s medical condition.
Post study treatment will not be provided as part of the protocol.  Upon discontinuation 
from assigned study treatment, subjects may receive additional (non protocol) anticancer 


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therapy at the discretion of the treating physician.  Every effort should be made to 
complete the end of study evaluations prior to initiating further anticancer therapy or 
dosing of an investigational agent (see Table 9).  
For subjects who discontinue for any other reasons other than progression, new anti-
cancer therapy will be recorded during the follow-up period until subject completion.  
New anticancer therapy should be documented on the eCRF with generic drug name, start 
and stop dates, regimen sequence, type of therapy, number of cycles/dose, dose units and 
reason for discontinuing post-study treatment.  
6.4.
Treatment of Study Treatment Overdose
There is no specific antidote for the inhibition of ErbB1 and/or ErbB2 tyrosine 
phosphorylation.  The maximum oral doses of lapatinib that have been administered to 
date are 1800 mg once daily and 900 mg twice daily.  Serum concentrations following 
900 mg twice daily dosing are approximately twice that of 1800 mg once daily.
Subjects with suspected lapatinib overdose should be monitored until drug can no longer 
be detected systemically (at least 2.5 days).  Follow-up physical examination with 
laboratory testing should be performed between 10 and 14 days after drug concentrations 
are undetectable and before the subject is discharged from the investigator’s care.
For additional information, site pharmacist or authorized site personnel should refer to 
the lapatinib product characteristics for instruction [Lapatinib Summary of Product 
Characteristics, 2015].
If an overdose with trastuzumab should occur, the investigator, site pharmacist or 
authorized site personnel should refer to the trastuzumab product characteristics for 
instruction [Trastuzumab Summary of Product Characteristics, 2013].
Any SAEs that occur as a result of an overdose with the study treatment should be 
reported to the medical lead (see Section 7.4.5).
7.
STUDY ASSESSMENTS AND PROCEDURES
The schedule of assessments is outlined in Table 9.  
A signed, written informed consent form must be obtained from the subject prior to any 
study-specific procedures or assessments.  
Refer to the Time and Events Table for the timing of all assessments (Table 9).  Details 
on efficacy and safety assessments are presented in Section 7.3 and Section 7.4, 
respectively.  Further details of study procedures and assessments can be found in the 
study procedures manual (SPM).
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging study) and obtained prior to signing of informed consent may be utilized 
for screening or baseline purposes provided the procedure meets the protocol-defined 
criteria and has been performed in the timeframe of the study.


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Table 9
Time and Events Table
STUDY PHASE
PRE-TREATMENT
TREATMENT
POST-TREATMENT 
VISIT
Screen
Day 1
Every 3 
weeks 
Every 9 
Weeks
Every 12 
Weeks
At Study Treatment 
Discontinuation
Follow-Up
Every 12 Weeks
until subject 
completion
VISIT WINDOW (±Days)
± 7
± 7
-7
±30
Procedures
Informed Consent
X
Inclusion / exclusion 
X
Demographics
Include birth year, race, 
ethnicity, and gender
X
Surgical history
X
Anti-cancer therapies
X1
X14
Past /current med conditions
X
X
Translational Sample Collection
Tumor Biopsy
 
 
 refer to Study 
Procedures Manual for 
biopsy sample collection, 
storage, and shipment 
X
X2


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STUDY PHASE
PRE-TREATMENT
TREATMENT
POST-TREATMENT 
VISIT
Screen
Day 1
Every 3 
weeks 
Every 9 
Weeks
Every 12 
Weeks
At Study Treatment 
Discontinuation
Follow-Up
Every 12 Weeks
until subject 
completion
VISIT WINDOW (±Days)
± 7
± 7
-7
±30
procedures
Archived/stored tumor tissue collection
Tumor tissue block or 15-
20 unstained slides 
required
X
Efficacy Assessments
Disease Assessment3
Target and nontarget 
lesions should be 
assessed using RECIST 
1.1 within 28 days prior to 
randomization; 
assessments are 
conducted every 9 weeks 
until 54 weeks then every 
X
X
X4
X5


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STUDY PHASE
PRE-TREATMENT
TREATMENT
POST-TREATMENT 
VISIT
Screen
Day 1
Every 3 
weeks 
Every 9 
Weeks
Every 12 
Weeks
At Study Treatment 
Discontinuation
Follow-Up
Every 12 Weeks
until subject 
completion
VISIT WINDOW (±Days)
± 7
± 7
-7
±30
24 weeks thereafter.  
Bone Scan6
Baseline bone scan is 
required for all subjects.  
For subjects without bone 
disease at baseline, 
subsequent bone scans 
should only be performed 
as clinically indicated. For 
subjects with bone 
disease at baseline, a 
bone scan is required 
every 18 weeks and at 
disease progression until 
Week 54 and then every 
24 weeks or as clinically 
indicated
X
Post study treatment efficacy for subjects 
who discontinued study treatment for 
reasons other than disease progression
Record dates of 
documented disease 
progression
X
Safety Assessments
Concurrent meds
X
X
X
X
Physical exam
X
X
X
X


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STUDY PHASE
PRE-TREATMENT
TREATMENT
POST-TREATMENT 
VISIT
Screen
Day 1
Every 3 
weeks 
Every 9 
Weeks
Every 12 
Weeks
At Study Treatment 
Discontinuation
Follow-Up
Every 12 Weeks
until subject 
completion
VISIT WINDOW (±Days)
± 7
± 7
-7
±30
Vital signs 
Temperature, blood 
pressure and heart rate
X
X
X
X
Weight & height
Height - screening only
X
X
X
ECOG PS
X
X
X
X
AE/toxicity
Subjects will be monitored 
every 6 weeks or at any 
contact with the subject 
during the study phases 
X
X
X7
X7
ECHO or MUGA scan8
The same method of 
evaluation should be used 
for a subject throughout 
study duration
X
X
X
12-lead ECG
X
X
X
Laboratory Assessments9
Hematology
Includes hemoglobin, 
hematocrit, red blood cell 
count, white blood cell 
count with absolute 
neutrophil count or 
differential, and platelet 
X
X
X
X


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STUDY PHASE
PRE-TREATMENT
TREATMENT
POST-TREATMENT 
VISIT
Screen
Day 1
Every 3 
weeks 
Every 9 
Weeks
Every 12 
Weeks
At Study Treatment 
Discontinuation
Follow-Up
Every 12 Weeks
until subject 
completion
VISIT WINDOW (±Days)
± 7
± 7
-7
±30
count
Serum chemistry10
Includes sodium, 
potassium, blood urea 
nitrogen, creatinine, 
glucose, calcium, 
aspartate 
aminotransferase, alanine 
aminotransferase, alkaline 
phosphatase, total 
bilirubin, and albumin. 
magnesium
X
X
X
X
Serum pregnancy test 
Required for all women of 
childbearing potential; to 
be performed within 7 
days prior to start of first 
dose of study treatment
X


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STUDY PHASE
PRE-TREATMENT
TREATMENT
POST-TREATMENT 
VISIT
Screen
Day 1
Every 3 
weeks 
Every 9 
Weeks
Every 12 
Weeks
At Study Treatment 
Discontinuation
Follow-Up
Every 12 Weeks
until subject 
completion
VISIT WINDOW (±Days)
± 7
± 7
-7
±30
Study Treatment Assessments
Dispense lapatinib
A supply of lapatinib will 
be dispensed to subject 
with instructions for 
administration
X
Trastuzumab administration
Weekly schedule is 
permitted in combination 
with chemotherapy.  
Window for dose 
administration is ± 3 days.
X
X
Chemotherapy administration11
Dose and schedule as 
prescribed by the 
investigator
X
Endocrine therapy with AI administration12
Dose and schedule as 
prescribed by the 
investigator in subjects 
with hormone receptor 
positive disease
X
Study drug compliance
A record of the number of 
tablets dispensed to and 
returned by each subject 
must be maintained
X
X


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1.
Prior therapies (screening visit only): include administration start and stop dates (month, year); date of radiographic confirmed progression.
2.
Window for progression biopsy is +14 days from date of progression and prior to start of new anti-cancer therapy.  Biopsy of metastatic tumor site only in subjects who 
discontinue study treatment due to disease progression.
3.
Use the same method of measurement for target and nontarget lesions at all time points.
4.
If the last radiographic assessment was obtained less than 9 weeks from study treatment discontinuation, radiographic assessments do not need to be repeated.
5.
Subjects who discontinue study treatment for reasons other than progression (e.g. due to an AE) will have disease assessments done every 9 weeks until Week 54, then 
every 24 weeks thereafter until unequivocal progression, initiation of new anticancer therapy, death,  withdrawal of consent, or end of study. At the end of study, if the last 
radiographic assessment was obtained less than 9 weeks earlier, radiographic assessment does not need to be repeated.
6.
All bone scan abnormalities that may indicate metastases must be evaluated by X-ray (e.g., plain film), computed tomography (CT), or magnetic resonance imaging to 
confirm and/or quantify malignant lesions.
7.
Safety monitoring will be performed until 30 days after the last dose for subjects who discontinued due to progression. Safety monitoring will continue for subjects who 
stopped study treatment for reasons other than disease progression until disease progression, new anticancer therapy, death, withdrawal of consent or end of study, 
whichever comes first. Monitor all AEs/Serious AEs that are ongoing until resolution or stabilization of the event.
8.
Additional ECHO/ MUGA scans should be performed when clinically indicated.
9.
At the pre-dose assessment on Day 1, all laboratory results will be reviewed by the investigator.  Any results outside of the normal range will be repeated (prior to the first 
dose) at the discretion of the investigator
10. Refer to Protocol Appendix 4 for further details
11. Chemotherapy will be administered throughout the study treatment phase based on the schedule chosen by investigator.
12. Endocrine therapy with AIs will be administered throughout the study treatment phase based on the schedule chosen by investigator.
For subjects who discontinue for any other reasons other than progression, new anti-cancer therapy will be recorded during the follow-up period until subject completion.Abbreviations: 
ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; ECG, electrocardiogram; MUGA, multigated acquisition scan.


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7.1.
Collection of Biopsies and Archival Tumor Tissue
Two biopsies will be collected for the study. In addition, archival/stored tumor tissue will 
be submitted to the central laboratory. 
The first biopsy, referred to as the pre-treatment biopsy, will be taken at screening.  This 
biopsy will be used to determine the breast molecular subtype of disease by central 
laboratory assessment.  In addition, this biopsy will be used to centrally determine the 
HER2 and hormone receptor status of the tumor.  
The second biopsy, referred to as the progression biopsy, will be taken at the time of 
radiologically determined disease progression.  Additional details are provided in the 
SPM.  The progression biopsy should be taken within 14 days of disease progression
and prior to the start of any new anti-cancer therapy. The site of the biopsy at disease 
progression should be taken from the site biopsied at screening.
7.2.
Critical Baseline Assessments
Cardiovascular medical history/risk factors will be assessed at baseline.
7.2.1.
Baseline Assessments
Baseline evaluations should be performed within 28 days prior to the first dose of 
study treatment, and include the following:
Demographic data: year of birth, race, ethnicity;
Vital signs:  height, body weight, blood pressure, heart rate, temperature;
ECOG Performance Status (defined in Section 12.3 - Appendix 3:  ECOG 
Performance Status);
Breast cancer history:

Details of the primary tumor: estrogen and progesterone receptor status 
(performed by immunohistochemical methods), and HER2 status, 
including IHC and /or FISH/CISH/SISH analysis

Clinical characteristics: date of diagnosis, stage and histology at initial diagnosis, 
date of documented diagnosis of metastatic disease by CT or MRI (if applicable), 
site(s) of metastases, line of therapy completed

Prior treatment history: neoadjuvant, adjuvant and metastatic
chemotherapy received (agent[s], date of last dose), biologic therapy, 
immunotherapy or hormonal therapy received 

This includes the date of documented radiological disease 
progression during the most recent treatment 
Document baseline CNS symptoms, if applicable.


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7.2.2.
Baseline documentation of target and non-target lesions
All baseline lesion assessments must be performed within 28 days prior to the first dose 
of study treatment. 
Lymph nodes that have a short axis of < 10 mm are considered non-pathological and 
should not be recorded or followed.
Pathological lymph nodes with < 15 mm and but 10 mm short axis are considered non 
measurable.
Pathological lymph nodes with 15 mm short axis are considered measurable and can be 
selected as target lesions; however lymph nodes should not be selected as target lesions 
when other suitable target lesions are available.  
Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions, and recorded 
and measured at baseline. These lesions should be selected on the basis of their size 
(lesions with the longest diameter) and their suitability for accurate repeated 
measurements (either by imaging techniques or clinically). 
Note:  Biopsied lesions should not be used as target lesions.
Note: Cystic lesions thought to represent cystic metastases should not be selected as 
target lesions when other suitable target lesions are available.
Note: Measurable lesions that have been previously irradiated and have not been shown 
to be progressing following irradiation should not be considered as target lesions. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by CT or MRI can be considered measurable.   Bone scans,
fluorodeoxyglucose-positron emission tomography (FDG-PET) scans or X-rays are not 
considered adequate imaging techniques to measure bone lesions.
All other lesions (or sites of disease) should be identified as non-target and should also be 
recorded at baseline. Non-target lesions will be grouped by organ. Measurements of 
these lesions are not required, but the presence or absence of each should be noted 
throughout follow-up. 
7.3.
Efficacy
Clinical endpoints regarding the assessment of tumor lesions must be performed using 
RECIST 1.1 [Eisenhauer, 2009].
7.3.1.
Efficacy Endpoints
The primary efficacy endpoint of this study is the change in biomarkers associated with 
immunomodulation which is defined as change in expression levels of biomarkers as 
measured in tissue from the disease progression tumor biopsy, compared with expression 
levels as measured in the pre-treatment tumor biopsy.


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The secondary efficacy endpoints of this study are:
Investigator-assessed PFS defined as the interval of time between randomization and 
disease progression or death due to any cause; investigator-assessed ORR defined as 
percentage of subjects with a CR or PR; and CBR defined as percentage of subjects with 
a CR, PR, or SD for at least 6 months.
7.3.2.
Clinical Efficacy Assessment
Disease progression and response evaluations will be determined according to the 
definitions established in RECIST 1.1 [Eisenhauer, 2009].
See the Time and Events Table (Table 9) for the schedule of efficacy assessments.  
Assessments must be performed on a calendar schedule and should not be affected by any 
study treatment dose interruptions/delays.  For post baseline assessments, a window of 
7 days is permitted to allow for flexible scheduling.
The following are required at baseline: CT for Chest/Abdomen/Pelvis or MRI for 
Abdomen/Pelvis and clinical disease assessment for palpable lesions. At each post 
baseline assessment, evaluations of the sites of disease identified by these scans are 
required.  
Confirmation of CR and PR are required per protocol.  Confirmation assessments must 
be performed no less than 4 weeks after the criteria for response have initially been met 
and may be performed at the next protocol scheduled assessment.  If a confirmation 
assessment is performed prior to the next protocol schedule assessment, the next protocol 
scheduled evaluation is still required (e.g., evaluations must occur at each protocol 
scheduled timepoint regardless of unscheduled assessments).
A baseline bone scan is required for all subjects.  For subjects without bone disease at 
baseline, subsequent bone scans should only be performed as clinically indicated (e.g.,
presentation of bone pain).  For subjects with bone disease at baseline, a bone scan is 
required every 18 weeks until Week 54 and then every 24 weeks or as clinically indicated
and at disease progression.In addition, in order to confirm a CR in a subject with bone 
disease at baseline, a bone scan must be performed 1 week prior to the first set of images 
showing CR to 4 weeks after the next protocol specified assessment.
For subjects without CNS disease at baseline, brain scans should only be performed as 
clinically indicated (e.g., symptoms suggestive of CNS progression).  For subjects with 
CNS disease at baseline, a brain scan is required every 9 weeks until Week 54 and then 
every 24 weeks or as clinically indicated.  In addition, in order to confirm a CR in a 
subject with brain disease at baseline, a brain scan must be performed 1 week prior to the 
first set of images showing CR to 4 weeks after the next protocol specified assessment.


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7.3.2.1.
Assessment Guidelines
Please note the following:
The same diagnostic method, including use of contrast when applicable, must be used 
throughout the study to evaluate a lesion unless medically contraindicated.
All measurements should be taken and recorded in millimeters (mm), using a ruler or
calipers.
Ultrasound is not a suitable modality of disease assessment.  If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required.
Fluorodeoxyglucose (FDG)-PET is generally not suitable for ongoing assessments of 
disease.  However FDG-PET can be useful in confirming new sites of disease where a 
positive FDG-PET scans correlates with the new site of disease present on CT/MRI or 
when a baseline FDG-PET was previously negative for the site of the new lesion. FDG-
PET may also be used in lieu of a standard bone scan providing coverage allows 
interrogation of all likely sites of bone disease and FDG-PET is performed at all 
assessments.
If PET/CT is performed then the CT component can only be used for standard response 
assessments if performed to diagnostic quality, which includes the required anatomical 
coverage and prescribed use of contrast.  The method of assessment should be noted as 
CT on the CRF.
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler/calipers to measure the size of the lesion, is 
required [Eisenhauer, 2009].
CT and MRI: Contrast enhanced CT with 5 mm contiguous slices is recommended.
Minimum size of a measurable baseline lesion should be twice the slice thickness, with a 
minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, 
but when used, the technical specification of the scanning sequences should be optimised 
for the evaluation of the type and site of disease and lesions must be measured in the 
same anatomic plane by use of the same imaging examinations.  Whenever possible, the 
same scanner should be used [Eisenhauer, 2009].
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition.  Lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung; however chest CT is preferred over chest 
X-ray [Eisenhauer, 2009].
Brain Scan:  If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT.
Bone Scan (typically bone scintigraphy):  If a bone scan is performed and a new 
lesion(s) is equivocal, then correlative imaging (i.e., X-ray, CT, or MRI) is required to 
demonstrate malignant characteristics of the lesion(s).  


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Note:  PET [FDG or fluoride] may be used in lieu of a standard bone scan providing 
coverage allows interrogation of all likely sites of bone disease and PET is performed at 
all assessments.
7.3.2.2.
Efficacy Assessment Schedule
Assessments within 4 Weeks Prior to First Dose
Clinical disease assessment for palpable or visual lesions;
Radiological disease assessments:

CT or MRI scan of the chest, abdomen and pelvis

Brain CT or MRI is required if previously documented brain metastases.  

Bone Scan (to include evaluation of skull, total spine, clavicle, ribs, pelvis, and 
long bones).  All bone scan abnormalities at screening that could indicate 
metastases, must be evaluated by X-ray (e.g., plain film, CT, or MRI) to confirm 
and /or quantify malignant lesions;

Documentation of tumor status at time of entry including all measurable disease 
and non-measurable disease. 
7.3.2.3.
Follow-up Assessments for Subjects Permanently Discontinued from 
Study Treatment
Refer to Section 4.2 Permanent Discontinuation from Study Treatment and Time and 
Events Schedule (Table 9) for follow-up assessment of subjects who are to be followed 
up for disease progression after permanently discontinuing study treatment for any 
reasons other than disease progression.
Efficacy Assessments at Withdrawal (From Study and/or Study Treatment)
The following assessments will be performed, if possible, when a subject is withdrawn 
from study treatment and/or from study for any reason:
Radiographic disease assessments should be obtained at withdrawal for subjects who 
have not had documented progression at a previous timepoint.  However, if the last 
radiographic assessment was obtained less than 9 weeks from withdrawal, radiographic 
assessments do not need to be repeated;
Efficacy Assessments for subjects who discontinued study treatment for 
reasons other than progression
Subjects who discontinue study treatment for reasons other than progression will have 
disease assessments done every 9 weeks until Week 54, then every 24 weeks thereafter 
until unequivocal progression, initiation of new anticancer therapy, death, withdrawal of 
consent or end of study (defined in section 10.5).


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7.3.2.4.
Assessment of Subject Completion
If the last radiographic assessment was more than 9 weeks prior to withdrawal from study 
and progressive disease has not been documented, a disease assessment should be 
obtained at the time of withdrawal from study. 
7.3.3.
Guidelines for Evaluation of Disease
Response to treatment will be determined for each evaluable subject according to 
definitions established in the Response Evaluation Criteria in Solid Tumors (RECIST 
1.1) [Eisenhauer, 2009].with modification to allow a minimum lesion size of 10 mm with 
contiguous cuts of 5 mm or less.
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules and palpable lymph nodes.)  In the case of 
skin lesions, documentation by physical measurement using a ruler to estimate the size of 
the lesion is required.  If skin lesions are being followed from baseline as target lesions, 
they must be evaluated at each time-point that requires tumor evaluations.
Conventional CT and MRI: Minimum sized lesion should be twice the reconstruction
interval, with a minimum lesion size of 10 mm.  The techniques should be performed
with contiguous cuts of 5 mm or less in slice thickness.  MRI is acceptable, but when
used, lesions must be measured in the same anatomic plane by use of the same imaging
sequences on subsequent examinations.  Whenever possible, the same scanner should 
be used.  If the slice thickness is greater than 5mm, the minimum size of a 
measurable lesion must be at least double the slice thickness (e.g., if the slice thickness is 
10 mm, a measurable lesion must be 20 mm).
Spiral CT: Minimum size of a baseline lesion may be 10 mm, provided the images are 
reconstructed contiguously at 5 mm intervals.  This specification applies to the tumors 
of the chest, abdomen, and pelvis.
Please note the following:
The same diagnostic method must be used throughout the study to evaluate a lesion
unless medically contraindicated.
PET scans and ultrasound are not acceptable methods of disease assessment.
All measurements should be taken and recorded in millimetres (mm), using a ruler or 
calipers.
7.3.3.1.
Measurable and Non-measurable Definitions
Measurable lesion:
A non-nodal lesion that can be accurately measured in at least one dimension (longest 
dimension) of


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10 mm with MRI or CT when the scan slice thickness is no greater than 5mm.  If the 
slice thickness is greater than 5mm, the minimum size of a measurable lesion must be at 
least double the slice thickness (e.g., if the slice thickness is 10 mm, a measurable lesion 
must be 20 mm).
10 mm caliper/ruler measurement by clinical exam or medical photography. 
20 mm by chest X-ray.
Additionally lymph nodes can be considered pathologically enlarged and measurable if
15 mm in the short axis when assessed by CT or MRI (slice thickness recommended to 
be no more than 5 mm).  At baseline and follow-up, only the short axis will be measured 
[Eisenhauer, 2009].
Non-measurable lesion:
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques [Eisenhauer, 2009].
Measurable disease: The presence of at least one measurable lesion.  Palpable lesions 
that are not measurable by radiologic or photographic evaluations may not be utilized as 
the only measurable lesion.
Non-Measurable only disease: The presence of only non-measurable lesions. 
7.3.4.
Response Criteria
7.3.4.1.
Evaluation of Target Lesions
Definitions for assessment of response for target lesion(s) are as follows:
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes must be <10mm in the short axis.
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as a reference, the baseline sum of the diameters (e.g., percent change 
from baseline).
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease.
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of target 
lesions, taking as a reference, the smallest sum of diameters recorded since the treatment 
started (e.g., percent change from nadir, where nadir is defined as the smallest sum of 
diameters recorded since treatment start). In addition, the sum must have an absolute 
increase from nadir of 5 mm.
Not Applicable (NA): No target lesions at baseline.


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Not Evaluable (NE): Cannot be classified by one of the five preceding definitions.
Note:
If lymph nodes are documented as target lesions the short axis is added into the sum of 
the diameters (e.g., sum of diameters is the sum of the longest diameters for non-nodal 
lesions and the short axis for nodal lesions).  When lymph nodes decrease to non-
pathological size (short axis <10 mm) they should still have a measurement reported in 
order not to overstate progression.
If at a given assessment time point all target lesions identified at baseline are not assessed, 
sum of the diameters cannot be calculated for purposes of assessing CR, PR, or SD, or for 
use as the nadir for future assessments.  However, the sum of the diameters of the 
assessed lesions and the percent change from nadir should be calculated to ensure that 
progression has not been documented.  If an assessment of PD cannot be made, the 
response assessment should be NE.
All lesions (nodal and non-nodal) should have their measurements recorded even when 
very small (e.g. 2 mm).  If lesions are present but too small to measure, 5 mm should be 
recorded and should contribute to the sum of the diameters, unless it is likely that the 
lesion has disappeared in which case 0 mm should be reported.
If a lesion disappears and reappears at a subsequent time point it should continue to be 
measured.  The response at the time when the lesion reappears will depend upon the 
status of the other lesions.  For example, if the disease had reached a CR status then PD 
would be documented at the time of reappearance.  However, if the response status was 
PR or SD, the diameter of the reappearing lesion should be added to the remaining 
diameters and response determined based on percent change from baseline and percent 
change from nadir.
7.3.4.2.
Evaluation of non-target lesions
Definitions for assessment of response for non-target lesions are as follows:
Complete Response (CR):  The disappearance of all non-target lesions. All lymph 
nodes identified as a site of disease at baseline must be non-pathological (e.g. <10 mm 
short axis).
Non-CR/Non-PD:  The persistence of 1 or more non-target lesion(s) or lymph nodes 
identified as a site of disease at baseline ≥ 10 mm short axis.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
Not Applicable (NA):  No non-target lesions at baseline.
Not Evaluable (NE):  Cannot be classified by one of the four preceding definitions.
Note:
In the presence of measurable disease, progression on the basis of solely non-target 
disease requires substantial worsening such that even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
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In the presence of non-measurable only disease consideration should be given to whether 
or not the increase in overall disease burden is comparable in magnitude to the increase 
that would be required to declare PD for measurable disease.
Sites of non-target lesions, which are not assessed at a particular timepoint based on the 
assessment schedule, should be excluded from the response determination (e.g., non-
target response does not have to be "Not Evaluable"). 
7.3.4.3.
New lesions
New malignancies denoting disease progression must be unequivocal.  Lesions 
identified in follow-up in an anatomical location not scanned at baseline are considered 
new lesions.
Any equivocal new lesions should continue to be followed.  Treatment can continue at 
the discretion of the investigator until the next scheduled assessment.  If at the next 
assessment the new lesion is considered to be unequivocal, progression should be 
documented.
7.3.4.4.
Evaluation of overall response
Table 10 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for subjects with measurable disease at baseline.
Table 10
Evaluation of Overall Response for Subjects with Measurable 
Disease at Baseline
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not applicable, and 
NE=Not Evaluable
Table 11 presents the overall response at an individual time point for all possible 
combinations of tumor responses in non-target lesions with or without the appearance of 
new lesions for subjects with non-measurable only disease at baseline.


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Table 11
Evaluation of Overall Response for Subjects with Non-Measurable 
Only Disease at Baseline
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non CR/Non PD
No
Non CR/Non PD
NE
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR=complete response,  PD=progressive disease, and NE=Not Evaluable
Note:

Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be classified as having "symptomatic deterioration." Objective response status is 
determined by evaluations of disease burden. Every effort should be made to 
document the objective progression even after discontinuation of treatment.  

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) to confirm the CR.
7.3.4.5.
Evaluation of best overall response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence and will be determined programmatically based on 
the investigator’s assessment of response at each time point. 
To be assigned a status of SD, follow-up disease assessment must have met the SD 
criteria at least once after randomization at a minimum interval of 56 days.
If the minimum time for SD is not met, best response will depend on the subsequent 
assessments.  For example if an assessment of PD follows the assessment of SD and SD 
does not meet the minimum time requirement the best response will be PD.  
Alternatively, subjects lost to follow-up after an SD assessment not meeting the 
minimum time criteria will be considered not evaluable.
Confirmation Criteria:
To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first met.
7.4.
Safety
7.4.1.
Safety Endpoints
This study will describe the safety and tolerability of trastuzumab in combination with 
lapatinib and of trastuzumab in combination with chemotherapy.


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7.4.2.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE as outlined in Section 7.4.2.1 and 
Section 7.4.2.2.
7.4.2.1.
Definition of an AE
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits, abuse, or misuse. Examples of events 
meeting the definition of an AE include:
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition
New conditions detected or diagnosed after study treatment administration even though it 
may have been present prior to the start of the study
Signs, symptoms, or the clinical sequelae of a suspected interaction
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-harming 
intent.  This should be reported regardless of sequelae).
“Lack of efficacy” or “failure of expected pharmacological action” per se is not to be 
reported as an AE or SAE.  However, any signs and symptoms and/or clinical sequelae 
resulting from “lack of efficacy” will be reported as an AE or SAE, if they fulfill the 
definition of an AE or SAE. 
Events that do not meet the definition of an AE include:
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads 
to the procedure is an AE.
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen.
The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition.


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7.4.2.2.
Definition of an SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
NOTE: Death due to disease under study is to be recorded on the Death CRF form 
and does not need to be reported as an SAE.   
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to 
an event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting. Complications that occur during hospitalization are 
AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (e.g.,
sprained ankle) which may interfere or prevent everyday life functions but do not 
constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect. 
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition.
These should also be considered 
serious. Examples of such events are invasive or malignant cancers, 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.
g.
Protocol-Specific SAEs:

All events of possible drug-induced liver injury with hyperbilirubinemia defined 
as ALT 3x ULN and bilirubin 2x ULN (>35% direct) (or ALT 3x ULN 
and INR > 1.5, if INR measured) termed ‘Hy’s Law’ events (INR measurement 


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is not required and the threshold value stated will not apply to patients receiving 
anticoagulants).

NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick 
indicating direct bilirubin elevations and suggesting liver injury. If testing is 
unavailable and a subject meets the criterion of total bilirubin 2x ULN, then 
the event is still reported as an SAE. If INR is obtained, include values on the 
SAE form. INR elevations > 1.5 suggest severe liver injury 

Any new primary cancers
Cardiovascular events have been seen in subjects taking other compounds that inhibit 
ErbB2 when used in combination with or following anthracyclines.  Interstitial 
pneumonitis has been reported in subjects taking compounds that inhibit ErbB1.  As a 
precaution, the following will be reported as SAEs:
Cardiac dysfunction will be reported as an SAE and will be defined as any sign(s) 
or symptom(s) of deterioration in left ventricular cardiac function that are Grade 3 
(NCI CTCAE V 4.0) or a 20% decrease in left ventricular cardiac ejection 
fraction relative to baseline, which is below the institution's lower limit of normal.  
Refer to NCI CTCAE grading of left ventricular cardiac function.  Also see
Section 5.8.4 Criteria for Evaluating Cardiac and Respiratory Events.
Any signs or symptoms of pneumonitis that are greater than Grade 3 (NCI 
CTCAE V 4.0) (defined as radiographic changes and requiring oxygen) 
dysfunction will be reported as an SAE.  Refer to NCI CTCAE grading of 
pneumonitis/pulmonary infiltrates.
Other hepatic events should be documented as an AE or an SAE as appropriate.
7.4.2.3.
Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements) 
including those that worsen from baseline, and event felt to be clinically significant in the 
medical and scientific judgment of the investigator are to be recorded as an AE or SAE, 
in accordance with the definitions provided.  
In addition, an associated AE or SAE is to be recorded for any laboratory test result or 
other safety assessment that led to an intervention, including permanent discontinuation 
of study treatment, dose reduction, and/or dose interruption/delay.  
Any new primary cancer must be reported as an SAE.  
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject's condition, are not to be reported as AEs or SAEs.  


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7.4.2.4.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.
7.4.2.5.
Death Events
In addition, all deaths, whether or not they are considered SAEs, will require a specific 
death data collection tool to be completed.  The death data collection tool includes 
questions regarding cardiovascular (including sudden cardiac death) and 
noncardiovascular death.
This information should be recorded in the specific death eCRF within one week of when 
the death is first reported.
7.4.2.6.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
an SAE. 
Death due to disease under study is to be recorded on the Death CRF form and does not 
need to be reported as SAE
However, if the underlying disease (i.e., progression) is greater than that which would 
normally be expected for the subject, or if the investigator considers that there was a 
causal relationship between treatment with study medication(s) or protocol 
design/procedures and the disease progression, then this must be reported as an SAE. 


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7.4.3.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
AEs will be collected from the time a subject consents to participate in the study until 30 
days following discontinuation of study treatment regardless of initiation of a new cancer 
therapy or transfer to hospice. 
SAEs (irrespective of causality) will be collected over the same time period as stated 
above for AEs.  In addition, any SAE assessed as related to study participation (e.g., 
protocol-mandated procedures, invasive tests, or change in existing therapy) or study 
treatment must be recorded promptly to Novartis from the time a subject consents to 
participate in the study up to and including any follow-up contact, as indicated in section
7.4.5 and Table 12.   
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  
7.4.4.
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:

“How are you feeling?” 

“Have you had any (other) medical problems since your last visit/contact?” 

“Have you taken any new medicines, other than those provided in this study, 
since your last visit/contact?” 
7.4.5.
Prompt Reporting of SAEs and Other Events 
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator as described in the following table once the 
investigator determines the event meets the protocol definition for that event.


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Table 12
Time and Events
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data 
collection tool
24 hours
Updated SAE data 
collection tool
CV events or death
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular 
event or death 
is reported
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
Pregnancy
24 hours
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow-
up Form
Liver chemistry abnormalities:
ALT3xULN and 
bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and 
INR>1.5, if INR 
measured)3
24 hours1
SAE data 
collection tool.
Liver Event Case 
Report Form 
(CRF) and liver 
imaging and/or 
biopsy CRFs if 
applicable2
24 hours
Updated SAE data 
collection tool. 
Updated Liver 
Event CRF2
ALT5xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN 4 weeks
24 hours1
Liver Event CRF2
24 hours
Updated Liver 
Event CRF2
ALT3xULN and 
<5xULN and bilirubin 
<2xULN
24 hours1
Liver Event CRF 
does not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks2
1.
Liver chemistry elevations should be notified at onset to discuss subject safety.
2.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible
3.
.INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
Methods for, recording, evaluating, and following up on AEs and SAEs and procedures 
for completing and transmitting SAE reports are provided in the SPM.  Procedures for 
post-study AEs and SAEs are provided in the SPM.


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7.4.6.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator is essential so that legal obligations and 
ethical responsibilities toward the safety of subjects are met.
There is a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  
Notification will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authorityand investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and are forwarded to investigators as 
necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) will file it with the IB and 
will notify the IRB/IEC, if appropriate according to local requirements.
7.4.7.
Pregnancy Testing, Prevention and Reporting
7.4.7.1.
Pregnancy Test and Prevention
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential.
A female of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant) is defined as any female who has had a hysterectomy, bilateral oophorectomy 
(ovariectomy) or bilateral tubal ligation, or is post-menopausal. 
A practical definition accepts menopause after 1 year without menses with an appropriate 
clinical profile, e.g., age appropriate, >45 years in the absence of hormone replacement 
therapy (HRT).  In questionable cases, the subject must have a follicle stimulating 
hormone (FSH) value >40 mIU/mL and an estradiol value < 40 pg/mL (<140 pmol/L).
A female of child-bearing potential is defined as any female who does not meet the 
criteria of non-childbearing potential as described in the previous paragraph. 
If a female subject is of childbearing potential, she must have a serum beta human 
chorionic gonadotropin (-HCG) pregnancy test performed within 7 days prior to the first 
dose of study treatment. Subjects with a positive pregnancy test result must be excluded 
from the study. Subjects with a negative pregnancy test result must agree to use an 
effective contraception method as described below during the study until 30 days
following the last dose of study treatment.
Novartis acceptable contraceptive methods, when used consistently and in accordance 
with both the product label and the instructions of the physician, are as follow:

An intrauterine device with a documented failure rate of less than 1% per year.

Vasectomized partner who is sterile prior to the female subject’s entry and is the sole 
sexual partner for that female.


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
Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and for at least 30 days after the last dose of 
study treatment.

Double-barrier contraception: condom and occlusive cap (diaphragm or cervical/vault 
caps) with a vaginal spermicidal agent (foam/gel/cream/suppository).

Implants of levonorgestrel where not contraindicated for this patient population or per 
local practice. 

Injectable progesterone where not contraindicated for this patient population or per 
local practice. 

Oral contraceptives (either combined or progesterone only) where not contraindicated 
for this patient population or per local practice. 
Female subjects who are lactating must discontinue nursing prior to the first dose of study 
treatment and must refrain from nursing throughout the treatment period and for 30 days
following the last dose of study treatment.
7.4.7.2.
Pregnancy Reporting
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to 
Novartis within 24 hours of learning of its occurrence.  The pregnancy must be followed 
up to determine outcome (including premature termination) and status of mother and 
child.  Pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to Novartis.
7.4.8.
Laboratory Assessments
All protocol required laboratory assessments must be performed by a local lab. 
Reference ranges for all safety parameters must be provided to Novartis and all 
laboratory results must be documented in the eCRF. 
Prior to administration of the first dose of study drug, results of laboratory assessments 
should be reviewed.  Any laboratory test with a value outside the normal range will be 
repeated (prior to the first dose) at the discretion of the investigator.  Before the first 
dose of study drug, all laboratory results must be within the values outlined in Section 
4.1.2.  All laboratory tests with values that are significantly abnormal during 
participation in the study or within 5 days after the last dose of study drug should be 
repeated until the values return to normal or baseline.  If such values do not return to 
normal within a period judged reasonable by the investigator, the etiology should be 
identified and the sponsor notified.


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Subjects will be required to have the laboratory assessments detailed in Table 13 (see 
Table 9 for specified study time-points).
Table 13
Laboratory Assessments
Hematology
Standard Chemistry1
  Hemoglobin
  sodium
  Hematocrit
  potassium
  red blood cell count
  calcium
  Platelets
  glucose
  white blood cell count with differential
  blood urea nitrogen (BUN) or urea
  total neutrophils or Absolute Neutrophil Count 
(ANC) 
  creatinine2
  AST
Serum Pregnancy3
  ALT
  serum β-hCG
  alkaline phosphatase 
  total bilirubin4
  
  albumin
  magnesium
1.
Chemistry evaluation of bicarbonate, chloride, and uric acid are not required
2.
If serum creatinine is >1.2 mg/dL or 106 μmol/L, calculate creatinine clearance using standard Cockcroft and 
Gault method (refer to Section 12.9  Appendix 9) 
3.
Refer to Section 7.4.7 for further details on serum pregnancy testing.
4.
Fractionated bilirubin (if testing is available) will also be assessed if total bilirubin ≥2 x ULN. See Section 5.9.1
Liver Chemistry Stopping and Follow-up Criteria 
Correction of electrolytes (most importantly, potassium, magnesium and calcium) to 
within normal ranges should take place prior to study entry and during study conduct as 
clinically indicated.
7.6.
Translational Research
Translational research will be performed on tissue and blood samples collected during the 
course of the trial to evaluate if immune markers are modulated by the treatment.  These 


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analyses will highlight eventual changes in expression levels and/or presence (and 
localization) of immunological cells/markers in relation to treatment.
Analyses to identify biomarkers or profiles correlating with response, or disease 
characteristics that include but are not be limited to breast cancer histological grade and 
molecular subtype may also be performed if sample numbers allow.
All samples may be retained for a maximum of 15 years after the last subject completes
the trial.
7.6.1.
Tumor Biomarker Analysis
Markers of the immune microenvironment will be analyzed in pre-treatment tumor 
biopsies and in paired tumor tissue obtained at disease progression. These analyses will 
include tumor infiltrating lymphocytes (TILs) and a seleted immune mRNA gene 
expression panel (e.g. Nanostring platform), including mRNA markers for specific 
immune cell populations (e.g. CD8 positive T-cells, B-cells, Tregs). Gene expression 
levels in the disease progression biopsy will be compared to the baseline biopsy to assess 
how the treatments affect the immune response at the level of the tumor.
In addition, immunological cells (and protein markers) may be investigated; such 
analyses may include, but are not limited to PD-L1, CD8 protein expression levels as 
determinded by immunohistochemistry, Treg cells, macrophages, and expression of 
additional checkpoint molecules, in the context of tumor and tumor associated stroma.For 
the archival stored tissue, a formalin-fixed, paraffin-embedded tumor tissue block taken 
at a metastatic site or obtained at the time of original primary cancer diagnosis (biopsy or 
from definitive surgery) is required to be submitted to the central laboratory. 
Alternatively, sites may send 15-20 freshly sectioned, unstained slides containing 5-
micron thick sections. 
As image guidance has been shown to significantly increase the probability of success in 
obtaining core needle biopsies, it is therefore required for both percutaneous pre-
treatment, and progression biopsies in this study.
Further details on sample collection, processing, storage and shipping procedures are 
provided in the SPM.


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8.
DATA MANAGEMENT
Data Management will identify and implement the most effective data acquisition and 
management strategy for each clinical trial protocol and deliver datasets which support 
the protocol objectives.
For this study subject data will be entered into the electronic case report forms (eCRFs), 
transmitted electronically to the sponsor (or designee) and be combined with data 
provided from other sources in a validated data system.  The electronic data capture 
system InForm will be used to collect all of the subject information by the investigator.
Management of clinical data will be performed in accordance with applicable standards 
and data cleaning procedures to ensure the integrity of the data, e.g. resolving errors and 
inconsistencies in the data.  Adverse events and concomitant medications terms will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) and a custom 
drug dictionary.  eCRFs (including queries and audit trails) will be retained by the 
sponsor, and copies will be sent to the investigator to maintain as the investigator copy.  
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
9.1.
Hypotheses
The primary objective of this study is to determine if trastuzumab in combination with
lapatinib or chemotherapy changes expression of biomarkers associated with 
immunomodulation.  The primary endpoint will be analyzed by treatment arm with a 
descriptive intent only.  The study is not powered to detect differences between the 
treatment arms and as such no formal treatment arm comparisons will be made.
9.2.
Study Design Considerations
9.2.1.
Sample Size Assumptions
This is a purely descriptive study. Due to difficulty in enrolling subjects into this trial, 
future enrolment was halted and the study will be terminated early. 
A pre-treatment biopsy and a biopsy at disease progression will provide the samples for 
biomarker analysis.  
9.2.2.
Sample Size Sensitivity
Not applicable
9.2.3.
Sample Size Re-estimation
Sample size re-estimation is not planned for this study.


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9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The Intent-to-Treat (ITT) Population will be used for the analysis of clinical efficacy and 
will consist of all subjects who were assigned to study treatment, regardless of whether 
they actually received study treatment.
The Evaluable Population (EP) will be used for the primary analysis of change in 
biomarkers at disease progression and will consist of all subjects who were assigned to 
study treatment and have both baseline and progression tumor biopsies available, with 
evaluable data for at least 1 biomarker.
The Safety Population will be used to assess clinical safety and tolerability and will 
consist of all subjects who were randomized and took at least 1 dose of study medication.  
This population will be based on the actual treatment received by the subjects.
9.3.2.
Analysis Data Sets
The primary dataset for evaluation of changes in biomarker expression will be the 
Evaluable Population as defined in Section 9.3.1.
The primary dataset for assessing safety will be the Safety Population as defined in 
Section 9.3.1.
The primary dataset for assessing clinical efficacy endpoints will be the ITT Population 
as defined in Section 9.3.1. The Evaluable Population will be utilized to assess the 
relationship between on-treatment changes in biomarker expression and clinical 
endpoints.
9.3.3.
Treatment Comparisons
9.3.3.1.
Primary Comparisons of Interest
There will be no formal statistical comparisons between treatment arms in this study.  
All data presented including summary statistics are descriptive in nature.  
The primary objective will be achieved by describing the change in biomarkers related to 
the specified mechanisms in the pre-treatment biopsy and the progression biopsy with 
each arm.  
The data cut-off for the primary analysis will be defined at 12 months after the last 
subject enrolled in the study or the last subject progressed/withdrew, whichever is earlier.
Following the cut-off date for the primary analysis, the study will remain open. Ongoing 
subjects will continue to receive study treatment and be followed as per the schedule of 
assessments, as long as subjects derive benefit from lapatinib. The end of study defined 
as the earliest occurrence of one of the following:
•       All patients have died or discontinued from the study


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•       Another clinical study becomes available that can continue to provide lapatinib 
in this patient population and all subjects ongoing are eligible to be transferred to that 
clinical study 
•    At the end of the study, every effort will be made to continue provision of study 
treatment outside this study through an alternative setting to subjects who in the opinion 
of the Investigator are still deriving clinical benefit. Details on the handling of missing 
data are provided in Section 9.3.5.
9.3.4.
Interim Analysis
No interim efficacy analyses are planned for this study.
9.3.5.
Key Elements of Analysis Plan
Data will be listed and summarized according to the Novartis reporting standards, where 
applicable.  Complete details will be documented in the reporting and analysis plan 
(RAP).  Any deviations from, or additions to, the original analysis plan described in this 
protocol will be documented in the RAP and final study report.
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis.  
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.  
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects.  Consequently there will be no 
imputation for missing data. 
Demographic and baseline characteristics will be summarized.
For the analysis of PFS during study treatment period, if the subject received subsequent 
anticancer therapy prior to the date of documented progression or death, PFS will be 
censored at the last adequate assessment (e.g., assessment where visit level response is 
CR, PR, or SD) prior to the initiation of therapy.  Otherwise, if the subject does not have 
a documented date of progression or death, PFS will be censored at the date of the last 
adequate assessment.  Further details on rules for censoring will be provided in the RAP. 
Details on the determination of tumor response are given in Section 7.3.4.
No adjustments for multiple comparisons will be made as there is no formal hypothesis 
testing.  
Additional details on efficacy analyses are provided in Section 9.3.5.1.  Similarly,
additional details on safety analyses are provided in Section 9.3.5.2.


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9.3.5.1.
Efficacy Analyses
9.3.5.1.1.
Primary Analysis
The primary biomarker endpoint is change in expression/percent presence levels of 
biomarkers as measured in tissue from the progression tumor biopsy, compared with 
expression/percent presence levels of these markers as measured in the screening tumor 
biopsy.  Marker levels may be derived from measurements of mRNA or protein from 
biopsy samples.
The primary endpoint of changes in biomarker expression will be presented for each 
treatment arm for the evaluable population. Due to limited number of subjects enrolled as 
well as limited number of subjects with baseline biopsy and biopsy at disease progression, 
no formal statistical comparisons will be performed. 
9.3.5.1.2.
Secondary Analyses
This study is not powered to detect a clinically meaningful difference between the 
treatment groups in the secondary endpoints. Therefore, these analyses are considered 
exploratory and no formal hypothesis testing will be performed.  Further details on these 
secondary endpoints will be documented in the RAP.
Overall Response Rate
ORR will be defined as the percentage of subjects achieving either a confirmed CR or PR 
tumor response at any time, according to the investigator assessment of response per 
RECIST 1.1 criteria. Subjects with unknown or missing response or who have 
withdrawn from the study will be included in the denominator as a nonresponder.  Exact 
95% CI for the tumor response rates in each arm will be calculated and the ITT 
Population will be used for the analysis.
Clinical Benefit Rate
CBR will be defined as the percentage of subjects achieving either a confirmed CR or PR 
tumor response at any time or maintaining SD for at least 24 weeks while on study, 
according to the investigator assessment of response per RECIST 1.1 criteria. Subjects 
with unknown or missing response or who have withdrawn from the study prior to 
completing 24 weeks of response assessments will be included in the denominator as a 
nonresponder. Exact 95% CI for the tumor response rates in each arm will be calculated 
and the ITT Population will be used for the analysis.
Progression-Free Survival
PFS will be defined as the interval of time between the date of randomization and the 
earlier of date of disease progression or date of death due to any cause. Disease 
progression will be based on the assessments by the investigator per RECIST 1.1 
criteria. The date of documented disease progression will be defined as the date of 
radiological disease progression as assessed by the investigator based on imaging data,
which will be the date of lesion evaluation. If a subject has neither progressed nor died, 
then PFS will be censored at the date of the last radiological scan assessed by the 


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investigator. Subjects who receive an alternative anticancer therapy will be censored at 
the initiation of the alternative therapy if scans or progression do not occur within a 14-
day window as defined above. Additional details on censoring rules will be described in 
the RAP.  PFS will be summarized using Kaplan-Meier curves. The Pike estimator 
[Berry, 1991] of the treatment HR based on the log-rank test will be provided, together 
with a 95% CI. The median PFS and first and third quartiles will be presented, along 
with 95% CI if there are sufficient numbers of progressions or deaths. These analyses 
will be done on the ITT population.
9.3.5.2.
Safety Analyses
Safety endpoints are described in Section 2 and Section 7.4.
The Safety Population will be used for the analysis of safety data up to 30 days post-
study treatment. Complete details of the safety analyses will be provided in the RAP.
Safety to be summarized to include at a minimum:
Exposure
Adverse events
Serious adverse events
Deaths
Adverse events leading to discontinuation of study treatment
Cardiotoxicity evaluations
Clinical laboratory evaluations
9.3.5.2.1.
Extent of Exposure
The number of subjects administered study treatment will be summarized according to 
the duration of therapy. 
9.3.5.2.2.
Adverse Events
Adverse events will be coded using the standard Medical Dictionary for Regulatory 
Activities (MedDRA) and grouped by system organ class.  AEs will be graded by the 
investigator according to the NCI-CTCAE (version 4.0).  
Events will be summarized by frequency and proportion of total subjects, system organ 
class, and preferred term. Separate summaries will be given for all AEs, drug-related 
AEs, serious AEs, and AEs leading to discontinuation of study treatment.
If the AE is listed in the NCI-CTCAE (version 4.0) table, the maximum grade will be 
summarized.
Characteristics (e.g., number of occurrences, action taken, grade, etc.) of the following 
AEs of special interest may be summarized separately: diarrhea, rash, LVEF, and liver 
toxicity.


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The incidence of deaths and the primary cause of death will be summarized.
9.3.5.2.3.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized at each scheduled 
assessment according to NCI-CTCAE grade (version 4.0).  The proportion of values 
lying outside the reference range will also be presented for laboratory tests that are not 
graded because there are no associated NCI-CTCAE criteria.  Summaries will include 
data from scheduled assessments only, and all data will be reported according to the 
nominal visit date for which they were recorded (i.e., no visit windows will be applied).  
Unscheduled data will be included in “overall” and “any post-screening” summaries,
which will capture a worst case across all scheduled and unscheduled visits post first dose 
of study treatment.  Further details will be provided in the RAP.
9.3.5.2.4.
Other Safety Measures
The results of scheduled assessments of vital signs, 12-lead ECG, ECHO (or MUGA 
scan), and ECOG performance status will be summarized.  Summaries will include data 
from scheduled assessments only.  All data will be reported according to the nominal 
visit date for which they were recorded (i.e., no visit windows will be applied).  All data 
will be listed. Further details will be provided in the RAP.
9.3.5.3.
Translational Research Analyses
The results of translational research investigations will be reported in the main clinical 
study report.  All endpoints of interest from all comparisons will be descriptively and/or 
graphically summarized as appropriate to the data.
Further details on the translational research analyses will be addressed in the RAP.
 
 
 
10.
STUDY CONDUCT CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial
registers before enrolment of subjects begins.


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10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, Novartis will obtain favourable opinion/approval from 
the appropriate regulatory agency to conduct the study in accordance with ICH Good 
Clinical Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and the ethical principles that are outlined in the 
Declaration of Helsinki 2008, including, but not limited to:
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favorable opinion/approval of study protocol and any subsequent amendments.
Subject informed consent.
Investigator reporting requirements.
Novartis will provide full details of the above procedures, either verbally, in writing, or 
both.
Written informed consent must be obtained from each subject prior to participation in the 
study.
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments e.g., PGx assessments 
described in Appendix 1, unless otherwise indicated.  Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study.  If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated.  When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will 
not be conducted.
10.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and Novartis procedures, the site will be 
contacted prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and Novartis 
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time to their staff to monitor to discuss findings and any issues.
Monitoring visits will be conducted in a manner to ensure that the:


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Data are authentic, accurate, and complete.
Safety and rights of subjects are being protected.
Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
10.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, Novartis 
may conduct a quality assurance assessment and/or audit of the site records, and the 
regulatory agencies may conduct a regulatory inspection at any time during or after 
completion of the study. In the event of an assessment, audit or inspection, the 
investigator (and institution) must agree to grant the advisor(s), auditor(s) and 
inspector(s) direct access to all relevant documents and to allocate their time and the time 
of their staff to discuss the conduct of the study, any findings/relevant issues and to 
implement any corrective and/or preventative actions to address any findings/issues 
identified
10.5.
Study and Site Closure
The study will end when all subjects have completed the study, i.e. presented with 
disease progression, started new anti-cancer therapy, died or withdrew from the study 
(whichever came first) during the study treatment period or the follow-up period after 
discontinuation due to any reasons other than disease progression.
All subjects will 
receive study treatment until disease progression, death, unacceptable toxicity, subject 
withdrawal of consent or any other reasons mentioned in section 4.2.1.  
In case of disease progression during the treatment period, the subject will be followed-
up for 30 days for safety evaluation and no further study-specific follow-up will be 
carried out; the subject will be considered as having completed the study. Similarly, in 
case of disease progression after the treatment period (i.e. in subjects who discontinued 
for any reasons other than disease progression) and before the end of the study, no further 
study-specific follow-up will be carried out; the subject will be considered as having 
completed the study. 
In case of study treatment discontinuation for any reasons other than disease progression, 
the subjects will be followed-up for safety and efficacy assessments (disease assessments 
done every 9 weeks until Week 54, then every 24 weeks) until disease progression, new 
anticancer therapy, death, withdrawal of consent or end of study, whichever comes first. 
Following the cut-off date for the primary analysis (defined at 12 months after the last 
subject enrolled in the study or the last subject progressed/withdrew, whichever is earlier), 
the study will remain open. Ongoing subjects will continue to receive study treatment and 
be followed as per the schedule of assessments, as long as subjects derive benefit from 
lapatinib. The end of study defined as the earliest occurrence of one of the following:
•       All patients have died or discontinued from the study


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•       Another clinical study becomes available that can continue to provide lapatinib 
in this patient population and all subjects ongoing are eligible to be transferred to that 
clinical study 
•       At the end of the study, every effort will be made to continue provision of study 
treatment outside this study through an alternative setting to subjects who in the opinion 
of the Investigator are still deriving clinical benefit.
Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, ICH GCP, and Novartis Standard Operating Procedures.
Novartis reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance.  If Novartis determines that such action is required, Novartis will 
discuss the reasons for taking such action with the investigator or head of the medical 
institution (where applicable).  When feasible, Novartis will provide advance notice to 
the investigator or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons,Novartis will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  Novartis will also promptly inform the relevant regulatory 
authorities of the suspension/termination along with the reasons for such action.  Where 
required by applicable regulations, the investigator or head of the medical institution 
must inform the IRB/IEC promptly and provide the reason(s) for the 
suspension/termination.
Novartis may close sites which fail to recruit within a predefined timeframe, as defined 
within the Study Procedures Manual.
10.6.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a Novartis audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure 
that an acceptable back-up of the reproductions exists and that there is an acceptable 
quality control procedure in place for creating the reproductions.
Essential documents (written and electronic) should be retained for a period of not less 
than fifteen (15) years from the completion of the Clinical Trial unless the Sponsor 


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provides written permission to dispose of them or, requires their retention for an 
additional period of time because of applicable laws, regulations and/or guidelines.
The investigator must notify Novartis of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
ownership of the records in the event that the investigator is no longer associated with the 
site.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a Novartis site or other mutually-
agreeable location.
Novartis will also provide the investigator with the full summary of the study results.  
The investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The sponsor aims to post a results summary to the Novartis Clinical Study Trial results 
website (www.novartisclinicaltrials.com) and other publicly available registers no later 
than twelve (12) months after the last subject’s last visit (LSLV). In addition, upon study 
completion and finalization of the study report, Novartis aims to submit results of the 
study for publication. When publication is not feasible, please refer to the Novartis 
Clinical Trial Results website (www.novartisclinicaltrials.com) for a summary of the trial 
results.A manuscript will be progressed for publication in the scientific literature if the 
results provide important scientific or medical knowledge.


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11.
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therapies in the neosphere study: Modulation of tumor lymphocyte infiltration (TIL) and 
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12.
APPENDICES


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12.2.
Appendix 2:  Country Specific Requirements
No country-specific requirements exist.


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12.3.
Appendix 3:  ECOG Performance Status
Grade
ECOG1
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity, but ambulatory and able to carry out work 
of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare, but unable to carry out any work activities. 
Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5
Dead
1.
As published in [Oken, 1982]


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12.4.
Appendix 4:  Liver Chemistry Monitoring, Interruption 
Stopping and Follow-up Criteria
Liver Safety Algorithm
IP may be re-challenged if protocol provides this option in Section 5.9.2.


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12.5.
Appendix 5: Liver Safety Drug Restart or Rechallenge 
Guidelines
1.
Drug restart may be considered for a subject exhibiting compelling benefit for a 
critical medicine following drug-induced liver injury, if favorable benefit: risk 
and no alternative medicine available.  
2.
Drug restart may be considered for liver safety events with a clear underlying 
cause (e.g., biliary, pancreatic events, hypotension, acute viral hepatitis), if not 
associated with drug-induced liver injury, alcoholic hepatitis, or hypersensitivity
(fever, rash or eosinophilia) and drug not associated with HLA genetic marker of
liver injury) when liver chemistries have improved to normal or are within 1.5 x
baseline and ALT <3 x ULN.
Liver Events Possibly Related to IP - Drug Restart/Rechallenge Following Possible 
Drug-induced Liver Injury Challenge Guidelines
Following drug-induced liver injury, drug restart or rechallenge is associated with a 
13% mortality across all drugs in prospective studies1 Clinical outcomes vary by drug, 
with nearly 50% fatality with halothane readministered in one month of initial injury. 
However, some drugs seldom result in recurrent liver injury or fatality.  Risk factors for 
a fatal drug restart/rechallenge outcome include: hypersensitivity1 with initial liver injury 
(e.g., fever, rash, eosinophilia), jaundice or bilirubin 2 x ULN or INR >1.5 suggesting 
severe liver injury, prior IP-related severe or fatal drug restart/rechallenge2,3 or evidence 
of drug-related preclinical liability / mitochondrial impairment3
Decision Process for Drug Restart Approval or Disapproval (also see Figure 2)
Principal Investigator (PI) requests consideration of drug restart for a subject receiving 
compelling benefit from a critical or life-saving drug, who exhibits liver chemistry 
elevation meeting subject stopping criteria, with no alternative treatment
Medical lead & Clinical Safety Physician to review the subject’s restart/rechallenge risk 
factors & complete checklist (Table 14)


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Table 14
Checklist for drug rechallenge for critical medicine (Following drug-
induced liver injury, drug rechallenge is associated with 13% 
mortality across all drugs in prospective studies)
Yes
No
Compelling benefit of the study treatment (ST) for this subject 
and no alternative therapy.  Provide brief explanation:
Relative benefit-risk favorable for drug restart/rechallenge, after 
considering the following high risk factors:
•
Initial liver injury event included: 
–
fever, rash, eosinophilia, or hypersensitivity
–
or bilirubin2xULN (direct bilirubin >35% of total)
•
Subject currently exhibits ALT 3xULN, bilirubin 2xULN (direct 
bilirubin >35% of total, if available), or INR1.5
•
Severe or fatal restart/rechallenge has earlier been observed 
with IP If yes, please provide brief explanation:
•
IP associated with known preclinical hepatic liability/ injury   
Principal Investigator (PI) Actions:
The PI must obtain Ethics Committee or Institutional Review Board review of drug 
reinitiation, as required. 
PI must discuss the possible benefits and risks of drug reinitiation with the subject.
The subject must sign informed consent with a clear description of possible benefits and 
risks of drug administration, including recurrent liver injury or death. Consent must be 
recorded in the study chart.
The drug must be reinitiated at Novartis approved dose(s). 
Liver chemistries should be followed twice weekly until stable.
The Ethics Committee or Institutional Review Board must be informed of the subject’s 
outcome, as required.
Notification of any adverse events, as per Section 7.4.2 - Section 7.4.6. 


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Figure 2
Process for drug restat after possible drug-induced liver injury
References:
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 
2010;52:2216-2222
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced liver 
injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90.


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Drug Restart Guidelines
Novartis Decision Process for Drug Restart Approval or Disapproval (also see 
Figure 3)
Principal Investigator (PI) requests consideration of drug reinitiation for a subject stable 
or improving on study treatment (ST), who exhibits liver chemistry elevation meeting 
subject stopping criteria, which is transient, non-drug-related, and resolves. 
Medical lead & Clinical Safety Physician to review the subject’s diagnosis, restart risk 
factors & complete checklist (Table 15).
Table 15
Checklist for Phase III drug restart after well-explained liver injury 
(e.g., biliary, pancreatic, hypotensive events, CHF, acute viral 
hepatitis), liver chemistries improving to normal or 1.5 x baseline 
and ALT <3 x ULN.
Yes
No
Is subject stable or improving on the study treatment (ST)?
Do not restart if the following risk factors at initial liver injury:

fever, rash, eosinophilia, or hypersensitivity 

drug-induced liver injury 

alcoholic hepatitis (ASTALT, typically <10xULN)    

IP associated with liver injury and an HLA genetic marker 
(e.g., lapatinib, abacavir, amoxicillin/clavulanate)   
Principal Investigator (PI) Actions
The PI must obtain Ethics Comm. or Institutional Review Board review of drug 
reinitiation, as required. 
PI must discuss the benefits and risks of drug reinitiation with the subject.
The subject must sign informed consent with a clear description of possible benefits and 
risks of drug administration, including recurrent liver injury or death. Consent must be 
recorded in the study chart. 
Liver chemistries should be followed weekly until stable.
The Ethics Committee or Institutional Review Board must be informed of the patient’s 
outcome, as required.
Notification of any adverse or serious adverse events, as per Section 7.4.2 - Section 7.4.7.


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Figure 3
Process for drug restart approvals
References:
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 
2010;52:2216-2222. 
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced liver 
injury following positive drug rechallenge.  Regul Tox Pharm. 2009; 54:84-90. 


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12.6.
Appendix 6: Asymptomatic Cardiac Event Assessment
LVEF decrease from baseline value
CONTINUE study drug and
MONITOR LVEF as per protocol 
LVEF same or worse
HOLD study drug and REPEAT LVEF
1 week to 3 weeks 
LVEF recovered 
LVEF decrease <=20% from
baseline and above or below LLN 
LVEF >= 20% and below LLN
CONTINUE study drug and 
REPEAT LVEF 1 week to 3 weeks 
Report as SAE and follow event to resolution
LVEF decrease >=20% from
baseline and above LLN
Check to see if event meets 
AE reporting criteria
CONTINUE study drug
and 
MONITOR LVEF as per
per protocol 
LVEF same or worse
LVEF recovered
:
:
RESTART treatment ONLY after Medical Monitor
Approval
continue to monitor LVEF every 2 weeks for 
4 weeks and then every 4 weeks 
PERMANENTLY DISCONTINUE
study drug 
and
continue to monitor LVEF every 
4 weeks for at least 16 weeks 
or until resolution
and
LVEF decrease from baseline value
CONTINUE study drug and
MONITOR LVEF as per protocol 
LVEF same or worse
HOLD study drug and REPEAT LVEF
1 week to 3 weeks 
LVEF recovered 
LVEF decrease <=20% from
baseline and above or below LLN 
LVEF >= 20% and below LLN
CONTINUE study drug and 
REPEAT LVEF 1 week to 3 weeks 
Report as SAE and follow event to resolution
LVEF decrease >=20% from
baseline and above LLN
Check to see if event meets 
AE reporting criteria
CONTINUE study drug
and 
MONITOR LVEF as per
per protocol 
LVEF same or worse
LVEF recovered
:
:
RESTART treatment ONLY after Medical Monitor
Approval
continue to monitor LVEF every 2 weeks for 
4 weeks and then every 4 weeks 
PERMANENTLY DISCONTINUE
study drug 
and
continue to monitor LVEF every 
4 weeks for at least 16 weeks 
or until resolution
and


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12.7.
Appendix 7: Diarrhea Mangement Guidelines
Background
Experience thus far suggests that when lapatinib is used as monotherapy 51% of patients 
experience diarrhea; most diarrhea presents as uncomplicated NCI CTCAE Grade 1 or 2 
(G1 30%, G2 15%, G3 6%, G4<1%) (Crown, 2008).
In rare cases, diarrhea can be debilitating, and potentially life threatening if accompanied 
by dehydration, renal insufficiency, and/or electrolyte imbalances.
Standardized and universal guidelines have been developed by an American Society of 
Clinical Oncology (ASCO) panel for treating chemotherapy-induced diarrhea (Benson, 
2004).  Presented in the sections below are the recommended guidelines for the 
management of diarrhea in subjects receiving lapatinib-based therapy; these guidelines 
were derived from the recommendations published by the ASCO panel (Benson, 2004).
Early identification and intervention is critical for the optimal management of diarrhea.  
A subject’s baseline bowel patterns should be established so that changes in patterns can 
be identified while subject is on treatment.
It is strongly recommended to give subjects receiving lapatinib-based therapy a 
prescription of loperamide with instructions to start loperamide at the onset of 
diarrhea as per the recommendations outlined below.
Subjects should be instructed to first notify their physician/healthcare provider at 
onset of diarrhea of any severity.
An assessment of frequency, consistency and duration as well as knowledge of other 
symptoms such as fever, cramping, pain, nausea, vomiting, dizziness and thirst should be 
taken at baseline. Consequently subjects at high risk of diarrhea can be identified.  
Subjects should be educated on signs and symptoms of diarrhea with instructions to 
report any changes in bowel patterns to the physician.
It is recommended that subjects keep a diary and record the number of diarrhea episodes 
and its characteristics.  They should also include information on any dietary changes or 
other observations that may be useful in the evaluation of their diarrhea history.
If subjects present with diarrhea of any Grade, check they are taking lapatinib correctly, 
i.e., single daily dose, rather than splitting it through the day.  Obtain information on 
food (solid and liquid) and over the counter (OTC) medication, including herbal 
supplements, taken during the lapatinib treatment period.
Definitions
National Cancer Institute (NCI) guidelines define diarrhea compared with baseline (Table 
16).


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Table 16
NCI Common Terminology Criteria for Grading Diarrhea Adverse 
Events1
Adverse 
Event Grade
Diarrhea
1
Increase of <4 stools/day over baseline; mild increase in ostomy output compared with
baseline
2
Increase of 4-6 stools/day over baseline; moderate increase in ostomy output 
compared with baseline;
3
Increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated; severe 
increase in ostomy output compared with baseline; limiting self care activities of daily 
living (ADL)
4
Life-threatening consequences; urgent intervention indicated
5
Death
1 National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0
Uncomplicated diarrhea is considered mild-to-moderate and defined as CTCAE 
Grade 1 or 2 with no complicating signs or symptoms.
Complicated diarrhea is severe and defined as any CTCAE Grade 3 or 4 diarrhea, 
or Grade 1 or 2 with one or more of the following signs or symptoms:

Moderate to severe abdominal cramping 

Nausea/vomiting ≥Grade2

Decreased performance status

Fever

Sepsis

Neutropenia

Frank bleeding (red blood in stool)

Dehydration
Management Guidelines for Subjects Receiving Lapatinib Alone or as Combination 
Therapy
A)
Uncomplicated Diarrhea
I.
CTCAE Grade 1
NOTE:  Subject should be instructed to: start supportive care immediately at the 
first episode of diarrhea (i.e., unformed stool) and call their physician.
1. Administer loperamide*
a.
Initial dose 4 mg followed by 2 mg after every unformed stool. Re-evaluate 
after 24 hours, if:
i.
Diarrhea is resolving:


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
Continue loperamide treatment at 2 mg dose after every unformed 
stool until diarrhea free (i.e., <Grade 1/bowel patterns returned to 
baseline) for 12 hours.
o
If diarrhea recurs, re-initiate loperamide treatment as needed to 
maintain normal bowel patterns
ii.
Diarrhea is not resolving:

Administer loperamide at 2 mg every 4 hours for the next 24 hour.  
Re-evaluate after 24 hours.  If diarrhea is resolving, administer 
loperamide at 2 mg after every unformed stool until diarrhea free (i.e., 
<Grade 1/bowel patterns returned to baseline) for 12 hours.  If 
diarrhea is not resolving continue loperamide treatment at 2 mg every 
4 hours and re-evaluate every 24 hours.
b. If Grade 1 diarrhea persists for more than 1 week with loperamide 
treatment, consider treatment with second-line agents (i.e., octreotide, 
budesonide or tincture of opium).
2. Dietary modifications which are essential in the management of diarrhea  
include the following recommendations (American Cancer Society; National 
Cancer Institute):
a.
Stop all lactose containing products and eat small meals
b. Avoid spicy, fried and fatty foods, raw vegetables and other foods high in 
fiber

Eat foods low in fiber (i.e., lean meat, rice, skinless chicken or 
turkey, fish, eggs, canned or cooked skinless fruits, cooked/pureed 
vegetables)
c.
Avoid caffeine and alcohol as they can irritate the bowel and increase motility
d. Hydration:  Drink 8-10 large glasses of clear liquids a day (e.g., water, 
electrolyte drink).

Avoid acidic drinks such as tomato juice and fizzy soft drinks
e.
Supplement diet to include foods rich in potassium (e.g., bananas, potatoes, 
and apricots) , evaluate their impact on diarrhea due to the fiber content (e.g., 
apricots)
3. Continue with study treatment (i.e., lapatinib-based treatment)
Continue with supportive care until diarrhea has resolved (diarrhea free for 12 
hours/bowel pattern return to baseline).  Once diarrhea has resolved, the subject can 
begin to gradually re-introduce foods from their normal diet.
If diarrhea recurs following stopping of loperamide treatment, resume loperamide 
treatment at the dose and schedule recommended above and re-introduce diet 
modifications.  Continue with study treatment.


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If Grade 1 diarrhea persists for ≥2 weeks, refer to the management guidelines for 
Persistent Grade 2 Diarrhea.
II.
CTCAE Grade 2
NOTE:  Subject should be instructed to call physician at first episode of diarrhea 
and start supportive care immediately
1. Administer loperamide*
a.
Initial dose 4 mg followed by 2 mg every 4 hours or after every unformed 
stool.  Re-evaluate after 24 hours.  If:
i.
Diarrhea is resolving, continue loperamide treatment at 2 mg dose after 
every unformed stool until diarrhea free (i.e., <Grade 1/bowel patterns 
returned to baseline) for 12 hours
o
If diarrhea recurs, re-initiate loperamide treatment as needed to 
maintain normal bowel patterns
ii.
Diarrhea is not resolving, consider loperamide dose of 2 mg every 2 hours 
for 24 hours. If Grade 2 diarrhea persists after total of 48 hours of 
loperamide treatment, start second-line agents (i.e.,octreotide, budesonide 
or tincture of opium).
o
Consider performing stool work-up, CBC, electrolytes and other 
tests as appropriate
2. Dietary modifications which are essential in the management of diarrhea include 
the following recommendations (American Cancer Society; National Cancer 
Institute):
a.
Stop all lactose containing products and eat small meals
b. Avoid spicy, fried and fatty foods, bran, raw vegetables and other foods high 
in fiber

Eat foods low in fiber (i.e., lean meat, rice, skinless chicken or 
turkey, fish, eggs, canned or cooked skinless fruits, cooked/pureed 
vegetables)
c.
Avoid caffeine and alcohol as they can irritate the bowel and increase motility
d. Hydration:  Drink 8-10 large glasses of clear liquids a day (e.g., water, 
electrolyte drink).

Avoid acidic drinks such as tomato juice and fizzy soft drinks
e.
Supplement diet to include foods rich in potassium (e.g., bananas, potatoes, 
and apricots), evaluate their impact on diarrhea due to the fiber content (e.g., 
apricots)


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3. Continue with study treatment (i.e., lapatinib-based treatment)
Continue with supportive care until diarrhea has resolved (diarrhea free for 12 
hours/bowel pattern return to baseline).  Once diarrhea has resolved, the subject can 
begin to gradually re-introduce foods from their normal diet.  Refer to Section IV 
“Recurrent Diarrhea” for study treatment guidelines.
If diarrhea recurs following stopping of loperamide treatment, resume loperamide 
treatment at the dose and schedule recommended above and re-introduce diet 
modifications.
III.
Persistent (≥ 3days/72 hours) Grade 2 Diarrhea: hold lapatinib and 
chemotherapy (if applicable) until diarrhea resolves (<Grade 1/return to baseline 
bowel pattern).
1. If supportive care measures and the interruption of study treatment (i.e., lapatinib 
and if applicable chemotherapy) are ineffective in treating persistent Grade 1 or 
Grade 2 diarrhea, perform stool work-up, CBC, electrolytes and other tests as 
appropriate, consider consulting with a gastrointestinal (GI) specialist.
a.
After diarrhea resolves (<Grade 1/return to baseline bowel pattern), resume 
treatment with lapatinib and chemotherapy (if applicable).
IV.
Recurrent Diarrhea (more than 1 occurrence of Grade 2 diarrhea): 
once the second occurrence of Grade 2 diarrhea resolves to ≤Grade 1, consider 
reducing the dose of lapatinib by 250 mg or 1 tablet, unless the lapatinib dose 
already had been reduced to 750 mg.  No further dose reduction is recommended 
for subjects taking lapatinib at 750mg.
1. Consider a dose reduction for chemotherapy (if applicable)
B)
Complicated Diarrhea
I.
CTCAE Grade 3 or Grade 1 or 2 with complicating features (severe 
cramping, severe nausea/vomiting, decreased performance status, fever, 
sepsis, Grade 3 or 4 neutropenia, frank bleeding, dehydration)
1. Subject must call physician immediately for any complicated severe diarrhea 
event
2. If loperamide has not been initiated, initiate loperamide immediately:  Initial 
dose 4 mg followed by 2 mg every 2 hours or after every unformed stool*
3. Refer to the dietary modification recommendations for Grade 1 and Grade 2 
uncomplicated diarrhea
4. For dehydration use intravenous fluids as appropriate, if subject presents with 
severe dehydration administer octreotide
5. Perform stool work-up, CBC, electrolytes and other tests as appropriate
6. Administer antibiotics as needed (example fluoroquinolones), especially if 
diarrhea is persistent beyond 24 hours or there is fever or Grade 3-4 neutropenia


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Hold lapatinib and chemotherapy (if applicable) until symptoms resolve to 
≤Grade 1 (without complicating features) and reintroduce lapatinib at a reduced 
dose (unless dose had been reduced to 750mg, contact medical lead for further 
guidance): 
a.
Consider a dose reduction for chemotherapy (if applicable)
7. Supportive care and other interventions should be continued until diarrhea free 
(i.e., <Grade 1/bowel patterns returned to baseline) for 24 hours
8. Intervention may require hospitalization for subjects most at risk for life 
threatening complications
II.
CTCAE Grade 4
1. Subject must call physician immediately for any Grade 4 diarrhea event
2. Hold treatment with lapatinib, hold chemotherapy or other concurrent anticancer 
therapy (if applicable)
o
Contact the medical lead to discuss the patient case history and the 
possibility of re-initiation of study treatment, including dose modifications, 
following resolution of diarrhea (≤Grade 1)
(INFO: NOTE: Can Modify Figure 4 Grade 4 with this guidance; For 
Investigator sponsored studies substitute the above recommendation  
with the following: Evaluate the patient case history when deciding on the 
re-initiation of study treatment, including dose modifications, following 
resolution of diarrhea (≤Grade 1)
3. If loperamide has not been initiated, initiate loperamide immediately:  Initial 
dose 4 mg followed by 2 mg every 2 hours or after every unformed stool*
4. For dehydration use intravenous fluids as appropriate, if subject presents with 
severe dehydration administer octreotide
5. Perform stool work-up, CBC, electrolyte and other tests as appropriate
6. Recommend consulting with GI specialist
7. Administer antibiotics as needed (example fluoroquinolones), especially if 
diarrhea is persistent beyond 24 hours or there is fever or Grade 3/4 neutropenia
8. Supportive care and other intervention should be continued until diarrhea free (i.e., 
<Grade 1/bowel patterns returned to baseline) for 24 hours
9. Intervention may require hospitalization for subjects most at risk for life 
threatening complications
*It is recommended that the maximum cumulative daily dose of loperamide follows local 
guidance 
Refer to and follow the recommended supportive care guidelines in the previous sections 
and as depicted in Figure 4.


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Figure 4
Algorithm for the management of diarrhea in subjects treated with 
lapatinib-based therapy
1.
For Grade 1 diarrhea that persists for 2 weeks or longer, refer to Section III
2.
For Grade 2 diarrhea that persists longer than 3 days/72 hours, refer to Uncomplicated Diarrhea 
Section III
3.
For recurrent diarrhea, refer to Uncomplicated Diarrhea Section IV for further management guidelines
RECOMMENDATION

Loperamide prescription with instructions on administration for all subjects receiving 
lapatinib

Patient diary to record baseline bowel patterns and changes; dietary changes
EVALUATION

Obtain history of onset and duration of diarrhea

Describe number of stools and stool composition (Refer to baseline)
UNCOMPLICATED
Grade 1 or Grade 2 with no complicating 
signs or symptoms
ADDED RISK 
FACTORS
COMPLICATED
Grade 3 or 4 diarrhea or Grade 1 or 2 with 
≥ 1 of these signs or symptoms:
•
Cramping (moderate/severe)
•
Nausea/vomiting (≥ Grade 2)
•
Decreased performance status
•
Fever
•
Sepsis
•
Neutropenia
MANAGEMENT
•
Subjects should be instructed to administer loperamide and notify physician
•
Discontinue lactose products 
•
Drink 8-10 large glasses of clear liquids per day
•
Eat frequent small meals 
•
Eat foods low in fiber 
Reassess 24 hours later
Diarrhea Resolving
•
Continue instructions for dietary 
modification
•
Gradually add solid food to diet
•
Discontinue standard anti-
diarrheal after 12-hour diarrhea-
free interval
•
If applicable resume treatment 
with lapatinib and chemotherapy
Diarrhea Unresolved

Continue  loperamide

Continue dietary 
modifications

Evaluate for possible 
infection (Grade 2)
Reassess 24 hours later
Diarrhea unresolved

Continue loperamide (Grade 1)

Start second line anti-diarrheal agents 
(Grade 2)

Start second-line anti-diarrheal agents 
for Grade 1 diarrhea that does not improve 
after 1 week of loperamide treatment
MANAGEMENT
•
Subject must call physician immediately
•
Grade 3: hold lapatinib and chemotherapy (if applicable)
•
Grade 4:hold all study treatment (lapatinib + chemotherapy)
•
Evaluate for possible infection 
•
Consider hospitalization  
SUGGESTED TREATMENT
•
Administer loperamide 
•
Hydration (i.v. fluids as needed)
•
Consider need for antibiotics and consider second line anti-
diarrheals 
•
Consider consulting with GI specialist 
Diarrhea Free for 24 hours

Discontinue diarrhea intervention
For Grade 3

Reintroduce lapatinib at a reduced 
dose (if dose was >750mg) and 
chemotherapy (if applicable)

Consider dose 
reduction for chemotherapy
For Grade 4
Refer to Section B, subsection II


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References
American Cancer Society. Coping with physical and emotional changes: Diarrhea: what 
the subject can do.  
Diahttp://www.cancer.org/docroot/MBC/content/MBC_2_3X_Diarrhea.asp
Benson A, Jaffer AA, Catalano RB, et al.  Recommended Guidelines for the Treatment 
of Cancer Treatment-Inducted Diarrhea.  Journal of Clinical Oncology 2004; 22:2918-
2926.
Crown JP, Burstein HA, Boyle F, et al.  Pooled analysis of diarrhea events in patients 
with cancer treated with lapatinib.  Breast Cancer Res Treat 2008; 112:317-325.


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12.8.
Appendix 8:  Dermatological Assessment
Dermatological Monitoring
As part of their physical exam, subjects must have a thorough skin exam prior to the Day 
1 of study therapy or randomization. The exam should include the scalp, previously 
radiated areas, hair, and nails.  In addition, if clinically indicated an examination of the 
oral/genital mucosa should be done.
Subsequent dermatological evaluations must be performed at every study visit unless a 
dermatological AE has developed, in which case a more frequent surveillance is 
warranted until the event resolves.
In addition, any subject who develops signs and symptoms of dermatological disease 
(pruritus, tenderness, visible skin or nail lesions) should undergo a full body skin exam.
12.8.1.
Purpose of Dermatological Monitoring

To facilitate dermatological safety throughout the trial in all subjects by 
applying an algorithm for the discontinuation of lapatinib or its combination.

To assess whether a holding/stopping rule imposed during the course of 
treatment leads to excessive dermatological toxicity.

To identify the incidence of dermatological adverse events (AEs) for lapatinib, 
or the combination of lapatinib with other agents by defining pre-specified 
dermatological toxicity.
12.8.2.
Evaluation and Grading Guide
12.8.2.1.
The Most Commonly Reported Dermatological Reactions

Papulopustular rash affecting especially the upper body, including face and 
scalp. Association with pruritus, burning or tenderness may occur;

Maculopapular rash affecting the upper body. Pruritus may also occur;

Nail or hair changes – any hair changes or loss, or paronychia;

Dry skin, pruritus, and photosensitivity (Table 17).


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Table 17
NCI-CTCAE Dermatological Reactions (version 4.0)
Adverse Event
(Short name)
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Rash maculo-
papular
Macules/papules 
covering
<10% body 
surface area 
(BSA) with or 
without
symptoms (e.g., 
pruritus,
burning, 
tightness)
Macules/papules 
covering 10
- 30% BSA with 
or without
symptoms (e.g., 
pruritus,
burning, 
tightness); 
limiting
instrumental 
ADL
Macules/papules 
covering
>30% BSA with or 
without
associated 
symptoms; limiting
self care ADL
-
-
Rash:
Acne/acneiform
(Acne)
Papules and/or 
pustules
covering <10% 
BSA, which
may or may not 
be associated
with symptoms of 
pruritus or
tenderness
Papules and/or 
pustules
covering 10 -
30% BSA, which
may or may not 
be associated
with symptoms 
of pruritus or
tenderness; 
associated with
psychosocial 
impact; limiting
instrumental 
ADL
Papules and/or 
pustules
covering >30% 
BSA, which
may or may not be 
associated
with symptoms of 
pruritus or
tenderness; limiting 
self care
ADL; associated 
with local
superinfection with 
oral
antibiotics indicated
Papules and/or 
pustules
covering 
any % BSA, 
which
may or may 
not be 
associated
with symptoms 
of pruritus or
tenderness 
and are
associated 
with extensive
superinfection 
with IV
antibiotics 
indicated; 
lifethreatening
consequences
Death
Nail discoloration
Asymptomatic; 
clinical or
diagnostic 
observations only;
intervention not 
indicated
-
-
-
-
Nail Loss
Asymptomatic 
separation of
the nail bed from 
the nail plate
or nail loss
Symptomatic 
separation of the
nail bed from the 
nail plate or
nail loss; limiting 
instrumental
ADL
-
-
-


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Adverse Event
(Short name)
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Nail ridging
Asymptomatic; 
clinical or
diagnostic 
observations only;
intervention not 
indicated
-
-
-
-
Paronychia
Nail fold edema 
or erythema;
disruption of the 
cuticle
Localized 
intervention
indicated; oral 
intervention
indicated (e.g., 
antibiotic,
antifungal, 
antiviral); nail 
fold
edema or 
erythema with 
pain;
associated with 
discharge or
nail plate 
separation; 
limiting
instrumental 
ADL
Surgical 
intervention or IV
antibiotics 
indicated; limiting
self care ADL
-
-
Pruritus/itching 
(Pruritus)
Mild or localized; 
topical
intervention 
indicated
IIntense or 
widespread;
intermittent; skin 
changes
from scratching 
(e.g., edema,
papulation, 
excoriations,
lichenification, 
oozing/crusts);
oral intervention 
indicated;
limiting 
instrumental 
ADL
Intense or 
widespread;
constant; limiting 
self care
ADL or sleep; oral
corticosteroid or
immunosuppressive 
therapy
indicated
-
Dry skin
(Dry skin)
Covering <10% 
BSA and no
associated 
erythema or
pruritus
Covering 10 -
30% BSA and
associated with 
erythema or
pruritus; limiting 
instrumental
ADL
Covering >30% 
BSA and
associated with 
pruritus;
limiting self care 
ADL
-
Alopecia
Hair loss of up to 
50% of
normal for that 
individual that
is not obvious 
Hair loss of 
>50% normal for
that individual 
that is readily
apparent to 
-
-


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Adverse Event
(Short name)
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
from a distance
but only on close 
inspection; a
different hair style 
may be
required to cover 
the hair loss
but it does not 
require a wig or
hair piece to 
camouflage
others; a wig or
hair piece is 
necessary if the
patient desires 
to completely
camouflage the 
hair loss;
associated with 
psychosocial
impact
Photosensitivity
(Photosensitivity)
Painless 
erythema and
erythema 
covering <10% 
BSA
Tender 
erythema 
covering 10
- 30% BSA
Erythema covering 
>30% BSA
and erythema with 
blistering;
photosensitivity; 
oral
corticosteroid 
therapy
indicated; pain 
control
indicated (e.g., 
narcotics or
NSAIDs)
Life-
threatening
consequences; 
urgent
intervention 
indicated
Death
12.8.3.
Severe Skin Events

Lapatinib-related severe dermatological events are infrequent (1-3%).  Table 
17 displays the NCI-CTCAE (version 4.0) Grade 3 skin events, which are 
defined as:Macules/papules covering >30% BSA with or without associated 
symptoms; limiting self care ADL

Surgical intervention or IV antibiotics indicated; limiting self care ADL

Intense or widespread; constant; limiting self care ADL or sleep; oral 
corticosteroid or immunosuppressive therapy indicated

Covering >30% BSA and associated with pruritus; limiting self care ADL

Erythema covering >30% BSA and erythema with blistering; photosensitivity; 
oral corticosteroid therapy indicated; pain control indicated (e.g., narcotics or 
NSAIDs
Despite the rarity of these events among subjects treated with lapatinib, it is 
recommended that subjects which present with these events be assessed for shortness of 
breath, angioedema, or generalized mucosal/cutaneous affectation with blisters or ulcers, 
suggestive of Type I hypersensitivity and/or NCI-CTCAE Grade 4 rash or dermatologic 
event, manifested as toxic epidermal necrolysis (i.e., Stevens-Johnson’s Syndrome etc).  
If Grade 4 rash or dermatologic event occurs, lapatinib must be permanently discontinued.


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12.8.4.
Stopping and holding rules
If any Grade 4 dermatologic event occurs, lapatinib must be permanently discontinued.
12.8.4.1.
Holding rule
For NCI-CTCAE Grade 3 dermatological reactions, or a Grade 2 dermatological reaction 
which is not improved after 2 weeks with recommended management strategies, a brief 
(up to 14 days) therapy interruption is recommended; the daily dose of lapatinib should 
then be reinstated.  In some cases, the skin event may improve without the need for 
interrupting therapy with lapatinib.  In the lapatinib clinical program to date, many 
subjects were able to resume lapatinib therapy at the same dose after resolution of skin 
event; these subjects had less extensive and/or severe skin events.
12.8.4.2.
Re-challenge
One re-challenge may be considered, if indicated in the opinion of the investigator, for 
subjects who present with NCI-CTCAE Grade 3 skin events which recover briskly to 
NCI-CTCAE Grade 1 (within 14 days) after holding lapatinib.
12.8.4.3.
Stopping rules
Lapatinib should be permanently discontinued if an NCI-CTCAE Grade 3 dermatological 
reaction is intolerable to the subject despite recommended treatment interventions, or if a 
Grade 3 reaction recurs after one drug interruption/re-challenge cycle.  For any 
occurrence of Stevens Johnson syndrome (toxic epidermal necrolysis), study therapy 
must be immediately and permanent discontinued.
12.8.5.
Treatment
It is strongly recommended that subjects who develop dermatological reactions receive 
evaluations for management on the specific side effect.
Subjects should be encouraged to avoid exposure to sunlight.  Broad spectrum 
sunscreens (containing titanium dioxide or zinc oxide) with an SPF of at least 30 should 
be applied.
A variety of agents can be used to manage skin reactions.  These include mild-to-
moderate strength steroid creams (fluticasone prioprionate 0.5%), topical or systemic 
antibiotics, topical or systemic antihistamines and immunomodulators, and 
hypoallergenic moisturizers and emolliens for dry skin (5-10% urea in cetomacrogel 
cream or soft paraffin).
There is no standard treatment, known or established, that is proven effective for drug-
related skin rashes or changes due to lapatinib.  A papulopustular rash has been the
most commonly observed skin adverse event, which frequently improves with an 
unchanged, uninterrupted dose of lapatinib therapy.  The need for oral or topical 
antibiotics (minocycline, doxycicline, flucolaciclline or metronidazole cream) and topical 
steroids is a clinical decision of the investigator and, if indicated, a dermatology 


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consultation.  For pruritic lesions oral antihistamine agents were reported successful.  
For paronychia antiseptic bath and local potent corticosteroids in addition to tetracycline 
therapy is recommended. If no improvement, a dermatology or surgery consultation is 
recommended.  For infected lesions appropriate, culture driven, systemic or topical 
antibiotics are indicated.
Oral retinoids are not recommended because of theoretical concerns about negatively 
affecting the lapatinib mechanism of action and topical steroids result in irritation/severe 
dryness.  Oral steroids may be used for a short treatment course (maximum of 14 days) 
which may help subjects to remain on study therapy.
For subjects with extensive or symptomatic NCI-CTCAE Grade 3 or 4 dermatologic 
event, or chronic, persistent or recurring lower grade skin events, dermatology 
consultation is encouraged.  Upon consultation with a dermatologist, other treatment 
options (including immunomodulators such as topical tacrolimis or pimecrolimus) may 
be recommended for difficult to treat/unresponsive skin toxicities.


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12.9.
Appendix 9:  Cockcroft and Gault Method for Calculated 
Creatinine Clearance
Creatinine clearance can be calculated from serum creatinine values by one of the two 
formulas below:
Calculated creatinine
clearance (mL/min)  =
(140 age [yrs] ) weight (kg)
72 serum creatinine (mg/DL)
Female patients: multiply by 0.85
In order to use SI units for creatinine (mol/L), the following formula may be used.
Calculated creatinine
clearance (mL/min)  =
(140 age [yrs] ) weight (kg) x 88.4
72 × 1 × serum creatinine (mol/L))
Female patients: multiply by 0.85
Data Source:  [Cockcroft, 1976] 


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12.10.
Appendix 10 List of protocol Changes Changes 
Note: deleted language is printed as strikethrough and added language is printed in bold.
12.10.1.
Protocol Amendment 1
Global amendment: This version was amended to remove the third biopsy (based on the 
feedback from the countries). This version was the first one dispatched to the countries.
12.10.2.
Protocol Amendment 2
Reason for change:
Description: The Primary Objective was updated to remove the evaluation of changes in 
the expression of biomarkers associated with HER family, apoptosis, and ABC 
transporters. The Primary Objective now evaluates the changes in the expression of 
biomarkers associated with immunomodulation.
Original text
All subjects will receive study treatment until disease progression, death, unacceptable 
toxicity, subject withdrawal or any other reasons mentioned in section 4.2.1.  The 
primary endpoint is to evaluate the changes in the expression of biomarkers associated 
with immunomodulation between the progression biopsy and the pre-treatment biopsy 
within each arm.  Secondary efficacy endpoints include overall response rate; clinical 
benefit rate; and progression-free survival (PFS) on treatment; as well as 
safety/tolerability. Due to difficulty in enrolling subjects, enrollment will be halted and 
the study will be terminated early. No formal comparisons between treatment arms will 
be undertaken.
Amended Text 
All subjects will receive study treatment until disease progression, death, unacceptable 
toxicity, or subject withdrawal or any other reasons mentioned in section 4.2.1, and 
after which, will be followed for subsequent anticancer therapy and disease progression 
events, and survival.  The primary endpoint is to evaluate the changes in the 
expression of biomarkers associated with immunomodulation between the 
progression biopsy and the pre-treatment biopsy within each arm.  Secondary 
efficacy endpoints include overall response rate; clinical benefit rate; and 
progression-free survival (PFS) on treatment; as well as safety/tolerability. The 
primary endpoint is to evaluate changes in the expression of biomarkers associated 
human epidermal growth factor receptor HER family or receptors and ligands, 
immunomodulation, apoptosis, and adenosine triphosphate binding cassette transporters 
in the progression biopsy compared with the pre-treatment biopsy within each arm.  Key 
secondary biomarker and efficacy endpoints include overall survival; overall response 
rate; clinical benefit rate; progression-free survival (PFS); PFS subsequent lines of 
therapy; safety; and patients reported outcomes.  Due to difficulty in enrolling subjects, 
enrollment will be halted and the study will be terminated early.  It is estimated that 
approximately up to 225 subjects will be recruited into the study to achieve 50 evaluable 


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subjects (defined as subjects with a pre-treatment and progression biopsy with evaluable 
data for at least one biomarker) in each treatment arm.  No formal comparisons between 
treatment arms will be undertaken. 
Reason for Change: List of Authors replaced by Novartis Study Team Members 
Original Text 
Author(s): 
 
 
Amended Text
Author(s):  
 
 
Reason for Change: 
Revision Chronology of amendment was added for the first time.  
Original Text 
No Revision Chronology table  
Amended Text 
Revision Chronology:
2013N170247_0
No publishing date Amendment No. 0 (original version): 
This version was never dispatched to 
the countries.
2013N170247_01
26-MAR-2014
Amendment No. 01: Global 
amendment: This version was 
amended to remove the third biopsy 
(based on the feedback from the 
countries). This version was the first 
one dispatched to the countries. 
2013N170247_02
23-Mar-2017
Amendment 
No. 
02: 
Global 
amendment: Study EGF117165 is a 
post-approval commitment required 
by 
the 
CHMP
to 
evaluate 
biomarkers of drug resistance in 
patients with HER2+ metastatic 
breast cancer whilst on treatment 
with trastuzumab in combination 
with 
either 
lapatinib 
or 


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chemotherapy. 
Recruitment 
of 
patients into study EGF117165 has 
been difficult. Efforts to boost 
recruitment were undertaken but 
the prospect to significantly improve 
recruitment is poor, thus preventing 
Novartis from meeting the agreed 
timelines for completion.
In addition, the results of this trial 
will likely become obsolete by the 
time 
of 
delayed 
completion. 
Therefore, Novartis proposes to 
terminate the study and to conduct a 
final 
analysis 
of 
the 
enrolled 
patients. 
In this context, the updates to the 
protocol are as follows:
The Primary Objective was updated 
to remove the evaluation of changes 
in the expression of biomarkers 
associated with HER family, 
apoptosis, and ABC transporters. 
The Primary Objective now 
evaluates the changes in the 
expression of biomarkers associated 
with immunomodulation.
The Secondary Objectives were 
updated to remove OS and PFS on 
first next line and subsequent lines 
of anti-cancer therapies. The Patient 
Reported Outcomes (PRO) and 
Health-Related Quality of Life 
(HRQOL) were also removed. 
 
 
 
 
 
 
 
 


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Section 4.2.3 Subject Completion: 
Follow-up time was re-defined as 
follows: A subject will be considered 
to have completed the study if the 
subject presents with disease 
progression, starts a new anti-cancer 
therapy, dies or withdraws from the 
study, or the study ends, whichever 
comes first. In case of disease 
progression during the treatment 
period, the subject will be followed-
up for 30 days for safety evaluation 
and no further study-specific follow-
up will be carried out; the subject 
will be considered as having 
completed the study. 
In case of study treatment 
discontinuation for any reasons 
other than disease progression, the 
subject will be followed-up for safety 
and efficacy assessments until 
disease progression, new anticancer 
therapy, death, withdrawal of 
consent or end of study, whichever 
comes first.   
Reason for Change: 
The contact information on the Sponsor Information Page was updated. 
Original Text 
Medical Monitor Contact Information:  Dr
E-mail: 
Telephone Number:
Mobile Number:
Amended Text
Dr.


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Novartis Pharma AG
Postfach
4002 Basel
Switzerland
Telephone:
Dr.
E-mail: 
Telephone Number:
Mobile Number: 
Reason for Change
LIST OF ABBREVIATIONS was updated to remove abbreviations that are no longer 
applicable to this amendment 
Original Text 
ABC
Adenosine triphosphate binding cassette
ADCC
Antibody-dependent cellular cytotoxicity
ADL
Activities of daily living
AE
Adverse event
AI
Aromatase inhibitor
ANC
Absolute neutrophil count
ALT
Alanine aminotransferase
AR
Amphiregulin
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
ATP
Adenosine triphosphate
AV
Atrioventricular
Bcl-2
B-cell lymphoma 2
Bcl-xl
B-cell lymphoma-extra large
Bcl2L11
Bcl-2-like protein 11
-HCG 
beta human chorionic gonadotropin
BIRC5
Baculoviral inhibitor of apoptosis repeat-containing 5
BSA
Body surface area
BTC
-cellulin
CAF
Cytokines and angiogenetic factors 
CBR
Clinical benefit rate
cfDNA
Circulating free DNA
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence interval


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CISH
Chromogenic in situ hybridization
CNS
Central nervous system
CR
Complete response
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4 
Cytotoxic T-lymphocyte antigen 4
DFS
Disease free survival
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EGF
Epidermal growth factor
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency
EP
Evaluable Population
EPGN
Epigen
EPR
Epiregulin
ER
Estrogen receptor
ERK
Extracellular signal-regulated kinase
ESMO
European Society for Medical Oncology
FACT-B
Functional Assessment of Cancer Therapy-Breast 
FDA
Food and Drug Administration
FDR
False discovery rate
FISH
Fluorescence in situ hybridization
FDG-PET
fluorodeoxyglucose-positron emission tomography
FOXP3
Forkhead box P3
FSH
Follicle stimulating hormone
g/dL
Grams/deciLiter
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HBEGF
Heparin-binding EGF-like growth factor
HER
Human epidermal growth factor receptor
HER2
Human epidermal growth factor receptor 2
HR
Hazard ratio
HRQOL
Health Related Quality of Life
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology System
ITT
Intent to Treat
IV
Intravenous(ly)
kg
Kilogram
L
Liter
LFT
Liver function test


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LLN
Lower limit of normal
LSLV
Last subject last visit
LVEF
Left ventricular ejection fraction
m2
Meter squared
MAPK
Mitogen-activated protein kinase
MAF
Multidimensional Assessment of Fatigue Scale
MBC
Metastatic breast cancer
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MSDS
Material Safety Data Sheet
MUGA
Multigated acquisition
MW
Molecular weight
NA
Not applicable
NCCN
National Comprehensive Cancer Network
NE
Not evaluable
NRG
Neuregulin
OR
Odds ratio
ORR
Overall response rate
OTR
Optimally tolerated regimen
PAM
Prediction Analysis of Microarray
PAM50
Prediction Analysis of Microarray 50
PBMC
Peripheral blood mononuclear cells
pCR
Pathological complete response
PD
Progressive disease
PD-1
Programmed cell death 1
PDL-1
Programmed cell death 1 ligand 1
PFS
Progression-free survival
PFS-NL
Progression-free survival on next-line therapy
PgR
Progesterone receptor
PI3K
Phosphoinositide 3-kinase
PK
Pharmacokinetics
PO
Per os (orally)
PR
Partial response
PRO
Patient reported outcomes
q3weekly
Every 3 weeks
QoL
Quality of life
QTcB
QT interval corrected for heart rate (Bazett’s formula)
QTcF
QT interval corrected for heart rate (Fridericia’s formula)
RAP
Reporting and analysis plan
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious adverse event
SD
Stable disease
SISH
Silver in situ hybridization
SPM
Study Procedures Manual
t½
Half life
TDM-1
Trastuzumab emtansine
TGF
Transforming growth factor 


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TKI
Tyrosine kinase inhibitor
TNF
Tumor necrosis factor
TRAIL 
Tumor necrosis factor-related apoptosis-induced 
TTP
Time to progression
ULN
Upper limit of normal
XIAP 
X-linked inhibitor of apoptosis protein  
Amended Text
ABC
Adenosine triphosphate binding cassette
ADCC
Antibody-dependent cellular cytotoxicity
ADL
Activities of daily living
AE
Adverse event
AI
Aromatase inhibitor
ANC
Absolute neutrophil count
ALT
Alanine aminotransferase
AR
Amphiregulin
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
ATP
Adenosine triphosphate
AV
Atrioventricular
Bcl-2
B-cell lymphoma 2
Bcl-xl
B-cell lymphoma-extra large
Bcl2L11
Bcl-2-like protein 11
-HCG 
beta human chorionic gonadotropin
BIRC5
Baculoviral inhibitor of apoptosis repeat-containing 5
BSA
Body surface area
BTC
-cellulin
CAF
Cytokines angiogenetic factors 
CBR
Clinical benefit rate
cfDNA
Circulating free DNA
CHMP
Committee for Medicinal Products for Human Use
CI
Confidence interval
CISH
Chromogenic in situ hybridization
CNS
Central nervous system
CR
Complete response
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4 
Cytotoxic T-lymphocyte antigen 4
DFS
Disease free survival
DLT
Dose-limiting toxicity
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EGF
Epidermal growth factor
EGFR
Epidermal growth factor receptor


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EMA
European Medicines Agency
EP
Evaluable Population
EPGN
Epigen
EPR
Epiregulin
ER
Estrogen receptor
ERK
Extracellular signal-regulated kinase
ESMO
European Society for Medical Oncology
FACT-B
Functional Assessment of Cancer Therapy-Breast 
FDA
Food and Drug Administration
FDR
False discovery rate
FISH
Fluorescence in situ hybridization
FDG-PET
fluorodeoxyglucose-positron emission tomography
FOXP3
Forkhead box P3
FSH
Follicle stimulating hormone
g/dL
Grams/deciLiter
GCP
Good Clinical Practice
GSK
GlaxoSmithKline
HBEGF
Heparin-binding EGF-like growth factor
HER
Human epidermal growth factor receptor
HER2
Human epidermal growth factor receptor 2
HR
Hazard ratio
HRQOL
Health Related Quality of Life
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
IP
Investigational product
IRB
Institutional Review Board
IRT
Interactive Response Technology System
ITT
Intent to Treat
IV
Intravenous(ly)
kg
Kilogram
L
Liter
LFT
Liver function test
LLN
Lower limit of normal
LSLV
Last subject last visit
LVEF
Left ventricular ejection fraction
m2
Meter squared
MAPK
Mitogen-activated protein kinase
MAF
Multidimensional Assessment of Fatigue Scale
MBC
Metastatic breast cancer
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
MSDS
Material Safety Data Sheet
MUGA
Multigated acquisition
MW
Molecular weight
NA
Not applicable


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NCCN
National Comprehensive Cancer Network
NE
Not evaluable
NRG
Neuregulin
OR
Odds ratio
ORR
Overall response rate
OTR
Optimally tolerated regimen
PAM
Prediction Analysis of Microarray
PAM50
Prediction Analysis of Microarray 50
PBMC
Peripheral blood mononuclear cells
pCR
Pathological complete response
PD
Progressive disease
PD-1
Programmed cell death 1
PDL-1
Programmed cell death 1 ligand 1
PFS
Progression-free survival
PFS-NL
Progression-free survival on next-line therapy
PgR
Progesterone receptor
PI3K
Phosphoinositide 3-kinase
PK
Pharmacokinetics
PO
Per os (orally)
PR
Partial response
PRO
Patient reported outcomes
q3weekly
Every 3 weeks
QoL
Quality of life
QTcB
QT interval corrected for heart rate (Bazett’s formula)
QTcF
QT interval corrected for heart rate (Fridericia’s formula)
RAP
Reporting and analysis plan
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious adverse event
SD
Stable disease
SISH
Silver in situ hybridization
SPM
Study Procedures Manual
t½
Half life
TDM-1
Trastuzumab emtansine
TGF
Transforming growth factor 
TKI
Tyrosine kinase inhibitor
TNF
Tumor necrosis factor
TRAIL 
Tumor necrosis factor-related apoptosis-inducing ligand 
TTP
Time to progression
ULN
Upper limit of normal
XIAP
X-linked inhibitor of apoptosis protein
Reason for Change 
Protocol Summary-Rationale was updated for primary, secondary 
 
 
Original Text 


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This unusual PFS/OS pattern has been observed in two phase III trials of two different 
combinations of anti-HER 2 agents. A potential mechanistic hypothesis to explain the 
unusual PFS/OS pattern is that Dual blockade may exert be a “post-treatment effect” on 
subsequent therapies by modulating sensitivity to subsequent chemotherapy(ies) 
regimens.
Protocol EGF117165 is a phase II study designed to evaluate whether treatment with 
Dual blockade promotes changes to biomarkers associated with the HER2 family, 
immunomodulation, apoptosis, and adenosine triphosphate binding cassette (ABC) 
transporters.  The biomarkers were selected due to the potential to correlate with altered 
the response to subsequent chemotherapy(ies) regimens.  
Primary Objective:

To evaluate changes in the expression of biomarkers associated with HER family, 
immunomodulation, apoptosis, and ABC transporters between the pre-treatment 
and  disease progression biopsy within each treatment arm. 
Secondary Objectives:

To describe overall response rate (ORR), clinical benefit rate (CBR), and PFS on 
study treatment and OS in subjects treated with trastuzumab in combination with 
lapatinib or chemotherapy.

To describe PFS on first next line (PFS-NL) and subsequent lines of anti-cancer 
therapies.

To explore association between changes in biomarkers  and PFS, PFS-NL and 
OS.

To describe the safety and tolerability of trastuzumab in combination with 
lapatinib and of trastuzumab in combination with chemotherapy.
 

To describe the changes of Patient Reported Outcomes (PRO) and Health-Related 
Quality of Life (HRQOL) within the study population and to describe the 
differences of PRO /HRQOL between treatment groups.
 
Amended Text 
This unusual PFS/OS pattern has been observed in two phase III trials of two different 
combinations of anti-HER 2 agents. A potential mechanistic hypothesis to explain the 


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unusual PFS/OS pattern is that Dual blockade may exert be a “post-treatment effect” on 
subsequent therapies by modulating sensitivity to subsequent chemotherapy(ies) 
regimens.
Protocol EGF117165 is a phase II study evaluating whether treatment with Dual 
blockade promotes changes of biomarkers associated with immunomodulation. 
Protocol EGF117165 is a phase II study designed to evaluate whether treatment with 
Dual blockade promotes changes to biomarkers associated with the HER2 family, 
immunomodulation, apoptosis, and adenosine triphosphate binding cassette (ABC) 
transporters.  The biomarkers were selected due to the potential to correlate with altered 
the response to subsequent chemotherapy(ies) regimens.  
Primary Objective:

To evaluate changes in the expression of biomarkers associated with HER family,
immunomodulation, apoptosis, and ABC transporters between the pre-treatment 
and disease progression biopsy within each treatment arm. 
Secondary Objectives:

To describe overall response rate (ORR), clinical benefit rate (CBR), and PFS on 
study treatment and OS in subjects treated with trastuzumab in combination with 
lapatinib or chemotherapy.

To describe PFS on first next line (PFS-NL) and subsequent lines of anti-cancer 
therapies.

To explore association between changes in biomarkers and PFS, PFS-NL and OS.

To describe the safety and tolerability of trastuzumab in combination with 
lapatinib and of trastuzumab in combination with chemotherapy.
 

To describe the changes of Patient Reported Outcomes (PRO) and Health-Related 
Quality of Life (HRQOL) within the study population and to describe the 
differences of PRO /HRQOL between treatment groups.
 
 


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Reason for Change:
Protocol Summary-Study Design was updated to remove the associated secondary 
objectives for the comparison of gene and/or protein expression.  Survivals follow up 
after study discontinuation is removed.  Also start date and stop date and progression on 
next line of anticancer therapy were removed.  
Original Text 
At disease progression a biopsy should be taken from the same site as the pre-treatment 
biopsy. The comparison of gene and/or protein expression changes in these biopsies will 
be the basis for the primary objective and associated secondary objectives.  
All subjects will receive study treatment until disease progression, unacceptable toxicity, 
or subject withdrawal and will be followed for survival.  After discontinuation of the 
study treatment, a subject will be followed for survival at approximately 12-week 
intervals until death or end of study.  Information on subsequent anti-cancer therapy(ies), 
start and stop dates of administrations of anti-cancer therapy,  and dates of documented 
disease progression will also be collected.  
Approximately 225 subjects will be recruited into the study to achieve a total of 150 
evaluable subjects, 50 evaluable subjects per arm.
Amended Text 
At disease progression a biopsy should be taken from the same site as the pre-treatment 
biopsy. The comparison of gene and/or protein expression changes in these paired 
biopsies will be the basis for the primary objective. and associated secondary objectives. 
All subjects will receive study treatment until disease progression, death, unacceptable 
toxicity, or subject withdrawal or any other reasons mentioned in section 4.2.1. and 
will be followed for survival.  After discontinuation of the study treatment, a subject 
will be followed for survival at approximately 12-week intervals until death or end of 
study.  Information on subsequent anti-cancer therapy(ies), start and stop dates of 
administrations of anti-cancer therapy,  and dates of documented disease progression 
will also be collected.  
Approximately 225 subjects will be recruited into the study to achieve a total of 150 
evaluable subjects, 50 evaluable subjects per arm.
Reason for Change: 


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Protocol Summary-Study Assessment was updated to remove the broader assessment of 
changes in the expression of biomarkers associated with expression of HER family, 
apoptosis, and adenosine triphosphate binding cassette (ABC). Patient Reported Outcome 
(PRO) and the Health Related Quality of Life (HRQOL) assessment were removed. 
Original Text 
The primary endpoint is to analyze the changes in gene and/or protein expression profile 
within each arm on a prespecified set of biomarkers associated with HER family,
immunomodulation, apoptosis, and ABC transporters compared between the pre-
treatment biopsy and disease progression biopsy.  The HER2-enriched and Non-HER2-
enriched cohorts will be analyzed separately
Amended Text 
The primary endpoint is to analyze the changes in gene and/or protein expression profile 
within each arm on a prespecified set of biomarkers associated with HER family,
immunomodulation, apoptosis, and ABC transporters compared between the pre-
treatment biopsy and disease progression biopsy.  The HER2-enriched and Non-HER2-
enriched cohorts will be analyzed separately.
Patient reported outcomes assessments including health-related quality of life will be 
done on Day 1, Week 3, Week 12, and at the time of withdrawal from the study treatment.
Reason for Change: 
Section 1.2.1 The reference of new trial PHEREXA was added. 
Original Text:
A similar divergence of PFS and OS durations was reported in a study that evaluated 
pertuzumab combined with trastuzumab in the first-line treatment of MBC [Baselga
2012a].  
Amended Text:
A similar divergence of PFS and OS durations was reported in a study that evaluated 
pertuzumab combined with trastuzumab in the first-line treatment of MBC [Baselga
2012a].  Similar divergence of PFS and OS durations was reported in the large 
phase III Cleopatra [Baselga 2012a] and PHEREXA [Urruticoechea 2016] trials 
evaluating dual HER2 blockade (pertuzumab plus trastuzumab) in HER2-positive 
MBC. 
Reason for Change: 
Section 1.2.2 The original text was revised according to the changes in the secondary 
endpoints (excluding OS assessment). Some editorial changes were added for the 
description of the HER2-enriched and non-HER2 enriched subgroups. 


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Original Text 
Therefore, this study will also enroll standard HER2 positive subjects as defined by 
standard histopathologic criteria with a non-HER2 enriched subtype that will be assigned 
to treatment with lapatinib in combination with trastuzumab. 
Amended Text 
Therefore, this study will also enroll standard HER2 positive subjects as defined by 
standard histopathologic criteria with a non-HER2 enriched subtype that will be 
assigned to treatment with lapatinib in combination with trastuzumab. In this HER2 
positive, non-HER2 enriched (i.e. luminal A, luminal B and basal-like) population, the 
study will investigate any biomarker changes associated with long-term benefit that may 
be inclusive of all HER2 positive subjects as well as those that may be specific to the 
HER2-enriched molecular subtype.
Reason for Change:
1.2.3 Updated to state that based on emerging data the focus of the study will be 
immunomodulation markers. 
Original Text 
1.2.3. Mechanisms to Investigate the Benefit of Dual blockade on Subsequent Lines of 
Therapy. Immunomodulation by Dual blockade as a putative mechanism affecting 
response to subsequent lines of therapy
The EGF104900 study population was heavily pretreated, with a median of 6 prior 
chemotherapeutic agents; as is standard in the treatment of breast cancer, the types of 
agents received were of different mechanistic classes (e.g., taxanes, anthracyclines, and 
alkylating agents).  Breast cancers may evade the therapeutic effects of these 
chemotherapies through intrinsic mechanisms, acquisition of genetic aberrations, or 
activation of compensatory pathways that provide a selective advantage and render the 
tumor resistant.  The primary mechanisms of resistance in this population are postulated 
to be broad, and resistance is assumed to be multifactorial, involving mechanisms that 
include direct/within-tumor effects and indirect/extrinsic effects [O’Connor 2009]. 
The primary hypothesis under evaluation in this study is that the chemotherapy-free 
period during which subjects receive treatment with Dual blockade in effect reverses 
resistance to chemotherapy, thus conferring the disease sensitive to subsequent anticancer 
therapy.  This suggests that the approach to elucidating the mechanisms or pathways by 
which Dual blockade reverses resistance to chemotherapy should be directed toward 
generalized mechanisms.  There are no validated markers of resistance to 
chemotherapeutic agents; therefore, the primary objective will focus on 4 mechanisms 
that have been described to impact response to chemotherapy.
Amended Text 


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1.2.3 Mechanisms to Investigate the Benefit of Dual blockade on Subsequent Lines of 
Therapy Immunomodulation by Dual blockade as a putative mechanism affecting 
response to subsequent lines of therapy
The EGF104900 study population was heavily pretreated, with a median of 6 prior 
chemotherapeutic agents; as is standard in the treatment of breast cancer, the types of 
agents received were of different mechanistic classes (e.g., taxanes, anthracyclines, and 
alkylating agents). The chemotherapy-free period during which subjects received 
treatment with Dual blockade in EGF104900 may have reversed resistance to 
chemotherapy, thus conferring the disease sensitive to subsequent anticancer 
therapy.
There is now mounting evidence that a pre-existing immunologic response might 
enhance the effects of conventional cytotoxic chemotherapy and HER2 targeted 
therapy in early HER2+ breast cancer [Denkert 2010, Issa-Nummer 2013, Denkert 
2015, Ignatiadis 2012, Loi 2013, Loi 2014] and anti-HER2 therapies seem to be able 
to engage the immune system in different ways. For instance, pre-clinical data 
suggest that Lapatinib enhances T-cell and IFN-γ-based immunity and affects the 
myeloid infiltrate (i.e. tumor-associated macrophages and monocytes) in tumors 
[Hannesdóttir 2013, Laoui 2013]. Emerging data from the neoadjuvant setting 
provide useful insights on molecular changes induced by HER2-targeted 
neoadjuvant treatment and recent studies are suggesting that single HER2 targeted 
agents and Dual blockade of the HER2 receptor induce changes in immune markers 
and the tumor microenvironment [Bianchini 2016, Dieci 2015]. The Neosphere trial 
showed that HER2 targeted agents and dual HER2 blockade modulate the amount 
of tumor infiltrating lymphocytes (TIL) - a surrogate biomarker of pre-existing host 
antitumour immunity - and the expression levels of selected mRNA immune 
markers [Bianchini 2016]. The investigators were also able to show that these 
patient-level immune modulations are linked to distant event free survival and the 
differential changes in stromal TILS (sTIL) levels actually seem to carry more 
prognostic information than either pre-or post-treatment sTIL levels.
Tumors with increased numbers of TIL after treatment may be able to elicit an 
antitumor immune response and may have a particularly strong response to 
subsequent treatment lines, as the immune cells may have been already sensitized 
against some tumor antigens before the onset of chemotherapy and therefore 
enhance the ability of chemotherapy to eliminate cancer cells. Immunomodulation 
by dual HER2 blockade is a plausible mechanism how molecular changes could help 
to overcome resistance to chemotherapeutic agents, eventually leading to increased 
clinical activity and augmented response seen in overall survival.
The primary hypothesis under evaluation in this study is that the chemotherapy-
free period during which subjects receive treatment with Dual blockade modulates 
the immune microenvironment, which in turn may influence the efficacy of 
sequential treatment. A recent study just revealed a comparable distribution and 
composition of infiltrating lymphocyte subtypes in metastasis when compared to the 
matched primary tumor [Sobottka 2016]. This pattern was found regardless of the 
anatomical site at which the metastasis had occurred, suggesting that primary 
tumor shapes the infiltrating immune cell composition rather than the metastases 


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with their local immunity [Sobottka 2016]. The EGF11765 study will support a 
better understanding if the rapidly accumulating evidence for the importance of the 
immune microenvironment in HER2-positive breast cancer and the observed 
immunomodulation in the neoadjuvant setting can be confirmed in the advanced 
setting and support the putative mechanism of action of HER2 dual blockade and its 
potential function on the tumor microenvironment.
Breast cancers may evade the therapeutic effects of these chemotherapies through 
intrinsic mechanisms, acquisition of genetic aberrations, or activation of compensatory 
pathways that provide a selective advantage and render the tumor resistant.  The primary 
mechanisms of resistance in this population are postulated to be broad, and resistance is 
assumed to be multifactorial, involving mechanisms that include direct/within-tumor 
effects and indirect/extrinsic effects [O’Connor, 2009]. 
The primary hypothesis under evaluation in this study is that the chemotherapy-free 
period during which subjects receive treatment with Dual blockade in effect reverses 
resistance to chemotherapy, thus conferring the disease sensitive to subsequent anticancer 
therapy.  This suggests that the approach to elucidating the mechanisms or pathways by 
which Dual blockade reverses resistance to chemotherapy should be directed toward 
generalized mechanisms.  There are no validated markers of resistance to 
chemotherapeutic agents; therefore, the primary objective will focus on 4 mechanisms 
that have been described to impact response to chemotherapy.
Reason for Change:
Section 1.2.3.1 on HER family of receptor and ligands, Section 1.2.3.2 on 
Immunomodulation, Section 1.2.3.3 on Apoptosis and Section 1.2.3.4 on ABC 
transporters and drug efflux pumps were all removed because section 1.2.3 was re-written 
to focus on immune markers moving forward. 
Original Text:
1.2.3.1 HER Family of Receptors and Ligands
EGFR, HER2, HER3, and HER4 are the 4 members comprising the family of Type I 
receptor tyrosine kinases.  These receptors share common structural and functional 
elements including an extracellular domain that consists of 4 subdomains involved in 
ligand binding (domain I, III) and in dimerization (domain II) and an intracellular 
tyrosine kinase domain.  Ligands have been identified for EGFR, HER3, and HER4, 
whereas no ligand has been identified for HER2.  Of the 11 ligands identified 
(amphiregulin [AR], -cellulin [BTC], epidermal growth factor [EGF], epigen [EPGN], 
epiregulin [EPR], heparin-binding EGF-like growth factor [HBEGF], transforming 
growth factor [TGF], and neuregulin [NRG1, NRG2, NRG3, and NRG4]), the 
majority are not specific for 1 receptor [Yarden, 2012].  Ligand binding to HER 
receptor(s) induces receptor dimerization, resulting in the formation of homodimers or 
heterodimers, with HER2 as the preferred heterodimerization partner due to its role in 
increasing receptor-ligand affinity and potentiating HER-mediated signalling.  HER 
signalling is also activated through a ligand-independent mechanism, an example of 
which is HER2 homodimers, whereby overexpression of HER2 generates their formation.  


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The HER receptor combination potential and repertoire of HER ligands as well as ligand-
independent mechanisms suggest a diverse signalling capacity for this family of receptors 
[Olayioye 2000]. 
Several preclinical and clinical studies have demonstrated an association between 
response to certain types of chemotherapies as well as HER2-directed agents and the 
expression of HER receptors or their associated ligands. 
HER2 overexpression was observed to be associated with intrinsic resistance to DNA 
damaging agents and paclitaxel potentially owing in part to the role of HER2 signalling 
in regulating cell cycle and survival [Tan, 2000]. A common standard of care for the 
treatment of HER2-positive breast cancer is chemotherapy in combination with HER2-
directed agents; mechanisms that adversely impact the efficacy of these agents may affect 
the efficacy of chemotherapy.  Therefore, as evidence supports a role for the expression 
of HER receptors and ligands in mediating response to HER2-directed agents such as 
trastuzumab and lapatinib [Arteaga, 2006; Ritter, 2007; Amin, 2010], treatment with 
Dual blockade may be a more effective treatment than either agent alone due to 
complementary mechanisms of action [Scaltriti, 2009; Ghosh, 2007; Maruyama, 2011; 
Sanchez-Martin, 2012].
The expression of HER receptors EGFR, HER2, HER3, and HER4 and their associated 
ligands will be measured by gene expression analyses.  The protein expression levels of 
the HER receptors will also be measured by IHC. 
1.2.3.2. Immunomodulation
The concept of tumor escape as a process of immunoediting involves the acquisition of 
adaptations that allow the tumor to evade detection and destruction by the immune 
system.  The mechanism by which tumor escape occurs is through induction of immune 
tolerance or inhibition of tumor recognition and resistance to killing by activated immune 
effector cells [Vesely, 2011].  Immunoediting may affect response to chemotherapy, as 
some chemotherapies induce immunogenic cell death and stimulate a secondary 
antitumor immune response [Kroemer, 2013].  
Alteration of expression of immune checkpoint proteins, such as programmed cell death 
1 ligand 1 (PDL-1), programmed cell death 1(PD-1), cytotoxic T-lymphocyte antigen 4 
(CTLA-4), and forkhead box P3 (FOXP3), a transcription factor expressed in regulatory 
T cells and involved in their suppressive function, may provide a mechanism by which 
the tumor cells evade the immune system [Melero, 2013; Huehn, 2009].  The expression 
of these proteins in addition to the expression of different subpopulations of tumor-
infiltrating lymphocytes, natural killer cells, and macrophages will be measured by gene 
expression profiling and IHC.
Several gene signatures, or metagenes, have been developed as surrogate representatives 
of immune function [Rody, 2009; Hanker, 2013; Nagalla, 2013].  The metagene 
signature from Nagalla et al. was developed through an integrated dataset of 1954 
clinically annotated breast tumor expression profiles to investigate the relationship 
between immunity and proliferation.  From these analyses, 3 distinct clusters with 
annotated immune function were defined and further postulated to reflect different tumor-


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infiltrating leukocyte populations: B cells/plasma cells, T cells/natural killer cells, and 
monocytes/dendritic cells.  These metagene clusters or other development signatures 
may be evaluated as part of the primary objective.  
1.2.3.3. Apoptosis
Alterations in the apoptotic pathways through inactivation of pro-apoptotic factors and 
overexpression of pro-survival factors have been implicated in resistance to 
chemotherapeutics, as these agents elicit their effect through activation of tumor cell 
death [O’Connor, 2009; Rebucci, 2013].  
B-cell lymphoma 2 (Bcl-2) and the family member B-cell lymphoma-extra large (Bcl-xl) 
will be evaluated in this study, as they are key anti-apoptotic factors.  Additional anti-
apoptotic factors under evaluation include survivin (baculoviral inhibitor of apoptosis 
repeat-containing 5 [BIRC5]) and X-linked inhibitor of apoptosis protein (XIAP).  BIM 
(Bcl-2-like protein 11[Bcl2L11]), p53, and tumor necrosis factor (TNF)-related 
apoptosis-inducing ligand (TRAIL) also will be evaluated, as they are key factors 
involved in activation of apoptotic pathways.  The expression of these factors will be 
measured by gene expression analysis and IHC if validated assays are available. 
1.2.3.4. ABC Transporters/Drug Efflux Pumps
Adenosine triphosphate binding cassette (ABC) proteins comprise a large family of 
transporters with a wide variety of substrates, such as the multidrug resistance 1 protein 
(ABCB1), breast cancer resistance protein (ABCG2), and multidrug resistance-related 
protein (ABCC1), all of which have been shown to promote de novo and acquired 
resistance to multiple chemotherapeutic agents with varying mechanisms of action.  
This study will evaluate the expression of these specific ABC transporters, as they have 
been purported to have the greatest therapeutic relevance for treatment of many common 
malignancies [O’Connor, 2009]. 
Amended Text:
HER Family of Receptors and Ligands
EGFR, HER2, HER3, and HER4 are the 4 members comprising the family of Type I 
receptor tyrosine kinases.  These receptors share common structural and functional 
elements including an extracellular domain that consists of 4 subdomains involved in 
ligand binding (domain I, III) and in dimerization (domain II) and an intracellular 
tyrosine kinase domain.  Ligands have been identified for EGFR, HER3, and HER4, 
whereas no ligand has been identified for HER2.  Of the 11 ligands identified 
(amphiregulin [AR], -cellulin [BTC], epidermal growth factor [EGF], epigen [EPGN], 
epiregulin [EPR], heparin-binding EGF-like growth factor [HBEGF], transforming 
growth factor [TGF], and neuregulin [NRG1, NRG2, NRG3, and NRG4]), the 
majority are not specific for 1 receptor [, 2012].  Ligand binding to HER receptor(s) 
induces receptor dimerization, resulting in the formation of homodimers or heterodimers, 
with HER2 as the preferred heterodimerization partner due to its role in increasing 


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receptor-ligand affinity and potentiating HER-mediated signalling.  HER signalling is 
also activated through a ligand-independent mechanism, an example of which is HER2 
homodimers, whereby overexpression of HER2 generates their formation.  The HER 
receptor combination potential and repertoire of HER ligands as well as ligand-
independent mechanisms suggest a diverse signalling capacity for this family of receptors 
[, 2000]. 
Several preclinical and clinical studies have demonstrated an association between 
response to certain types of chemotherapies as well as HER2-directed agents and the 
expression of HER receptors or their associated ligands. 
HER2 overexpression was observed to be associated with intrinsic resistance to DNA 
damaging agents and paclitaxel potentially owing in part to the role of HER2 signalling 
in regulating cell cycle and survival [Tan, 2000]. A common standard of care for the 
treatment of HER2-positive breast cancer is chemotherapy in combination with HER2-
directed agents; mechanisms that adversely impact the efficacy of these agents may affect 
the efficacy of chemotherapy.  Therefore, as evidence supports a role for the expression 
of HER receptors and ligands in mediating response to HER2-directed agents such as 
trastuzumab and lapatinib [Arteaga, 2006; Ritter, 2007; Amin, 2010], treatment with 
Dual blockade may be a more effective treatment than either agent alone due to 
complementary mechanisms of action [Scaltriti, 2009; Ghosh, 2007; Maruyama, 2011; 
Sánchez-Martín, 2012].
The expression of HER receptors EGFR, HER2, HER3, and HER4 and their associated 
ligands will be measured by gene expression analyses.  The protein expression levels of 
the HER receptors will also be measured by IHC. 
Immunomodulation
The concept of tumor escape as a process of immunoediting involves the acquisition of 
adaptations that allow the tumor to evade detection and destruction by the immune 
system.  The mechanism by which tumor escape occurs is through induction of immune 
tolerance or inhibition of tumor recognition and resistance to killing by activated immune 
effector cells [, 2011].  Immunoediting may affect response to chemotherapy, as some 
chemotherapies induce immunogenic cell death and stimulate a secondary antitumor 
immune response [, 2013].  
Alteration of expression of immune checkpoint proteins, such as programmed cell death 
1 ligand 1 (PDL-1), programmed cell death 1(PD-1), cytotoxic T-lymphocyte antigen 4 
(CTLA-4), and forkhead box P3 (FOXP3), a transcription factor expressed in regulatory 
T cells and involved in their suppressive function, may provide a mechanism by which 
the tumor cells evade the immune system [, 2013; , 2009].  The expression of these 
proteins in addition to the expression of different subpopulations of tumor-infiltrating 
lymphocytes, natural killer cells, and macrophages will be measured by gene expression 
profiling and IHC.
Several gene signatures, or metagenes, have been developed as surrogate representatives 
of immune function [, 2009; , 2013; , 2013].  The metagene signature from Nagalla et al. 
was developed through an integrated dataset of 1954 clinically annotated breast tumor 


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expression profiles to investigate the relationship between immunity and proliferation.  
From these analyses, 3 distinct clusters with annotated immune function were defined 
and further postulated to reflect different tumor-infiltrating leukocyte populations: B 
cells/plasma cells, T cells/natural killer cells, and monocytes/dendritic cells.  These 
metagene clusters or other development signatures may be evaluated as part of the 
primary objective.  
Apoptosis
Alterations in the apoptotic pathways through inactivation of pro-apoptotic factors and 
overexpression of pro-survival factors have been implicated in resistance to 
chemotherapeutics, as these agents elicit their effect through activation of tumor cell 
death [, 2009; Rebucci, 2013].  
B-cell lymphoma 2 (Bcl-2) and the family member B-cell lymphoma-extra large (Bcl-xl) 
will be evaluated in this study, as they are key anti-apoptotic factors.  Additional anti-
apoptotic factors under evaluation include survivin (baculoviral inhibitor of apoptosis 
repeat-containing 5 [BIRC5]) and X-linked inhibitor of apoptosis protein (XIAP).  BIM 
(Bcl-2-like protein 11[Bcl2L11]), p53, and tumor necrosis factor (TNF)-related 
apoptosis-inducing ligand (TRAIL) also will be evaluated, as they are key factors 
involved in activation of apoptotic pathways.  The expression of these factors will be 
measured by gene expression analysis and IHC if validated assays are available. 
ABC Transporters/Drug Efflux Pumps
Adenosine triphosphate binding cassette (ABC) proteins comprise a large family of 
transporters with a wide variety of substrates, such as the multidrug resistance 1 protein 
(ABCB1), breast cancer resistance protein (ABCG2), and multidrug resistance-related 
protein (ABCC1), all of which have been shown to promote de novo and acquired 
resistance to multiple chemotherapeutic agents with varying mechanisms of action.  
This study will evaluate the expression of these specific ABC transporters, as they have 
been purported to have the greatest therapeutic relevance for treatment of many common 
malignancies [, 2009]. 
Reason for Change 
Section 1.2.4 Hypothesis Based on emerging data, the focus of the study will be based on 
immunomodulation markers only 
Original Text 
It is postulated that treatment with Dual blockade (lapatinib in combination with 
trastuzumab) will cause molecular changes in at least 1 of 4 biomarker groups that may 
sensitize tumors to subsequent post-study therapies.  Furthermore, the sensitization to 
subsequent post-study therapies is expected to result in an OS benefit.  The primary 
endpoint of the study will be to evaluate changes in expression of biomarkers associated 
with the HER family or receptors and ligands, immunomodulation, apopotsis, and ABC 
transports between a pre-treatment biopsy and the disease progression biopsy.


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This Phase II study will evaluate potential mechanisms to explore the antitumor activity 
of dual blockade and gain insight into the observed post-study treatment effect on 
survival in EGF104900.  In addition, it will provide a descriptive clinical outcome for 
subjects treated with trastuzumab in combination with lapatinib or chemotherapy.  
Amended Text 
It is postulated that treatment with Dual blockade (lapatinib in combination with 
trastuzumab) will may cause molecular changes in at least 1 of 4 biomarker groups that 
may sensitize tumors to subsequent post-study therapies. As discussed above, based on 
emerging data the focus will be on immunomodulation markers. Furthermore, the 
sensitization to subsequent post-study therapies is expected to result in an OS benefit.  
The primary endpoint of the study will be to evaluate changes in expression of 
biomarkers associated with the HER family or receptors and ligands,
immunomodulationapopotsis, and ABC transports between a pre-treatment biopsy and 
the disease progression biopsy.
This Phase II study will evaluate potential mechanisms related to immunomodulation
to explore the antitumor activity of dual blockade and gain insight into the observed post-
study treatment effect on survival in EGF104900.  In addition, it will provide a
descriptive clinical outcome for subjects treated with trastuzumab in combination with 
lapatinib or chemotherapy.  
Reason for Change:
Section 1.3.3 Usage of various cancers was removed for the development of lapatinib 
Original Text:
Lapatinib is a tyrosine kinase inhibitor that is being developed for various cancers, including 
MBC.  
Amended Text:
Lapatinib is a tyrosine kinase inhibitor that is indicated in the treatment of being 
developed for various cancers, including MBC.  
Reason for Change:
Section 2 OBJECTIVES AND ENDPOINTS The Primary Object was updated to 
remove the study of changes in biomarkers associated with the HER2 family, apoptosis, 
adenosine triphosphate binding cassette (ABC) transporters.  
The Secondary Objective was updated to remove OS, PFS on first next line and 
subsequent lines of anti-cancer therapies.  Patient Reported Outcomes (PRO) and 
Health-Related Quality of Life (HRQOL) was also removed 
 
 


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Original Text:
Objectives
Endpoints
Primary

To evaluate changes in the expression of 
biomarkers associated with HER family, 
immunomodulation, apoptosis, and ABC 
transporters within each treatment arm between 
the pre-treatment biopsy and the disease 
progression biopsy. 

Changes in gene and/or protein expression 
profile within each arm on a prespecified set of 
biomarkers associated with HER family, 
immunomodulation, apoptosis, and ABC 
transporters compared between the pre-
treatment biopsy and disease progression 
biopsy.  The HER2-enriched and Non-HER2-
enriched cohorts will be analyzed separately.
Secondary

To describe, ORR, CBR, and PFS on study 
treatment and OS in subjects treated with 
trastuzumab in combination with lapatinib or 
chemotherapy.

To describe PFS on first next line (PFS-NL) and 
subsequent lines of anti-cancer therapies.

To explore association between changes  in 
biomarkersand PFS, PFS-NL and OS.

To describe the safety and tolerability of trastuzumab 
in combination with lapatinib and of trastuzumab in 
combination with chemotherapy.
 

To describe changes of Patient Reported Outcomes 
(PRO)(Health Related Quality of Life (HRQOL)) 
within the study population and to describe the 
differences of PRO/HRQOL between treatment 
groups.

OS defined as the interval of time between 
randomization and death due to any cause; 
investigator-assessed PFS defined as the 
interval of time between randomization and 
disease progression or death due to any cause; 
investigator-assessed ORR defined as 
percentage of subjects with a CR or PR; and 
CBR defined as percentage of subjects with a 
CR, PR, or SD for at least 6 months

PFS on all subsequent lines of anti-cancer 
therapies defined as the interval of time 
between start of next-line anticancer therapy 
and disease progression or discontinuation of 
that next-line therapy for any cause

Determine if a change at disease progression in 
biomarker correlates with PFS, PFS-NL or OS

Summary AE profile for both treatment arms
  
 

Summarize the results of the Functional 
Assessment of Cancer Therapy – Breast 
(FACT-B)   and Multidimensional Assessment 
of Fatigue (MAF) Scalefor each arm
Abbreviations: ABC, adenosine triphosphate binding cassette; AE, adverse event; CBR, clinical benefit rate; CR, 
complete response; HER, human epidermal growth factor receptor;
 


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Objectives
Endpoints
PD, progressive disease; PFS, progression-free survival; PFS-NL, progression-free survival on next-line therapy; 
PR, partial response; ORR, overall response rate; OS, overall survival; SD, stable disease.
Amended Text:
Objectives
Endpoints
Primary

To evaluate changes in the expression of 
biomarkers associated with HER family, 
immunomodulation, apoptosis, and ABC 
transporters within each treatment arm between 
the pre-treatment biopsy and the disease 
progression biopsy. 

Changes in gene and/or protein expression 
profile within each arm on a prespecified set of 
biomarkers associated with with HER family,
immunomodulation, apoptosis, and ABC 
transporters compared between the pre-
treatment biopsy and disease progression 
biopsy.  The HER2-enriched and Non-HER2-
enriched cohorts will be analyzed separately.
Secondary

To describe ORR, CBR, and PFS on study treatment 
and OS in subjects treated with trastuzumab in 
combination with lapatinib or chemotherapy.

To describe PFS on first next line (PFS-NL) and 
subsequent lines of anti-cancer therapies.

To explore association between changes in 
biomarkersand PFS, PFS-NL and OS.

To describe the safety and tolerability of trastuzumab 
in combination with lapatinib and of trastuzumab in 
combination with chemotherapy.
 

To describe changes of Patient Reported Outcomes 
(PRO)(Health Related Quality of Life (HRQOL)) 
within the study population and to describe the 
differences of PRO/HRQOL between treatment 
groups.

OS defined as the interval of time between 
randomization and death due to any cause;
investigator-assessed PFS defined as the 
interval of time between randomization and 
disease progression or death due to any cause; 
investigator-assessed ORR defined as 
percentage of subjects with a CR or PR; and 
CBR defined as percentage of subjects with a 
CR, PR, or SD for at least 6 months

PFS on all subsequent lines of anti-cancer 
therapies defined as the interval of time 
between start of next-line anticancer therapy 
and disease progression or discontinuation of 
that next-line therapy for any cause

Determine Describe if a change at disease 
progression in biomarker correlates with PFS, 
PFS-NL or OS

Summary AE profile for both treatment arms
  
 
Summarize the results of the Functional 
Assessment of Cancer Therapy – Breast 
(FACT-B)   and Multidimensional Assessment 
of Fatigue (MAF) Scalefor each arm


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Abbreviations: ABC, adenosine triphosphate binding cassette; AE, adverse event; CBR, clinical benefit rate; CR, 
complete response; HER, human epidermal growth factor receptor; 
 
PD, progressive disease; PFS, progression-free survival; PFS-NL, progression-free survival on next-line therapy; 
PR, partial response; ORR, overall response rate; OS, overall survival; SD, stable disease.
Reason for change 
Section 3 Study Design schema figure was updated to remove the number of evaluable 
patient per arm and data collection on the next regimen and survival.  
Original Text 


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Amended Text 
Reason for Change 
Section 3 Subject Completion: Follow-up time was re-defined as follows: A subject will 
be considered to have completed the study if the subject presents with disease 
progression, starts a new anti-cancer therapy, dies or withdraws from the study, or the 
study ends, whichever comes first. In case of disease progression during the treatment 
period, the subject will be followed-up for 30 days for safety evaluation and no further 
study-specific follow-up will be carried out; the subject will be considered as having 
completed the study. The data cutoff and end of study are defined.  
Original Text 
Biopsies of a metastatic site will be collected at two timepoints: screening (pre-treatment) 
and at disease progression (progression).  The primary objective is to evaluate changes 
in biomarkers associated with HER family, immunomodulation, apoptosis, and ABC 
transporters between the pre-treatment biopsy and the progression  biopsy within each 
arm.  Radiologic disease assessments will be performed every 9 weeks until 54 weeks 
then every 24 weeks thereafter until disease progression or withdrawal from study 
treatment for any reason. 
 
Safety assessments including physical examination, Eastern Cooperative Oncology 
Group (ECOG) performance status, vital signs and weight, adverse event (AE) 


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monitoring, and laboratory tests (complete blood count, blood chemistry including liver 
function test) will be done at screening and then every 3 weeks for the duration of therapy.  
Additional safety assessments, such as cardiac monitoring, are required for all subjects 
every 12 weeks until discontinuation from the study therapy.
All subjects will receive study treatment until disease progression, unacceptable toxicity, 
or subject withdrawal of consent.  After discontinuation of the study treatment, a subject 
will be followed for survival at approximately 12-week intervals until death or end of 
study.  Information on subsequent anti-cancer therapy(ies), start and stop dates of 
administrations of anti-cancer therapy, and dates of documented disease progression will 
also be collected.  
It is estimated that approximately 85% of subjects will discontinue study treatment due to 
disease progression and of these, 80% will have evaluable paired tumor biopsies.  
Therefore, to achieve a total of 150 evaluable subjects, 50 evaluable subjects in each 
treatment arm, approximately 225 subjects may be recruited into the study.
After discontinuation from study treatment, subjects will be followed for subsequent 
disease progressions and overall survival until all criteria below are met:

75% of the subjects have died

100% of  subjects have completed study treatment;

all subjects who go onto first next line therapy have completed first next line 
therapy.
During survival follow-up, information on all post-study anticancer therapies will be 
collected, including generic name, regimen number, start date, stop date, reason for 
discontinuing post-study treatment anticancer therapy regimen, date of disease 
progression (clinical and/or radiologic if applicable), and number of cycles/doses until 
death or conclusion of the study.
At the time any arm accrues 50 evaluable subjects (Arms A and B will require both to 
have accrued 50 evaluable subjects each), that arm(s) will be closed to further enrollment.  
It is expected that the Non-HER2-enriched Dual blockade arm will accrue 50 evaluable 
subjects prior to the HER2-enriched arms. 
When an arm or arms is closed to further enrollment, GSK will notify all investigators in 
writing.  Subjects who have signed consent prior to receipt of the written notification, if 
determined eligible for a cohort (HER2-enriched or Non-HER2-enriched) to which 
treatment arm(s) is closed, will be permitted to continue in the study. 
Subjects signing consent after receipt of written notification and who are allocated to a 
cohort where the treatment arm(s) is closed will be considered screen failures for the 
remaining open cohort (see Section 4.3).


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Amended Text 
Biopsies of a metastatic site will be collected at two timepoints: screening (pre-treatment) 
and at disease progression (progression).  The primary objective is to evaluate changes 
in biomarkers associated with HER family, immunomodulation, apoptosis, and ABC
transporters between the pre-treatment biopsy and the progression biopsy within each 
arm.  Radiologic disease assessments will be performed every 9 weeks until 54 weeks 
then every 24 weeks thereafter until disease progression, death, or withdrawal from study 
treatment for any reason (e.g. unacceptable toxicity).  
 
 
Safety assessments including physical examination, Eastern Cooperative Oncology 
Group (ECOG) performance status, vital signs and weight, adverse event (AE) 
monitoring, and laboratory tests (complete blood count, blood chemistry including liver 
function test) will be done at screening and then every 3 weeks for the duration of therapy.  
Additional safety assessments, such as cardiac monitoring, are required for all subjects 
every 12 weeks until discontinuation from the study therapy.
All subjects will receive study treatment until disease progression, death, unacceptable 
toxicity, or subject withdrawal of consent or any other reasons mentioned in section 
4.2.1.  
In case of disease progression during the treatment period, the patientsubject will be 
followed-up for 30 days for safety evaluation and no further study-specific follow-up 
will be carried out in the protocol; the patientsubject will be considered as having 
completed the study. 
Similarly, in case of disease progression after the treatment period (i.e. in subjects 
who discontinued for any reasons other than disease progression) and before the 
end of the study (defined as all subjects having completed the study, i.e. presented 
with disease progression, started new anti-cancer therapy, died or withdrew from 
the study (whichever came first) during the study treatment period or the follow-up 
period after discontinuation due to any reasons other than disease progression), no 
further study-specific follow-up will be carried out in the protocol; the patientsubject 
will be considered as having completed the study. 
In case of stoppingstudy treatment discontinuation for any reasons in the absence 
ofother than disease progression, the patientsubject will be followed-up for safety 
and efficacy assessments until disease progression, new anticancer therapy, death, 
withdrawal of consent or end of study, whichever comes first. 
The data cut-off for the primary analysis will be defined at 12 months after the last 
subject enrolled in the study or the last subject progressed/withdrew, whichever is 
earlier. Following the cut-off date for the primary analysis, the study will remain 
open. Ongoing subjects will continue to receive study treatment and be followed as 
per the schedule of assessments, as long as subjects derive benefit from lapatinib. 
The end of study defined as the earliest occurrence of one of the following:
•       All patients have died or discontinued from the study


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•       Another clinical study becomes available that can continue to provide 
lapatinib in this patient population and all subjects ongoing are eligible to be 
transferred to that clinical study 
•       At the end of the study, every effort will be made to continue provision of 
study treatment outside this study through an alternative setting to subjects who in 
the opinion of the Investigator are still deriving clinical benefit. 
After discontinuation of the study treatment, a subject will be followed for survival at 
approximately 12-week intervals until death or end of study.  Information on subsequent 
anti-cancer therapy(ies), start and stop dates of administrations of anti-cancer therapy, 
and dates of documented disease progression will also be collected
Due to difficulty in enrolling subjects into this trial, future enrolment will be halted 
and the study will be terminated early. 
It is estimated that approximately 85% of subjects will discontinue study treatment due to 
disease progression and of these, 80% will have evaluable paired tumor biopsies.  
Therefore, to achieve a total of 150 evaluable subjects, 50 evaluable subjects in each 
treatment arm, approximately 225 subjects may be recruited into the study. 
After discontinuation from study treatment, subjects will be followed for subsequent 
disease progressions and overall survival until all criteria below are met:

75% of the subjects have died

100% of  subjects have completed study treatment;

all subjects who go onto first next line therapy have completed first next line therapy.
During survival follow-up, information on all post-study anticancer therapies will be 
collected, including generic name, regimen number, start date, stop date, reason for 
discontinuing post-study treatment anticancer therapy regimen, date of disease 
progression (clinical and/or radiologic if applicable), and number of cycles/doses until 
death or conclusion of the study.
At the time any arm accrues 50 evaluable subjects (Arms A and B will require both to 
have accrued 50 evaluable subjects each), that arm(s) will be closed to further enrollment.  
It is expected that the Non-HER2-enriched Dual blockade arm will accrue 50 evaluable 
subjects prior to the HER2-enriched arms. 
When an arm or arms is closed to further enrollment, GSK will notify all investigators in 
writing. At the time of stopping the enrollment, the sponsor will notify all the 
investigators in writing. Subjects who have signed consent prior to receipt of the written 
notification, if determined eligible for a cohort (HER2-enriched or Non-HER2-enriched) 
to which treatment arm(s) is closed, will be permitted to continue in the study. 
Subjects signing consent after receipt of written notification and who are allocated to a 
cohort where the treatment arm(s) is closed will be considered screen failures for the 
remaining open cohort (see Section 4.3).


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Reason for Change 
Section 3.1 Discussion of biomarkers was updated to remove HER2 family, apoptosis, 
and adenosine triphosphate binding cassette (ABC)
Original Text 
This study is a post-approval commitment with regulatory authorities.  It is designed 
with the primary endpoint to evaluate the changes in biomarkers associated with HER 
family, immunomodulation, apoptosis, and ABC transporters between the pre-treatment 
and disease progression biopsy.  It is hypothesized that these  changes in biomarkers 
may modulate resistance mechanisms and thereby alter the response to subsequent 
chemotherapy based regimens.  Therefore, in addition to the description of the clinical 
outcome of ORR, CBR, PFS and OS for each arm, PFS on next-line therapies will be 
collected and summarized for each arm.
… Therefore, this study will also enroll a standard HER2 positive population as defined 
by standard histopathologic criteria that will be assigned to treatment with lapatinib in 
combination with trastuzumab. In this HER2 positive, non-HER2 enriched (i.e. luminal A, 
luminal B and basal-like) population, the study will investigate any biomarker changes 
associated with long-term benefit that may be inclusive of all HER2 positive patients as 
well as those that may be specific to the HER2-enriched molecular subtype.  Both 
cohorts will be treated with dual blockade (trastuzumab in combination with lapatinib). 
The inclusion of these two cohorts was discussed and agreed upon with the scientific 
advice working party of the Committee for Medicinal Products for Human Use (CHMP).  
In addition, common clinical practice in these heavily pretreated patients is to continue 
trastuzumab in combination with chemotherapy.  As such, the effect of dual blockade 
and trastuzumab plus chemotherapy in the HER2-enriched cohort will be evaluated in 
this study
Amended Text 
This study is a post-approval commitment with regulatory authorities.  It is designed 
with the primary endpoint to evaluate the changes in biomarkers associated with HER 
family, immunomodulation, apoptosis, and ABC transporters between the pre-treatment 
and disease progression biopsy.  It is hypothesized that these  changes in biomarkers 
may modulate resistance mechanisms and thereby alter the response to subsequent 
chemotherapy based regimens.  Therefore, in addition to the description of the clinical 
outcome of ORR, CBR, PFS and OS for each arm, PFS on next-line therapies will be 
collected and summarized for each arm.
… Therefore, this study will also enroll a standard HER2 positive population as defined 
by standard histopathologic criteria with non-HER2-enriched subtype that will be 
assigned to treatment with lapatinib in combination with trastuzumab. In this HER2 
positive, non-HER2 enriched (i.e. luminal A, luminal B and basal-like) population, the 


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study will investigate any biomarker changes associated with long-term benefit that may 
be inclusive of all HER2 positive patients as well as those that may be specific to the 
HER2-enriched molecular subtype. Both cohorts will be treated with dual blockade 
(trastuzumab in combination with lapatinib). The inclusion of these two cohorts was 
discussed and agreed upon with the scientific advice working party of the Committee for 
Medicinal Products for Human Use (CHMP).  
In addition, common clinical practice in these heavily pretreated patients is to continue 
trastuzumab in combination with chemotherapy.  As such, the effect of dual blockade 
and trastuzumab plus chemotherapy in the HER2-enriched cohort will be evaluated in 
this study
Reason for Change 
Section 3.1.3 Analysis of the biomarker was updated to emphasize immunomodulation
Original Text 
This study will have tumor biopsies taken at screening (pre-treatment biopsy) and at 
disease progression (progression biopsy), to analyze candidate biomarkers defined for 
each of the 4 primary mechanisms associated with impacting response to chemotherapy 
(see Section 1.2.3).  The primary endpoint will evaluate changes in the candidate 
biomarkers measured in the progression  biopsy compared to the pre-treatment biopsy.  
Analysis of these candidate biomarkers in pre-treatment tumor tissue and at disease 
progression may provide key information on modulation, as an effect of treatment, or 
persistence of the breast molecular subtype through the course of the history of the 
disease.  
The site of the pre-treatment biopsy and progression  biopsy should remain the same if 
possible.  CNS and bone biopsies are excluded organs. 
 
  
 
 Subpopulations of natural killer cells, monocytes/macrophages, and T-cells, 
as resting and activated phenotypes, will be evaluated as well as levels of cytokines and 
chemokines associated with immune responses.
Amended Text 
This study will have tumor biopsies taken at screening (pre-treatment biopsy) and at 
disease progression (progression biopsy) to analyze candidatebiomarkers associated with 
immunomodulation potentially defined for each of the 4 primary mechanisms 
associatedconnected withto an impact on theimpacting response to chemotherapy (see 
Section 1.2.3).  The primary endpoint will evaluate changes in these candidate 
biomarkers measured in the progression biopsy compared to the pre-treatment biopsy.  


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Analysis of these candidate biomarkers in pre-treatment tumor tissue and at disease 
progression may provide indicative information on immunomodulation, as an effect 
of treatment.
Analysis of these candidate biomarkers in pre-treatment tumor tissue and at disease 
progression may provide key information on modulation, as an effect of treatment, or 
persistence of the breast molecular subtype through the course of the history of the 
disease.  
The site of the pre-treatment biopsy and progression biopsy should remain the same if 
possible.  CNS and bone biopsies are excluded organs. 
 
  
 
 Subpopulations of natural killer cells, monocytes/macrophages, and T-cells, 
as resting and activated phenotypes, will be evaluated as well as levels of cytokines and 
chemokines associated with immune responses.
Reason for Change 
Section 4.1.1 Number of current enrollment provided.  Novartis will stop enrollment 
completely when study termination proposal agreement is received from HA. The 
projection on the analysis of the originally planned number of patient was deleted due to 
early study termination.  
Original Text 
The study will analyze a minimum of 150 evaluable subjects, 50 in each arm. To achieve 
150 evaluable subjects, it is estimated that approximately 225 subjects will be enrolled 
(75 in each treatment arm) based on the assumption that approximately 85% of subjects 
will discontinue study treatment due to disease progression and of these, 80% will have 
evaluable paired tumor biopsies.  
See Section 9.2.1 for sample size assumptions.
Amended Text 
Since the initiation of this trial, the enrollment has been poor due to lack of interest 
by investigators and patients. Therefore, future enrolment will be halted and the 
study will be terminated early. Up to 31 Jul 2016, 29 patients have been enrolled. 
The study will analyze a minimum of 150 evaluable subjects, 50 in each arm. To achieve 
150 evaluable subjects, it is estimated that approximately 225 subjects will be enrolled 
(75 in each treatment arm) based on the assumption that approximately 85% of subjects 
will discontinue study treatment due to disease progression and of these, 80% will have 
evaluable paired tumor biopsies.  
See Section 9.2.1 for sample size assumptions.


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Reason for Change 
Section 4.2.1 Withdraw of consent was added for study discontinuation definition.  
Follow up time was re-defined 
Original Text
Subjects will receive study treatment until disease progression, death or unacceptable 
adverse event, including meeting stopping criteria for liver chemistry defined in Section 
5.9 or for hematologic and other non-hematologic toxicity.  In addition, study treatment 
may be permanently discontinued for any of the following reasons:
All subjects who discontinues from study treatment will have safety and efficacy 
assessments performed as specified in the Time and Events table (Table 9) and results 
documented in the eCRF.
After discontinuation of the study treatment for any reason, a subject will be followed for 
survival at approximately 12-week intervals until death or end of study.  Information on 
subsequent anti-cancer therapy(ies), start and stop dates of administrations of anti-cancer 
therapy,  and dates of documented disease progression will also be collected.  
If subjects are unable or unwilling to attend clinic visits during follow-up, contact to 
assess survival may be made via another form of communication (e.g., phone, email, etc.).  
All details of post-study anticancer treatments including start dates, stop dates, reason for 
ending treatment, and dates of documented disease progression (radiologic and/or 
clinical), will be captured in the relevant sections of the eCRF until death or end of study.
All subjects who discontinue from study treatment without disease progression will be 
followed for progression according to the protocol schedule (Table 9) until new 
anticancer therapy is initiated, progression or death is documented, or study closes.
Survival follow-up will continue until all criteria below are met:

75% of the subjects have died

100% of  subjects have completed study treatment;

all subjects who go onto first next line therapy have completed first next line 
therapy.
At such time, the study will be closed for further follow-up and collection of all post-
study information will cease.  . 
Amended Text
Subjects will receive study treatment until disease progression, death, withdrawal of 
consent or any other reasons mentioned in this section, including or unacceptable 


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adverse event (as well asincluding meeting stopping criteria for liver chemistry defined 
in Section 5.9 or for hematologic and other non-hematologic toxicity).  
In addition, sStudy treatment may be permanently discontinued for any of the following 
reasons:
All subjects who discontinue from study treatment due to an AE or any other reasons 
other than disease progression will have safety and efficacy assessments performed
until disease progression, new anticancer therapy, death, withdrawal or until the 
end of study (defined as all subjects having completed the study, i.e. presented with 
disease progression, started new anti-cancer therapy, died or withdrew from the 
study (whichever came first) during the study treatment period or the follow-up 
period after discontinuation due to any reasons other than disease progression) as 
specified in the Time and Events table (Table 9) and results documented in the eCRF.
In case of disease progression during the treatment period, the subject will be 
followed-up for 30 days for safety evaluation and no further study-specific follow-up 
will be carried out; the subject will be considered as having completed the study. 
Similarly, in case of disease progression after the treatment period (i.e. in subjects 
who discontinued for any reasons other than disease progression) and before the 
end of the study (defined as all subjects having completed the study, i.e. presented 
with disease progression, started new anti-cancer therapy, died or withdrew from 
the study (whichever came first) during the study treatment period or the follow-up 
period after discontinuation due to any reasons other than disease progression), no 
further study-specific follow-up will be carried out; the subject will be considered as 
having completed the study. 
Following the cut-off date for the primary analysis (defined at 12 months after the 
last subject enrolled in the study or the last subject progressed/withdrew, whichever 
is earlier), the study will remain open. Ongoing subjects will continue to receive 
study treatment and be followed as per the schedule of assessments, as long as 
subjects derive benefit from lapatinib. The end of study defined as the earliest 
occurrence of one of the following:
•       All patients have died or discontinued from the study
•       Another clinical study becomes available that can continue to provide 
lapatinib in this patient population and all subjects ongoing are eligible to be 
transferred to that clinical study 
•       At the end of the study, every effort will be made to continue provision of 
study treatment outside this study through an alternative setting to subjects who in 
the opinion of the Investigator are still deriving clinical benefit.
After discontinuation of the study treatment for any reason, a subject will be followed for 
survival at approximately 12-week intervals until death or end of study.  Information on 
subsequent anti-cancer therapy(ies), start and stop dates of administrations of anti-cancer 
therapy,  and dates of documented disease progression will also be collected.  
If subjects are unable or unwilling to attend clinic visits during follow-up, contact to 
assess survival may be made via another form of communication (e.g., phone, email, etc.).  


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All details of post-study anticancer treatments including start dates, stop dates, reason for 
ending treatment, and dates of documented disease progression (radiologic and/or 
clinical), will be captured in the relevant sections of the eCRF until death or end of study.
All subjects who discontinue from study treatment without disease progression will be 
followed for progression according to the protocol schedule (Table 9) until new 
anticancer therapy is initiated, progression or death is documented, or study closes.
Survival follow-up will continue until all criteria below are met:

75% of the subjects have died

100% of  subjects have completed study treatment;

all subjects who go onto first next line therapy have completed first next line therapy.
At such time, the study will be closed for further follow-up and collection of all post-
study information will cease.  
Reason for Change 
Section 4.2.2 Minor editorial changes to clarify the timing of lost to follow up
Original Text 
If any of the trial subjects are lost to follow up, contact will initially be attempted through the trial 
research nurse and the lead investigator at each centre.
Amended Text 
If any of the trial subjects are lost to follow-up prior to subject completion, contact will initially 
be attempted through the trial research nurse and the lead investigator at each centre.
Reason for Change 
Section 4.2.3 Subject Completion: Follow-up time was re-defined
Original Text 
A subject will be considered to have completed the study if the subject dies during the 
study treatment or follow-up period.  Document the cause of death in the eCRF. 
A subject will be considered to have withdrawn from the study if the subject has not died 
and is lost to follow-up, has withdrawn consent, at the investigator’s discretion is no 
longer being followed or if the study is closed/terminated. 
Data collection will continue until a subject has completed or discontinued the study.  
Collection of follow-up data will continue until 

75% of the subjects have died (or at most 25% subjects are censored)


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
100% of  subjects have completed study treatment;

all subjects who go onto first next line therapy have completed first next line 
therapy.
Amended Text 
A subject will be considered to have completed the study if the subject presents with 
disease progression, starts a new anti-cancer therapy, dies or withdraws from the 
study, starts a new anti-cancer therapy or the study ends whichever comes first 
during the study treatment or follow-up period.  Document the cause of death 
completion in the eCRF. 
A subject will be considered to have withdrawn from the study if the subject has not died 
experienced disease progression and is lost to follow-up, has withdrawn consent, or has 
withdrawn at the investigator’s discretion. is no longer being followed or if the study is 
closed/terminated. All subjects will receive study treatment until disease progression, 
death, unacceptable toxicity, subject withdrawal of consent or any other reasons 
mentioned in section 4.2.1.  
In case of disease progression during the treatment period, the subject will be 
followed-up for 30 days for safety evaluation and no further study-specific follow-up 
will be carried out; the subject will be considered as having completed the study. 
Similarly, in case of disease progression after the treatment period (i.e. in subjects 
who discontinued for any reasons other than disease progression) and before the 
end of the study (defined as all subjects having completed the study, i.e. presented 
with disease progression, started new anti-cancer therapy, died or withdrew from 
the study (whichever came first) during the study treatment period or the follow-up 
period after discontinuation due to any reasons other than disease progression), no 
further study-specific follow-up will be carried out; the subject will be considered as 
having completed the study. 
In case of study treatment discontinuation for any reasons other than disease 
progression, the subject will be followed-up for safety and efficacy assessments until 
disease progression, new anticancer therapy, death, withdrawal of consent or end of 
study, whichever comes first. 
Following the cut-off date for the primary analysis (defined at 12 months after the 
last subject enrolled in the study or the last subject progressed/withdrew, whichever 
is earlier), the study will remain open. Ongoing subjects will continue to receive 
study treatment and be followed as per the schedule of assessments, as long as 
subjects derive benefit from lapatinib. The end of study defined as the earliest 
occurrence of one of the following:
•       All patients have died or discontinued from the study
•       Another clinical study becomes available that can continue to provide 
lapatinib in this patient population and all subjects ongoing are eligible to be 
transferred to that clinical study 


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•       At the end of the study, every effort will be made to continue provision of 
study treatment outside this study through an alternative setting to subjects who in 
the opinion of the Investigator are still deriving clinical benefit.
Data collection will continue until a subject has completed or discontinued the study.
  Collection of follow-up data will continue until 

75% of the subjects have died (or at most 25% subjects are censored)

100% of  subjects have completed study treatment;

all subjects who go onto first next line therapy have completed first next line therapy.
Reason for Change 
Section 4.3 Requirement of number of evaluable patient was removed for screen failures 
Original Text 
When a treatment arm(s) has enrolled the required 50 evaluable subjects, subjects who 
signed consent after receipt of the notification letter and are newly screened with the 
molecular subtype of the fully enrolled arm will be considered screen failures.  
Amended Text 
When a treatment arm(s) has enrolled the required 50 evaluable subjects, subjects who 
signed consent after receipt of the notification letter and are newly screened with the 
molecular subtype of the fully enrolled arm will be considered screen failures.  
Reason for Change 
Section 5.1.1 Commercial lapatinib is allowed to be used 
Original Text 
Lapatinib is supplied as 250-mg orange tablets that are oval, biconvex, and orange film-
coated with 1 side plain and the opposite side debossed with FG HLS.  
Amended Text 
Commercially packed supplies or non-commercial Lapatinib lapatinib is supplied as 
250-mg orange tablets that are oval, biconvex, and orange film-coated with 1 side plain 
and the opposite side debossed with FG HLS.
Reason for Change 


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Section 5.4 Requirement of number of evaluable patient was removed for treatment 
assignment
Original Text 
After an arm enrolled at least 50 evaluable subjects, that arm will be closed for further 
enrolled.  It is likely that Non-HER2-enriched Dual blockade arm will accrue 50 
evaluable subjects before the HER2-enriched arms.  If the Non-HER2-enriched Dual 
blockade arm is closed to further enrollment, subjects who sign consent after receipt of 
written notification and have a pre-treatment biopsy that is Non-HER2-enriched will be 
considered as screen failures (Section 4.3).  
Amended Text 
After an arm enrolled at least 50 evaluable subjects, that arm will be closed for further 
enrolled.  It is likely that Non-HER2-enriched Dual blockade arm will accrue 50 
evaluable subjects before the HER2-enriched arms.  If the Non-HER2-enriched Dual 
blockade arm is closed to further enrollment, subjects who sign consent after receipt of 
written notification and have a pre-treatment biopsy that is Non-HER2-enriched will be 
considered as screen failures (Section 4.3).  
Reason for Change 
Section 5.8 Death was added to define the end of study treatment administration
Original Text 
Study treatment will be administered until disease progression or discontinuation of study 
treatment due to unacceptable toxicity or other reasons (i.e., consent withdrawal, non-
compliance).  
Amended Text 
Study treatment will be administered until disease progression or death or 
discontinuation of study treatment due to unacceptable toxicity or other reasons (i.e. 
consent withdrawal, non-compliance).  
Reason for Change 
Section 5.9.1.1 Survival and progression follow-up were removed after discontinuation 
from the study due to hepatobiliary events 
Original Text 

Withdraw the subject from the study after completion of the liver chemistry 
monitoring as described below (unless further safety follow up is required or GSK 
Medical Governance approval of drug restart is granted, as described in Section 5.9.2).
For studies where survival or progression is an endpoint, follow-up for overall 
survival or progression is required following discontinuation from study 
treatment


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
Do not restart investigational product unless written approval for drug restart is 
granted by GSK Medical Governance (details for restarting investigational product 
are described in Section 5.9.2), whereupon the subject continues in the study after 
completion of the liver chemistry monitoring described in Section 5.9).  
Amended Text

Withdraw the subject from the study after completion of the liver chemistry 
monitoring as described below (unless further safety follow-up is required or GSK 
Medical Governance approval of drug restart is granted, as described in Section 5.9.2).
For studies where survival or progression is an endpoint, follow-up for overall 
survival or progression is required following discontinuation from study 
treatment

Do not restart investigational product study treatment unless written approval for 
drug restart is granted by GSK Medical Governance (details for restarting 
investigational product study treatment are described in Section 5.9.2), whereupon 
the subject continues in the study after completion of the liver chemistry monitoring 
described in Section 5.9).  
Reason for Change 
Section 6.3 Overall survival and progression follow up were removed for subjects who 
discontinued from study.  For subjects who discontinue for any other reasons other than 
progression, new anti-cancer therapy will be recorded during the follow-up period until 
subject completion.  
Original Text 
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the subject’s medical condition whether or not GSK is providing 
specific post-study treatment. Refer to Section 4.2.3 for follow-up assessment of subjects 
who are to be followed up for disease progression and/or survival after permanently 
discontinuing study treatment.
Post study treatment will not be provided as part of the protocol.  Upon discontinuation 
from assigned study treatment, subjects may receive additional (non protocol) anticancer 
therapy at the discretion of the treating physician.  Every effort should be made to 
complete the required withdrawal and follow-up evaluations prior to initiating further 
anticancer therapy or dosing of an investigational agent (see Table 9) or follow-up 
assessments and procedures).  
New anticancer therapy should be documented on the eCRF with generic drug name, start 
and stop dates, regimen sequence, type of therapy, number of cycles/dose, dose units, 
date of disease progression (if applicable), and reason for discontinuing post-study 
treatment.  
Subjects will be followed for survival even if other assessments are not performed.


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Amended Text 
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the subject’s medical conditionwhether or not GSK is providing 
specific post-study treatment. Refer to Section  for follow-up assessment of subjects 
who are to be followed up for disease progression and/or survival after permanently 
discontinuing study treatment.
Post study treatment will not be provided as part of the protocol.  Upon discontinuation 
from assigned study treatment, subjects may receive additional (non protocol) anticancer 
therapy at the discretion of the treating physician.  Every effort should be made to 
complete the required withdrawal end of study and follow-up evaluations prior to 
initiating further anticancer therapy or dosing of an investigational agent (see Table 9) or 
follow-up assessments and procedures).  
For subjects who discontinue for any other reasons other than progression, new 
anti-cancer therapy will be recorded during the follow-up period until subject 
completion.  New anticancer therapy should be documented on the eCRF with generic 
drug name, start and stop dates, regimen sequence, type of therapy, number of 
cycles/dose, dose units date of disease progression (if applicable), and reason for 
discontinuing post-study treatment.  
Subjects will be followed for survival even if other assessments are not performed.
Reason for Change 
Section 7 Time and Events are updated.  Overall survival follow-up and new anticancer 
therapy were removed for subjects who stopped study treatment due to progression.  
Progression follow-up was kept for subjects who discontinued treatment for any other 
reasons than progression.
Original Text 
STUDY PHASE
PRE-
TREATMENT
TREATMENT
POST-TREATMENT 
VISIT
Screen
Day 
1
Every 3 
weeks 
Every 
9 
Weeks
Every 
12 
Weeks
Study 
Treatment 
Discontinuation
Follow-
Up
Every 
12 
Weeks
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
Procedures
Informed Consent
X
Inclusion / 
exclusion 
X


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STUDY PHASE
PRE-
TREATMENT
TREATMENT
POST-TREATMENT 
VISIT
Screen
Day 
1
Every 3 
weeks 
Every 
9 
Weeks
Every 
12 
Weeks
Study 
Treatment 
Discontinuation
Follow-
Up
Every 
12 
Weeks
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
Demographics
Include birth year, 
race, ethnicity, and 
gender
X
Surgical history
X
Anti-cancer 
therapies
X1
X2
Past /current med 
conditions
X
X
Translational Sample Collection
Tumor Biopsy
 
refer to Study 
Procedures Manual 
for biopsy sample 
collection, storage, 
and shipment 
procedures
X
X3
Archived/stored 
tumor tissue 
collection
Tumor tissue block 
or 15-20 unstained 
slides required
X


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STUDY PHASE
PRE-
TREATMENT
TREATMENT
POST-TREATMENT 
VISIT
Screen
Day 
1
Every 3 
weeks 
Every 
9 
Weeks
Every 
12 
Weeks
Study 
Treatment 
Discontinuation
Follow-
Up
Every 
12 
Weeks
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
Efficacy Assessments
Disease 
Assessment4
Target and 
nontarget lesions 
should be assessed 
using RECIST 1.1 
within 28 days prior 
to randomization; 
assessments are 
conducted every 9 
weeks until 54 
weeks then every 24 
weeks thereafter.  
X
X
X5
X6
Bone Scan7
Baseline bone scan 
is required for all 
subjects.  For 
subjects without 
bone disease at 
baseline, 
subsequent bone 
scans should only 
be performed as 
clinically indicated. 
For subjects with 
bone disease at 
baseline, a bone 
scan is required 
every 18 weeks and 
at disease 
progression until 
Week 54 and then 
every 24 weeks or 
as clinically 
indicated
X
Post study 
treatment efficacy
Record dates of 
documented disease 
progression
X
Survival
X
Safety Assessments
Concurrent meds
X
X
X


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STUDY PHASE
PRE-
TREATMENT
TREATMENT
POST-TREATMENT 
VISIT
Screen
Day 
1
Every 3 
weeks 
Every 
9 
Weeks
Every 
12 
Weeks
Study 
Treatment 
Discontinuation
Follow-
Up
Every 
12 
Weeks
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
Physical exam
X
X
X
X
Vital signs 
Temperature, blood 
pressure and heart 
rate
X
X
X
Weight & height
Height - screening 
only
X
X
X
ECOG PS
X
X
X
X
AE/toxicity
Subjects will be 
monitored every 6 
weeks or at any 
contact with the 
subject during the 
study phases 
X
X
X
X8
ECHO or  MUGA 
scan9
The same method of 
evaluation should be 
used for a subject 
throughout study 
duration
X
X
X
12-lead ECG
X
X
X
Laboratory Assessments10
Hematology
Includes 
hemoglobin, 
hematocrit, red 
blood cell count, 
white blood cell 
count with absolute 
neutrophil count or 
differential, and 
platelet count
X
X
X
X
Serum chemistry11
Includes sodium, 
potassium, blood 
urea nitrogen, 
creatinine, glucose, 
calcium, aspartate 
aminotransferase, 
alanine 
aminotransferase, 
X
X
X
X


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STUDY PHASE
PRE-
TREATMENT
TREATMENT
POST-TREATMENT 
VISIT
Screen
Day 
1
Every 3 
weeks 
Every 
9 
Weeks
Every 
12 
Weeks
Study 
Treatment 
Discontinuation
Follow-
Up
Every 
12 
Weeks
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
alkaline 
phosphatase, total 
bilirubin, and 
albumin. magnesium
Serum pregnancy 
test 
Required for all 
women of 
childbearing 
potential; to be 
performed within 7 
days  prior to start 
of first dose of study 
treatment
X


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STUDY PHASE
PRE-
TREATMENT
TREATMENT
POST-TREATMENT 
VISIT
Screen
Day 
1
Every 3 
weeks 
Every 
9 
Weeks
Every 
12 
Weeks
Study 
Treatment 
Discontinuation
Follow-
Up
Every 
12 
Weeks
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
Study Treatment Assessments
Dispense lapatinib
A supply of lapatinib 
will be dispensed to 
subject with 
instructions for 
administration
X
Trastuzumab 
administration
Weekly schedule is 
permitted in 
combination with 
chemotherapy.  
Window for dose 
administration is ± 3 
days.
X
X
Chemotherapy 
administration12
Dose and schedule 
as prescribed by the 
investigator
X
Endocrine therapy 
with AI  
administration13
Dose and schedule 
as prescribed by the 
investigator in 
subjects with 
hormone receptor 
positive disease
X
Study drug 
compliance
A record of the 
number of tablets 
dispensed to and 
returned by each 
subject must be 
maintained
X
X


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STUDY PHASE
PRE-
TREATMENT
TREATMENT
POST-TREATMENT 
VISIT
Screen
Day 
1
Every 3 
weeks 
Every 
9 
Weeks
Every 
12 
Weeks
Study 
Treatment 
Discontinuation
Follow-
Up
Every 
12 
Weeks
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
Quality of Life Assessments
FACT-B 
questionnaire & 
MAF
questionnaire
On Day 1 collected 
at start of study 
treatment. 
Subsequent 
assessments in 
treatment phase 
include Week 3, 
week 6, and Week 
12.
X
X
X
X
1.
Prior therapies (screening visit only): include administration start and stop dates (month, year); date of 
radiographic confirmed progression.
2.
Post study therapies: After study treatment discontinuation follow subject for start and stop dates of all anti-
cancer therapies administered.  
3.
Window for progression biopsy is +14 days from date of progression and prior to start of new anti-cancer 
therapy.  Biopsy of metastatic tumor site only in subjects who discontinue study treatment due to disease 
progression.
4.
Use the same method of measurement for target and nontarget lesions at all time points.
5.
If the last radiographic assessment was obtained less than 9 weeks from study treatment discontinuation, 
radiographic assessments do not need to be repeated.
6.
Subjects who discontinue study treatment for reasons other than progression will have disease assessments 
done every 9 weeks until Week 54, then every 24 weeks thereafter until unequivocal progression, initiation of 
new anticancer therapy, or death
7.
All bone scan abnormalities that may indicate metastases must be evaluated by X-ray (e.g., plain film), 
computed tomography(CT), or magnetic resonance imaging to confirm and/or quantify malignant lesions.
8.
Monitor all AEs/Serious AEs that are ongoing until resolution or stabilization of the event
9.
Additional ECHO/ MUGA scans should be performed when clinically indicated.
10. At the pre-dose assessment on Day 1, all laboratory results will be reviewed by the investigator.  Any 
results outside of the normal range will be repeated (prior to the first dose) at the discretion of the investigator
11. Refer to Protocol Appendix 4 for further details
12. Chemotherapy will be administered throughout the study treatment phase based on the schedule chosen by 
investigator.
13. Endocrine therapy with AIs will be administered throughout the study treatment phase based on the schedule 
chosen by investigator.
 
15. Abbreviations: ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; ECG, 
electrocardiogram; MUGA, multigated acquisition scan.


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Amended Text 
STUDY PHASE
PRE-
TREATMEN
T
TREATMENT
POST-TREATMENT 
VISIT
Scree
n
Da
y 1
Every 
3 
week
s 
Every 
9 
Weeks
Eve
ry 
12 
Wee
ks
At Study 
Treatment 
Discontinuatio
n
Follow-
Up
Every 12 
Weeks 
until 
subject 
completi
on
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
Procedures
Informed Consent
X
Inclusion / exclusion 
X
Demographics
Include birth 
year, race, 
ethnicity, and 
gender
X
Surgical history
X
Anti-cancer therapies
X1
X2X14
Past /current med 
conditions
X
X
Translational Sample Collection
Tumor Biopsy
 
 
 
 refer to 
Study 
Procedures 
Manual for 
biopsy sample 
collection, 
storage, and 
X
X3X2


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STUDY PHASE
PRE-
TREATMEN
T
TREATMENT
POST-TREATMENT 
VISIT
Scree
n
Da
y 1
Every 
3 
week
s 
Every 
9 
Weeks
Eve
ry 
12 
Wee
ks
At Study 
Treatment 
Discontinuatio
n
Follow-
Up
Every 12 
Weeks 
until 
subject 
completi
on
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
shipment 
procedures
Archived/stored tumor 
tissue collection
Tumor tissue 
block or 15-20 
unstained slides 
required
X
Efficacy Assessments
Disease 
Assessment4Assessment3
Target and 
nontarget 
lesions should 
be assessed 
using RECIST 
1.1 within 28 
days prior to 
randomization; 
assessments 
are conducted 
every 9 weeks 
X
X
X5X4
X56


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STUDY PHASE
PRE-
TREATMEN
T
TREATMENT
POST-TREATMENT 
VISIT
Scree
n
Da
y 1
Every 
3 
week
s 
Every 
9 
Weeks
Eve
ry 
12 
Wee
ks
At Study 
Treatment 
Discontinuatio
n
Follow-
Up
Every 12 
Weeks 
until 
subject 
completi
on
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
until 54 weeks 
then every 24 
weeks 
thereafter.  
Bone Scan7Scan6
Baseline bone 
scan is required 
for all subjects.  
For subjects 
without bone 
disease at 
baseline, 
subsequent 
bone scans 
should only be 
performed as 
clinically 
indicated. For 
subjects with 
bone disease at 
baseline, a bone 
scan is required 
every 18 weeks 
and at disease 
progression until 
Week 54 and 
then every 24 
weeks or as 
clinically 
indicated
X
Post study treatment 
efficacy for subjects who 
discontinued study 
treatment for reasons 
other than disease 
progression
Record dates of 
documented 
disease 
progression
X
Survival
X
Safety Assessments


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STUDY PHASE
PRE-
TREATMEN
T
TREATMENT
POST-TREATMENT 
VISIT
Scree
n
Da
y 1
Every 
3 
week
s 
Every 
9 
Weeks
Eve
ry 
12 
Wee
ks
At Study 
Treatment 
Discontinuatio
n
Follow-
Up
Every 12 
Weeks 
until 
subject 
completi
on
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
Concurrent meds
X
X
X
X
Physical exam
X
X
X
X
Vital signs 
Temperature, 
blood pressure 
and heart rate
X
X
X
X
Weight & height
Height -
screening only
X
X
X
ECOG PS
X
X
X
X
AE/toxicity
Subjects will be 
monitored every 
6 weeks or at 
any contact with 
the subject 
during the study 
phases 
X
X
X7
X8X7
ECHO or MUGA 
scan9scan8
The same 
method of 
evaluation 
should be used 
for a subject 
throughout 
study duration
X
X
X
12-lead ECG
X
X
X
Laboratory Assessments10Assessments9
Hematology
Includes 
hemoglobin, 
hematocrit, red 
blood cell count, 
white blood cell 
count with 
absolute 
neutrophil count 
or differential, 
X
X
X
X


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STUDY PHASE
PRE-
TREATMEN
T
TREATMENT
POST-TREATMENT 
VISIT
Scree
n
Da
y 1
Every 
3 
week
s 
Every 
9 
Weeks
Eve
ry 
12 
Wee
ks
At Study 
Treatment 
Discontinuatio
n
Follow-
Up
Every 12 
Weeks 
until 
subject 
completi
on
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
and platelet 
count
Serum 
chemistry11chemistry10
Includes 
sodium, 
potassium, 
blood urea 
nitrogen, 
creatinine, 
glucose, 
calcium, 
aspartate 
aminotransferas
e, alanine 
aminotransferas
e, alkaline 
phosphatase, 
total bilirubin, 
and albumin. 
magnesium
X
X
X
X
Serum pregnancy test 
Required for all 
women of 
childbearing 
potential; to be 
performed within 
7 days  prior to 
start of first dose 
of study 
treatment
X


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STUDY PHASE
PRE-
TREATMEN
T
TREATMENT
POST-TREATMENT 
VISIT
Scree
n
Da
y 1
Every 
3 
week
s 
Every 
9 
Weeks
Eve
ry 
12 
Wee
ks
At Study 
Treatment 
Discontinuatio
n
Follow-
Up
Every 12 
Weeks 
until 
subject 
completi
on
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
Study Treatment Assessments
Dispense lapatinib
A supply of 
lapatinib will be 
dispensed to 
subject with 
instructions for 
administration
X
Trastuzumab administration
Weekly 
schedule is 
permitted in 
combination 
with 
chemotherapy.  
Window for 
dose 
administration is 
± 3 days.
X
X
Chemotherapy 
administration12administrat
ion11
Dose and 
schedule as 
prescribed by 
the investigator
X
Endocrine therapy with AI  
administration13administrat
ion12
Dose and 
schedule as 
prescribed by 
the investigator 
in subjects with 
hormone 
receptor positive 
disease
X
Study drug compliance
A record of the 
number of 
tablets 
dispensed to 
and returned by 
each subject 
must be 
maintained
X
X


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STUDY PHASE
PRE-
TREATMEN
T
TREATMENT
POST-TREATMENT 
VISIT
Scree
n
Da
y 1
Every 
3 
week
s 
Every 
9 
Weeks
Eve
ry 
12 
Wee
ks
At Study 
Treatment 
Discontinuatio
n
Follow-
Up
Every 12 
Weeks 
until 
subject 
completi
on
VISIT WINDOW (±Days)
± 7
± 7 
-7 
±30
Quality of Life Assessments
FACT-B questionnaire & MAF
questionnaire
On Day 1 
collected at 
start of study 
treatment. 
Subsequent 
assessments 
in treatment 
phase 
include Week 
3, week 6, 
and Week 
12.
X
X
X
X
1.
Prior therapies (screening visit only): include administration start and stop dates (month, year); date of 
radiographic confirmed progression.
2.
Post study therapies: After study treatment discontinuation follow subject for start and stop dates of all anti-
cancer therapies administered.  
3.
Window for progression biopsy is +14 days from date of progression and prior to start of new anti-cancer 
therapy.  Biopsy of metastatic tumor site only in subjects who discontinue study treatment due to disease 
progression.
4.
Use the same method of measurement for target and nontarget lesions at all time points.
5.
If the last radiographic assessment was obtained less than 9 weeks from study treatment discontinuation, 
radiographic assessments do not need to be repeated.
6.
Subjects who discontinue study treatment for reasons other than progression (e.g. due to an AE) will have 
disease assessments done every 9 weeks until Week 54, then every 24 weeks thereafter until unequivocal 
progression, initiation of new anticancer therapy, death,  withdrawal of consent, or deathor end of study. 
At the end of study, if the last radiographic assessment was obtained less than 9 weeks earlier, 
radiographic assessment does not need to be repeated.
7.
All bone scan abnormalities that may indicate metastases must be evaluated by X-ray (e.g., plain film), 
computed tomography (CT), or magnetic resonance imaging to confirm and/or quantify malignant lesions.
8.
Safety monitoring will be performed until 30 days after the last dose for subjects who discontinued 
due to progression. Safety monitoring will continue for subjects who stopped study treatment for 
reasons other than disease progression until disease progression, new anticancer therapy, death, 
withdrawal of consent or end of study, whichever comes first. Monitor all AEs/Serious AEs that are 
ongoing until resolution or stabilization of the event.
9.
Additional ECHO/ MUGA scans should be performed when clinically indicated.


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10. At the pre-dose assessment on Day 1, all laboratory results will be reviewed by the investigator.  Any 
results outside of the normal range will be repeated (prior to the first dose) at the discretion of the investigator
11. Refer to Protocol Appendix 4 for further details
12. Chemotherapy will be administered throughout the study treatment phase based on the schedule chosen by 
investigator.
13. Endocrine therapy with AIs will be administered throughout the study treatment phase based on the schedule 
chosen by investigator.
 
15. For subjects who discontinue for any other reasons other than progression, new anti-cancer therapy 
will be recorded during the follow-up period until subject completion.
Abbreviations: ECHO, echocardiogram; ECOG, Eastern Cooperative Oncology Group; ECG, electrocardiogram; 
MUGA, multigated acquisition scan.
Reason for Change 
Section 7.3.1 Efficacy endpoints was updated to remove OS, and PFS on first next-line 
and subsequent line of anti-cancer therapies and to remove the wider assessment of the 
biomarkers 
Original Text 
The primary efficacy endpoint of this study is the change in biomarkers associated with 
human epidermal growth factor (HER) family, immunomodulation, apoptosis, and ABC 
transporters which is defined as change in expression levels of biomarkers as measured in 
tissue from the disease progression tumor biopsy, compared with expression levels of 
these markers as measured in the pre-treatment tumor biopsy.
The secondary efficacy endpoints of this study are: 

OS defined as the interval of time between randomization and death due to any cause; 
investigator-assessed PFS defined as the interval of time between randomization and 
disease progression or death due to any cause; investigator-assessed ORR defined as 
percentage of subjects with a CR or PR; and CBR defined as percentage of subjects 
with a CR, PR, or SD for at least 6 months

PFS on all subsequent lines of anti-cancer therapies defined as the interval of time 
between start of next-line anticancer therapy and disease progression or 
discontinuation of that next-line therapy for any cause

Determine if 1) an on-treatment change or 2) change at disease progression in 
biomarker correlates with PFS, PFS-NL or OS
 
Amended Text 
The primary efficacy endpoint of this study is the change in biomarkers associated with 
human epidermal growth factor (HER) family, immunomodulation, apoptosis, and ABC 


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transporters which is defined as change in expression levels of biomarkers as measured in 
tissue from the disease progression tumor biopsy , compared with expression levels of 
these markers as measured in the pre-treatment tumor biopsy.
The secondary efficacy endpoints of this study are: 
OS defined as the interval of time between randomization and death due to any cause;
Iinvestigator-assessed PFS defined as the interval of time between randomization and 
disease progression or death due to any cause; investigator-assessed ORR defined as 
percentage of subjects with a CR or PR; and CBR defined as percentage of subjects with 
a CR, PR, or SD for at least 6 months.

PFS on all subsequent lines of anti-cancer therapies defined as the interval of time 
between start of next-line anticancer therapy and disease progression or 
discontinuation of that next-line therapy for any cause

Determine if 1) an on-treatment change or 2) change at disease progression in 
biomarker correlates with PFS, PFS-NL or OS
 
Reason for Change 
Section 7.3.2 Minor editorial change to clarify the bone scans timeline
Original Text 
For subjects with bone disease at baseline, a bone scan is required every 18 weeks and at 
disease progression until Week 54 and then every 24 weeks or as clinically indicated.
Amended Text 
For subjects with bone disease at baseline, a bone scan is required every 18 weeks until 
Week 54 and then every 24 weeks or as clinically indicated and at disease progression
until Week 54 and then every 24 weeks or as clinically indicated.  
Reason for Change 
Section 7.3.2.1 Removal of reference to Image Acquistion Guidelines as not applicable 
for this study.
Original Text 
Contrast agents must be used in accordance with the Image Acquisition Guidelines.
Amended Text 


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Contrast agents must be used in accordance with the Image Acquisition Guidelines.
Reason for Change 
Section 7.3.2.3 updated to follow up for disease progression only, not survival. Efficacy 
assessment update is the same as in Section 7. 
Original Text 
Refer to Section 4.2 Permanent Discontinuation from Study Treatment and Time and 
Events Schedule (Table 9) for follow-up assessment of subjects who are to be followed 
up for disease progression and/or survival after permanently discontinuing from study 
treatment
Efficacy Assessments at Follow-up
All subjects who discontinue study treatment will be followed for survival and any 
subsequent anticancer therapy including start date, stop date, reason for stopping therapy, 
and date of progression, if applicable, every 12 weeks until death or end of study.  
Clinical or radiographic disease progression can be used in survival follow up. 
Amended Text 
Refer to Section 4.2 Permanent Discontinuation from Study Treatment and Time and 
Events Schedule (Table 9) for follow-up assessment of subjects who are to be followed 
up for disease progression and/or survival after permanently discontinuing from study 
treatment for any reasons other than disease progression.
Efficacy Assessments at Follow-upfor subjects who discontinued study 
treatment for reasons other than progression
All subjects who discontinue study treatment will be followed for survival and any 
subsequent anticancer therapy including start date, stop date, reason for stopping therapy, 
and date of progression, if applicable, every 12 weeks until death or end of study. 
Clinical or radiographic disease progression can be used in survival follow up. 
Subjects who discontinue study treatment for reasons other than progression will 
have disease assessments done every 9 weeks until Week 54, then every 24 weeks 
thereafter until unequivocal progression, initiation of new anticancer therapy, death,
withdrawal of consent or end of study (defined in section 10.5).
Reason for Change 


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Section 7.4.3 Removed the language about AE (related to study drug) follow-up after 30 
days. 
Original Text 
SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), study treatment or GSK concomitant 
medication must be recorded from the time a subject consents to participate in the study 
up to and including any follow-up contact.  All SAEs will be reported to GSK within 24 
hours, as indicated in Section 7.4.5.   
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  At any time after 30 days the investigator may report any adverse event that 
they believe possibly related to study treatment.
Amended Text 
SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or study treatment or GSK concomitant 
medication must be recorded from the time a subject consents to participate in the study 
up to and including any follow-up contact.  All SAEs will be reported to GSK within 24 
hours, as indicated in Section 7.4.5.   
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  At any time after 30 days the investigator may report any adverse event that 
they believe possibly related to study treatment.
Reason for Change 
Section 7.6 The analyses will be focused on biomarkers associated with immuno-
modulation
Original Text 
Translational research will be performed on tissue and blood samples collected during the 
course of the trial to evaluate or identify factors or profiles that correlate with measures 
of response to study treatment or response to subsequent anti-cancer treatments. Analyses 
to identify biomarker profiles correlating with other factors or disease characteristics that 
include but are not be limited to breast cancer histological grade and molecular subtype 
may also be performed.
Comparative examination of pre-dosing tumor-derived or blood-derived profiles may 
uncover known or novel candidate biomarkers/profiles that could be used to predict 


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response to study treatment, subsequent anti-cancer treatment, or provide new insights 
into breast cancer or medically related conditions.  Comparative examination of post-
dosing profiles in conjunction with pre-dosing profiles may yield known and novel 
candidate biomarkers/profiles and new insights which relate to the action of study 
treatment.
All samples may be retained for a maximum of 15 years after the last subject completes 
the trial.
Candidate biomarkers, novel biomarkers, profiles, and subsequently discovered 
biomarkers/profiles of biological response associated with breast cancer or medically 
related conditions and/or the action of study treatment may be identified by application 
of:

DNA/gene and protein analysis of tumor tissue

Circulating/systemic biomarkers
o
cytokines and angiogenic factors (CAF) analysis of blood sample
o
peripheral blood mononuclear cells (PBMC) analysis of whole blood
o
Cell-free DNA (cfDNA)

RNA transcriptome analysis of blood and tumor tissue samples

Measurement of the levels of a subset of RNA species on blood and tumor tissue 
samples

Proteome analysis of blood sample and tumor tissue samples
DNA research on tumor tissue or circulating cfDNA may include methods that determine 
the prescence of known mutations in specific genes (e.g., PIK3CA, TP53, and PTEN) or 
approaches that sequence the whole genome or whole exome of tumor-derived DNA. 
RNA research and/or RNA expression research of a subset of RNA species may be 
included as relevant for the study. RNA expression studies may be conducted using 
methods that provide whole transcriptome analysis, quantitative measurement of defined 
RNA species, and/or the application of emerging technologies that can facilitate the 
simultaneous measurement of the abundances of RNA species resulting in a RNA 
expression profile for the blood samples.
Amended Text 
Translational research will be performed on tissue and blood samples collected during the 
course of the trial to evaluate if immune markers are modulated by the treatment.  
These analyses will highlight eventual changes in expression levels and/or presence 
(and localization) of immunological cells/markers in relation to treatment.or identify 


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factors or profiles that correlate with measures of response to study treatment or response 
to subsequent anti-cancer treatments.
Analyses to identify biomarkers or profiles correlating with response, other factors or 
disease characteristics that include but are not be limited to breast cancer histological 
grade and molecular subtype may also be performed if sample numbers allow.
Comparative examination of pre-dosing tumor-derived or blood-derived profiles may 
uncover known or novel candidate biomarkers/profiles that could be used to predict 
response to study treatment , subsequent anti-cancer treatment, or provide new insights 
into breast cancer or medically related conditions.  Comparative examination of post-
dosing profiles in conjunction with pre-dosing profiles may yield known and novel 
candidate biomarkers/profiles and new insights which relate to the action of study 
treatment.
All samples may be retained for a maximum of 15 years after the last subject completes 
the trial.
Candidate biomarkers, novel biomarkers, profiles, and subsequently discovered 
biomarkers/profiles of biological response associated with breast cancer or medically 
related conditions and/or the action of study treatment may be identified by application 
of:

DNA/gene and protein analysis of tumor tissue

Circulating/systemic biomarkers
o
cytokines and angiogenic factors (CAF) analysis of blood sample
o
peripheral blood mononuclear cells (PBMC) analysis of whole blood
o
Cell-free DNA (cfDNA)

RNA transcriptome analysis of blood and tumor tissue samples

Measurement of the levels of a subset of RNA species on blood and tumor tissue 
samples

Proteome analysis of blood sample and tumor tissue samples
DNA research on tumor tissue or circulating cfDNA may include methods that determine 
the prescence of known mutations in specific genes (e.g., PIK3CA, TP53, and PTEN) or 
approaches that sequence the whole genome or whole exome of tumor-derived DNA. 
RNA research and/or RNA expression research of a subset of RNA species may be 
included as relevant for the study. RNA expression studies may be conducted using 
methods that provide whole transcriptome analysis, quantitative measurement of defined 
RNA species, and/or the application of emerging technologies that can facilitate the 


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simultaneous measurement of the abundances of RNA species resulting in a RNA 
expression profile for the blood samples.
Reason for Change 
Section 7.6.1 Tumor biomarker analysis was clarified 
Original Text 
In order to further characterize the subject population, DNA, RNA, and protein 
biomarkers (e.g., tumor/somatic gene mutations, expression of genes and proteins) and/or 
profiles related to breast cancer and the activity of the study treatment will be assessed in 
archival/stored tissue (original diagnosis or a recent biopsy), fresh pre-treatment tumor 
biopsy  and in tumor tissue obtained at disease progression. 
Additional analyses may include the evaluation of histological features to include but are 
not limited to the enumeration of cell type populations such as lymphocytes.
For the archival stored tissue, a formalin-fixed, paraffin-embedded tumor tissue block 
taken at a metastatic site or obtained at the time of original primary cancer diagnosis 
(biopsy or from definitive surgery) is required to be submitted to the central laboratory. 
Alternatively, sites may send 15-20 freshly sectioned, unstained slides containing 5-
micron thick sections. 
Amended Text 
Markers of the immune microenvironment will be analyzed in pre-treatment tumor 
biopsies and in paired tumor tissue obtained at disease progression. These analyses 
will include tumor infiltrating lymphocytes (TILs) and a seleted immune mRNA 
gene expression panel (e.g. Nanostring platform), including mRNA markers for 
specific immune cell populations (e.g. CD8 positive T-cells, B-cells, Tregs). Gene 
expression levels in the disease progression biopsy will be compared to the baseline 
biopsy to assess how the treatments affect the immune response at the level of the 
tumor.
In addition, immunological cells (and protein markers) may be investigated; such 
analyses may include, but are not limited to PD-L1, CD8 protein expression levels as 
determinded by immunohistochemistry, Treg cells, macrophages, and expression of 
additional checkpoint molecules, in the context of tumor and tumor associated 
stroma.
In order to further characterize the subject population, DNA, RNA, and protein 
biomarkers (e.g., tumor/somatic gene mutations, expression of genes and proteins) and/or 
profiles related to breast cancer and the activity of the study treatment will be assessed in 
archival/stored tissue (original diagnosis or a recent biopsy), fresh pre-treatment tumor 
biopsy  and in tumor tissue obtained at disease progression. 


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Additional analyses may include the evaluation of histological features to include but are 
not limited to the enumeration of cell type populations such as lymphocytes.
Reason for Change 
Section 8 Data Management is modified to be consistent with the Novartis Data Management 
process 
Orignial Text 
Data Management will identify and implement the most effective data acquisition and 
management strategy for each clinical trial protocol and deliver datasets which support 
the protocol objectives.
For this study subject data will be entered into the electronic case report forms (eCRFs), 
transmitted electronically to the sponsor (or designee) and be combined with data 
provided from other sources in a validated data system.  The electronic data capture 
system InForm will be used to collect all of the subject information by the investigator.
Management of clinical data will be performed in accordance with applicable standards 
and data cleaning procedures to ensure the integrity of the data, e.g. resolving errors and 


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inconsistencies in the data.  Adverse events and concomitant medications terms will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) and a custom 
drug dictionary.  eCRFs (including queries and audit trails) will be retained by the 
sponsor, and copies will be sent to the investigator to maintain as the investigator copy.  
Amended Text 
Data Management will identify and implement the most effective data acquisition 
and management strategy for each clinical trial protocol and deliver datasets which 
support the protocol objectives.
For this study subject data will be entered into GSK defined electronic case report 
forms (eCRFs), transmitted electronically to GSK or designee and combined with 
data provided from other sources in a validated data system.  The electronic data 
capture system InForm will be used to collect all of the subject information by the 
investigator.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., 
removing errors and inconsistencies in the data.  Adverse events and concomitant 
medications terms will be coded using MedDRA and an internal validated 
medication dictionary, GSKDrug.  eCRFs (including queries and audit trails) will 
be retained by GSK, and copies will be sent to the investigator to maintain as the 
investigator copy.  
In all cases, subject initials will not be collected or transmitted to GSK according to 
GSK policy.
Reason for Change 
Section 9.1 HER2 family, apoptosis, and adenosine triphosphate binding cassette (ABC) 
were removed from the hypothesis
Original Text 
The primary objective of this study is to determine if trastuzumab in combination with 
lapatinib or chemotherapy changes expression of biomarkers associated with HER family 
of receptor and ligands, immunomodulation, apoptosis, and ABC transporters.  The 
primary endpoint will be analyzed by treatment arm with a descriptive intent only.  The 
study is not powered to detect differences between the treatment arms and as such no 
formal treatment arm comparisons will be made.
Amended Text 
The primary objective of this study is to determine if trastuzumab in combination with 
lapatinib or chemotherapy changes expression of biomarkers associated with HER family 
of receptor and ligands, immunomodulation, apoptosis, and ABC transporters.  The 
primary endpoint will be analyzed by treatment arm with a descriptive intent only.  The 
study is not powered to detect differences between the treatment arms and as such no 
formal treatment arm comparisons will be made.


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Reason for Change 
Section 9.2.1 Sample size was removed and added the current number of enrolled 
patients.  
Original Text 
A pre-treatment biopsyand a biopsy at disease progression will provide the samples for 
biomarker analysis.  
A multigene platform such as Nanostring, microarray, or RNA-seq may be utilized to 
assess gene expression changes. Subsets of genes of interest have been a priori defined 
and changes from baseline of these genes will be assessed. To address the issue of 
multiple comparisons, metagene analysis, false discovery rate (FDR) or other adjustments 
will be implemented within each group of genes, as appropriate.
Sample size requirements for detection of global on-treatment changes in biomarker 
expression in a multigene platform such as a microarray require many assumptions about 
structure of the data. Table 14 shows sample size calculations using the approach of Shao 
and Tseng [Shao, 2007]. This approach assumes 10,000 hypothesis tests with a range of 
m true positive changes, an effect size=1 (δ=1, based on log2 expression, reflecting a 2 
fold change in gene expression), 5% FDR, and detection of 80% of true positives with 
80% probability. In addition, a general correlation of 0.1 among all genes is assumed, and 
a range of possible block-wise correlations in null and alternative genes, as indicated in 
Table 14 is considered.
Table 17
Sample size estimates for a range of data structures
Number true positives (m)
Correlation
20
200
1000
0.2
48
37
28
0.5
49
38
30
0.8
51
40
31
Based on this assessment, a 1:1 randomization scheme for HER2-enriched cohort and 
enrolment into treatment arm C for Non-HER2-enriched cohort will be used with 
approximately 225 subjects to achieve 50 evaluable subjects in each arm. This sample 
size ensures adequate power for global on-treatment changes in biomarker expression as 
well as for individual genes, metagenes, or specific subsets of genes of interest. For 
individual genes or metagenes, the probability of detecting  statistically significant gene 
expression differences between pre-treatment and progression samples, with an effect 
size of 1 and α=0.05, and a sample size of 50, is >95%. Adjustments for multiple 
comparisons will be made for groups of individual genes, pre specified in the analysis 


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plan. For example, HER family of receptors and ligands may form a group of genes, with 
a total of 15 genes in the group (HER Receptors: EGFR, HER2, HER3, HER4; HER 
Ligands: AR, BTC, EGF, EPGN, EPR, HBEGF, TGFα, NRG1, NRG2, NRG3, and 
NRG4). In this example, a total of 15 genes would be assessed for on treatment changes 
in expression, with each comparison having power of >95% (α=0.05, δ=1). In order to 
adjust for multiple comparisons, FDR at a level of 0.05 would be recommended. Smaller 
prespecified groups of genes (5 genes or less) may be adjusted using the Bonferroni 
adjustment.
This sample size will also allow for a sufficient number of subjects to estimate a key 
secondary endpoint, PFS on next line anti-cancer therapy (PFS-NL). Based on 
EGF104900, approximately 70% of subjects are expected to continue on next line anti-
cancer therapy, thus data from approximately 35 subjects per arm may be available for 
PFS-NL. 
Amended Text 
This is a purely descriptive study. Due to difficulty in enrolling subjects into this 
trial, future enrolment will be halted and the study will be terminated early. Up to 
31 Jul 2016, 29 patients have been enrolled.
A pre-treatment biopsy and a biopsy at disease progression will provide the samples for 
biomarker analysis.  
A multigene platform such as Nanostring, microarray, or RNA-seq may be utilized to 
assess gene expression changes. Subsets of genes of interest have been a priori defined 
and changes from baseline of these genes will be assessed. To address the issue of 
multiple comparisons, metagene analysis, false discovery rate (FDR) or other adjustments 
will be implemented within each group of genes, as appropriate.
Sample size requirements for detection of global on-treatment changes in biomarker 
expression in a multigene platform such as a microarray require many assumptions about 
structure of the data. Table 13 shows sample size calculations using the approach of Shao 
and Tseng [Shao, 2007]. This approach assumes 10,000 hypothesis tests with a range of 
m true positive changes, an effect size=1 (δ=1, based on log2 expression, reflecting a 2 
fold change in gene expression), 5% FDR, and detection of 80% of true positives with 
80% probability. In addition, a general correlation of 0.1 among all genes is assumed, and 
a range of possible block-wise correlations in null and alternative genes, as indicated in 
Table 13 is considered.


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Table 18
Sample size estimates for a range of data structures
Number true positives (m)
Correlation
20
200
1000
0.2
48
37
28
0.5
49
38
30
0.8
51
40
31
Based on this assessment, a 1:1 randomization scheme for HER2-enriched cohort and 
enrolment into treatment arm C for Non-HER2-enriched cohort will be used with 
approximately 225 subjects to achieve 50 evaluable subjects in each arm. This sample 
size ensures adequate power for global on-treatment changes in biomarker expression as 
well as for individual genes, metagenes, or specific subsets of genes of interest. For 
individual genes or metagenes, the probability of detecting  statistically significant gene 
expression differences between pre-treatment and progression samples, with an effect 
size of 1 and α=0.05, and a sample size of 50, is >95%. Adjustments for multiple 
comparisons will be made for groups of individual genes, pre specified in the analysis 
plan. For example, HER family of receptors and ligands may form a group of genes, with 
a total of 15 genes in the group (HER Receptors: EGFR, HER2, HER3, HER4; HER 
Ligands: AR, BTC, EGF, EPGN, EPR, HBEGF, TGFα, NRG1, NRG2, NRG3, and 
NRG4). In this example, a total of 15 genes would be assessed for on treatment changes 
in expression, with each comparison having power of >95% (α=0.05, δ=1). In order to 
adjust for multiple comparisons, FDR at a level of 0.05 would be recommended. Smaller 
prespecified groups of genes (5 genes or less) may be adjusted using the Bonferroni 
adjustment.
This sample size will also allow for a sufficient number of subjects to estimate a key 
secondary endpoint, PFS on next line anti-cancer therapy (PFS-NL). Based on 
EGF104900, approximately 70% of subjects are expected to continue on next line anti-
cancer therapy, thus data from approximately 35 subjects per arm may be available for 
PFS-NL. 
Reason for Change 
Section 9.2.2 Sample size sensitivity whole section was removed and changed to “not 
applicable” due to low enrollment and the early termination of the study 
Original Text 
Table 14 lists sample size estimations using the data structure, effect size, and FDR rate, 
as described in Shao and Tseng [Shao, 2007]. If the effect size is larger than expected, the 
sample size estimates will increase accordingly. On the log2 scale, an effect size of 1 
corresponds to a 2-fold change in gene expression with a standard deviation of 1.0, or a 
4-fold change in gene expression with a standard deviation of 2.0, etc. An effect size of 
0.8 corresponds to a 2-fold change with a standard deviation of 1.25, or a 3-fold change 


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with a standard deviation of 2. Similarly, if FDR criteria are relaxed, sample size 
estimates will decrease. Table 14 examines the impact of a smaller effect size and a larger 
FDR on sample size estimates, using the correlation structure described in Section 9.2.1
TTable 19
Sample size estimates for a range of data structures
Number true positives (m)
FDR
Effect Size
Correlation
20
200
1000
0.05
1.0
0.2
48
37
28
0.05
1.0
0.5
49
38
30
0.05
1.0
0.8
51
40
31
0.10
1.0
0.2
46
34
25
0.10
1.0
0.5
49
36
27
0.10
1.0
0.8
51
39
30
0.05
0.8
0.2
78
58
44
0.05
0.8
0.5
83
63
49
0.05
0.8
0.8
88
68
53
0.10
0.8
0.2
72
52
38
0.10
0.8
0.5
77
57
42
0.10
0.8
0.8
81
61
46
For individual genes or metagenes, the probability of detecting a statistically significant 
on treatment difference, with an effect size of 0.8 and α=0.05, and a sample size of 50, is 
>95%. 
Amended Text 
Not applicable
Table 14 lists sample size estimations using the data structure, effect size, and FDR rate, 
as described in Shao and Tseng [Shao, 2007]. If the effect size is larger than expected, the 
sample size estimates will increase accordingly. On the log2 scale, an effect size of 1 
corresponds to a 2-fold change in gene expression with a standard deviation of 1.0, or a
4-fold change in gene expression with a standard deviation of 2.0, etc. An effect size of 
0.8 corresponds to a 2-fold change with a standard deviation of 1.25, or a 3-fold change 
with a standard deviation of 2. Similarly, if FDR criteria are relaxed, sample size 
estimates will decrease. Table 14 examines the impact of a smaller effect size and a larger 
FDR on sample size estimates, using the correlation structure described in Section 9.2.1


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Table 20
Sample size estimates for a range of data structures
Number true positives (m)
FDR
Effect Size
Correlation
20
200
1000
0.05
1.0
0.2
48
37
28
0.05
1.0
0.5
49
38
30
0.05
1.0
0.8
51
40
31
0.10
1.0
0.2
46
34
25
0.10
1.0
0.5
49
36
27
0.10
1.0
0.8
51
39
30
0.05
0.8
0.2
78
58
44
0.05
0.8
0.5
83
63
49
0.05
0.8
0.8
88
68
53
0.10
0.8
0.2
72
52
38
0.10
0.8
0.5
77
57
42
0.10
0.8
0.8
81
61
46
For individual genes or metagenes, the probability of detecting a statistically significant 
on treatment difference, with an effect size of 0.8 and α=0.05, and a sample size of 50, is 
>95%. 
Reason for Change 
Section 9.3.3.1 The primary objective is updated to describe the change in biomarkers 
related to the specified mechanisms in the pre-treatment biopsy and the progression 
biopsy with each arm.  The data cut-off for the primary analysis will be defined at 12 
months after the last subject was enrolled in the study or after the last subject
progressed/withdrew, whichever is earlier. End of Study was re-defined. 
Original Text 
The primary objective will be achieved through a test of the hypothesis (see Section 9.1) 
evaluating the change in biomarkers related to the specified mechanisms in the pre-
treatment biopsy and the progression biopsy with each arm.  

The primary analysis of changes in biomarker expressions and evaluation of PFS 
and PFS-NL will be performed approximately 12 months after the last subject is 
randomized.  This will allow for exploring the association between on-treatment 


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changes in biomarkers and PFS-NL.  Other secondary endpoints will also be 
reported to compliment the primary analysis.  The second and final analysis for 
OS will be performed at the time when

75% of the subjects have died

100% of  subjects have completed study treatment;

all subjects who go onto first next line therapy have completed first next line 
therapy.
Details on the handling of missing data are provided in Section 9.3.5
Amended Text
The primary objective will be achieved by describing the change in biomarkers 
related to the specified mechanisms in the pre-treatment biopsy and the progression 
biopsy with each arm.  
The primary objective will be achieved through a test of the hypothesis (see Section 9.1) 
evaluating the change in biomarkers related to the specified mechanisms in the pre-
treatment biopsy and the progression biopsy with each arm.  
The data cut-off for the primary analysis will be defined at 12 months after the last 
subject enrolled in the study or the last subject progressed/withdrew, whichever is 
earlier. Following the cut-off date for the primary analysis, the study will remain 
open. Ongoing subjects will continue to receive study treatment and be followed as 
per the schedule of assessments, as long as subjects derive benefit from lapatinib. 
The end of study defined as the earliest occurrence of one of the following:
•
All patients have died or discontinued from the study
•
Another clinical study becomes available that can continue to provide 
lapatinib in this patient population and all subjects ongoing are eligible to be 
transferred to that clinical study 
•
At the end of the study, every effort will be made to continue provision of 
study treatment outside this study through an alternative setting to subjects 
who in the opinion of the Investigator are still deriving clinical benefit. The 
primary analysis of changes in biomarker expressions and evaluation of PFS and 
PFS-NL will be performed approximately 12 months after the last subject is 
randomized.  This will allow for exploring the association between on-treatment 
changes in biomarkers and PFS-NL.  Other secondary endpoints will also be 
reported to compliment the primary analysis.  The second and final analysis for 
OS will be performed at the time when

75% of the subjects have died

100% of  subjects have completed study treatment;

all subjects who go onto first next line therapy have completed first next line therapy.
Section 9.3.5.


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Reason for Change 
Section 9.3.5 No adjustments for multiple comparisons will be made as there is no formal 
hypothesis testing.  Removed the sentence for the analysis of OS regarding the last date 
of known contact 
Original Text 
For the analysis of OS, the last date of known contact will be used for those subjects who 
have not died at the time of analysis; such subjects will be considered censored.
For the analysis of PFS, if the subject received subsequent anticancer therapy prior to the 
date of documented progression or death, PFS will be censored at the last adequate 
assessment (e.g., assessment where visit level response is CR, PR, or SD) prior to the 
initiation of therapy.  Otherwise, if the subject does not have a documented date of 
progression or death, PFS will be censored at the date of the last adequate assessment.  
Further details on rules for censoring will be provided in the RAP. 
Details on the determination of tumor response are given in Section 7.3.4.
For the primary objective, adjustments for multiple comparisons will be as described in 
Section 9.2.1.  
Amended Text 
For the analysis of OS, the last date of known contact will be used for those subjects who 
have not died at the time of analysis; such subjects will be considered censored.
For the analysis of PFS during  study treatment period, if the subject received 
subsequent anticancer therapy prior to the date of documented progression or death, PFS 
will be censored at the last adequate assessment (e.g., assessment where visit level 
response is CR, PR, or SD) prior to the initiation of therapy.  Otherwise, if the subject 
does not have a documented date of progression or death, PFS will be censored at the 
date of the last adequate assessment.  Further details on rules for censoring will be 
provided in the RAP. 
Details on the determination of tumor response are given in Section 7.3.4.
No adjustments for multiple comparisons will be made as there is no formal 
hypothesis testing.  
For the primary objective, adjustments for multiple comparisons will be as described in 
Section 9.2.1.  
Reason for Change 


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Section 9.3.5.1.1 The primary biomarker endpoint was updated to be the change in 
expression/percent presence levels of biomarkers as measured in tissue from the 
progression tumor biopsy, compared with expression/percent presence levels of these 
markers as measured in the screening tumor biopsy.  Marker levels may be derived from 
measurements of mRNA or protein from biopsy samples or changes in blood-derived 
biomarkers.
Original Text 
The primary biomarker endpoint is change in expression levels of biomarkers as 
measured in tissue from the progression tumor biopsy, compared with expression levels 
of these markers as measured in the screening tumor biopsy.  Marker levels may be 
derived from measurements of mRNA or protein from biopsy samples or changes in 
blood-derived biomarkers.
The primary endpoint of changes in biomarker expression will be analyzed using paired 
t-tests or related nonparametric approaches, or paired analysis of metagenes, as 
appropriate. This will be done within each treatment arm. This analysis will be done 
using the Evaluable Population, which will consist of all subjects who were assigned to 
study treatment and have both baseline and progression biopsies available.  Further 
details will be described in the RAP.
Amended Text 
The primary biomarker endpoint is change in expression/percent presence levels of 
biomarkers as measured in tissue from the progression tumor biopsy, compared 
with expression/percent presence levels of these markers as measured in the 
screening tumor biopsy.  Marker levels may be derived from measurements of 
mRNA or protein from biopsy samples.
The primary biomarker endpoint is change in expression levels of biomarkers as 
measured in tissue from the progression tumor biopsy, compared with expression levels 
of these markers as measured in the screening tumor biopsy.  Marker levels may be 
derived from measurements of mRNA or protein from biopsy samples or changes in 
blood-derived biomarkers.
The primary endpoint of changes in biomarker expression will be presented for 
each treatment arm for the evaluable population. Due to limited number of subjects 
enrolled as well as limited number of subjects with baseline biopsy and biopsy at 
disease progression, no statistical analyses will be performed. 
The primary endpoint of changes in biomarker expression will be analyzed using paired 
t-tests or related nonparametric approaches, or paired analysis of metagenes, as 
appropriate. This will be done within each treatment arm. This analysis will be done 
using the Evaluable Population, which will consist of all subjects who were assigned to 
study treatment and have both baseline and progression biopsies available. Further 
details will be described in the RAP.


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Reason for Change 
Section 9.3.5.1.2 Overall Survival, Progression Free Survival on new anticancer 
treatment, association between progression changes in biomarkers and PFS on next line 
of anticancer treatment were removed 
Original Text
Overall survival is defined as the time from randomization until death due to any cause.  
For subjects who do not die, time of death will be censored at the date of last contact.  
This analysis will be done using the ITT population.  
Overall survival will be summarized using Kaplan-Meier curves.  The Pike estimator 
[Berry, 1991] of the treatment HR based on the log-rank test along with 95% CIs will be 
provided.  In addition, for each treatment group, the Kaplan-Meier estimates for the 
median OS time and the first and third quartiles will be presented along with approximate 
95% CIs.
These analyses will be done on the ITT population.
Amended Text 
Overall Survival
Overall survival is defined as the time from randomization until death due to any cause.  
For subjects who do not die, time of death will be censored at the date of last contact.  
This analysis will be done using the ITT population.  
Overall survival will be summarized using Kaplan-Meier curves.  The Pike estimator 
[Berry, 1991] of the treatment HR based on the log-rank test along with 95% CIs will be 
provided.  In addition, for each treatment group, the Kaplan-Meier estimates for the 
median OS time and the first and third quartiles will be presented along with approximate 
95% CIs.
These analyses will be done on the ITT population.
Reason for Change 
Section 9.3.5.5 PRO and HRQOL were removed 
Original Text 
The objective of collecting PRO and HRQOL data is to describe the PRO and HRQOL of 
trastuzumab in combination with lapatinib and of trastuzumab in combination with 
chemotherapy. It has been found in some studies that chemotherapies have significant 
detrimental impact on cancer patients. For example, in Hwang et al (2013) [Hwang,2013] 
study on adjuvant breast cancer patients, they found that breast cancer patients who 
underwent adjuvant chemotherapy experienced significantly worse quality of life than 
those who did not receive chemotherapy. It is valuable to understand whether 
chemotherapy has impact on PRO and HRQOL in the metastatic setting, and also what 


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adverse events associated with chemotherapy contribute to the changes of PRO and 
HRQOL. PRO and HRQOL data will be collected using FACT-B and Multidimensional 
Assessment of Fatigue (MAF) scales. These data will be collected at baseline, week 3, 
week 6, week 12, and discontinuation/end of the study. Further details on PRO and 
HRQOL analyses will be addressed in the RAP.
Amended Text 
The objective of collecting PRO and HRQOL data is to describe the PRO and HRQOL of 
trastuzumab in combination with lapatinib and of trastuzumab in combination with 
chemotherapy. It has been found in some studies that chemotherapies have significant 
detrimental impact on cancer patients. For example, in Hwang et al (2013) [Hwang,2013] 
study on adjuvant breast cancer patients, they found that breast cancer patients who 
underwent adjuvant chemotherapy experienced significantly worse quality of life than 
those who did not receive chemotherapy. It is valuable to understand whether 
chemotherapy has impact on PRO and HRQOL in the metastatic setting, and also what 
adverse events associated with chemotherapy contribute to the changes of PRO and 
HRQOL. PRO and HRQOL data will be collected using FACT-B and Multidimensional 
Assessment of Fatigue (MAF) scales. These data will be collected at baseline, week 3, 
week 6, week 12, and discontinuation/end of the study. Further details on PRO and 
HRQOL analyses will be addressed in the RAP.
Reason for Change 
Section 10.5 End of study assessment and follow up were re-fined for the purpose of site 
closure per section 7.  
Original Text 
The study will end when all criteria below are met:

75% of the subjects have died

100% of  subjects have completed study treatment;

all subjects who go onto first next line therapy have completed first next line 
therapy.
Amended Text 
The study will end when all subjects have completed the study, i.e. presented with 
disease progression, started new anti-cancer therapy, died or withdrew from the 
study (whichever came first) during the study treatment period or the follow-up 
period after discontinuation due to any reasons in the absence of other than disease 
progression. when all criteria below are met:


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All subjects will receive study treatment until disease progression, death, 
unacceptable toxicity, subject withdrawal of consent or any other reasons 
mentioned in section 4.2.1.  
In case of disease progression during the treatment period, the subject will be 
followed-up for 30 days for safety evaluation and no further study-specific follow-up 
will be carried out; the subject will be considered as having completed the study. 
Similarly, in case of disease progression after the treatment period (i.e. in subjects 
who discontinued for any reasons other than disease progression) and before the 
end of the study, no further study-specific follow-up will be carried out; the subject 
will be considered as having completed the study. 
In case of study treatment discontinuation for any reasons other than disease 
progression, the subjects will be followed-up for safety and efficacy assessments 
(disease assessments done every 9 weeks until Week 54, then every 24 weeks) until 
disease progression, new anticancer therapy, death, withdrawal of consent or end of 
study, whichever comes first. 
75% of the subjects have died Following the cut-off date for the primary analysis 
(defined at 12 months after the last subject enrolled in the study or the last subject 
progressed/withdrew, whichever is earlier), the study will remain open. Ongoing 
subjects will continue to receive study treatment and be followed as per the schedule 
of assessments, as long as subjects derive benefit from lapatinib. The end of study 
defined as the earliest occurrence of one of the following:
•
All patients have died or discontinued from the study
•
Another clinical study becomes available that can continue to provide
lapatinib in this patient population and all subjects ongoing are eligible to be 
transferred to that clinical study 
•
At the end of the study, every effort will be made to continue provision of 
study treatment outside this study through an alternative setting to subjects 
who in the opinion of the Investigator are still deriving clinical benefit.
100% of  subjects have completed study treatment;
All subjects who go onto first next line therapy have completed first next line therapy.
Reason for Change 
 
 
Reason for Change 
Section 12.4. Appendix 4:  Liver Chemistry Monitoring, Interruption Stopping and 
Follow-up Criteria was updated to remove GSK 


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Original Text 
•Instruct subject to stop investigational product (IP)
•Notify GSK and arrange clinical follow -up within 24h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Report as an SAE (excl. hepatic impairment or cirrhosis 
studies) and complete liver event CRF, SAE data 
collection tool, and liver imaging and/or biopsy CRFs if 
tests performed.
•Obtain twice weekly liver chemistries until resolved, 
stabilised or returned to baseline values
•Consultation with hepatologist/specialist recommended
•Withdraw subject from study after monitoring 
complete or from study treatment for protocols with 
survival follow up unless protocol has an option to 
restart drug 
ALT>3xULN
plus Bilirubin>2xULN 
(>35% direct) (or plus
INR>1.5, if measured)*
No
Yes
Yes
•Instruct subject to stop investigational product (IP)
•Notify GSK within 24h and arrange clinical follow -up 
within 24-72h
•Perform liver chemistries  and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Complete liver event CRF, SAE data collection tool if 
appropriate, and liver imaging and/or biopsy CRFs if 
these tests performed.
•Obtain weekly liver chemistries [**as far as possible for 
these subjects] until resolved, stabilized or returned to 
baseline 
•Withdraw subject from study after monitoring 
complete or from study treatment for protocols with 
survival follow up unless protocol has an option to 
restart drug
ALT>5xULN
Hepatitis 
symptoms
or rash?
No
Able to monitor 
weekly  for 4 wks?                      
No
Notify GSK within 24h to discuss 
subject safety; continue IP;
check liver chemistry weekly for 4 
weeks
No
No**
Yes
Yes
Continue IP
Obtain twice monthly liver 
chemistries until normalised 
or back to baseline values
Yes
Yes
ALT>3xULN and 
bilirubin >2xULN? 
Yes
*INR value not applicable to subjects on anticoagulants
Yes


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Amended Text 
Reason for Change 
Section 12.5 Appendix 5 Figure 2 and Figure 3 were updated to remove GSK 
Original Text 


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Amended Text 


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Reason for Change 
List of references was updated to reflect changes in the references in the protocol. 
Added References 
Bianchini G, Pienkowski T, Im YH, et al (2016) Residual disease after HER2-
directed therapies in the neosphere study: Modulation of tumor lymphocyte 
infiltration (TIL) and prognosis. J Clin Oncol 34 (suppl; abstr 517).
Denkert C, Loibl S, Noske A, et al (2010) Tumor-associated lymphocytes as an 
independent predictor of response to neoadjuvant chemotherapy in breast cancer. J 
Clin Oncol.;28(1):105-13. 
Denkert C, von Minckwitz G, Brase JC, et al (2015) Tumor-infiltrating lymphocytes 
and response to neoadjuvant chemotherapy with or without carboplatin in human 
epidermal growth factor receptor 2-positive and triple-negative primary breast 
cancers. J Clin Oncol.;33(9):983-91.


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Dieci MV, Bisagni G, Cagossi K, et al (2015) Tumor infiltrating lymphocytes and 
correlation with outcome in the Cher-LOB study. Cancer Res (9 Supplement) 
SABCS14-PD1-1, 1538-7445.
Hannesdóttir L, Tymoszuk P, Parajuli N, et al (2013) Lapatinib and doxorubicin 
enhance the Stat1-dependent antitumor immune response. Eur J 
Immunol.;43(10):2718-29. Ignatiadis M, et al. J Clin Oncol. 2012 Jun 1;30(16):1996-
2004
Issa-Nummer Y, Darb-Esfahani S, Loibl S, et al (2013) Prospective validation of 
immunological infiltrate for prediction of response to neoadjuvant chemotherapy in 
HER2-negative breast cancer--a substudy of the neoadjuvant GeparQuinto trial. 
PLoS One.;8(12):e79775. Laoui D, et al. Eur. J. Immunol. 2013. 43: 2538–2542
Loi S, Sirtaine N, Piette F, et al. (2013) Prognostic and predictive value of tumor-
infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in 
node-positive breast cancer comparing the addition of docetaxel to doxorubicin with 
doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol.;31(7):860-7. 
Loi S, Michiels S, Salgado R, Sirtaine N, Jose V, Fumagalli D, Kellokumpu-
Lehtinen PL, Bono P, Kataja V, Desmedt C, Piccart MJ, Loibl S, Denkert C, Smyth 
MJ, Joensuu H, Sotiriou C (2014) Tumor infiltrating lymphocytes are prognostic in 
triple negative breast cancer and predictive for trastuzumab benefit in early breast 
cancer: results from the FinHER trial. Ann Oncol. 2014 Aug;25(8):1544-50. 
Sobottka B, Pestalozzi B, Fink D, et al (2016) Similar lymphocytic infiltration 
pattern in primary breast cancer and their corresponding distant metastases. 
Oncoimmunology. 5;5(6):e1153208. 
Urruticoechea A, Rizwanullah M, Im SA, et al (2016) PHEREXA: A phase III study 
of trastuzumab (H) + capecitabine (X) ± pertuzumab (P) for patients (pts) who 
progressed during/after one line of H-based therapy in the HER2-positive metastatic 
breast cancer (MBC) setting. J Clin Oncol 34, 2016 (suppl; abstr 504)
Updated References
Lapatinib Summary of Product Characteristics. Glaxo Group Ltd, UK.  06 May 2013. 
Novartis Europharm Limited, UK. 11 August 2015.
TYKERB TYVERB (lapatinib) Product Information. June, 2013. Package Leaflet. 
Novartis Europharm Limited, UK. 11 August 2015.
Deleted References 
Hanker LC, Rody A, Holtrich U, Pusztai L, et al. Prognostic evaluation of the B cell/IL-8 
metagene in different intrinsic breast cancer subtypes. Breast Cancer Res Treat. 2013; 
137(2): 407-16.Huehn J, Plansky J, Hamann A. Epigenetic control of FOXP3 expression: 
the key to a stable regulatory T-cell lineage. Nat Rev Immunol. 2009; 9: 83-9.


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Kroemer G, Galluzzi L, Kepp O, Zitvogel L, et al. Immunogenic cell death in cancer 
therapy. Annu Rev Immunol. 2013; 31: 51-72.
Melero I, Grimaldi AM, Perez-Gracia JL, Ascierto PA.  Clinical development of 
immunostimulatory monoclonal antibodies and opportunities for combination.  Clin 
Cancer Res. 2013; 19(5):  997-1008.
Nagalla S, Chou J, Willingham M,  et al. Interactions between immunity, proliferation 
and molecular subtype in breast cancer prognosis. Genome Biol. 2013; 14(4): R34.
O’Connor R. A review of mechanisms of circumvention and modulation of 
chemotherapeutic drug resistance. Curr Cancer Drug Targets. 2009; 9(3): 273-80.
Rody A, Holtrich U, Pusztai L, Liedtke C. T-cell metagene predicts a favorable prognosis 
in estrogen receptor-negative and HER2-positive breast cancers. Breast Cancer Res. 
2009; 11(2): R15.
Shao Y, Tseng C-H. Sample size calculation with dependence adjustment for FDR-
control in microarray studies. Stat Med. 2007; 26: 4219-37.
Vesely MD, Kershaw MH, Schreiber RD, Smyth MJ. Natural innate and adaptive 
immunity to cancer. Annu Rev Immunol. 2011; 29: 235-71.


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12.10.3.
Protocol Amendment 3
Due to the sponsorship transfer from GSK to Novartis, references to GSK and GSK roles
have been replaced with Novartis and Novartis roles. Additionally, administrative 
changes have been made to align with Novartis processes and procedures.
Reason for Change:
Front page and the following page have been updated to comply with the Novartis 
protocol template
Original Text:
TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
An Open-Label, Phase II, Study to Evaluate Biomarkers 
Associated with Response to Subsequent Therapies in Subjects
with HER2-Positive Metastatic Breast Cancer Receiving 
Treatment with Trastuzumab in Combination with Lapatinib or 
Chemotherapy (EGF117165)
Compound Number:
GW572016
Development Phase
II
Effective Date:
23-MAR-2017 (final)
Copyright 2014 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
Amended Text: 


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Clinical Development
GW572016                                  
Protocol EGF114299     
An Open-Label, Phase II, Study to Evaluate Biomarkers 
Associated with Response to Subsequent Therapies in 
Subjects with HER2-Positive Metastatic Breast Cancer 
Receiving Treatment with Trastuzumab in Combination 
with Lapatinib or Chemotherapy                      
Authors
 
Document type
Amended Protocol Version (Clean)
EUDRACT number
2014-001220-30
Version number
03
Development phase
Phase II
Document status
Final
Release date
15-May-2017
Novartis internal 
reference number
CLAP016A2206
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Amendment 3 
Amendment rationale
Subsequent to the acquisition of GlaxoSmithKline (GSK) compound GW572016, the 
purpose of this protocol Amendment 3 is to:
–
Delete or replace references to GlaxoSmithKline or its staff with that of 
Novartis and its authorized agents to align with the change of sponsorship;
–
Make administrative changes to align with Novartis processes and 
procedures;
As of May 2017:
42 patients have received study treatment in five countries; 
34 patients have completed or discontinued study treatment.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities (HAs).
The changes herein affect the Informed Consent and all sites are required to update 
and submit for approval, a revised Informed Consent that takes into account the 
change of study sponsorship described in the protocol amendment.
Upon approval of this amendment, patients who have already been enrolled in the 
study will sign a new informed consent form indicating Novartis is the new study 
sponsor and continue the appropriate visit schedule.
TITLE PAGE
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
An Open-Label, Phase II, Study to Evaluate Biomarkers 
Associated with Response to Subsequent Therapies in Subjects 
with HER2-Positive Metastatic Breast Cancer Receiving 
Treatment with Trastuzumab in Combination with Lapatinib or 
Chemotherapy (EGF117165)
Compound Number:
GW572016


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Development Phase
II
Effective Date:
23-MAR-2017 (final)
Copyright 2014 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
Reason for Change:
Enrolment was halted and the text in the description section has been updated to past 
tense. Authors are included on front page and have therefore been deleted in this section.
Original Text:
Description:  This is a multicenter, open-label, Phase II study in subjects with HER2-
positive metastatic breast cancer who received at least 2 prior lines of anti-HER2-targeted 
therapies of which at least one included a trastuzumab-containing regimen.  Eligible 
subjects will have confirmed HER2-positive and hormonal status from a biopsy taken at 
screening (pre-treatment biopsy).
Subjects will have consented to a subsequent biopsy 
at disease progression.  Subjects will be assigned to one of two cohorts based on the
molecular subtype of the pre-treatment biopsy by Prosigna.  Eligible subjects with a 
HER2-enriched molecular subtype will be randomized in a 1:1 ratio to 1 of 2 treatment 
arms: trastuzumab in combination with lapatinib (trastuzumab loading dose of 8 mg/kg 
followed by 6-mg/kg infusions every 3 weeks (q3weekly) and 1000 mg of lapatinib once 
daily) or trastuzumab in combination with chemotherapy of the investigator’s choice 
(trastuzumab loading dose of 8 mg/kg followed by 6-mg/kg q3weekly infusions and 
chemotherapy as decided by investigator).  Eligible subjects with breast cancer 
classified as a molecular subtype complementary to the HER2-enriched referred to as 
Non-HER2-enriched (i.e., luminal A, luminal B or basal-like) will be enrolled into an 
additional arm treated with trastuzumab in combination with lapatinib (trastuzumab 
loading dose of 8 mg/kg followed by 6-mg/kg infusions every 3 weeks (q3weekly) and 
1000 mg of lapatinib once daily).
Subjects with hormone receptor positive breast cancer 
assigned to receive treatment with lapatinib and trastuzumab will be required to receive 
concomitant endocrine therapy with an aromatase inhibitor of the investigator’s choice.  
Subjects with hormone receptor-positive disease assigned to the treatment arm of 
trastuzumab in combination with chemotherapy may receive concomitant endocrine 
therapy with an aromatase inhibitor, of the investigator’s choice and at the discretion of 
the investigator.  All subjects will receive study treatment until disease progression, 
death, unacceptable toxicity, subject withdrawal or any other reasons mentioned in 
section 4.2.1.  The primary endpoint is to evaluate the changes in the expression of 
biomarkers associated with immunomodulation between the progression biopsy and the 
pre-treatment biopsy within each arm.  Secondary efficacy endpoints include overall 
response rate; clinical benefit rate; and progression-free survival (PFS) on treatment; as 
well as safety/tolerability. Due to difficulty in enrolling subjects, enrollment will be 


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halted and the study will be terminated early. No formal comparisons between treatment
arms will be undertaken.
Subject: lapatinib, HER2-overexpressing metastatic breast cancer, trastuzumab, ErbB2, 
HER2, biomarker, PAM50, HER2-enriched, Prosigna
Author(s):  
 
Amended text: 
Description:  This is a multicenter, open-label, Phase II study in subjects with HER2-
positive metastatic breast cancer who received at least 2 prior lines of anti-HER2-targeted 
therapies of which at least one included a trastuzumab-containing regimen.  Eligible 
subjects will have confirmed HER2-positive and hormonal status from a biopsy taken at 
screening (pre-treatment biopsy).
Subjects will have consented to a subsequent biopsy 
at disease progression.  Subjects will be assigned to one of two cohorts based on the
molecular subtype of the pre-treatment biopsy by Prosigna.  Eligible subjects with a 
HER2-enriched molecular subtype will be randomized in a 1:1 ratio to 1 of 2 treatment 
arms: trastuzumab in combination with lapatinib (trastuzumab loading dose of 8 mg/kg 
followed by 6-mg/kg infusions every 3 weeks (q3weekly) and 1000 mg of lapatinib once 
daily) or trastuzumab in combination with chemotherapy of the investigator’s choice 
(trastuzumab loading dose of 8 mg/kg followed by 6-mg/kg q3weekly infusions and 
chemotherapy as decided by investigator).  Eligible subjects with breast cancer 
classified as a molecular subtype complementary to the HER2-enriched referred to as 
Non-HER2-enriched (i.e., luminal A, luminal B or basal-like) will be enrolled into an 
additional arm treated with trastuzumab in combination with lapatinib (trastuzumab 
loading dose of 8 mg/kg followed by 6-mg/kg infusions every 3 weeks (q3weekly) and 
1000 mg of lapatinib once daily).
Subjects with hormone receptor positive breast cancer 
assigned to receive treatment with lapatinib and trastuzumab will be required to receive 
concomitant endocrine therapy with an aromatase inhibitor of the investigator’s choice.  
Subjects with hormone receptor-positive disease assigned to the treatment arm of 
trastuzumab in combination with chemotherapy may receive concomitant endocrine 
therapy with an aromatase inhibitor, of the investigator’s choice and at the discretion of 
the investigator.  All subjects will receive study treatment until disease progression, 
death, unacceptable toxicity, subject withdrawal or any other reasons mentioned in 
section 4.2.1.  The primary endpoint is to evaluate the changes in the expression of 
biomarkers associated with immunomodulation between the progression biopsy and the 
pre-treatment biopsy within each arm.  Secondary efficacy endpoints include overall 
response rate; clinical benefit rate; and progression-free survival (PFS) on treatment; as 
well as safety/tolerability. Due to difficulty in enrolling subjects, enrolment was will be
halted and the study will be terminated early. No formal comparisons between treatment
arms will be undertaken.
Subject: lapatinib, HER2-overexpressing metastatic breast cancer, trastuzumab, ErbB2, 
HER2, biomarker, PAM50, HER2-enriched, Prosigna


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Author(s):  
 
Reason for Change:
Description of protocol amendment number 3 has been added to Revision Chronology
section
Original Text:
N/A
Amended Text: 
2013N170247_03
15-May-2017
Amendment 
No. 
03: 
Global 
amendment:
Delete or replace references to GSK 
or 
its 
staff 
with 
that 
of 
Novartis/Novartis and its authorized 
agents.
Make administrative changes to 
align with Novartis processes and 
procedures.
Reason for Change:
Sponsor signature page has been updated to comply with the Novartis protocol template.
Original Text:
Signature:
Dr.
Novartis Pharma AG
Postfach
4002 Basel
Switzerland
Telephone:
Date


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Amended Text: 
Sponsor Signatory:
Signature
Date
Dr.
Signature:
Dr.
Postfach
4002 Basel
Switzerland
Telephone: 
Date
Reason for Change:
Sponsor contact information has been updated to Novartis contact information and the
IND number for the study has been added.  
Original Text:
SPONSOR INFORMATION PAGE
Clinical Study Identifier:
EGF117165
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address


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GlaxoSmithKline Research & Development Limited
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone: 
GlaxoSmithKline Research & Development Limited
1250 South Collegeville Road
Collegeville, PA 19426, USA
Telephone Number: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee).  Where applicable, the details of the Sponsor and contact 
person will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Medical Monitor Contact Information
Dr.
Novartis Pharma AG
Postfach
4002 Basel
Switzerland
Telephone:
Regulatory Agency Identifying Number(s): 
Eudra CT number: 2014-001220-30
Amended Text: 
SPONSOR INFORMATION PAGE
Clinical Study Identifier:
EGF117165
Sponsor Legal Registered Address 
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address Information
Novartis Pharma Services AG 


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In some countries, the clinical trial sponsor may be the local Novartis and its authorized 
agents.  Where applicable, the details of the Sponsor and contact person will be 
provided to the relevant regulatory authority as part of the clinical trial submission.
Sponsor Serious Adverse Events (SAE) Contact Information:
Please refer to the study procedures manual.
For study conduct questions not related to patient safety, the first line of contact 
should be with the designated local country company contact. In the event that the 
designated company contact is not available, please contact the Medical Lead.
Contact Information:
Dr.
 MD, PhD
Novartis Pharma AG
Postfach CH-4002 Basel
CH-4002 Basel
Switzerland
Telephone:
Email:
GlaxoSmithKline Research & Development Limited
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone:  
 
GlaxoSmithKline Research & Development Limited
1250 South Collegeville Road
Collegeville, PA 19426, USA
Telephone Number: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee).  Where applicable, the details of the Sponsor and contact 
person will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Regulatory Agency Identifying Number(s): 
Eudra CT number: 2014-001220-30
IND Number: 61362


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Reason for Change:
To align with Novartis processes and procedures.
Original Text:
Section 7.4.3
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
AEs will be collected from the time the first dose of study treatment is administered until 
30 days following discontinuation of study treatment regardless of initiation of a new 
cancer therapy or transfer to hospice. 
SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy) or study treatment must be recorded from 
the time a subject consents to participate in the study up to and including any follow-up 
contact.  All SAEs will be reported within 24 hours, as indicated in Section 7.4.5.   
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  
Amended Text: 
Section 7.4.3
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
AEs will be collected from the time a subject consents to participate in the study the 
first dose of study treatment is administered until 30 days following discontinuation of 
study treatment regardless of initiation of a new cancer therapy or transfer to hospice. 
SAEs (irrespective of causality) will be collected over the same time period as stated 
above for AEs.  In addition, any SAE assessed as related to study participation (e.g., 
protocol-mandated procedures, invasive tests, or change in existing therapy) or study 
treatment must be recorded promptly to Novartis from the time a subject consents to 
participate in the study up to and including any follow-up contact, as indicated in section
7.4.5 and Table 12.
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  


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Reason for Change:
To align with Novartis processes and procedures. Additional, with the update to section 
7.4.3, there is a referral to the table with events and reporting timelines and table number 
and table title have therefore been added.
Original Text:
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data 
collection tool
24 hours
Updated SAE data 
collection tool
CV events or death
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular 
event or death 
is reported
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
Pregnancy
2 Weeks
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow-
up Form
Liver chemistry abnormalities:
ALT3xULN and 
bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and 
INR>1.5, if INR 
measured)3
24 hours1
SAE data 
collection tool.
Liver Event Case 
Report Form 
(CRF) and liver 
imaging and/or 
biopsy CRFs if 
applicable2
24 hours
Updated SAE data 
collection tool. 
Updated Liver 
Event CRF2
ALT5xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN 4 weeks
24 hours1
Liver Event CRF2
24 hours
Updated Liver 
Event CRF2
ALT3xULN and 
<5xULN and bilirubin 
<2xULN
24 hours1
Liver Event CRF 
does not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks2
1.
Liver chemistry elevations should be notified at onset to discuss subject safety.


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2.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible
3.
.INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
Amended Text: 
Table 12
Time and Events
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data 
collection tool
24 hours
Updated SAE data 
collection tool
CV events or death
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular 
event or death 
is reported
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
Pregnancy
2 Weeks 24 
hours
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow-
up Form
Liver chemistry abnormalities:
ALT3xULN and 
bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and 
INR>1.5, if INR 
measured)3
24 hours1
SAE data 
collection tool.
Liver Event Case 
Report Form 
(CRF) and liver 
imaging and/or 
biopsy CRFs if 
applicable2
24 hours
Updated SAE data 
collection tool. 
Updated Liver 
Event CRF2
ALT5xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN 4 weeks
24 hours1
Liver Event CRF2
24 hours
Updated Liver 
Event CRF2
ALT3xULN and 
<5xULN and bilirubin 
<2xULN
24 hours1
Liver Event CRF 
does not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks2
4.
Liver chemistry elevations should be notified at onset to discuss subject safety.


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5.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible
6.
.INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
Reason for Change:
Dublicate text removed. 
Original Text:
7.4.6
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator is essential so that legal obligations and 
ethical responsibilities toward the safety of subjects are met.
There is a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  
Notification will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and are forwarded to investigators as 
necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) will file it with the IB and 
will notify the IRB/IEC, if appropriate according to local requirements.
Amended Text: 
7.4.6
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator is essential so that legal obligations and 
ethical responsibilities toward the safety of subjects are met.
There is a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  
Notification will comply with country specific regulatory requirements relating to safety 
reporting to the regulatory authority, Institutional Review Board (IRB)/Independent 
Ethics Committee (IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and are forwarded to investigators as 
necessary.


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An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) will file it with the IB and 
will notify the IRB/IEC, if appropriate according to local requirements.
Reason for Change: 
To align with Novartis processes and procedures.
Original Text:
7.4.7.2
Pregnancy Reporting
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to 
GSK within 2 weeks of learning of its occurrence.  The pregnancy must be followed up 
to determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK.
Amended Text: 
7.4.7.2
Pregnancy Reporting
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to 
GSK Novartis within 2 weeks 24 hours of learning of its occurrence.  The pregnancy 
must be followed up to determine outcome (including premature termination) and status 
of mother and child.  Pregnancy complications and elective terminations for medical 
reasons must be reported as an AE or SAE.  Spontaneous abortions must be reported as 
an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK Novartis.
Reason for Change: 
Enrolment was halted and the text has been updated to past tense. The status of enrolment 
per 31 Jul 2016 was deleted as it is no longer relevant. 
Original Text:


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9.2.1
Sample Size Assumptions
This is a purely descriptive study. Due to difficulty in enrolling subjects into this trial, 
future enrolment will be halted and the study will be terminated early. Up to 31 Jul 2016, 
29 patients have been enrolled.
A pre-treatment biopsy and a biopsy at disease progression will provide the samples for 
biomarker analysis.  
Amended text: 
9.2.1
Sample Size Assumptions
This is a purely descriptive study. Due to difficulty in enrolling subjects into this trial, 
future enrolment was will be halted and the study will be terminated early. Up to 31 Jul 
2016, 29 patients have been enrolled.
This is a purely descriptive study. Due to difficulty in enrolling subjects into this trial, 
future enrolment was halted and the study will be terminated early. 
Reason for Change: 
To align with Novartis processes and procedures.
Original Text:
10.6
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure 
that an acceptable back-up of the reproductions exists and that there is an acceptable 
quality control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time 


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will meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
Amended Text: 
10.6
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK Novartis audit or regulatory 
inspection) and must be available for review in conjunction with assessment of the 
facility, supporting systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure 
that an acceptable back-up of the reproductions exists and that there is an acceptable 
quality control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time 
will meet the strictest standard applicable to a particular site, as dictated by local
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
Essential documents (written and electronic) should be retained for a period of not 
less than fifteen (15) years from the completion of the Clinical Trial unless the 
Sponsor provides written permission to dispose of them or, requires their retention 
for an additional period of time because of applicable laws, regulations and/or 
guidelines.
The investigator must notify GSK Novartis of any changes in the archival arrangements, 
including, but not limited to archival of records at an off-site facility or transfer of 
ownership of the records in the event that the investigator is no longer associated with the 
site.
Reason for Change: 
To align with Novartis processes and procedures.


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Original Text:
10.7
Provision of Study Results to Investigators, Posting of Information on 
Publicly Available Clinical Trials Registers and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome.  In addition, a manuscript may be submitted to a peer reviewed 
journal for publication no later than 18 months after the last subject’s last visit (LSLV).  
When manuscript publication in a peer reviewed journal is not feasible, a statement will 
be added to the register to explain the reason for not publishing.
When manuscript publication in a peer-reviewed journal is not feasible, further study 
information will be posted to the GSK Clinical Study Register to supplement the results 
summary. 
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
Amended Text: 
10.7
Provision of Study Results to Investigators, Posting of Information on 
Publicly Available Clinical Trials Registers and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK Novartis site or other 
mutually-agreeable location.
GSK Novartis will also provide the investigator with the full summary of the study 
results.  The investigator is encouraged to share the summary results with the study 
subjects, as appropriate.
The sponsor aims to post a results summary to the Novartis Clinical Study Trial 
results website (www.novartisclinicaltrials.com) and other publicly available 
registers no later than twelve (12) months after the last subject’s last visit (LSLV). 
In addition, upon study completion and finalization of the study report, Novartis 


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aims to submit results of the study for publication. When publication is not feasible, 
please refer to the Novartis Clinical Trial Results website 
(www.novartisclinicaltrials.com) for a summary of the trial results. A manuscript 
will be progressed for publication in the scientific literature if the results provide 
important scientific or medical knowledge.
The results summary will be posted to the Clinical Study Register no later than eight 
months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome.  In addition, a manuscript may be submitted to a peer reviewed 
journal for publication no later than 18 months after the last subject’s last visit (LSLV).  
When manuscript publication in a peer reviewed journal is not feasible, a statement will 
be added to the register to explain the reason for not publishing.
When manuscript publication in a peer-reviewed journal is not feasible, further study 
information will be posted to the GSK Clinical Study Register to supplement the results 
summary. 

SAP_001.pdf: 
Clinical Development
LAP016/Lapatinib/Tykerb®
CLAP016A2206 / NCT02213042
An Open-Label, Phase II, Study to Evaluate Biomarkers 
Associated with Response to Subsequent Therapies in 
Subjects with HER2-Positive Metastatic Breast Cancer 
Receiving Treatment with Trastuzumab in Combination 
with Lapatinib or Chemotherapy (EGF117165)
Statistical Analysis Plan (SAP) for final CSR
Author:
Statistician: 
Document type:
SAP Documentation
Document status:
Final Amendment 2
Release date:
10-NOV-2020
Number of pages:
32
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
10-
JUN-
2020
Prior to 
DB 
lock
Creation of 
final version
N/A - First version for final 
analysis
NA
24-
JUL-
2020
Prior to 
DB 
lock
Creation of 
Amendment 1
Revised MedDRA version #
The study team planned to
upgrade MedDRA to newer 
version. However, there was a 
concern that implementing 
MedDRA upgrade might 
invalidate investigator 
signatures for certain closed 
sites. Consequently the team 
agreed to not upgrade 
MedDRA.
Section 2.8.1
10-
NOV-
2020
Prior to 
DB 
lock
Creation of 
Amendment 2
Revised the text for producing 
the outputs for regulatory 
disclosure
Section 2.8.1 
Section 2.8.3


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................9
1.2.1
Primary objective ....................................................................................9
1.2.2
Secondary objectives...............................................................................9
10
1.2.4
Primary endpoint...................................................................................10
1.2.5
Secondary endpoints .............................................................................10
10
10
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
Data analysis .........................................................................................10
2.1.2
General definitions................................................................................11
2.2
Analysis sets ..........................................................................................................14
2.2.1
Subgroup of interest ..............................................................................15
2.3
Patient disposition, demographics and other baseline characteristics ...................15
2.3.1
Patient disposition.................................................................................15
2.3.2
Protocol deviations................................................................................15
2.3.3
Demographic and baseline characteristics ............................................15
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................15
2.4.1
Study treatment / compliance................................................................15
2.4.2
Extent of exposure.................................................................................16
2.4.3
Prior, concomitant and post therapies...................................................17
2.5
Analysis of the primary objective..........................................................................17
2.5.1
Primary endpoint...................................................................................17
2.5.2
Statistical hypothesis, model, and method of analysis..........................17
2.5.3
Handling of missing values/censoring/discontinuations.......................19
2.5.4
Supportive analyses...............................................................................19
2.6
Analysis of the secondary objective ......................................................................19
2.6.1
Secondary endpoint...............................................................................19
23
2.8
Safety analyses.......................................................................................................23


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2.8.1
Adverse events (AEs)............................................................................23
2.8.2
Adverse events of special interest / grouping of AEs ...........................25
2.8.3
Deaths and serious adverse events (SAEs) ...........................................27
2.8.4
Adverse events leading to discontinuation of study treatment 
and/or withdrawal from the study and other significant adverse 
events.....................................................................................................27
2.8.5
Clinical laboratory evaluations .............................................................28
2.8.6
Analyses of liver function test...............................................................28
2.8.7
Liver toxicity.........................................................................................29
2.8.8
Other safety measures ...........................................................................29
2.9
Pharmacokinetic endpoints....................................................................................31
2.10
Patient-reported outcomes .....................................................................................31
2.11
Biomarkers.............................................................................................................31
2.12
Interim analysis......................................................................................................32
3
Sample size calculation .....................................................................................................32
4
Change to protocol specified analyses ..............................................................................32
5
Reference...........................................................................................................................32


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List of abbreviations
AE
Adverse Event
AI
Aromatase Inhibitor
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Aminotransferase
ATC
Anatomical Therapeutic Classification
CBR
Clinical Benefit Rate
CI
Confidence Interval
CR
Complete Response
CSR
Clinical Study Report
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
DBL
Database Lock
DILI
Drug Induced Liver Injury
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EMA
European Medicines Agency
EOS
End of Study
EP
Evaluable Population 
ER
Estrogen Receptor
EU
Europian Union
FAS
Full Analysis set
GCP
Good Clinical Practice
HER2
Human Epidermal growth factor Receptor 2
IHC
Immunohistochemistry
IP
Investigational Product
ITT
Intent-to Treat
IV
Intra-Venous
MBC
Metastatic Breast Cancer
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MRI
Magnetic Resonance Image
NCI
National Cancer Institute
NE
Not Evaluable
ORR
Overall Response Rate
PAM50
Prediction Analysis of Microarray 50
PD
Progressive Disease
PFS
Progression-Free Survival
PP
Per-Protocol
PR
Partial Response
RECIST
Response Evaluation Criteria in Solid Tumors


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RUCAM
Roussel Uclaf Causality Assessment Method
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SD
Stable Disease
SOC
System Organ Class
TIL
Tumor Infiltrating Lymphocytes
LVEF
Left Ventricular Ejection Fraction


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1
Introduction
This statistical analysis plan (SAP) is for the final clinical study report (CSR). It is based on the 
SAP Amendment 1 for the primary CSR of CLAP016A2206 (originally the GSK study 
EGF117165) with minimal updates.  CLAP016A2206 is a multicenter, open-label, Phase II 
study in patients with HER2-positive metastatic breast cancer who received at least 2 prior lines 
of anti-HER2-targeted therapies of which at least one included a trastuzumab-containing 
regimen. The primary objective is to evaluate the changes in the expression of biomarkers 
associated with immunomodulation between the pre-treatment biopsy and the progression 
biopsy and within each arm.  Secondary efficacy objectives are to evaluate overall response rate
(ORR); clinical benefit rate (CBR); and progression-free survival (PFS) on study treatment; to 
explore association between changes in biomarkers and PFS; as well as safety/tolerability. The
recruitment was stopped on 31 March 2017due to difficulty in enrolling patients, and the study 
was terminated early. There were 42 of the 225 planned subjects enrolled. Primary analysis 
had been performed with data cut-off date of 27-Mar-2018 and treatment was ongoing for 4 
subjects at the time. In this SAP, references will be made to the following documents:

Protocol Amendment 03, 2013N170247_03 (effective 15May2017)

Electronic Case Report Form (eCRF) for EGF117165

Statistical Analysis Plan Amendment 1 for EGF117165 primary CSR
1.1
Study design
This is a Phase II, 3 arm, open-label study (see Figure 1-1 for study schema).  The study 
population is comprised of patients with HER2-positive metastatic breast cancer who received 
at least two prior regimens containing trastuzumab in the metastatic setting.  The last regimen 
must have included trastuzumab plus chemotherapy.  The molecular subtype of a biopsy of a 
metastatic site will be centrally determined by the Prosigna assay.  HER2 and hormone receptor 
status will be centrally determined.  Patients with centrally determined HER2 positive disease 
will be allocated to one of two cohorts depending on the molecular subtype of their biopsy:  

COHORT 1 - HER2-Enriched contains HER2+ patients with a HER2-enriched molecular 
subtype.  Patients with HER2-enriched molecular subtype will be randomized  1:1 to 
either:
o
ARM A - Trastuzumab in combination with lapatinib: lapatinib 1000 mg PO once 
daily plus trastuzumab (loading dose of 8 mg/kg) followed by the maintenance dose of 
6 mg/kg IV q3weekly.  Weekly trastuzumab (loading dose of 4 mg/kg) followed by 
maintenance dose of 2 mg/kg IV weekly is acceptable at the discretion of the 
investigator. Patients with hormone receptor (ER and/or PgR)-positive, HER2-positive 
MBC (metastatic breast cancer) randomized to this arm will be required to be treated 
with an aromatase inhibitor of the investigator’s choice. 
o
ARM B - Trastuzumab in combination with chemotherapy: trastuzumab (loading dose 
of 8 mg/kg) followed by maintenance dose of 6 mg/kg IV q3weekly plus 
chemotherapy of the investigator’s choice.  Weekly trastuzumab (loading dose of 4 
mg/kg) followed by maintenance dose of 2 mg/kg IV weekly is acceptable at the 
discretion of the investigator.  An aromatase inhibitor may be used for hormone 
receptor-positive, HER2-positive patients at the discretion of the investigator.


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
COHORT 2 - Non-HER2-Enriched contains HER2+ patients with luminal A, luminal B 
and basal-like molecular subtypes
o
Patients in the Non-HER2 enriched cohort will be assigned to a third arm:  ARM C -
Trastuzumab in combination with lapatinib: lapatinib 1000 mg PO once daily plus 
trastuzumab (loading dose of 8 mg/kg) followed by the maintenance dose of 6 mg/kg 
IV q3weeks.  Weekly trastuzumab (loading dose of 4 mg/kg) followed by maintenance 
dose of 2 mg/kg IV weekly is acceptable at the discretion of the investigator. Patients 
with hormone receptor (ER and/or PgR)-positive, HER2-positive MBC randomized to 
this arm will be required to be treated with an aromatase inhibitor of the investigator’s 
choice.
Figure 1-1
Study Schema
Biopsies of a metastatic site will be collected at two time points: screening (pre-treatment) and 
at disease progression (PD).  The primary objective is to evaluate changes in biomarkers 
associated with immunomodulation, between the pre-treatment biopsy and the progression 
biopsy within each arm.  Radiologic disease assessments will be performed every 9 weeks until 
54 weeks then every 24 weeks thereafter until disease progression, death, or withdrawal from 
study treatment for any reason (e.g. unacceptable toxicity). 
 
 
 
Safety assessments including physical examination, Eastern Cooperative Oncology Group 
(ECOG) performance status, vital signs and weight, adverse event (AE) monitoring, and 


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laboratory tests (complete blood count, blood chemistry including liver function test) will be 
done at screening and then every 3 weeks for the duration of therapy.  Additional safety 
assessments, such as cardiac monitoring, are required for all patients every 12 weeks until 
discontinuation from the study therapy. All patients will receive study treatment until disease 
progression, death, unacceptable toxicity, and withdrawal of consent or any other reasons.
Study completion
A subject will be considered to have completed the study if the subject presents with disease 
progression, starts a new anti-cancer therapy, dies or withdraws from the study, or the study 
ends, whichever comes first. In case of disease progression during the treatment period, the 
subject will be followed-up for 30 days for safety evaluation and no further study-specific 
follow-up will be carried out; the subject will be considered as having completed the study.
In case of study treatment discontinuation for any reason other than disease progression, the 
subject will be followed-up for safety and efficacy assessments until disease progression, new 
anticancer therapy, death, withdrawal of consent or end of study, whichever comes first.
Following the data cut-off date for the primary analysis on 27-Mar-2018, the study remained
open. Ongoing patients continued to receive study treatment and be followed as per the schedule 
of assessments, as long as patients derive benefit from lapatinib. The end of study is defined as 
the earliest occurrence of one of the following:

All patients have died or discontinued from the study

Another clinical study becomes available that can continue to provide lapatinib in this 
patient population and all patients ongoing are eligible to be transferred to that clinical 
study 
1.2
Study objectives and endpoints
1.2.1
Primary objective
To evaluate changes in the expression of biomarkers associated with immunomodulation. 
1.2.2
Secondary objectives

To describe overall response rate (ORR), clinical benefit rate (CBR), and progression 
free survival (PFS) on study treatment in patients treated with trastuzumab in 
combination with lapatinib or chemotherapy.

To explore association between changes in biomarkers and PFS.

To describe the safety and tolerability of trastuzumab in combination with lapatinib 
and of trastuzumab in combination with chemotherapy.
Analysis for correlation between changes in expression profile of biomarkers from baseline to 
disease progression and PFS will not be conducted due to insufficient sample size from the early 
closure. 


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1.2.4
Primary endpoint
The primary efficacy endpoint of this study is the change in expression profile of genes and/or 
proteins from baseline to disease progression biopsies within each arm on a set of biomarkers
associated with immunomodulation.  As described above, the HER2-enriched cohort (Arm A 
and Arm B) will contain HER2+ patients with a HER2-enriched molecular subtype determined 
by PAM50; while HER2-non enriched cohort (Arm C) will contain HER2+ patients with the 
luminal A, luminal B and basal-like molecular subtypes.
1.2.5
Secondary endpoints
The secondary endpoints of this study are:

Investigator-assessed PFS (defined as the interval of time between randomization and 
disease progression or death due to any cause); 

Investigator-assessed ORR (defined as percentage of patients with a CR or PR);

CBR (defined as percentage of patients with a CR, PR, or SD for at least 6 months);

AE, laboratory parameters, ECG and vital signs
2
Statistical methods
2.1
Data analysis general information
The final analysis will take place once all patients have discontinued treatment and completed 
the study. All the data collected during the entire period of the study will be included in the 
final analysis.
2.1.1
Data analysis

All analyses and outputs will be performed and produced by Novartis;

All programming will be performed using SAS version 9.4 or a later release, in a UNIX 
environment;

The treatments were assigned to patients using a central randomization independent of 
centers.  As it is anticipated that accrual will be spread thinly across centres and 


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summaries of data by centre would be unlikely to be informative, data from all 
participating centres will be pooled prior to analysis.

Continuous variables will be summarized with the statistics mean, median, standard 
deviation (SD), minimum and maximum, and categorical variables will be summarized 
with frequency counts and percentages;

All confidence intervals will be two-sided and will use 95% confidence levels. If sample 
size permits, any analysis requiring significance testing will use a two-sided test at the 
0.05 significance level, unless otherwise specified;

P-values will be rounded to three decimal places.  P-values that round to 0.000 will be 
presented as ‘<0.001’ and p-values that round to 1.000 will be presented as ‘>0.999’.  
Any p-value considered statistically significant will be marked with one asterisk (e.g., 
0.022*);

All listings will be sorted for presentation in order of treatment regimen, country, study 
center, patient, and date of procedure or event;

All analysis and summary tables will have the analysis population sample size (i.e., 
number of patients);

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) 
will be included in listings but omitted from figures, summaries and statistical analyses.
2.1.2
General definitions
2.1.2.1
Treatment groups
Table 2-1
Treatment groups
Treatment Arm
Descriptor
Table Order &
Label
COHORT 1 - HER2-Enriched contains 
HER2+ patients with a HER2-enriched 
molecular subtype.  Patients with HER2-
enriched molecular subtype will be 
randomized  1:1 to either:
Treatment Arm A: Trastuzumab in 
combination with lapatinib: lapatinib 
1000 mg PO once daily plus trastuzumab 
(loading dose of 8 mg/kg) followed by 
the maintenance dose of 6 mg/kg IV 
q3weekly.  Weekly trastuzumab (loading 
dose of 4 mg/kg) followed by 
maintenance dose of 2 mg/kg IV weekly 
is acceptable at the discretion of the 
investigator. Patients with hormone 
receptor (ER and/or PgR)-positive, 
HER2-positive MBC randomized to this 
arm will be required to be treated with an 
HER2-Enriched -
Lapatinib (1000mg) 
+Trastuzumab (6mg per 
kg)+AI
1st column
HER2-Enriched
LAP+TRAS+AI
Arm A


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aromatase inhibitor of the investigator’s 
choice. 
Treatment Arm B: Trastuzumab in 
combination with chemotherapy: 
trastuzumab (loading dose of 8 mg/kg) 
followed by maintenance dose of 6 
mg/kg IV q3weekly plus chemotherapy 
of the investigator’s choice.  Weekly 
trastuzumab (loading dose of 4 mg/kg) 
followed by maintenance dose of 2 
mg/kg IV weekly is acceptable at the 
discretion of the investigator.  An 
aromatase inhibitor may be used for 
hormone receptor-positive, HER2-
positive patients at the discretion of the 
investigator.
HER2-Enriched -
Trastuzumab (6mg per 
kg)+Chemo +AI
2nd column
HER2-Enriched
TRAS+ 
CHEM+AI
Arm B
COHORT 2 - Non-HER2-Enriched 
contains HER2+ patients with luminal A, 
luminal B and basal-like molecular 
subtypes
Treatment Arm C: Trastuzumab in 
combination with lapatinib: lapatinib 
1000 mg PO once daily plus trastuzumab 
(loading dose of 8 mg/kg) followed by 
the maintenance dose of 6 mg/kg IV 
q3weeks.  Weekly trastuzumab (loading 
dose of 4 mg/kg) followed by 
maintenance dose of 2 mg/kg IV weekly 
is acceptable at the discretion of the 
investigator. Patients with hormone 
receptor (ER and/or PgR)-positive, 
HER2-positive MBC randomized to this 
arm will be required to be treated with an 
aromatase inhibitor of the investigator’s 
choice.
Non-HER2-Enriched -
Lapatinib (1000mg) 
+Trastuzumab (6mg per 
kg)+AI
3rd column
Non-HER2-
Enriched
LAP+TRAS+AI
Arm C
The patients’ actual treatment will be derived from exposure data. If a patient’s actual 
treatment is the same as the assigned treatment, then actual treatment is the assigned treatment.  
If a patient receives a study treatment that is different from the assigned treatment for the entire 
time of treatment, then actual treatment is the different treatment (the treatment actually 
received).


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2.1.2.2
Study day
For randomized subjects, the date of randomization will be used as the reference date for 
efficacy and the date of the first dose will be used as the reference date for safety; for subjects
in Arm C, the date of the first dose will be used as the reference date for both efficacy and safety.
For safety measures and other measurements (demographics, disease history, medical history, 
etc.), if the date of interest occurs on or after the safety reference date then the safety study day 
will be calculated as (date of interest - safety reference date) + 1. If the date of interest occurs 
before the safety reference date then the safety study day will be calculated as (date of interest 
– safety reference date). There is no safety study day 0.
For efficacy, If the date of interest occurs on or after the efficacy reference date then efficacy 
study day will be calculated as (date of interest - efficacy reference date) + 1. If the date of 
interest occurs prior to the efficacy reference date then efficacy study day will be calculated as 
(date of interest – efficacy reference date). There is no efficacy study day 0. 
2.1.2.3
Duration
Durations (e.g., the duration of an adverse event, duration of exposure, etc.) are calculated as 
the stop date minus the start date plus one.
For elapsed time (e.g., the time since initial diagnosis):

If the reference date is on or after the event date, then the elapsed time is the reference 
date minus the event date + 1.

If the reference date is before the event date then the elapsed time is the reference date 
minus the event date.
When reporting time-to-event durations in months, divide the number of days by 30.4375; to 
report in weeks divide the number of days by 7; to report in years divide the number of days by 
365.25. These algorithms for time to event return decimal numbers, and ignore the actual 
numbers of days in the months or years between start date and stop date. The "year" used in 
these algorithms is 365.25 days long, and the "month" is one twelfth of that year.
For converting all other durations (e.g., duration of adverse events, duration of exposure, age) 
to weeks, months or years use the following:

To report the duration in weeks divides the number of days by 7.

To report the duration in months use:
(YEAR(stop date + 1) - YEAR(start date)) x 12 + (MONTH(stop date + 1) -
month(start date) - 1) + (DAY(stop date + 1) > = DAY(start date))

To report the duration in years use:
intck('year', start date, stop date + 1) - (month(stop date + 1) < month(start date) or
(month(stop date + 1) = month(start date) and day(stop date + 1) < day(start date)))
The algorithms above for age and duration return whole numbers for months and years, 
accurately accounting for the actual numbers of days in the months or years between the start 
date and the stop date.


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2.1.2.4
Baseline and change from baseline
Baseline value will be defined as the last value before the first dose of study drug administered.
For the purposes of calculating change from baseline data, the screening or “Pre-dose/ Day 1” 
value will be used as baseline in all calculations. If this is missing then the change from baseline 
will also be missing. If more than one screening / pre-dose assessment is performed, then the 
one closest to and preceding start of treatment will be used for summaries.
For records occurring after baseline: change from baseline = (visit value) – baseline value. If 
either the baseline or visit value is missing, the change value is set to missing.  
2.1.2.5
Follow-up period
In case of disease progression during the treatment period, the patient will be followed-up for 
30 days for safety evaluation.
In case of study treatment discontinuation for any reasons other than disease progression, the 
patient will be followed-up for safety and efficacy assessments until disease progression, new 
anticancer therapy, death, withdrawal of consent or end of study, whichever comes first.
The safety data, up to 30 days after last dose, will be included in the summary statistics. For 
efficacy, any follow-up data will be included in the PFS analysis. Listings of safety and efficacy 
data will be provided to include all time-points captured.
2.1.2.6
Time windows and unscheduled visits
Time windows will not be applied. Visit based summaries will include scheduled assessments 
only and will be summarized according to the planned assessment time.  The only exceptions 
to this are summaries of Left Ventricular Ejection Fraction (LVEF) change from baseline and, 
laboratory parameters where maximum toxicity grades and values outside laboratory reference 
ranges from any post-screening visit (include all scheduled and unscheduled visits) will be used.
Multiple assessments on ECG collected within a short timeframe (within 30 minutes) will
qualify as a triplicate. The mean of one scheduled and the first two unscheduled measurements 
within 30 minutes will be considered as a point estimate of observed replicates. For ECG result 
(interpretation) the worst result should be taken (i.e., worst of the recorded of the following 
choices: abnormal – clinically significant, abnormal- not clinically significant, normal).
All assessments (scheduled and unscheduled) will be included in listings.
2.2
Analysis sets
The Intent-to-Treat (ITT) Population as defined in the protocol, also referred to as Full Analysis 
Set (FAS), will be used for the analysis of demography, baseline disease characteristic and 
secondary efficacy data and will consist of all patients who were: 1) randomized to study Arm 
A or Arm B, or (2) assigned to study Arm C, regardless of whether they actually received study 
treatment.
The Evaluable Population (EP) as defined in the protocol will be used for the primary analysis 
of change in biomarkers at disease progression, and will consist of all patients who actually 


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received the study treatment and have both baseline and progression tumor biopsies available, 
with evaluable data for at least 1 biomarker.
The Safety Population as defined in the protocol also referred to as Safety Set, will be used to 
assess clinical safety and tolerability and will consist of all patients who took at least 1 dose of 
study medication.  This population will be based on the actual treatment received by the patients.
2.2.1
Subgroup of interest
As the study has a small sample size, there will be no subgroup analyses.
2.3
Patient disposition, demographics and other baseline 
characteristics
Unless otherwise stated, all tables and listings in this section will be based on the FAS, and all 
summaries and data listings will use treatment labels as specified in Section 2.1.4.1.
2.3.1
Patient disposition
Summary of patients screened by country and center was reported in the primary CSR. A 
summary of the number of patients in each of the analysis populations described was also 
produced for the primary CSR. These summary tables and corresponding listings will not be 
repeated. A summary of patient status and reason for study treatment discontinuation will be 
provided. This display will show the number and percentage of patients who discontinued from 
study treatment, and the primary reasons for treatment discontinuation which will be presented 
in the order they are displayed in the eCRF. 
2.3.2
Protocol deviations
A summary and listing of all patients with important protocol deviations will be provided. 
2.3.3
Demographic and baseline characteristics
Demographic and baseline characteristics, which were reported in the primary CSR, will not 
change and therefore will not be repeated for the final analysis. The summary and listing of the 
past and current medical conditions will be updated.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Treatment compliance will be assessed for lapatinib, trastuzumab, chemotherapy, and 
aromatase inhibitor (AI).       
Planned and actual treatments will be displayed for all study treatments under listing of 
exposure to that treatment. 
A summary of overall compliance for lapatinib, oral chemotherapy and AI based on the 
exposure data will be produced. Percentage overall compliance will be summarized using the 


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mean, standard deviation, minimum, median, and maximum.  In addition, percentage overall 
compliance will be categorized by <80%, 80%-120%, and >120%.    
Overall compliance (%) = [total cumulative actual dose / (duration of study treatment x planned 
dose)] x 100, where duration of study treatment is last dose date - first dose date + 1. 
Planned dose for lapatinib is 1000mg daily. 
In addition, summaries of exposure to study medication (trastuzumab, lapatinib, chemotherapy
and AI) and dose modifications (e.g., number of dose reductions, escalations, and interruptions) 
will further characterize compliance. These analyses are described in Section ‘Extent of 
Exposure’.
2.4.2
Extent of exposure
The mean daily dose, cumulative dose,  duration of treatment period, calculated as the number 
of days between start of treatment and end of treatment inclusive (i.e., treatment stop date minus 
treatment start date + 1), and relative dose intensity (%) will be summarized for lapatinib, 
chemotherapy and AIs. 
The exposure to trastuzumab by visit will be summarized. 
Exposure to study treatment will also be listed. 
The following calculations will be performed for lapatinib, chemotherapy and AI exposure:
[1] Daily dose = Cumulative dose/ (Last administration date - First administration date + 1).
[2] Cumulative dose = Sum of dosing intervals [(Last date in interval - First date in interval 
+1) x Dose level in interval].
[3] Duration of exposure (week) = (Last administration date - First administration date + 1)/7.
[4] Relative dose intensity (%) = 100 x Dose intensity /Planned dose intensity.
Following definition will be used in the computation:

Planned Treatment Duration (days): it is the planned time between two consecutive 
administration (planned cycle duration)

Dose Intensity (mg/week) (DI): Cumulative dose (mg) / Treatment duration (weeks)

Planned DI (mg/week): (PDI) Cumulative planned dose (mg) / Planned Treatment 
duration (weeks)

Relative DI (%) (RDI): 100 x DI (mg/w) / PDI (mg/w). An RDI of 100% indicates 
that the drug was administered at the right dose within the planned timeframe (e.g. 
every 28 days).
Dose reductions for lapatinib will be summarized by number of reductions, reasons for 
reductions, and number of reductions at each visit. Dose interruptions for lapatinib will be 
summarized by number of interruptions, reasons for the interruption, duration of interruption 
(days), and number of interruptions at each visit.  
Dose delays for trastuzumab will be summarized by number of delays, reasons for the delay, 
delay duration (days), and number of delays at each visit.  These data will also be listed.


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A summary of study treatment status will be provided. This display will show the number and 
percentage of patients who are ongoing or discontinued study treatment and a summary of the 
primary reasons for discontinuation of study treatment. Reasons for study treatment 
discontinuation will be presented in the order they are displayed in the eCRF. A listing of study 
treatment discontinuation will be generated; this will include last dose date, and reasons for 
study treatment discontinuation. 
2.4.3
Prior, concomitant and post therapies
A listing of concomitant medications will be presented. The concomitant medications taken by 
each patient and the relationship between the Anatomical-Therapeutic-Chemical (ATC) Level 
1, preferred term and verbatim text will be displayed.  All medication verbatim text will be 
coded using the most recent version of WHO Drug Dictionary to obtain appropriate ATC Level 
1 classification and ingredients. A summary and listing of prior and concomitant medications 
by ATC Level 1 and ingredients by treatment arm will be provided.
2.5
Analysis of the primary objective
The analysis of the primary objective will be based on the evaluable population (or EP or 
Evaluable Set). All supportive analyses of primary endpoint will be based on the FAS Set. 
2.5.1
Primary endpoint
The primary endpoint of this study is the change in expression profile of genes and/or proteins
within each arm on a set of biomarkers (more than 700 immune genes on nanostring panel)
associated with immunomodulation between the pre-treatment biopsy and disease progression 
biopsy.
2.5.2
Statistical hypothesis, model, and method of analysis
2.5.2.1
Biomarker data normalization
mRNA gene expression panel derived from Nanostring platform will be transformed and 
normalized by the vendor before it can be used in the analysis. The method is described as 
follows: There are 5 housekeeping genes recommended by the lab: ACTB, MRPL19, PSMC4, 
RPLP0 and SF3A1. The normalization factor will be computed as the geometric mean of 
housekeeping genes across samples.  The expression of each gene will be divided by this
normalization factor. 
2.5.2.2
Data summaries
Tissue biopsies are taken at two time points: baseline and disease progression, whereas whole 
blood is taken every 9 weeks. Tumor infiltrating lymphocytes (TILs),
, ER & PR will 
be tested on the tissue biopsies at both time points (at baseline and at disease progression). Flow 
cytometry data will be generated on whole blood samples that were taken every 9 weeks.
For all tissue biopsy samples, data will be summarized at the baseline and on-progression visits. 

The expression of genes and/or proteins will be for both baseline and on-progression 
visits. 


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
The fold-change of expression of genes and/or proteins will be only on-progression
Flow cytometry data will not be summarized due to insufficient number of subjects. The flow 
cytometry data will be listed.
Changes in TILs in paired pre-treatment tumor biopsies and those obtained at disease 
progression for each arm will be summarized in tables that include sample size, geometric mean, 
SD, geometric %CV, median, minimum and maximum. In addition, known markers CD4 and 
CD8A for immune cell populations and immune microenvironment will be analyzed comparing 
their levels at disease progression to the baseline to assess how the treatments affect the immune 
response at the level of the tumor. In case there are more than one data points at baseline, mean 
value will be used as baseline. TILs changes from pre-treatment to disease progression will also 
be listed.
The fold-change from baseline to disease progression of gene expression values will be 
summarized for each arm. The summary tables will present sample size, geometric mean, SD, 
geometric %CV, median, 95% CI of the median, minimum and maximum. The fold-changes 
from pre-treatment to disease progression for the gene expression will also be listed. 
Since the panel of genes is very large, results will be displayed only for a selected subset of 
these genes. 
Ranking and selection of genes
The gene subset will be selected based on the largest changes (increase or decrease) from 
baseline to disease progression, within each treatment arm separately. Biomarker data should 
have sample collection date from which it should be possible to derive the study day/visit.
The following algorithm will be implemented within each arm separately, to select up to 100 
genes for display:
1. The significant fold-change will be flagged. 
a. if the 95% CI of the median fold change of a gene does not include 1,  
Flag.significant=1, otherwise Flag.significant =0.
2. Flag the genes with increase from baseline 
a. If median fold change >1, flag.gt=yes, otherwise flag.gt=no. 
3. Flag the genes with decrease from baseline 
a. If median fold change <1, flag.lt=yes, otherwise flag.lt=no. 
4. Rank those genes with increase from baseline (i.e. flag.gt=yes)
a. rank first by the significance flag (Flag.significant) 
b. then rank in order of median fold change value, from largest to smallest fold-
change values.
c. Select the genes list based on those that have ranks from 1 to 50. If there are less 
and 50 genes that increase from baseline, select all. 
5. Rank those genes with decrease from baseline (i.e. flag.lt=yes)
a. rank first by the significance flag (Flag.significant)
b. then rank in order of median fold change value,  from smallest to largest fold-
change value.


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c. Select the genes list based on those that have ranks from 1 to 50. If there are less 
and 50 genes that decrease from baseline, select all.
6. The complete summary table (for each arm) will be presented for the selected genes.
2.5.3
Handling of missing values/censoring/discontinuations
Missing data will not be imputed for biomarkers.
2.5.4
Supportive analyses
No additional analysis will be conducted due to a small number of subject sample collected.
2.6
Analysis of the secondary objective
All secondary analyses are intended to describe the summary statistics by the treatment arm.  
All the changes will be evaluated within each individual arm. No pooling of patients over arms 
will be done for secondary analyses.
2.6.1
Secondary endpoint
2.6.1.1
Progression free survival (PFS)
PFS is defined as the interval of time (in months) between the date of randomization and the 
earlier of date of disease progression and the date of death due to any cause.
Disease 
progression will be based on the assessments by the investigator using RECIST 1.1, and is based 
on FAS. 
The date of documented disease progression will be defined as the date of radiological disease 
progression as assessed by the investigator based on imaging data only.  The date of documented 
disease progression will be taken from the Response Assessment page.  This should be the date 
of the lesion evaluation corresponding to the documented disease progression. If there are 
multiple scan dates for a given assessment then the first date in the series of scans that shows 
progression of the disease should be used.   It should be noted that in the cases of patients who 
have PD determined by non-radiological evidence (e.g. lab data or symptomatic progression);
it will not be considered an event.  Such patients’ data should be checked for any later 
radiological evidence if this available and only censored in line with the following rules.

The date of death should be taken from the Record of Death page.  Death on study due 
to any cause will be included.

If a patient has neither progressed by radiological assessment nor died, then PFS will 
be censored at the date of the last radiological scan as assessed by the investigator. This 
applies also in the case of patients who are withdrawn from the study prior to 
progression or death.  Such patients will be censored at the last radiological scan 
assessment.

Patients who receive subsequent anti-cancer therapy (including radiotherapy and 
surgeries with anti-cancer intent) in the absence of documented disease progression will 
be censored at the initiation of the subsequent therapy if scans or progression do not 
occur within 14 days of the initiation of therapy.  
For patients who receive subsequent anti-cancer therapy, the following rules will apply:


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
If the start date of the anti-cancer therapy is partial (i.e. either missing the day but has 
the month and year available or missing both day and month), the imputation rules 
described in the SAP for the primary CSR will be applied.

If such therapy is started without evidence of documented disease progression, then 
PFS will be censored at the date of the last radiological assessment that is no later than 
the date of initiation of subsequent anti-cancer therapy if the scan assessment does not 
document PD.  If there are multiple scan dates for a given assessment then PFS will be 
censored at the first date of the series of scan dates.

If the start of the subsequent anti-cancer therapy plus 14 days is after the date of 
documented disease progression (defined as the first date if there are multiple dates in 
a series of scans) then the patient will be considered to have had a progression event 
and not censored.

If the start of the subsequent anti-cancer therapy plus 14 days is prior to the date of 
documented disease progression, then the patient will be censored on the date of the 
previous scan.

If initiation of subsequent anti-cancer therapy plus the 14-day window is prior to 
documented disease progression and the anti-cancer therapy start date is between the 
first and last date of a set of multiple scans, and the date of subsequent disease 
progression is also between the first and last date of a set of multiple scans, then PFS
will be censored at the first scan date of the previous assessment.
If a patient has only a baseline visit or does not have a date of radiological scan that is no later 
than the date of initiation of anti-cancer therapy, PFS will be censored at the date of 
randomization.
2.6.1.2
Handling of missing values/censoring/discontinuations for PFS
Missing values will not be imputed. The censoring of PFS is described in Section 2.6.1.1.
2.6.1.3
PFS estimates
PFS will be summarized using Kaplan-Meier curves. Percentage of patients with progression
free status at monthly intervals will be obtained from the Kaplan-Meier estimate of the 
progression free survival function. This will include at a minimum the following time points: 3 
months, 6 months, 9 months and 12 months. Time point estimates will be provided as is 
reasonable based on the available data. Approximate 95% confidence limits will be calculated, 
based on Greenwood’s formula for the standard error of the Kaplan-Meier estimate. For each 
treatment arm, the Kaplan-Meier estimates for the median PFS time, the first and third quartiles 
will be presented along with approximate 95% CI’s.
PFS time will be fitted to a Cox proportional hazard model with treatment as a covariate.  The 
hazard ratios between the treatment and the corresponding 95% CI will be presented.
2.6.1.4
Overall response rate (ORR)
The response for each visit is ‘according to the investigator assessment of response’. Use the 
response for each visit from CRF, not re-compute the response at each time-point using target, 
non-target lesions measurement. However, the best overall response is computed.  Table 2-2


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presents the overall response at an individual time-point for all possible combinations of tumor 
responses in target and non-target lesions with or without the appearance of new lesions for 
patients with measurable disease at baseline according to RECIST.
Table 2-2
Evaluation of Overall Response for Patients with Measurable Disease 
at Baseline
Target 
Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not applicable, 
and NE=Not Evaluable
Table 2-3 presents the overall response at an individual time-point for all possible combinations 
of tumor responses in non-target lesions with or without the appearance of new lesions for 
patients with non-measurable only disease at baseline.
Table 2-3
Evaluation of Overall Response for Patients with Non-Measurable 
Disease at Baseline
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non CR/Non PD
No
Non CR/Non PD
NE
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR=complete response,  PD=progressive disease, and NE=Not Evaluable
Note:

Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having "symptomatic deterioration."  Objective response status is 
determined by evaluations of disease burden.  Every effort should be made to 
document the objective progression even after discontinuation of treatment.  

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) to confirm the 
CR.
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence and will be determined programmatically based on the 
investigators assessment of response at each time-point. 


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
To be assigned a status of SD, follow-up disease assessment must have met the SD 
criteria at least once after randomization at a minimum interval of 56 days (8 weeks). 

If the minimum time for SD is not met, best response will depend on the subsequent 
assessments.  For example if an assessment of PD follows the assessment of SD and 
SD does not meet the minimum time requirement the best response will be PD.  
Alternatively, patients lost to follow-up after an SD assessment not meeting the 
minimum time criteria will be considered not evaluable.
Confirmed ORR is defined as the percentage of patients achieving either a confirmed CR or PR.  
Tabular summary will be produced for all patients (patients with measurable and non-
measurable disease).

Confirmed CR -  at least two determinations of CR at least 4 weeks apart before disease 
progression; 

Confirmed PR - at least two determinations of PR or better at least 4 weeks apart before 
progression (and not qualifying for a CR).
Confirmed ORR will be calculated from the investigator’s assessment of response.  Patients 
with unknown or missing response will be treated as non-responders; i.e. they will be included 
in the denominator when calculating the percentages.  Further if a patient only has a baseline 
measurement, per RECIST version 1.1, they should be classified as NE and appear in the table 
as such, so that the sum of the individual response categories (CR, PR, SD, PD, NE) sum up to 
the big N, where N is the number of patients in the denominator (i.e. the number of patients in 
the FAS in each treatment arm).  
ORR will be summarized along with the exact 95% confidence interval (CI) for each treatment 
arm.  
The data on target, non-target and new lesion will be listed.
2.6.1.5
Clinical benefit rate (CBR)
CBR is defined as the percentage of patients achieving either a confirmed CR or PR tumor 
response at any time or maintaining SD for at least 24 weeks while on study, according to the 
investigator assessment of response per RECIST 1.1 criteria. The SD should last at least 24 
weeks.  All patients who achieve a CR, PR or SD will be included in these analyses, including 
any patients with non-measurable disease who achieve a CR, (according to the qualifying 
criteria in Table 2-3), which has a duration of at least 26 weeks.   
An estimate of the proportion of patients who experience clinical benefit will be summarized 
and analyzed similarly as described above for ORR.  Patients with unknown or missing response 
will be treated as non-responders (i.e. not CR, PR or SD<24 weeks).  Patients who have 
withdrawn from the study prior to completing 6 months of response assessments will still be 
counted in this analysis in the denominator, and hence considered as patients who do not 
experience clinical benefit in the numerator.
2.6.1.6
Handling of missing values/censoring/discontinuations
Missing values on the response are considered as non-responses for ORR. Please refer to 
censoring rules for PFS in Section 2.6.1.1.


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2.6.1.7
Derivation of lesion summary variables
When any target lesion data was updated at any visit and/or if scheduled or unscheduled 
assessments were entered out of order, the derived fields should also be updated using the 
‘Recalculate’ button on target lesion assessment CRF page. In order to ensure the accuracy of 
the derived fields, the values of the following variables will be derived at each visit for the 
analysis dataset. 

Sum of diameters

Baseline sum of diameters

Percent change in the sum of diameters of target lesions, taking as reference the baseline  
[% change from baseline = (sum of lesion - sum of lesion at baseline) / sum of lesion 
at baseline x 100]

Smallest sum of diameters (nadir)

Absolute change in the sum of diameters of target lesions, taking as reference the 
smallest sum of diameters (nadir) recorded at previous assessments including baseline 
[absolute change from nadir = sum of lesion - nadir (smallest prior)]

Percent change in the sum of diameters of target lesions, taking as reference the smallest
sum of diameters (nadir) recorded at previous assessments including baseline [% 
change from nadir = (sum of lesion - nadir sum of lesion) / nadir sum of lesion x 
100]Association between biomarkers and PFS
Analysis of association between biomarkers and PFS will not be performed due to insufficient 
sample size from early closure of the study.
2.8
Safety analyses
The Safety population as defined in Section 2.2 will be used for the analysis of safety data.
Safety data, up to 30 days after last dose, will be included in the summary. All safety data will 
be listed.
2.8.1
Adverse events (AEs)
All AE summaries will be based on AEs collected during the on-therapy period (from start of 
first dose of study medication to last dose of study medication) plus 30 days after last dose.  All 
AEs and SAEs will be listed for all patients with pre- and post-treatment flag (indicated by
study day).
An overview summary of AEs collected during the study, including counts and percentages of 
patients with any AE, AEs related to study treatment, AEs leading to permanent discontinuation 


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of study treatment, SAEs, SAEs related to study treatment, fatal SAEs, and fatal SAEs related 
to study treatment will be produced.   
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables for on-
treatment AEs that are not serious with an incidence greater than 5% and on-treatment SAEs 
and SAEs suspected to be related to study treatment will be provided by system organ class and 
preferred term on the safety set population.
If for the same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

A single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

More than one occurrences will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE/SAE suspected to be related to study treatment 
/non SAE has to be checked in a block e.g., among AEs in a ≤ 1 day gap block. If at least one 
SAE is occurring, then one occurrence is counted for that SAE.
Adverse events (AEs) will be graded according to the CTCAE, Version 4.0. Adverse events 
will be grouped by system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Affairs (MedDRA). MedDRA version 20.1, which was used for 
coding AEs for the primary CSR, will continue to be used for the final CSR. Note that incorrect 
MedDRA version 21.0 was cited in the SAP for primary CSR.The summary of on-treatment
AEs, treatment-related AEs, AEs leading to permanent discontinuation of study treatment and 
AEs related to treatment will be presented for each treatment arm. 
A study treatment-related AE is defined as an AE for which the investigator classifies the 
relationship to study treatment as “Yes”. The summary table will include events with the 
relationship to study treatment as ‘Yes’ or missing.
Adverse events will also be presented by treatment arm and the maximum NCI CTCAE toxicity 
grade reported.  
For all AE tables, AEs will be sorted by SOC. SOC will be presented in descending order from 
the SOC with the highest total incidence to the SOC with the lowest total incidence. A SOC 
will not be presented when the overall total incidence is zero. Within each SOC preferred terms 
will be presented in descending order from the preferred term with the highest total incidence 
to the preferred term with the lowest total incidence. Where two or more preferred terms within 
an SOC have the same total incidence, they will be sorted alphabetically. Terms relating to
either diarrhea or rash will be collapsed and presented as one preferred term in the overall 
summaries of adverse events. If the SOC for rash terms is ‘Infections’, it will be recoded to 
‘Skin and Subcutaneous Tissue’ SOC to ensure correct reporting. A further summary of the 
individual terms will also be provided.
A summary of the most common adverse events will be presented by treatment arm. A preferred 
term will be considered amongst the most common adverse events if its occurrence is ≥ 10% 
(before rounding). This summary will differ from the one detailed above in that only preferred 
terms will be presented, not SOCs.  


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Separate listings will be provided to support each AE summary. Listings identifying patient
numbers for the individual adverse events will be provided. Relationship of AE system organ 
class, preferred terms and verbatim text will also be listed.
2.8.2
Adverse events of special interest / grouping of AEs
The following AEs have been defined as AEs of special interest (AESI): rash-related events, 
diarrhea related events, hepatobiliary events, cardiac related events and interstitial lung disease.
The AESI groups and the preferred terms are shown in Table 2-4.
Table 2-4
Adverse Events of Special Interest
AE of Special Interest
AE Preferred Term
Rash Related Events
Acne
Dermatitis
Dermatitis acneiform
Eczema
Erythema
Exfoliative rash
Photosensitivity reaction
Rash
Rash generalized
Rash macular
Rash maculo-papular
Rash papular
Rash pruritic
Skin ulcer
Rash pustular*
Diarrhea Related Events
Diarrhea
Frequent bowel movements
Cardiac Related Events
Acute left ventricular failure
Acute right ventricular failure
Cardiac failure
Cardiac failure acute
Cardiac failure chronic
Cardiac failure congestive
Chronic left ventricular failure
Chronic right ventricular failure
Cor pulmonale
Cor pulmonale acute
Cor pulmonale chronic
Ejection fraction abnormal
Ejection fraction decreased
Left ventricular dysfunction
Left ventricular failure
Right ventricular failure
Ventricular dysfunction


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Ventricular failure
Hepatobiliary events
Acute hepatic failure
Alanine aminotransferase
Alanine aminotransferase abnormal
Alanine aminotransferase increased
Ammonia abnormal
Ammonia increased
Aspartate aminotransferase
Aspartate aminotransferase abnormal
Aspartate aminotransferase increased
Autoimmune hepatitis
Bilirubin conjugated abnormal
Bilirubin conjugated increased
Bilirubin urine
Blood alkaline phosphatase
Blood alkaline phosphatase abnormal
Blood alkaline phosphatase increased
Blood bilirubin
Blood bilirubin abnormal
Blood bilirubin increased
Blood bilirubin unconjugated
Blood bilirubin unconjugated increased
Cholestatic liver injury
Cytolytic hepatitis
Gamma-glutamyltransferase
Gamma-glutamyltransferase abnormal
Gamma-glutamyltransferase increased
Hepatic encephalopathy
Hepatic enzyme abnormal
Hepatic enzyme increased
Hepatic failure
Hepatic function abnormal
Hepatic infiltration eosinophilic
Hepatic necrosis
Hepatic steatosis
Hepatitis
Hepatitis acute
Hepatitis cholestatic
Hepatitis fulminant
Hepatitis toxic
Hepatobiliary disease
Hepatocellular injury
Hepatotoxicity
Hyperammonaemia
Hyperbilirubinaemia
Hypertransaminasaemia


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Jaundice
Jaundice cholestatic
Jaundice hepatocellular
Liver disorder
Liver function test
Liver function test abnormal
Liver injury
Subacute hepatic failure
Transaminases
Transaminases abnormal
Transaminases increased
Interstitial lung disease 
Acute interstitial pneumonitis 
Lung Infiltration 
Interstitial lung disease 
Pneumonitis 
               * SOC will be recoded to ‘Skin and subcutaneous tissue disorders’
The number and percentage of patients having at least one event within each AESI group will 
be summarized by treatment group and toxicity grade (all grades, grades ≥ 3). The AESIs will 
also be summarized by SOC and PT within each treatment group. Patient listing of AESIs will 
also be produced.
2.8.3
Deaths and serious adverse events (SAEs)
SAEs will be summarized for each treatment arm by system organ class and preferred term.  
The summary of on-treatment SAEs, treatment-related SAEs, ‘SAEs leading to permanent
discontinuation of study treatment’, ‘On-treatment deaths and Serious Adverse Events’ and 
‘Fatal AEs related to study treatment’ will be presented for each treatment arm. 
All deaths recorded on the Record of Death eCRF page will be summarized and listed. The 
primary reason for death will be coded.
Further, a summary detailing all on-treatment deaths will be produced.   This will consist of all 
deaths that occurred prior to the discontinuation of study treatment, with the allowance of a 
window of 30 days.  Hence, on-treatment deaths should be selected as any deaths occurring 
from day 1 of first dose received until last dose received + 30 safety follow-up days.  
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
Separate listings will be provided to support each non-fatal SAE and fatal SAE summary. 
2.8.4
Adverse events leading to discontinuation of study treatment and/or 
withdrawal from the study and other significant adverse events
All adverse events leading to permanent discontinuation of the study treatment will be 
summarized and listed. Summary of adverse events leading to dose modification, dose delay, 
and dose reduction, dose escalation, early stopping of infusion and infusion interruption but 
with infusion completion will also be provided.


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2.8.5
Clinical laboratory evaluations
Laboratory parameters will be summarized using descriptive statistics. Shifts from baseline will 
be categorized as Normal range High, within Normal range and Normal range Low. 
Additionally, lab toxicities will be displayed by Maximum toxicity grade. Laboratory toxicity
grades will be based on worst toxicity grade.
Hematology and clinical chemistry data will be summarized at each scheduled assessment, and
at study treatment discontinuation. Summaries of worst-case grade increase from baseline grade 
will be provided for all the lab tests that are gradable by CTCAE v4.0. These summaries will 
display the number and percentage of patients with a maximum post-baseline grade increasing 
from their baseline grade. Any increase in grade from baseline will be summarized along with 
any increase to a maximum grade of 3 and any increase to a maximum grade of 4. Missing 
baseline grade will be assumed as grade 0.  For laboratory tests that are graded for both low and 
high values, summaries will be done separately and labelled by direction, e.g., sodium will be 
summarized as hyponatremia and hypernatremia.
For lab tests that are not gradable by CTCAE v4.0, summaries of worst-case changes from 
baseline with respect to normal range will be generated. Decreases to low, changes to normal 
or no changes from baseline, and increases to high will be summarized for the worst case post-
baseline. If a patient has a decrease to low and an increase to high during the same time interval, 
then the patient is counted in both the “Decrease to Low” categories and the “Increase to High” 
categories. 
Supporting listings for haematology and chemistry laboratory tests will be produced.
A supporting listing of laboratory data for patients with abnormalities of CTC grade 3 or 4 will 
be provided. Unless otherwise specified, the denominator in percentage calculation at each 
scheduled visit will be based on the number of patients with non-missing value at each particular 
visit.
Laboratory test results will be reported in International System of Units (SI).
Summary and listing of hematology and serum chemistry parameters will be presented in SI 
unit. The listing of local labs by country, center, sex, and age will also be displayed with local 
lab name, address, original unit of lab parameters and normal ranges. 
2.8.6
Analyses of liver function test
Hepatobiliary lab abnormalities will be summarized and listed for any patients with lab 
abnormalities for aspartate aminotransferase (AST), alanine aminotransferase (ALT), total 
bilirubin and alkaline phosphatase (ALP) according to the categories listed in Table 2-5
:
Table 2-5
Hepatobiliary Lab Abnormality Criteria
Category
Possible Hy’s Law: >3x ULN ALT & ≥2x ULN BIL [1] &  (<2x ULN ALP or ALP missing)
>3x ULN ALT & ≥ 2x ULN BIL [1]
Hepato-cellular injury [2]


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> 3x ULN ALT or AST
> 5x ULN ALT or AST
> 8x ULN ALT or AST
> 20x ULN ALT or AST
> 3x ULN ALT
> 5x ULN ALT
> 8x ULN ALT
> 20x ULN ALT
> 3x ULN ALT and ≤ 3x ULN ALT Baseline
≥ 2x ULN BIL [1] and < 2x ULN BIL Baseline
≥ 3x ULN ALP and < 3x ULN ALP Baseline
≥ 2x ULN BIL [1]
≥ 3x ULN ALP
ALT: alanine aminotransferase; AST: aspartate aminotransferase; ALP: alkaline phosphatase; 
BIL: Total Bilirubin; ULN=Upper Limit of Normal.
[1] If Direct Bilirubin is available, then Direct Bilirubin must also be >35% when Total Bilirubin is ≥2x 
ULN in order to satisfy the criteria.  Bilirubin value can occur up to 28 days on or after ALT value.
[2] Hepato-cellular injury is defined as R=[Patient’s ALT / ULN of ALT] / [Patient’s ALP / ULN of ALP] 
≥5
Possible Hy’s law cases are defined as any elevated ALT>3×ULN, total bilirubin≥2×ULN and 
ALP<2×ULN/missing. Total bilirubin≥2×ULN can be within 30 days following the ALT 
elevation and if direct bilirubin is available on the same day, it must be ≥ 35% of total bilirubin. 
ALP<2xULN/missing means the criteria is satisfied unless the ALP is >2xULN at any time of 
bilirubin elevation within the 30 day window.
2.8.7
Liver toxicity
All liver events meeting either stopping or follow-up criteria as defined in Section 5.9.1 of the 
protocol will be listed. Results of liver chemistry, imaging, and other parameters as required 
will be listed. Liver pharmacokinetic measurements obtained for patients experiencing a 
respective hepatobiliary event will be listed with time elapsed since onset of the event.
The assessment of causality of a hepatobiliary event will be done with the use of the data 
collected for Roussel Uclaf Causality Assessment Method (RUCAM). RUCAM scores will not 
be calculated. The data collected will be presented in a listing.
2.8.8
Other safety measures
2.8.8.1
LVEF
Absolute change from baseline in LVEF will be summarized at each scheduled assessment 
time and in the worst case post-baseline. Only the post-baseline assessments that used the same 
method (ECHO or MUGA) as the baseline assessments will be used to derive the change from 


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baseline. The change from baseline (LVEF decrease from baseline value) will be categorized 
as below.

No change or any increase

Any decrease

>0-<10% decrease

10-19% decrease

20% decrease

10% decrease and LLN

10% decrease and below LLN

20% decrease and LLN

20% decrease and below LLN
LVEF results will also be listed with patient level details including absolute change from 
baseline.
2.8.8.2
ECG 
The ECG parameters include: QT, HR, and QTcB. QTcB considers both: QTcB = machine read 
and QTcBc = calculated manually from QTc using Bazett formula.
Summaries of 12-lead ECG data will include data from scheduled assessments only. In case of 
a scheduled record occurred with multiple unscheduled records, the scheduled record with the 
first two unscheduled assessments occurring within 30 minutes form a triplicate. The mean of 
the triplicate will be used as a point estimate instead for the triplicate. All data will be reported 
according to the nominal visit date for which they were recorded (i.e., no visit windows will be 
applied). Missing value will not be imputed. If unexpected value occurs (such as text where 
numeric is expected) then it will be set to missing.
The standard 12-lead ECG results at baseline and post-baseline visits will be summarized as 
normal, abnormal - clinically significant, or abnormal - not clinically significant. All data on 
ECG will be listed. For ECG result (interpretation) the worst result should be taken (i.e., worst 
of the recorded of the following choices: abnormal – clinically significant, abnormal- not 
clinically significant, normal).
Clinical notable (CN) criteria will be assessed through the descriptive displays listed below.  In 
all cases, post baseline refers to any post-baseline assessment including unscheduled visits. If 
unscheduled visits are associated with a triplicate, then the mean of the triplicate will be used.
Notable criteria for QT and QTcB:

Increase >30 to <=60 ms

Increase >60 ms

New >450 to <=480 ms

New >480 to <=500 ms

New >500 ms
Notable criteria for HR:


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
Increase >25% and HR >100 bpm 

Decrease >25% and HR <50 bpm
‘Increase/decrease’ refers to change from baseline; ‘new’ is also relative to baseline. For 
example, if a subject has QTcB of 450 ms at baseline and 451 ms at a post-baseline visit, then 
this post-baseline measure from the subject meets this criteria: ‘New >450 to <=480 ms’. 
Listing of cardiovascular events (CV) occurred during the study period will be displayed.
2.8.8.3
Vital signs
Vital sign assessments include weight, blood pressures (diastolic and systolic), heart rate, and 
temperature.  Change from baseline in vital signs will be summarized by treatment arm. 
Descriptive statistics will be shown for baseline, the result at each IP dose, and at the EOS visit, 
and the change from baseline to each IP dose result and at the EOS visit.
Post-baseline vital signs will be defined as clinically notable if they meet the criterion value 
listed in the table below.  The number and percentage of subjects who meet the criterion value 
and the number and percentage of subjects who meet both the criterion value and the change 
from baseline criterion will be summarized for any time post-baseline for each vital sign 
parameter.  Data from unscheduled visits will be included.
Table 2-6
Criteria for Treatment Emergent Clinically Notable Vital Signs
Vital Sign Parameter
Flag
Criterion Value
Change from Baseline
SBP (mmHg)
High (CH)
≥180
Increase of ≥20 mmHg
Low (CL)
≤90
Decrease of ≥20 mmHg
DBP (mmHg)
High (CH)
≥105
Increase of ≥15 mmHg
Low (CL)
≤50
Decrease of ≥15 mmHg
Heart Rate (bpm)
High (CH)
≥120
Increase of ≥15 bpm
Low (CL)
≤50
Decrease of ≥15 bpm
The listing of vital sign data will be displayed.
2.9
Pharmacokinetic endpoints
Liver pharmacokinetic data from any patient who experiences a liver adverse event as defined 
by the protocol will be listed.    
2.10
Patient-reported outcomes
Up to approval of protocol amendment 2, the multidimensional assessment of fatigue (MAF) 
and the FACT-B questionnaire were not collected anymore. The previously collected data were 
listed in the primary CSR. 
2.11
Biomarkers
The biomarker analyses are the primary analyses. These are defined in Section 2.5. If any further 
biomarker analyses are required, they will be defined according to the results of the primary 


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analysis. These analyses will be the presented in a separate analysis plan and study report if 
such analysis is conducted.
2.12
Interim analysis
Other than the analysis for the primary CSR, there is no interim analysis. 
3
Sample size calculation
Sample size is not based on statistical power to detect difference between the treatment arms. 
The number of patients in the study is based on the patient accrual rate. Eighty-seven patients 
were screened, 42 patients have been randomized (32 patients with HER2- enriched and 10 
patients with HER2- Non-enriched population). A decision was made to close the study early.
Recruitment was closed on 31 March 2017.
4
Change to protocol specified analyses
No change from protocol specified analysis was made.
5
Reference
Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th Ed. New 
York, NY: Springer, 2010, pp 347-76.
Gaby Danan and Rolf Teschke. RUCAM in Drug and Herb Induced Liver Injury: The Update. 
International Journal of Molecular Sciences; 2016; 17: 14.