Clinical trial NCT02294786
Conditions: Cancer
Keywords: Randomised Octreotide Diarrhoea Phase II Capecitabine Quality of life Metastatic breast cancer HER2 Lapatinib Diarrhoea diary
Sponsor: Novartis Pharmaceuticals
Start date: 2014-12-17; Completion date: 2017-10-19
Enrollment: 62 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Diarrhoea is the most commonly reported adverse event (AE) associated with Lapatinib treatment, and is also commonly associated with Capecitabine treatment. Although these events are generally mild to moderate in severity, diarrhoea adversely affects the tolerability of cancer treatment, and in severe cases diarrhoea has the potential to affect the efficacy of treatment due to poor compliance, or treatment interruption or withdrawal. The efficacy of Octreotide in the management of cancer treatment-associated diarrhoea has not been extensively evaluated in large, well-controlled studies. This is a randomised, multi-centre, open-label Phase II study in subjects with Human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer which has progressed following prior therapy, which must have included anthracyclines and taxanes and therapy with Trastuzumab in the metastatic setting. This study is not placebo controlled, and there is no active comparator. The study evaluates whether the prophylactic use of Octreotide Long Acting Release (LAR) offers a clinically meaningful benefit by reducing the frequency and severity of diarrhoea associated with treatment with Lapatinib and Capecitabine. Study completion for a subject is defined as the completion of 24 weeks of treatment with Lapatinib and Capecitabine, or progression of cancer or the death of the subject during treatment, whichever occurs first. Approximately 140 subjects were planned to be randomized out of which 70 were planned to receive octreotide and 70 were planned to receive no Octreotide.

Detailed description:

Arms: arm 1: Subjects randomised to receive Octreotide were administered with Octreotide (Sandostatin LAR™) 40mg 7 days before the start of treatment with Lapatinib and Capecitabine and again 28 days later. All subjects received treatment with Lapatinib 1250milligram (mg) once daily and Capecitabine 1000 milligram/square meter (mg/m\^2) twice daily until disease progression. Lapatinib was given every day; Capecitabine was given in 3 week cycles of two weeks treatment followed by one week off treatment. SANDOSTATIN™ is a trademark of Novartis. arm 2: Subjects randomised to receive no octreotide, treatment with Lapatinib and Capecitabine was initiated immediately following enrolment. All subjects received treatment with Lapatinib 1250mg once daily and Capecitabine 1000mg/m\^2 twice daily until disease progression. Lapatinib was given every day; Capecitabine was given in 3 week cycles of two weeks treatment followed by one week off treatment
Interventions: intervention 1: Lapatinib intervention 2: Capecitabine intervention 3: Octreotide
Intervention descriptions: intervention 1: Lapatinib was supplied as 250mg tablets that are oval, biconvex, and orange film-coated with one side plain and the opposite side debossed, or as 250mg tablets that are oval, biconvex, and yellow film-coated with one side plain and the opposite side debossed. Each tablet contained 405mg of Lapatinib ditosylate monohydrate, equivalent to 250mg Lapatinib free base intervention 2: Capecitabine (Xeloda™) was supplied as a biconvex, oblong, light peach or peach colored film-coated tablet for oral administration. Each light peach colored tablet contained 150mg Capecitabine and each peach colored tablet contained 500mg Capecitabine. Generic versions of capecitabine may have been used within the study if Xeloda cannot be provided. XELODA™ is a trademark of Hoffmann-La Roche AG. intervention 3: Octreotide (Sandostatin LAR™) was supplied as sterile 5milliliter (mL) vials delivering 20mg Octreotide as the free peptide. When mixed with diluent (approximately 2mL or 2.5 mL) it becomes a suspension that is given as an intramuscular injection. Two 20mg intramuscular injections were given to deliver a total dose of 40mg. The Octreotide is uniformly distributed within the microspheres which are made of a biodegradable glucose star polymer, D,L-lactic and glycolic acids copolymer. Sterile mannitol was added to the microspheres to improve suspendability

Protocol documents:
Prot_000.pdf: 
2012N152651_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
LAP117314
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Randomised, Multicentre, Open Label, Phase II study of 
Prophylactic Octreotide to Prevent or Reduce the Frequency and 
Severity of Diarrhoea in Subjects Receiving Lapatinib with 
Capecitabine for the Treatment of Metastatic Breast Cancer
Compound Number: GW572016 / NCT02294786
Development Phase: 
II
Effective Date: 
11-SEP-2015
Protocol Amendment Number:02
Author (s):
 
Copyright 2015 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.


2012N152651_03
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LAP117314
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2012N152651_00
2014-FEB-17
Original
2012N152651_01
2014-AUG-11
Amendment No. 01
In Amendment 01:

Prior treatment with lapatinib was added as an exclusion criterion;

Additional detail was provided for dermatological monitoring;

Secondary endpoints related to patient reported outcomes were updated;

The schedule for completion of the Diarrhoea Management Diary and FACIT-D was
clarified;

The schedule of study visits relative to the week numbers and cycles of treatment
with lapatinib and capecitabine was clarified;

The use of octreotide s.c. within the diarrhoea management guidelines was clarified.
2012N152651_02
2014-AUG-23
Republishing Amendment 1
In Amendment 01:

Errors identified in Time and Events Tables 16 and Table 17 were corrected.
2012N152651_03
2015-SEP-11
Amendment No. 02
In Amendment 02:

Details of planned interim analysis included in Protocol Summary, Study
Assessments, for early assessment of the primary endpoint.

Recruitment Plan Section was included as an interim analysis was being
incorporated.

Blinding Section was updated with further clarification to support addition of an
interim analysis.

Number of subjects undergoing formal review of safety data was updated to reflect
consistency with planned interim analysis.

Details of tertiary Sponsor Medical Monitor Contact Information added. Author list,
Sponsor Signatory, address and telephone numbers of medical monitors updated

Instructive text presented in Appendix for Country Specific Requirements deleted.

Statement regarding application of amendment 01 to all participating sites added to
improve the quality of the protocol.


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SPONSOR SIGNATORY
 ,DO, 
Date


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SPONSOR INFORMATION PAGE
Clinical Study Identifier:
LAP117314
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address
GlaxoSmithKline Research & Development Limited
Stockley Park West,
1-3 Iron Bridge Road,
Uxbridge,
Middlesex, UB11 1BU
UK
Telephone:
 
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.
Sponsor Medical Monitor Contact Information
, MD
Novartis Farmaceutica S. A., Madrid Site
Office:
Mobile:
e mail:
Sponsor Secondary Medical Monitor Contact Information: 
, MD
Novartis Farma S. p. A.
Office:
Mobile:
e mail:


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Sponsor Tertiary Medical Monitor Contact Information: 
Novartis Pharmaceuticals
Office: 
Mobile: 
Email: 
Principal Investigator Information:
Professor 
 
 MD PhD
Professor 
 BSc, D.Phil, 
 
 
Regulatory Agency Identifying Number(s): 2014-000256-28


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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number LAP117314
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described 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 receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................11
PROTOCOL SUMMARY...............................................................................................13
1.
INTRODUCTION....................................................................................................19
1.1.
Background ................................................................................................19
1.2.
Study Rationale ..........................................................................................28
1.3.
Benefit:Risk Assessment ............................................................................30
1.3.1.
Risk Assessment .........................................................................30
1.3.2.
Benefit Assessment.....................................................................32
1.3.3.
Overall Benefit:Risk Conclusion...................................................32
2.
OBJECTIVES AND ENDPOINTS...........................................................................33
3.
INVESTIGATIONAL PLAN.....................................................................................37
3.1.
Study Design ..............................................................................................37
3.2.
Discussion of Design ..................................................................................40
3.3.
Recruitment Plan ........................................................................................42
4.
SUBJECT SELECTION AND DISCONTINUATION/ COMPLETION 
CRITERIA ..............................................................................................................43
4.1.
Subject Selection Criteria............................................................................43
4.1.1.
Number of Subjects .....................................................................43
4.1.2.
Inclusion Criteria..........................................................................43
4.1.3.
Exclusion Criteria.........................................................................44
4.2.
Other Eligibility Criteria Considerations.......................................................45
4.3.
Permanent Discontinuation from Study Treatment and Subject 
Completion Criteria.....................................................................................46
4.3.1.
Discontinuation from Treatment with Octreotide...........................46
4.3.2.
Discontinuation from Treatment with Lapatinib and 
Capecitabine................................................................................47
4.3.3.
Subject Completion......................................................................47
5.
STUDY TREATMENTS..........................................................................................48
5.1.
Lapatinib.....................................................................................................48
5.1.1.
Lapatinib Dosage and Administration...........................................49
5.2.
Capecitabine...............................................................................................49
5.2.1.
Capecitabine Dosage and Administration ....................................49
5.3.
Octreotide...................................................................................................50
5.3.1.
Octreotide Dosage and Administration.........................................50
5.4.
Handling and Storage of Study Treatment ..................................................51
5.5.
Treatment Assignment................................................................................51
5.6.
Blinding.......................................................................................................51
5.7.
Product Accountability ................................................................................51
5.8.
Treatment Compliance................................................................................52
5.9.
Dose Adjustment ........................................................................................52
5.10.
Dose Delays and Reductions for Lapatinib .................................................53
5.11.
Dose Delays and Reductions for Capecitabine ...........................................54


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5.12.
Guidelines for Events of Special Interest and Dose Modifications...............55
5.12.1.
Dermatological Events.................................................................56
5.12.1.1.
Dermatological Monitoring..........................................56
5.12.1.2.
Frequency Evaluation and Grading Guide of 
Dermatological AEs....................................................56
5.12.1.3.
Stopping and holding rules .........................................59
5.12.1.3.1.
Holding rule ............................................59
5.12.1.3.2.
Re-challenge ..........................................60
5.12.1.3.3.
Stopping rules.........................................60
5.12.1.4.
Treatment...................................................................60
5.12.2.
Gastrointestinal Events................................................................61
5.12.2.1.
Nausea and vomiting..................................................61
5.12.2.2.
Diarrhoea ...................................................................61
5.12.3.
Cardiac and Respiratory Events ..................................................61
5.12.4.
Hand and Foot Syndrome............................................................62
5.13.
Monitoring, Interruption, and Stopping Criteria for Hepatobiliary 
Events ........................................................................................................63
5.13.1.
Liver Chemistry Stopping Criteria ................................................63
5.13.1.1.
Liver event follow up assessments .............................65
5.13.2.
Liver Chemistry Monitoring Criteria..............................................66
6.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .........................66
6.1.
Permitted Medications and Non-Drug Therapies.........................................66
6.2.
Prohibited Medications and Non-Drug Therapies........................................67
6.3.
Treatment after Discontinuation of the 24 Week Study Treatment or 
Withdrawal from/Completion of Study.........................................................69
6.4.
Treatment of Study Treatment Overdose....................................................70
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................71
7.1.
Assessments and Procedures ....................................................................74
7.1.1.
Critical Baseline Assessments.....................................................74
7.1.2.
Screening and Baseline Assessments and Procedures ...............74
7.1.3.
Prior to Randomisation ................................................................76
7.1.4.
Post-Randomisation ....................................................................76
7.1.5.
One Week after the First Dose of Octreotide LAR 
(Subjects Randomised to Receive Octreotide only) .....................77
7.1.6.
Assessments Every 3 Weeks.......................................................77
7.1.7.
Unscheduled Visits ......................................................................78
7.1.8.
Study Completion (24 weeks) or Early Withdrawal from 
Study and/or Study Treatment .....................................................78
7.1.9.
Assessments after Study Completion: Long Term Follow 
Up................................................................................................79
7.1.10.
Procedures and Assessments: Additional Information .................80
7.1.11.
Disease Assessments..................................................................80
7.2.
Efficacy Endpoints ......................................................................................81
7.3.
Safety Endpoints.........................................................................................81
7.4.
Adverse Events...........................................................................................81
7.4.1.
Definition of an AE.......................................................................82
7.4.2.
Definition of a SAE.......................................................................83
7.4.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................84
7.4.4.
Cardiovascular Events.................................................................85


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7.4.5.
Death Events...............................................................................85
7.4.6.
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs...............................................85
7.4.7.
Time Period and Frequency of Detecting AEs and SAEs.............86
7.4.8.
Method of Detecting AEs and SAEs.............................................86
7.4.9.
Prompt Reporting of SAEs and Other Events to GSK ..................86
7.4.10.
Regulatory Reporting Requirements for SAEs .............................88
7.5.
Pregnancy Testing, Prevention and Reporting............................................88
7.5.1.
Pregnancy Test and Prevention...................................................88
7.5.2.
Pregnancy Reporting ...................................................................90
7.6.
Laboratory Assessments ............................................................................90
7.7.
Health Outcomes........................................................................................90
7.7.1.
Health Outcomes Endpoints ........................................................90
7.7.2.
Health Outcomes Assessments...................................................90
91
8.
DATA MANAGEMENT ...........................................................................................91
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................92
9.1.
Hypotheses.................................................................................................92
9.2.
Study Design Considerations......................................................................92
9.2.1.
Sample Size Assumptions ...........................................................92
9.2.2.
Sample Size Sensitivity................................................................92
9.2.3.
Sample Size Re-estimation..........................................................93
9.3.
Data Analysis Considerations .....................................................................93
9.3.1.
Analysis Populations....................................................................93
9.3.2.
Analysis Data Sets.......................................................................94
9.3.3.
Treatment Comparisons ..............................................................94
9.3.3.1.
Primary comparison of interest ...................................94
9.3.3.2.
Other comparisons of interest.....................................94
9.3.4.
Interim Analysis ...........................................................................95
9.3.4.1.
Interim Review of Safety Profile..................................95
9.3.4.2.
Futility Analysis of Primary Endpoint...........................95
9.3.5.
Key Elements of Analysis Plan ....................................................96
9.3.5.1.
Efficacy analyses........................................................97
9.3.5.1.1.
Primary endpoint analysis.......................97
9.3.5.1.2.
Secondary endpoint analysis: 
Investigator-reported endpoints ..............98
9.3.5.1.3.
Secondary analyses: Patient-
reported endpoints................................100
9.3.5.2.
Safety analyses........................................................101
9.3.5.2.1.
Extent of exposure................................102
9.3.5.2.2.
Adverse events.....................................102
9.3.5.2.3.
Clinical laboratory evaluations ..............102
9.3.5.2.4.
Other safety measures .........................102
9.3.5.3.
Health Outcomes analyses.......................................103
103
10. STUDY CONDUCT CONSIDERATIONS .............................................................104
10.1.
Posting of Information on Publicly Available Clinical Trial Registers..........104
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................104


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10.3.
Quality Control (Study Monitoring) ............................................................105
10.4.
Quality Assurance.....................................................................................105
10.5.
Study and Site Closure .............................................................................105
10.6.
Records Retention....................................................................................106
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication..................106
10.8.
Safety Review Team.................................................................................107
11. REFERENCES.....................................................................................................108
12. APPENDICES......................................................................................................112
12.1.
Appendix 1 Diarrhoea Management Guidelines........................................112
12.2.
Appendix 2 FACIT-D Questionnaire..........................................................120
124
12.4.
Appendix 4 Eastern Cooperative Oncology Group Performance 
Status .......................................................................................................129
12.5.
Appendix 5 Country Specific Requirements..............................................130
12.6.
Appendix 6 Cockcroft-Gault Equation for Calculating Creatinine 
Clearance .................................................................................................131
12.7.
Appendix 7 Liver Chemistry Monitoring, Interruption Stopping and 
Follow-up Criteria......................................................................................132
12.8.
Appendix 8 Protocol Changes...................................................................133


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LIST OF ABBREVIATIONS
ADL
Activities of daily living
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
ASCO
(the) American Society of Clinical Oncology
AST
Aspartate aminotransferase
CBR
Clinical benefit response
CI
Confidence interval
CR
Complete response
(e)CRF
(Electronic) Case report form
DMD
Diarrhoea Management Diary
DSS
Diarrhoea symptom subscale
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group 
EGFR
Epidermal growth factor receptor
EWB
Emotional wellbeing
FACIT-D
Functional Assessment of Chronic Illness Therapy-Diarrhoea
FACT-G
Functional Assessment of Cancer Therapy-General
5-FU
5 Fluorouracil
FWB
Functional wellbeing
GCP
Good clinical practice
GSK
GlaxoSmithKline
hCG
Human chorionic gonadotrophin
HER2
Human epidermal growth factor receptor 2
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IgM
Immunoglobulin M
INR
International normalized ratio
IRB
Institutional Review Board
ITT
Intention to treat
IVR
Interactive voice response
LAR
Long acting release
LLN
Lower limit of the normal range
LTFU
Long term follow up
MBC
Metastatic breast cancer
m-ITT
Modified intention to treat
MedDRA
Medical Dictionary for Regulatory Activities
NA
Not applicable
NCI CTCAE
National Cancer Institute common terminology criteria for 
adverse events
NE
Not evaluable
ORR
Overall response rate
PD
Progressive disease
PFS
Progression free survival


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PP
Per protocol
PR
Partial response
PRO
Patient-reported outcome
PWB
Physical wellbeing
RAMOS
Registration and Medication Ordering System
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria In Solid Tumours
SAE
Serious adverse event
s.c.
Subcutaneous
SD
Stable disease
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
SPM
Study Procedures Manual
SRT
Safety Review Team
SWB
Social wellbeing
ULN
Upper limit of the normal range
VIP
Vasoactive intestinal polypeptide
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
TYKERB
Sandostatin
TYVERB
Xeloda


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PROTOCOL SUMMARY
Rationale
The combination of lapatinib with capecitabine is approved for the treatment of patients 
with human epidermal growth factor receptor 2 (HER2)-positive breast cancer which has
progressed following prior therapy, which must have included anthracyclines and taxanes 
and trastuzumab in the metastatic setting.  
Diarrhoea is a common adverse event (AE) reported in studies of both lapatinib and 
capecitabine.  Diarrhoea associated with cancer treatment is usually managed reactively, 
and standardised guidelines have been developed by the American Society of Clinical 
Oncology (ASCO); these guidelines have been modified by GlaxoSmithKline (GSK) for 
the management of diarrhoea associated with lapatinib use.  Most episodes of diarrhoea 
reported in studies of lapatinib were mild to moderate in severity and uncomplicated, and 
were managed by dietary modification and by the use of loperamide, which is the first 
line approach recommended in both the ASCO and GSK diarrhoea management 
guidelines.  
Octreotide is approved for the treatment of the severe diarrhoea and flushing episodes 
associated with metastatic carcinoid tumors and for the treatment of diarrhoea associated 
with vasoactive intestinal polypeptide-secreting tumours. Octreotide is effective in the
treatment of diarrhoea associated with a number of conditions including carcinoid 
syndrome, short-bowel syndrome, and dumping syndrome.  Octreotide provides effective 
control of chemotherapy-associated diarrhoea.  Octreotide is also effective in the 
management of chemotherapy-associated diarrhoea which is unresponsive to treatment 
with loperamide, and is included as a second line agent in the ASCO and GSK guidelines
for the management of more persistent diarrhoea.
Octreotide is available as a short acting formulation for subcutaneous injection, usually 
given three times daily, and as a long acting release (LAR) depot formulation for 
intramuscular injection, to be given once every 28 days.  Treatment with octreotide is 
generally well tolerated, and the benefits and risks associated with the use of octreotide in 
its approved indications are described in the Octreotide SPC and the Octreotide LAR 
SPC.  Gastrointestinal AEs are common, and include both diarrhoea and constipation.  
Adverse events related to the mechanism of action of octreotide have also been reported, 
including hyperglycaemia, hypoglycaemia, impaired glucose tolerance, hypothyroidism, 
thyroid dysfunction and cholelithiasis.  However, these mechanism-related AEs are more 
usually associated with longer term treatment.
Diarrhoea associated with cancer therapy may affect the patients’ sense of wellbeing and 
can result in treatment interruption or dose reduction, potentially reducing the therapeutic 
benefit of the cancer treatment.  The frequency and severity of diarrhoea associated with 
cancer treatment has been extensively evaluated in clinical studies, but it is not known 
how accurately these data reflect the occurrence of diarrhoea in the wider patient 
population.  It is also possible that diarrhoea is under-reported within the context of a 
clinical study, and that the effects of diarrhoea on patient wellbeing may not be reflected 
in the investigator-reported outcomes recorded in a clinical study.  Furthermore it is 


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likely that diarrhoea might affect treatment compliance, which is known to be sub-
optimal with many oral anti-cancer treatments, and episodes of diarrhoea might adversely 
influence the acceptability of subsequent cycles of treatment.
The prevention of diarrhoea associated with cancer treatment has the potential to benefit 
patients by reducing the frequency and severity of adverse events, improving patients’ 
sense of wellbeing and improving treatment compliance.  The efficacy of loperamide and
octreotide in the treatment of chemotherapy-associated diarrhoea is established and has 
been included in the diarrhoea management guidelines developed by ASCO and by GSK.  
However, few studies have evaluated the efficacy of prophylactic loperamide or 
octreotide in the prevention of cancer treatment-associated diarrhoea, and no well 
controlled large studies have been conducted.  The results of the few studies which have 
been reported are equivocal.
LAP117314 is an open label, randomised study to explore the potential benefit of the 
prophylactic use of octreotide in the prevention or reduction of diarrhoea associated with 
treatment with lapatinib and capecitabine.  The primary endpoint of the study is 
investigator- reported diarrhoea with a severity of Grade 2 and above, as defined by the 
National Cancer Institute common terminology criteria for adverse events (NCI CTCAE), 
version 4.03.  The definition of AEs in accordance with the NCI CTCAE criteria is 
consistent with the definitions used in previous studies of lapatinib in combination with 
capecitabine.  Diarrhoea with a severity of Grade 2 or more has a significant effect on the 
tolerability of treatment, the acceptability of continued treatment, and the subject’s sense 
of wellbeing.  Management of Grade 2 diarrhoea includes treatment interruption for 
capecitabine when the first episode occurs, and treatment interruption for lapatinib after 
the second episode.  Secondary endpoints include other aspects of the frequency and 
severity of diarrhoea of all grades of severity and of the consequences and management 
of diarrhoea, which will be recorded by the investigator using standard methodology and 
also by patient reported outcome (PRO) measures in the study-specific Diarrhoea 
Management Diary (DMD) and in the Functional Assessment of Chronic Illness 
Therapy-Diarrhoea (FACIT-D).  Inclusion of PROs in this study provides an opportunity 
to contrast and compare outcomes reported by investigators and by subjects within each 
treatment group, although differences between the electronic Case Report Form (eCRF) 
data and the PRO data will preclude formal comparisons.  Disease progression measured 
as overall response rate and clinical benefit response is a secondary endpoint.
The prevention of diarrhoea associated with cancer treatment has the potential to improve 
treatment compliance and to improve the patients’ sense of wellbeing.  LAP117314 will 
evaluate the efficacy of the prophylactic use of octreotide in the prevention or reduction 
of diarrhoea associated with treatment with lapatinib and capecitabine.
Objectives
The primary objective of this study will be to evaluate the efficacy of octreotide 
prophylaxis in reducing the proportion of subjects experiencing diarrhoea with a severity 
of Grade 2 and above, as defined by the NCI CTCAE, version 4.03.


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The secondary objectives will be to determine the efficacy of octreotide prophylaxis in
reducing:

the proportion of subjects experiencing diarrhoea with a severity of Grade 3 and 
above;

the proportion of subjects experiencing at least one episode of diarrhoea of each
grade of severity;

the time to onset of the first episode of diarrhoea of any grade of severity;

the duration of each episode of diarrhoea of any grade of severity;

the proportion of subjects taking medication as a result of diarrhoea;

the proportion of subjects making dietary changes to manage diarrhoea (PRO 
only);

the proportion of subjects making unscheduled visits to healthcare professionals 
as a result of diarrhoea;

the proportion of subjects making or requiring changes to treatment with 
lapatinib and capecitabine (missed doses, dose delays, dose reductions and 
treatment withdrawal) as a result of diarrhoea;

the proportion of subjects requiring treatment with intravenous fluids as a result 
of diarrhoea;
and to determine the effect of octreotide prophylaxis on:

compliance with treatment with lapatinib and capecitabine;

treatment efficacy (overall response rate and clinical benefit response);

quality of life;

overall safety and tolerability of treatment with lapatinib and capecitabine.
Data will be recorded by the investigators in the eCRF at each study visit, and by subjects 
in the DMD every week and in the FACIT-D every 3 weeks.  The eCRF, DMD and 
FACIT-D are considered to be independent sources of study data, and investigators must 
not use information collected in the DMD and FACIT-D to supplement data entry into 
the eCRF.  
 
 


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Study Design
This is a randomised, parallel group, multicentre, open label Phase II study of 
prophylactic octreotide to prevent or reduce the frequency and severity of diarrhoea in 
subjects receiving lapatinib with capecitabine for the treatment of advanced or metastatic 
breast cancer.  This study is not placebo controlled, and there is no active comparator.
The study will enroll 140 women with histologically or cytologically confirmed HER2-
positive advanced or metastatic breast cancer which has progressed following prior 
therapy, which must have included anthracyclines and taxanes and trastuzumab in the 
metastatic setting.  LAP117314 is an exploratory Phase II study, and the sample size is 
not based on the number of subjects required to achieve a pre-specified reduction in the 
control incidence of diarrhoea.  All subjects will receive treatment with lapatinib 1250mg 
once daily and capecitabine 1000mg/m2 twice daily.  The study duration is 24 weeks, but 
subjects will receive treatment with lapatinib and capecitabine until disease progression.  
Lapatinib will be given every day; capecitabine will be given in 3 week cycles of two 
weeks treatment followed by one week off treatment.  This treatment regimen and the 
subject population are consistent with the approved indication for the use of lapatinib 
with capecitabine in patients with advanced or metastatic breast cancer.  Dose 
modification, treatment interruption and withdrawal from study treatment will be in 
accordance with the Lapatinib SPC and Capecitabine SPC.
Subjects will be randomised in a 1:1 ratio to receive either: 

Octreotide (Sandostatin LAR) 40mg 7 days before the start of treatment with 
lapatinib and capecitabine and again 28 days later, or

No octreotide treatment.
Subjects randomised to receive octreotide LAR will be given octreotide 0.1mg in the 
subcutaneous (s.c.) formulation at least one hour before the first dose of octreotide in the 
LAR formulation is administered, to assess the tolerability of octreotide.  Subjects with 
significant intolerance to octreotide 0.1mg s.c. will not receive treatment with octreotide 
LAR, but will receive treatment with lapatinib and capecitabine as scheduled.
The study subject population and the dosage regimen for lapatinib and capecitabine are 
consistent with the approved indication for the use of this combination in patients with 
metastatic breast cancer (MBC).  The benefits and risks associated with lapatinib and 
capecitabine treatment in this study are presented in the Lapatinib SPC.  Treatment with 
octreotide in this study is not consistent with the approved indications for octreotide.
Study Assessments
The primary endpoint of LAP117314 is the proportion of subjects experiencing diarrhoea 
with a severity of Grade 2 and above, as defined by the NCI CTCAE, version 4.03.  The 
frequency and severity of episodes of diarrhoea will be recorded at each visit, by 
completion of the AE modules in the eCRF.  Action taken as a result of diarrhoea (anti-
diarrhoeal medication, unscheduled visits to healthcare professionals, dose reduction or 


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delay in treatment with lapatinib and capecitabine, treatment withdrawal, and intravenous 
fluid rehydration) will be recorded in the eCRF at each visit.  
All subjects will complete the baseline DMD and FACIT-D during the 3 days prior to 
randomisation, before any study-related treatment is administered.  Subjects randomised 
to receive octreotide will complete a second baseline DMD and FACIT-D before starting 
the first cycle of treatment with lapatinib and capecitabine.  Subjects will then complete 
the DMD every week and the FACIT-D every 3 weeks until the end of 24 weeks of 
treatment with lapatinib and capecitabine or subject withdrawal, whichever is sooner.  
The DMD and FACIT-D will not be completed beyond 24 weeks of treatment.
Disease status will be assessed prior to the start of treatment with lapatinib and 
capecitabine in accordance with the Response Evaluation Criteria In Solid Tumours 
(RECIST), version 1.1.  Disease progression will be evaluated by the investigator in 
accordance with local clinical practice during the course of treatment with lapatinib and 
capecitabine, and in accordance with RECIST version 1.1 at the end of study visit 
(subject withdrawal or at the end of 24 weeks of treatment with lapatinib and 
capecitabine, whichever is sooner). Treatment with lapatinib and capecitabine may 
continue beyond 24 weeks until disease progression occurs, but there will be no further 
data collection of disease progression beyond 24 weeks of treatment.
The safety and tolerability of treatment with octreotide, lapatinib and capecitabine will be 
evaluated by AE and serious AE reporting at each visit until subject withdrawal or the 
end of 24 weeks of treatment with lapatinib and capecitabine.  Serious AEs and other 
specific safety assessments will be reported in subjects who continue treatment with 
lapatinib and capecitabine beyond 24 weeks.  Serious AEs will be followed up until
resolution or stabilisation of the event or until the subject is lost to follow-up.  
All subjects with episodes of diarrhoea will be encouraged to follow the GSK diarrhoea 
management guidelines for subjects receiving lapatinib.  The use of octreotide in the s.c. 
formulation for the management of diarrhoea refractory to treatment with loperamide is 
not excluded.  Investigators should use their clinical judgement concerning the use of 
octreotide s.c. in subjects randomised to receive treatment with octreotide LAR, 
particularly during Week 2 through to Week 12 of treatment with lapatinib and 
capecitabine, when circulating concentrations of octreotide should already be within the 
clinically effective range.
Cardiac function will be evaluated prior to the start of treatment, in accordance with the 
Lapatinib SPC.  Physical examination findings, vital signs, clinical laboratory tests, 
clinical monitoring and observations will be reported at the start of the study in 
accordance with the protocol baseline and screening requirements, during the course of 
the study in accordance with local clinical practice and the requirements of the Lapatinib, 
Capecitabine and Octreotide SPCs, and at subject withdrawal or after 24 weeks of 
treatment with lapatinib and capecitabine, whichever is sooner, in accordance with the 
protocol.  Dermatological monitoring and assessment will be conducted in accordance 
with the guidance provided in the Lapatinib SPC.


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A GSK Safety Review Team will review safety data on an ongoing basis and at pre-
defined points during the course of the study to protect the interests of subjects and to 
ensure their safety.
An interim analysis is planned when approximately 40% of the patients have been 
recruited and when those subjects have received 3 cycles of study treatment (lapatinib 
plus capecitabine), i.e. after 9 weeks of study treatment. The first safety review will take 
place at the same time as the interim analysis.


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1.
INTRODUCTION
1.1.
Background
Breast cancer is the most common form of cancer in women in the USA and in Europe 
[American Cancer Society, 2013; Ferlay, 2013]  In the USA, there were more than 
230,000 new cases of invasive breast cancer and over 39,000 deaths from breast cancer in 
2011 [American Cancer Society, 2013].  In Europe, there were an estimated 464,000 new 
cases and approximately 131,000 deaths from breast cancer in 2012 [Ferlay, 2013].  
Lapatinib is a reversible, orally active tyrosine kinase inhibitor that potently inhibits both 
epidermal growth factor receptor 1 (EGFR) and human epidermal growth factor receptor 
2 (HER2) [Lapatinib SPC].  Capecitabine is a non-cytotoxic fluoropyrimidine carbamate, 
which functions as an orally administered precursor of the cytotoxic moiety 5-
fluorouracil (5-FU) [Capecitabine SPC].  Lapatinib is indicated for the treatment of adult 
patients with breast cancer, whose tumours overexpress HER2, in combination with 
capecitabine for patients with advanced or metastatic disease with progression following 
prior therapy, which must have included anthracyclines and taxanes and therapy with 
trastuzumab in the metastatic setting.
The efficacy of lapatinib with capecitabine in subjects with metastatic breast cancer 
(MBC) was demonstrated in the registration study EGF100151, which compared the 
efficacy and tolerability of lapatinib with capecitabine to that of capecitabine alone 
[Cameron, 2008].  The efficacy of lapatinib with capecitabine was greater than that of 
capecitabine alone with respect to time to progression (the interval between the date of 
randomisation and the earliest date of disease progression or death due to breast cancer), 
progression free survival (PFS; the time from randomisation until the earliest date of 
either disease progression or death due to any cause), response rate (the percentage of 
subjects achieving either a complete or partial tumour response) and clinical benefit 
response (the percentage of subjects with evidence of complete or partial tumor response 
or stable disease for at least 6 months; Table 1).  Similar efficacy was shown for the 
combination of lapatinib with capecitabine in 271 subjects in a subsequent study, 
EGF111438 [GlaxoSmithKline Document Number 2012N144830_00], in which the 
median duration of PFS was 6.60 months (95% confidence interval [CI]: 5.72-8.11 
months), equivalent to 28.6 weeks (95% CI: 24.8-35.1 weeks).


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Table 1
EGF100151: Summary of efficacy (ITT Population)
Lapatinib with 
capecitabine
(n=198)
Capecitabine 
monotherapy
(n=201)
Hazard ratio
p
Time to disease progression, 
weeks (95% CI);
Independent review
27.1
18.6
0.57
(0.43-0.77)
0.00013
Time to disease progression, 
weeks (95% CI)
Investigator assessed
23.9
18.3
0.72
(0.56-0.92)
0.00762
Progression free survival, 
weeks (95% CI)
27.1
(24.1-36.9)
17.6
(13.3-20.1)
0.55
(0.41-0.74)
0.000033
Odds ratio
Response rate, %
(95% CI)
Independent review
23.7
(18.0-30.3)
13.9
(9.5-19.5)
1.9
(1.1-3.4)
0.017
Response rate, %
(95% CI)
Investigator assessed
31.8
(25.4-38.8)
17.4
(12.4-23.4)
2.2
(1.3-3.6)
0.002
Clinical benefit response, %
(95% CI)
Independent review
29
17
2.0
(1.2-3.3)
0.008
Clinical benefit response, %
(95% CI)
Investigator assessed
37
21
0.001
CI=confidence interval; ITT=Intention to treat; p=probability
The most common adverse events (AE) reported during treatment in EGF100151 were 
gastrointestinal (diarrhoea, nausea, and vomiting) or dermatologic (palmer plantar 
erythrodysesthesia and rash); most were National Cancer Institute common terminology 
criteria for adverse events (NCI-CTCAE) Grade 1 or 2 and were controlled by standard
therapy.  Published EGF100151 data [Cameron, 2008] are based on a safety population 
of 198 subjects who received treatment with lapatinib and capecitabine.  Diarrhoea was 
reported by 65% of subjects overall, and diarrhoea with a severity of Grade 2 or more 
was reported by 34% of subjects. 


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Gastrointestinal and dermatological AEs in a later analysis of data based on 210 subjects 
who received lapatinib with capecitabine in EGF100151 are summarised in Table 2.  
These data are taken from the EGF100151clinical study report [GlaxoSmithKline 
Document Number UM2004/00001/00] and are cited in the Lapatinib Investigator’s 
Brochure [Lapatinib Investigator’s Brochure GlaxoSmithKline Document Number
RM2000/00481/12, 2013].
Table 2
EGF100151: Summary of gastrointestinal and dermatological 
adverse events in subjects who received lapatinib with capecitabine 
(Safety Population; N=210)
Lapatinib + Capecitabine Arm (N=210); n (%)
Preferred Term
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
TOTAL
Diarrhoea
64 (30)
48 (23)
31 (15)
2 (<1)
0
145 (69)
PPE
27 (13)
67 (32)
36 (17)
0
0
130 (62)
Nausea
62 (30)
31 (15)
5 (2)
0
0
98 (47)
Vomiting
36 (17)
22 (10)
5 (2)
0
0
63 (30)
Rash
41 (20)
18 (9)
2 (<1)
0
0
61 (29)
Decreased 
Appetite
31 (15)
12 (96)
1 (<1)
0
0
44 (21)
Stomatitis
25 (12)
12 (6)
0
0
0
37 (18)
Mucosal 
Inflammation
23 (11)
10 (5)
0
0
0
33 (16)
Abdominal Pain
18 (9)
10 (5)
3 (1)
0
0
31 (18)
Constipation
20 (10)
4 (2)
0
0
0
24 (11)
Dyspepsia
15 (7)
8 (4)
1 (<1)
0
0
24 (11)
Dry Skin
22 (10)
1 (<1)
0
0
0
23 (11)
Upper Abdominal 
Pain
11 (5)
9 (4)
0
0
0
20 (10)
PPE = Palmer plantar erythrodysesthesia
In EGF100151, diarrhoea was reported as a serious AE (SAE) in 15 subjects (7%) who 
received lapatinib with capecitabine and in 12 subjects (6%) who received capecitabine 
monotherapy [GlaxoSmithKline Document Number UM2004/00001/00].  Overall, 
episodes of diarrhoea were well managed, and only 9 subjects (5%) who received 
lapatinib with capecitabine and 5 subjects (3%) who received capecitabine monotherapy 
were withdrawn from study treatment due to diarrhoea.  
Diarrhoea was reported by 121 subjects (45%) who received lapatinib with capecitabine 
in EGF111438 [GlaxoSmithKline Document Number 2012N144830_00].  The majority 
of events were Grade 1 or 2, and were considered related to study medication (Table 3).
Diarrhoea was reported as a SAE in 3 subjects (1%) and 1 subject (<1%) was withdrawn 
from study treatment due to diarrhoea.  


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Table 3
EGF111438: Gastrointestinal adverse events occurring in at least 
10% of subjects who received lapatinib with capecitabine (Safety 
Population, N=269)
Adverse event
Total n (%)
Treatment related
Grade 3 or 4
Diarrhoea
121 (45)
116 (43)
16 (6)
Nausea
78 (29)
68 (25)
3 (1)
Vomiting
33 (12)
29 (11)
4 (1)
Decreased appetite
27 (10)
20 (7)
0
Most subjects in EGF111438 reported only one episode of diarrhoea.  The median time to 
onset of the first episode of diarrhoea in EGF111438 was 12 days, and the median 
duration of the first episode of diarrhoea was 6 days.  Treatment was interrupted in 16 
subjects due to diarrhoea (Table 4).  


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Table 4
EGF111438: Summary of characteristics of diarrhoea in subjects 
who received lapatinib with capecitabine (Safety Population; 
subjects who reported diarrhoea, N=121)
n (%)
Number of occurrences
One
64 (53)
Two
23 (19)
Three or more
34 (28)
Maximum Severity
Grade 1
67 (55)
Grade 2
38 (31)
Grade 3 or 4
16 (13)
Number of study treatment interruptions
One
16 (13)
Two
1 (<1)
Three or more
2 (<1)
Time to onsetof diarrhoea (days)
1-14
67 (55)
15-28
22 (18)
>28
32 (26)
Mean (SD)
28.6 (55.30)
Median (Min-Max)
12.0 (1-411)
Duration (days)
Number of subjects
113
1-5
53 (47)
6-10
16 (14)
>10
44 (39)
Mean (SD)
23.8 (43.01)
Median (Min-Max)
6.0 (1-253)
Duration is unknown for some events as not all were resolved
EGF100151 and EGF111438 are the only large studies which provide data on the 
incidence of diarrhoea with a severity of Grade 2 or more.  The incidence of Grade 2 or 
more diarrhoea differs between these studies and also between subsequent analyses of 
data from EGF100151; 20% in EGF111438, 33% in EGF100151 based on 164 subjects 
[Geyer, 2006], 34% in EGF100151 based on 198 subjects [Cameron, 2008] and 39% in 
EGF100151 based on 210 subjects [GlaxoSmithKline Document Number
UM2004/00001/00], possibly reflecting an increasing incidence of diarrhoea with a later 
onset as the duration of treatment within the study increases.  Four additional 


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GlaxoSmithKline (GSK) studies (EGF105084, EGF107671, EGF109491 and 
EGF109749) [Lapatinib Investigator’s Brochure, GlaxoSmithKline Document Number
RM2000/00481/12, 2013] and the LANDSCAPE study [Bachelot, 2013] together report 
the incidence of diarrhoea associated with treatment with lapatinib and capecitabine in a 
total of 212 subjects.  The EMILIA study [Verma, 2012] reports the incidence of 
diarrhoea in 488 subjects who received treatment with lapatinib and capecitabine, but the 
incidence of diarrhoea with a severity of Grade 2 or more is not presented.  The overall 
incidence of diarrhoea associated with treatment with lapatinib and capecitabine in these 
studies ranges from less than 40% to more than 80%.  This variability may be due to a 
number of factors, such as differences in study populations, study durations, and 
implementation of active diarrhoea management guidelines. 
Diarrhoea is a recognised adverse event associated with cancer treatment.  Diarrhoea may 
affect the patients’ sense of wellbeing and can result in treatment interruption or dose 
reduction, potentially reducing the therapeutic benefit of the cancer treatment.  In rare 
cases, diarrhoea can be debilitating, and potentially life threatening if accompanied by 
dehydration, renal insufficiency or electrolyte imbalances. 
Diarrhoea should be managed actively during cancer treatment to avoid complications or 
worsening of the subject’s condition. Standardised guidelines for treating chemotherapy-
associated diarrhoea have been developed by ASCO [Benson, 2004] and these guidelines
have been modified by GSK for the management of diarrhoea associated with lapatinib 
use (Appendix 1).  In general, mild to moderate diarrhoea can be managed by dietary 
modification and by the use of loperamide, which is the first line approach recommended 
in both the ASCO and GSK diarrhoea management guidelines.  
Octreotide is included as a second line treatment in the ASCO and GSK diarrhoea 
management guidelines, for the management of more persistent diarrhoea which is 
refractory to treatment with loperamide and dietary modification.  Octreotide is a cyclic 
octapeptide analogue of the natural hormone somatostatin. It has similar 
pharmacological properties to those of somatostatin, but has a longer duration of action 
than somatostatin.  Octreotide is available as a solution for subcutaneous (s.c.) injection, 
usually given three times daily, and is approved for the treatment of symptoms associated 
with gastroenteropancreatic tumours, including carcinoid tumours with features of 
carcinoid syndrome, vasoactive intestinal polypeptide (VIP)-secreting tumours and 
glucagonomas [Octreotide SPC].  Octreotide is also available as a depot formulation 
(Sandostatin long acting release [LAR]) to be given by deep intramuscular injection once 
every 28 days, which is approved for use in patients in whom initial treatment with 
octreotide in the formulation for s.c. injection has been shown to be effective and well 
tolerated, for the long-term treatment of the severe diarrhoea and flushing episodes 
associated with metastatic carcinoid tumors and the long-term treatment of the profuse 
watery diarrhoea associated with VIP-secreting tumours [Octreotide LAR SPC].  
Treatment with octreotide is generally well tolerated.  Gastrointestinal AEs are common;
diarrhoea, abdominal pain, nausea, constipation, flatulence, dyspepsia, vomiting, 
abdominal bloating, steatorrhoea, loose stools and discolouration of faeces have been 
reported in clinical studies.  Other AEs related to the mechanism of action of octreotide 
have also been reported, including hyperglycaemia, hypoglycaemia, impaired glucose 


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tolerance, hypothyroidism, thyroid dysfunction and cholelithiasis, but these mechanism-
related AEs tend to be associated with chronic treatment with octreotide [Octreotide SPC].
Octreotide given by s.c. injection was effective in the control of diarrhoea associated with 
a number of conditions including carcinoid syndrome [Kvols, 1986], short-bowel 
syndrome [Cooper, 1986] and dumping syndrome [Santangelo, 1987].  Octreotide also 
provided effective control of diarrhoea associated with treatment with 5-FU [Cascinu, 
1993; Gebbia, 1993 Goumas, 1998; Nikou, 1994; Topkan, 2006; Zidan, 2001] and pelvic 
radiation therapy [Yavuz, 2002)].
Octreotide 20mg LAR given once every 28 days by deep intramuscular injection was as 
effective as the s.c. formulation given three times daily in controlling the symptoms of 
carcinoid syndrome [Rubin, 1999], and in a summary of 11 case studies of patients with 
advanced cancer octreotide 30mg LAR provided complete resolution of severe diarrhoea 
which had not responded to treatment with loperamide and diphenoxylate-atropine
[Rosenhoff, 2004].  
Diarrhoea associated with cancer therapy may affect the patients’ sense of wellbeing and 
can result in treatment interruption or dose reduction, potentially reducing the therapeutic 
benefit of the cancer treatment.  The frequency and severity of diarrhoea associated with 
cancer treatment has been extensively evaluated in clinical studies, but it is not known 
how accurately these data reflect the occurrence of diarrhoea in the wider patient 
population.  It is possible that diarrhoea is under-reported within the context of a clinical 
study, and that the effects of diarrhoea on patient wellbeing may not be reflected in the 
investigator-reported outcomes recorded in a clinical study [Basch, 2010].  Furthermore it 
is likely that diarrhoea might affect treatment compliance, which is known to be sub-
optimal with many oral anti-cancer treatments [Ruddy, 2009], and episodes of diarrhoea 
might adversely influence the acceptability of subsequent cycles of treatment.  
Prophylactic treatment to prevent cancer treatment-associated diarrhoea has the potential 
to improve the overall tolerability of treatment and to improve treatment compliance.  
These effects together could improve treatment efficacy by reducing the frequency of 
treatment dose reductions and treatment interruptions.  
Loperamide is recommended as a first-line agent for the treatment of chemotherapy-
associated diarrhoea [Benson, 2004], and could be considered as a first choice agent for 
prophylactic management of cancer treatment-associated diarrhoea.  Loperamide is 
inexpensive and is provided as a tablet formulation, and is therefore easy to self-
administer.  However, there are no published data from studies evaluating the efficacy of 
prophylactic loperamide in the prevention of cancer treatment-associated diarrhoea.  In a 
small study to explore the efficacy and tolerability of lapatinib in combination with 
trastuzumab and paclitaxel, EGF104383, subjects received various combinations of 
dosages of these agents (Table 5), and prophylactic treatment with loperamide was 
included for subjects in treatment cohorts 2 and 3 [EGF104383 Clinical study report; 
GlaxoSmithKline Document Number HM2009/00365/00]. 


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Table 5
Treatment regimens in EGF104383
Paclitaxel
Trastuzumab
Lapatinib
Cohort 1
80mg/m2 IV weekly for 3 weeks 
of a 4 week cycle
4 mg/kg IV loading dose 
and 2 mg/kg IV weekly
1000 mg PO daily
Cohort 2
70mg/m2 IV weekly for 3 weeks 
of a 4 week cyclea
4 mg/kg IV loading dose 
and 2 mg/kg IV weekly
1000 mg PO daily
Cohort 3
80mg/m2 IV weekly for 3 weeks 
of a 4 week cycle
4 mg/kg IV loading dose 
and 2 mg/kg IV weekly
750 mg PO dailyb
a.
Paclitaxel dose was to be systematically increased to 80 mg/m2 after 2 cycles if 70mg/m2 was tolerated
b.
Lapatinib dose was to be systematically increased to 1000 mg after 2 cycles if 750mg was tolerated.
Overall, diarrhoea was reported by 28 subjects (97%) in cohort 1, 13 subjects (94%) in 
cohort 2 and 13 subjects (65%) in cohort3, which suggested that prophylactic treatment 
with loperamide had little effect on diarrhoea associated with this treatment regimen.  
Interpretation of data within this study was complicated by differences in treatment 
dosages of lapatinib and paclitaxel used in each cohort, and also by differences in the 
duration of follow up, which was shorter for subjects in cohort 3.  However, there was an 
apparent trend towards less frequent and less severe diarrhoea in subjects in cohort 2 and 
cohort 3 who received prophylactic treatment with loperamide (Table 6).
Table 6
Characteristics of diarrhoea adverse events in EGF104383
Cohort 1
80/1000
N=29
Cohort 2
70/1000
N=14
Cohort 3
80/750
N=20
Number of subjects with diarrhoea 
events; n (%)
28 (97)
13 (93)
13 (65)
Total number of diarrhoea events
358
90
37
Number of events per subject; n (%)
n=28
n=13
n=13
1
4 (14)
3 (23)
4 (31)
2
2 (7)
2 (15)
2 (15)
3 or more
22 (79)
8 (62)
7 (54)
Maximum severity; n (%)
n=28
n=13
n=13
Grade 1
4 (14)
2 (15)
4 (31)
Grade 2
6 (21)
4 (31)
5 (38)
Grade 3
18 (64)
7 (54)
4 (31)
Time to onset of first event (days)
n=28
n=13
n=13
Median (min-max)
4.0 (1-17)
9.0 (2-85)
15.0 (2-131)
Duration (days)
n=28
n=13
n=13
Median (min-max)
8.0 (1-233)
8.0 (1-231)
8.0 (1-277)
80/1000, 70/1000 and 80/750 refer to dosages of paclitaxel/lapatinib.


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Although the efficacy of octreotide in the treatment of diarrhoea is established, few 
studies have assessed the efficacy of prophylactic octreotide in the prevention of 
diarrhoea.  Prophylactic treatment with octreotide 20mg LAR did not prevent diarrhoea 
associated with pelvic radiation therapy [Martenson, 2008], and octreotide 30mg LAR 
was ineffective in a placebo-controlled study of 215 patients with rectal cancer receiving 
5-FU based chemoradiation [Zachariah, 2010].  In addition, in a study of 139 patients 
with colorectal cancer treated with 5-FU and capecitabine with or without irinotecan, 
diarrhoea was reported in 76.1% of patients randomised to receive prophylactic treatment 
with octreotide 30mg LAR and in 78.9% of patients who received the physician’s choice
of treatment for diarrhea (loperamide in the majority of cases). In this study, no benefit 
from octreotide LAR was identified in terms of the need for diarrhoea treatment, use of 
opioids, intravenous hydration, the rate of hospitalisation, or quality-of-life [Hoff, 2012]. 
These controlled studies suggest prophylactic treatment with octreotide does not prevent 
chemotherapy-associated diarrhoea.  
In a study of 124 evaluable chemotherapy-treated patients, severe diarrhoea was reported 
for 61.7% and 48.4% who received prophylactic treatment with octreotide 30mg LAR or 
40mg LAR, respectively [Rosenhoff, 2006].  In a single arm study of 10 patients, 
octreotide 150 µg twice daily did not prevent diarrhoea associated with 5-FU plus 
leucovorin treatment [Meropol, 1998].  However, the efficacy of prophylactic octreotide 
in these uncontrolled studies cannot be assessed due to the lack of an active comparator 
group, such as placebo, loperamide or octreotide in the s.c. formulation to manage 
episodes of diarrhoea. 
The evaluation of prophylactic octreotide in these controlled and uncontrolled studies is 
complicated by the characteristics of the subject populations and by differences in study 
design.  It is possible that subjects with colorectal cancer, subjects receiving pelvic 
radiation therapy, and subjects with a prior history of diarrhoea associated with treatment 
may be pre-disposed to a more refractory type of treatment-associated diarrhoea, and the 
treatment regimens studied may be associated with a greater risk of more severe 
diarrhoea.  Also, in studies of octreotide in the LAR formulation, there may not have 
been a sufficient interval between the administration of octreotide and the start of cancer 
treatment for the circulating concentration of octreotide to achieve clinically effective 
levels.  Therefore, the results of these studies may not reflect the potential value of 
prophylactic treatment with octreotide for the prevention of diarrhoea in subjects with 
other types of cancer or receiving other combinations of anti-cancer agents.
The efficacy of octreotide LAR as a prophylactic treatment for diarrhoea associated with 
cancer treatment is not yet established, and has not been studied in patients with MBC.  
LAP117314 will explore the potential benefit of the prophylactic use of octreotide in the 
prevention and reduction of diarrhoea associated with treatment with lapatinib and 
capecitabine in subjects with MBC which has progressed following prior therapy. Patient 
reported outcome (PRO) measures may provide an alternative approach to the assessment 
of the tolerability of cancer treatment.  Inclusion of PROs in this study provides an 
opportunity to contrast and compare outcomes reported by investigators and by subjects 
for each treatment group within a single study, although differences between the 
electronic Case Report Form (eCRF) data and the PRO data will preclude formal 
comparisons.


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1.2.
Study Rationale
Diarrhoea is the most commonly reported AE associated with lapatinib treatment, and is 
also commonly associated with capecitabine treatment.  Although these events are 
generally mild to moderate in severity, diarrhoea adversely affects the tolerability of 
cancer treatment, and in severe cases diarrhoea has the potential to affect the efficacy of 
treatment due to poor compliance, or treatment interruption or withdrawal.  Management 
of diarrhoea is currently reactive, and includes the use of loperamide and dietary 
modification for acute episodes of mild to moderate diarrhoea and the use of octreotide 
and rehydration therapy for more persistent diarrhoea.  
The efficacy of octreotide in the management of cancer treatment-associated diarrhoea 
has not been extensively evaluated in large, well-controlled studies.  Octreotide is 
available as a short acting formulation which is usually administered three times daily by 
s.c. injection and as a slow release (LAR) formulation which is given by deep 
intramuscular injection once every 28 days.  This study will evaluate whether the 
prophylactic use of octreotide LAR offers a clinically meaningful benefit by reducing the 
frequency and severity of diarrhoea associated with treatment with lapatinib and 
capecitabine.  Octreotide LAR will be administered 7 days prior to the start of treatment 
with lapatinib and capecitabine, then again 28 days later.  All subjects with episodes of 
diarrhoea will be recommended to follow the standard guidelines for the management of 
diarrhoea (Appendix 1).  The use of loperamide and other anti-diarrhoeal agents and 
other actions taken to manage diarrhoea will be secondary measures of the frequency of 
diarrhoea in both treatment groups.  Subjects will receive treatment with lapatinib and 
capecitabine until disease progression, but study data will only be collected for up to a 
maximum of 24 weeks.
Therapeutically relevant circulating concentrations of octreotide should be achieved 7-14 
days after the first dose of octreotide LAR, and should be maintained for at least four 
weeks following the second dose of octreotide LAR.  The dose of octreotide LAR 
employed in LAP117314, 40mg, is higher than the standard starting dose of octreotide 
LAR, 20mg, in order to achieve clinically relevant circulating concentrations of 
octreotide more rapidly, reducing the delay required before the start of treatment with 
lapatinib and capecitabine.  The primary analysis of efficacy will be based on data from 
the first three cycles of treatment with lapatinib and capecitabine (ie up to 9 weeks), when 
circulating concentrations of octreotide are predicted to be within the clinically relevant 
range.  Supplementary analyses of efficacy will be based on the subsequent period of the 
study (ie nominally from week 12 to week 24) and for the total duration of the study (ie 
from the start of treatment with lapatinib and capecitabine to week 24). 
It is unknown how accurately AE reporting within the context of a clinical study reflects 
the actual incidence of AEs.  It is possible that the incidence of diarrhoea associated with 
cancer treatment is under-reported when recorded by investigators at each study visit, 
particularly if episodes of diarrhoea are mild or isolated.  The completion of diaries by 
subjects to record episodes of diarrhoea may more accurately reflect the true incidence of 
these events.  


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In this study, the frequency and severity of diarrhoea will be recorded by the completion 
of AE forms in the eCRF by the investigator in a manner consistent with the method of 
AE recording used in previous studies.  Episodes of diarrhoea and the effects of diarrhoea 
will also be evaluated indirectly by assessing the use of anti-diarrhoeal medication, 
treatment compliance, unscheduled visits to healthcare professionals, and the use of 
rehydration therapy as recorded in the eCRF.  
In addition, subjects will complete the Diarrhoea Management Diary (DMD), which  will 
collect information on the frequency and form of bowel movements, and information on 
the actions taken as a result of diarrhoea.  Subjects will also complete the Functional 
Assessment of Chronic Illness Therapy-Diarrhoea (FACIT-D), which includes a sub-
scale related to diarrhoea, to determine the effects of octreotide on quality of life during 
treatment with lapatinib and capecitabine.  
The eCRF, the DMD and the FACIT-D are considered to be independent source data, and 
the investigator must not use the DMD and FACIT-D to supplement information 
recorded in the eCRF.  This study provides an opportunity to compare and contrast 
investigator-reported outcomes and PROs for each treatment group within the setting of a 
single controlled clinical study, although differences between the eCRF data and the PRO 
data will preclude formal comparisons.
Diarrhoea is an AE associated with octreotide treatment in more than 10% of patients 
[Octreotide SPC].  Octreotide-associated diarrhoea usually occurs following the first dose 
of octreotide, and is usually mild in severity lasting only a few days [McKeage, 2003].  
Diarrhoea associated with octreotide treatment could potentially confound the subsequent 
assessment of diarrhoea associated with treatment with lapatinib and capecitabine.  The 
primary analysis of efficacy will be based on the total ITT population (Section 9.3.1).  
Supplementary analyses of efficacy will be based on a modified intent-to-treat (m-ITT) 
population, which will exclude subjects with diarrhoea reported following the first dose 
of octreotide LAR and prior to the first dose of lapatinib and capecitabine and will also 
exclude subjects with intolerance to the octreotide 0.1mg s.c. dose (Section 9.3.1).  
The efficacy of prophylactic octreotide in the prevention of diarrhoea associated with 
treatment with lapatinib and capecitabine or in the management of diarrhoea associated 
with treatment of MBC is not known and is being explored for the first time in 
LAP117314.  It is possible that prophylactic treatment with octreotide may provide no 
benefit for subjects, and could potentially worsen the frequency and severity of diarrhoea 
in this study.  However, it is difficult to predict what the incidence or severity of 
octreotide-associated diarrhoea (and other AEs) might be in LAP117314, where subjects 
will receive only two doses of octreotide LAR, where the time taken to achieve clinically 
relevant circulating concentrations of octreotide is unknown, and where exposure to 
octreotide at clinically relevant doses is expected to last for no more than 12 weeks.  A 
GSK Safety Review Team (SRT) will be established to review safety data in this study 
on an ongoing basis, in order to protect subjects’ interests and to ensure their safety.


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1.3.
Benefit:Risk Assessment
LAP117314 will evaluate the efficacy and safety of octreotide used as a prophylactic 
treatment to prevent or reduce the frequency and severity of diarrhoea associated with 
treatment with lapatinib and capecitabine in subjects with HER2-positive MBC.  
Octreotide, lapatinib and capecitabine are all marketed products with approved 
indications and there is extensive post-approval experience of patient exposure.  The 
overall benefits and risks associated with the use of octreotide, lapatinib and capecitabine 
are well established within the approved indications, and are presented in the Octreotide
SPC, Lapatinib SPC and Capecitabine SPC.  
Lapatinib is approved for use in combination with capecitabine in patients with
histologically or cytologically confirmed HER2-positive breast cancer which has
progressed following prior therapy, which must have included treatment with 
anthracyclines and taxanes and trastuzumab in the metastatic setting [Lapatinib SPC].  
The subject population to be enrolled in LAP117314 and the treatment regimen for 
lapatinib and capecitabine are consistent with this approved indication.  The benefits and 
risks associated with the use of lapatinib and capecitabine in LAP117314 are assumed to 
be consistent with the benefits and risks as described in the Lapatinib SPC and will not be 
discussed further in this analysis of benefit and risk.
Octreotide is approved for several indications; the most relevant of these with respect to 
LAP117314 is the treatment of symptoms (ie diarrhoea) associated with gastroentero-
pancreatic tumours, including carcinoid tumours with features of carcinoid syndrome,
VIP-secreting tumours and glucagonomas [Octreotide SPC].  Octreotide is not approved 
for the treatment or prevention of diarrhoea associated with cancer treatment.  The 
evaluation of prophylactic octreotide for the prevention or reduction of diarrhoea in 
LAP117314 is not within an approved indication, and octreotide is considered to be the 
exploratory agent in this study.  However, the efficacy of octreotide in the treatment of 
chemotherapy-associated diarrhoea is established and has been included in the diarrhoea 
management guidelines developed by ASCO [Benson, 2004] and by GSK (Appendix 1).
Subjects in LAP117314 will be randomised in a 1:1 ratio to receive octreotide or to 
receive no octreotide.  For subjects who receive no octreotide, the consideration of 
benefit and risk is consistent with the data presented in the Lapatinib SPC.  The 
additional risks and benefits for subjects who receive treatment with octreotide are 
considered in Section 1.3.1 and Section 1.3.2
1.3.1.
Risk Assessment
The analysis of risk associated with octreotide treatment in LAP117314 is based 
primarily on potential risks identified in the Octreotide SPC.  These risks are considered 
relative to the subject population and study treatments and procedures in LAP117314. 
Octreotide LAR is approved for use in patients in whom initial treatment with octreotide 
in the formulation for s.c. injection has been shown to be effective and well tolerated.  
Prior treatment with octreotide is not required for subjects to be enrolled in LAP117314, 
and the tolerance to treatment with octreotide is unlikely to be known for most subjects 


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prior to enrollment in the study.  Subjects randomised to receive octreotide must receive 
one 0.1mg dose of octreotide by s.c. injection to assess tolerability at least one hour 
before the first dose of the LAR formulation is administered.  Following s.c. 
administration of octreotide, peak circulating concentrations are achieved within 30 
minutes, and the elimination half life of octreotide is approximately 100 minutes 
[Octreotide SPC].  This single s.c. dose of octreotide should identify subjects who have a 
hypersensitivity reaction to octreotide or its’ excipients (the only contraindication for the 
use of octreotide).
Treatment with octreotide in both the s.c. and LAR formulations is generally well 
tolerated [McKeage, 2003].  Adverse events related to the mechanism of action of 
octreotide have been reported, including hyperglycaemia, hypoglycaemia, impaired 
glucose tolerance, hypothyroidism, thyroid dysfunction and cholelithiasis.  These 
mechanism-related AEs tend to be associated with chronic treatment with octreotide 
[Octreotide SPC], and are therefore unlikely to be relevant within the context of 
LAP117314.  In this study, octreotide will be administered as only one dose of the s.c. 
formulation and two doses of the LAR formulation over a period of 28 days, and the total 
duration of exposure to clinically relevant concentrations of octreotide is expected to be 
no more than 12 weeks.
Octreotide-associated gastrointestinal AEs are common, and are directly relevant to the 
conduct of LAP117314.  Diarrhoea, abdominal pain, nausea, constipation and flatulence
are reported to be very common (occurring in more than 10% of patients), and dyspepsia, 
vomiting, abdominal bloating, steatorrhoea, loose stools and discolouration of faeces
have been reported as common AEs (occurring in 1% to 10% of patients) [Octreotide
SPC].  Diarrhoea and constipation are of particular relevance within the context of 
LAP117314, and additional guidance is provided for the management of these AEs.  
Diarrhoea will be managed in accordance with the GSK guidelines (Appendix 1); 
subjects with severe diarrhoea unresponsive to loperamide who have received octreotide 
LAR may receive further treatment with octreotide s.c. at the investigators discretion,.  
Subjects who report constipation with a severity of NCI CTCAE Grade 2 and above
following the first dose of octreotide LAR must not receive the second dose of octreotide 
LAR, but will continue to receive treatment with lapatinib and capecitabine as scheduled.
Specific issues relating to warnings, precautions, contraindications and potential 
drug:drug interactions identified in the Octreotide SPC and the Octreotide LAR SPC are 
addressed in the inclusion criteria (Section 4.1.2), exclusion criteria (Section 4.1.3) and 
other eligibility considerations (Section 4.2).  It is considered unlikely that drug:drug 
interactions between octreotide and lapatinib or capecitabine will occur based on the 
absorption, distribution, metabolism and excretion information provided in the Octreotide
SPC , Lapatinib SPC and Capecitabine SPC or in published studies.
Subjects randomised to receive treatment with octreotide must wait a further 7 days to 
allow clinically relevant circulating concentrations of octreotide to be achieved before 
treatment with lapatinib and capecitabine is initiated.  This delay is required as a 
consequence of the pharmacokinetic profile of the LAR formulation of octreotide.  
Following deep intramuscular injection of the LAR formulation, circulating 
concentrations of octreotide increase over a period of 7 to 14 days before a stable plateau 


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circulating concentration is achieved.  The standard starting dose of octreotide LAR is 
20mg; the dose of octreotide LAR used in LAP117314 is 40mg, to ensure clinically 
relevant circulating concentrations of octreotide will be achieved in most subjects within 
7 days after dosing, and to minimise the delay before starting treatment with lapatinib and 
capecitabine.  
The efficacy of octreotide in the prevention of diarrhoea associated with treatment with 
lapatinib and capecitabine is unknown.  Octreotide-associated gastrointestinal AEs are 
common, and could potentially worsen the overall incidence of diarrhoea and other AEs 
in subjects who receive octreotide LAR together with lapatinib and capecitabine.  An 
independent SRT will review safety data in this study on an ongoing basis, in order to 
protect subjects’ interests and to ensure their safety (Section 10.8).  There are no pre-
specified stopping criteria in LAP117314, but the SRT can recommend changes to the 
study protocol to ensure the subjects’ safety if necessary. 
1.3.2.
Benefit Assessment
The objective of LAP117314 is to evaluate the potential efficacy of octreotide in 
preventing or reducing the frequency and severity of diarrhoea associated with treatment 
with lapatinib and capecitabine.  Diarrhoea is a common AE reported in studies of both 
lapatinib and capecitabine [Lapatinib SPC; Capecitabine SPC].  Diarrhoea associated 
with cancer therapy may affect the patients’ sense of wellbeing and can result in 
treatment interruption or dose reduction, potentially reducing the therapeutic benefit of 
the cancer treatment.  
The efficacy of octreotide has been demonstrated in the treatment of diarrhoea associated 
with a number of conditions (Section 1.1). Diarrhoea associated with cancer treatment is 
usually managed reactively, but the experience of diarrhoea associated with cancer 
treatment may adversely influence the acceptability of subsequent cycles of treatment.  
Prophylactic treatment to prevent diarrhoea associated with cancer treatment has the 
potential to improve the overall tolerability of treatment and to improve treatment 
compliance.  These effects together could potentially improve treatment efficacy by 
reducing the frequency of treatment dose reductions and treatment interruptions.  
1.3.3.
Overall Benefit:Risk Conclusion
The potential benefits and risks associated with treatment with octreotide, lapatinib and 
capecitabine are considered to be acceptable within the context of LAP117314.


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2.
OBJECTIVES AND ENDPOINTS
The objectives and endpoints of the study are summarised in Table 7.
Table 7
Objectives and endpoints
Objectives
Endpoints
Primary: Investigator reported (eCRF)
To determine the efficacy of prophylactic octreotide 
in reducing the proportion of subjects experiencing 
diarrhoea with a severity of NCI CTCAE Grade 2 
and above.
Proportion of subjects experiencing 
diarrhoea with a severity of Grade 2 and 
above, as defined by the NCI CTCAE, 
version 4.03, recorded as AEs in the eCRF.
Secondary: Investigator reported (eCRF)
To determine the efficacy of prophylactic octreotide 
in reducing the proportion of subjects experiencing 
diarrhoea with a severity of NCI CTCAE Grade 3 
and above.
To determine the efficacy of prophylactic octreotide 
in reducing the proportion of subjects experiencing 
diarrhoea of any grade of severity.
To determine the efficacy of prophylactic octreotide 
in reducing the duration of diarrhoea of any grade 
of severity.
To determine the efficacy of prophylactic octreotide 
in increasing the time to onset of the first episode 
of diarrhoea of any grade of severity.
To determine the efficacy of prophylactic octreotide 
in reducing the proportion of subjects taking anti-
diarrhoeal medication.
To determine the efficacy of prophylactic octreotide 
in reducing the proportion of subjects making 
unscheduled visits to healthcare professionals as a 
result of diarrhoea.
To determine the efficacy of prophylactic octreotide 
in reducing the proportion of subjects requiring 
changes in cancer therapy (dose delays, dose 
reductions and treatment withdrawal) as a result of 
diarrhoea.
Proportion of subjects experiencing 
diarrhoea with a severity of Grade 3 and 
above, as defined by the NCI CTCAE, 
version 4.03, recorded as AEs in the eCRF.
Proportion of subjects experiencing 
diarrhoea of any grade of severity as defined 
by the NCI CTCAE, version 4.03, recorded 
as AEs in the eCRF.
Duration of diarrhoea of any grade of 
severity, recorded as AEs in the eCRF.
Time to onset of the first episode of 
diarrhoea of any grade of severity, recorded 
as an AE in the eCRF.
Proportion of subjects taking anti-diarrhoeal 
medication, recorded in the eCRF.
Proportion of subjects making diarrhoea-
related unscheduled visits to healthcare 
professionals, recorded in the eCRF.
Proportion of subjects requiring diarrhoea-
related lapatinib and capecitabine dose 
reduction, dose delay and treatment 
withdrawal, recorded in the eCRF.


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Objectives
Endpoints
Secondary: Investigator reported (eCRF)
To determine the efficacy of prophylactic octreotide 
in reducing the proportion of subjects requiring 
treatment with intravenous fluids resulting from 
diarrhoea. 
To determine the effect of prophylactic octreotide 
on compliance with lapatinib and capecitabine 
treatment.
To determine the effect of prophylactic octreotide 
on the efficacy of treatment with lapatinib and 
capecitabine.
To determine the effect of prophylactic octreotide 
on the safety and tolerability of cancer treatment.
Proportion of subjects requiring use of 
diarrhoea-related intravenous fluids for 
rehydration, recorded in the eCRF.
Number of lapatinib and capecitabine tablets 
dispensed and returned, recorded in the 
eCRF.
Overall response rate and clinical benefit 
response measured in accordance with the 
Response Evaluation Criteria In Solid 
Tumours (RECIST) version 1.1.
Proportion of subjects with AEs and SAEs, 
recorded in the eCRF.


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Objectives
Endpoints
Secondary: Patient1 reported (DMD)
To determine the effect of prophylactic octreotide 
on patient-reported diarrhoea.
To determine the effect of prophylactic octreotide in 
delaying patient reported diarrhoea.
To determine the effect of prophylactic octreotide in 
reducing the proportion of patients taking anti-
diarrhoeal medication. 
To determine the effect of prophylactic octreotide in 
reducing the proportion of patients making dietary 
changes to control diarrhoea.
To determine the effect of prophylactic octreotide 
on the proportion of patients contacting other non-
hospital healthcare professionals to discuss
diarrhoea.
To determine the effect of prophylactic octreotide in 
reducing the proportion of patients reporting non-
adherence due to diarrhoea.
Proportion of patients reporting changes in 
bowel movements from baseline (frequency 
and/or consistency), recorded in the DMD.
Time to the first patient reported change in 
frequency and/or consistency of bowel 
movements from baseline, recorded in the 
DMD.
Proportion of patients taking anti-diarrhoeal 
medication, recorded in the DMD.
Proportion of patients making dietary 
changes due to diarrhoea, recorded in the 
DMD.
Proportion of patients contacting other non-
hospital healthcare professionals to discuss
diarrhoea, recorded in the DMD.
Proportion of patients reporting stopping 
completely or missing doses of anti-cancer 
tablets due to diarrhoea, recorded in the 
DMD.
Quality of Life (FACIT-D)
To determine the effect of prophylactic octreotide 
on health-related quality of life.
Proportion of patients with changes in 
health-related quality of life, recorded by 
FACIT-D.  
Trial Outcomes Index will be the primary 
endpoint; FACT-G total, FACIT-D total, and 
sub-scales will be secondary endpoints..
1.
The term ‘patient’ refers to study subject in the context of DMD- and FACIT-D-related objectives 
and endpoints.


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Consistent recording of diarrhoea AEs is a key component of this study.  It is essential 
that the investigator understands fully the classification of diarrhoea and the definitions of 
severity used in this study (Table 8)  For each diarrhoea AE report, the investigator 
should assess the change in stool form and frequency relative to the normal form and 
frequency for the subject to accurately ascertain the grade of diarrhoea.
Table 8
National Cancer Institute common terminology criteria for grading 
diarrhoea adverse events
Adverse 
Event Grade
Diarrhoea
1
Increase of <4 stools/day over baseline; mild increase in ostomy output compared to 
baseline
2
Increase of 4-6 stools/day over baseline; moderate increase in ostomy output 
compared to baseline;
3
Increase of ≥7 stools/day over baseline; incontinence; hospitalisation indicated; severe 
increase in ostomy output compared to baseline; limiting self care activities of daily 
living
4
Life-threatening consequences; urgent intervention indicated
5
Death
Data will be recorded by the investigators in the eCRF at each study visit and by subjects 
in the DMD every week and in the FACIT-D every 3 weeks.  These are considered to be
independent sources of study data, and investigators must not use information collected 
in the DMD and FACIT-D to supplement data entry into the eCRF.  Where comparable 
data are collected in the eCRF and in the DMD, secondary endpoints will be evaluated to 
contrast and compare these data within each treatment group, although differences 
between the eCRF data and the PRO data will preclude formal comparisons. 
All subjects will complete the baseline DMD and the FACIT-D during the 3 days prior to 
randomisation, before any study-related treatment is administered.  Subjects randomised 
to receive octreotide will complete a second baseline DMD and the FACIT-D before 
starting the first cycle of treatment with lapatinib and capecitabine.  Hence, subjects 
randomised to receive octreotide will complete the baseline DMD and the FACIT-D 
(Week -1) prior to receiving the first dose of octreotide (0.1mg subcutaneous tolerability 
test dose), and all subjects will complete the baseline DMD and the FACIT-D prior to 
receiving the first dose of lapatinib and capecitabine (Week 0).  
The DMD will be completed every week after the first dose of lapatinib and capecitabine 
is administered (Week 1, Week 2, Week 3, etc), until the end of study visit (Week 24,
disease progression, unacceptable toxicity or subject withdrawal if this is sooner).  The 
FACIT-D will be completed every 3 weeks during treatment with lapatinib and 
capecitabine (Week 3, Week 6, Week 9, etc), until the end of study visit (Week 24,
disease progression, unacceptable toxicity or subject withdrawal if this is sooner). The 
DMD and FACIT-D will not be completed beyond 24 weeks of treatment.  


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The baseline DMD comprises 3 questions to record stool form and consistency.  The 
DMD to be completed throughout the rest of the study comprises the 3 questions in the 
baseline DMD and a further 5 questions and 6 sub-questions to evaluate the 
consequences and management of diarrhoea.  A copy of the baseline DMD and the DMD 
is included in the Study Procedures Manual (SPM).
The FACIT-D (Appendix 2) comprises the 27 item Functional Assessment of Cancer 
Therapy-General (FACT-G) questionnaire which has physical (PWB), social (SWB), 
emotional (EWB) and functional wellbeing (FWB) subscales and an 11 item diarrhoea 
symptom subscale (DSS) which measures quality of life specific to diarrhoea.  The 
primary endpoint derived from the FACIT-D will be the Trial Outcome Index, which is a 
summation of the PWB, FWB and diarrhoea symptom subscales.  Secondary endpoints 
will be overall quality of life (total FACT-G), total FACIT-D and scores from each of the 
individual subscales.  
Disease progression in accordance with RECIST version 1.1 is required only at the end of 
study visit.  Disease assessments during the course of treatment with lapatinib and 
capecitabine may be conducted in accordance with local practice.  The assessment of 
disease progression in LAP117314 is less rigorous than that employed in EGF100151 and 
EGF111438.  LAP117314 is an exploratory study, and disease efficacy data may not be 
comparable with that reported in other studies.
3.
INVESTIGATIONAL PLAN
3.1.
Study Design
This is a randomised, parallel group, multi-centre, open-label Phase II study in subjects 
with HER2-positive metastatic breast cancer which has progressed following prior 
therapy, which must have included anthracyclines and taxanes and therapy with 
trastuzumab in the metastatic setting.  This study is not placebo controlled, and there is 
no active comparator.
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 Schedule (Table 16, and Table 17), is essential and 
required for study conduct.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying SPM.  The SPM will provide the site personnel with 
administrative and detailed technical information that does not impact subject safety.
Subjects must be screened for eligibility and informed consent must be given before any 
study-related procedures are conducted.  
All subjects will receive treatment with lapatinib 1250mg once daily and capecitabine 
1000mg/m2 twice daily until disease progression.  Lapatinib will be given every day; 
capecitabine will be given in 3 week cycles of two weeks treatment followed by one 
week off treatment.  


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Subjects will be randomised in a 1:1 ratio to receive either: 

Octreotide (Sandostatin LAR) 40mg 7 days before the start of treatment with 
lapatinib and capecitabine and again 28 days later, or

No octreotide treatment.
For subjects randomised to receive octreotide, treatment with lapatinib and capecitabine 
will be initiated 7 days after the first dose of octreotide given as the LAR formulation.  
For subjects randomised to receive no octreotide, treatment with lapatinib and 
capecitabine will be initiated immediately following enrolment.  
Subjects randomised to receive octreotide LAR must be given one 0.1mg dose of the 
standard formulation of octreotide s.c. to assess tolerability at least one hour before the 
first dose of the LAR formulation is administered.  Subjects with significant intolerance 
to octreotide 0.1mg s.c. will not receive treatment with octreotide LAR, but will receive 
treatment with lapatinib and capecitabine as scheduled. 
All subjects with episodes of diarrhoea will be encouraged to follow the GSK diarrhoea 
management guidelines for subjects receiving lapatinib (Appendix 1). In subjects 
randomised to receive octreotide, episodes of mild diarrhoea which occur following the 
first dose of octreotide LAR should be managed in accordance with the diarrhoea 
management guidelines.  The use of octreotide in the s.c. formulation for the management 
of diarrhoea refractory to treatment with loperamide is not excluded.  Investigators 
should use their clinical judgement concerning the use of octreotide s.c. in subjects 
randomised to receive treatment with octreotide LAR, particularly during Week 2 
through to Week 12 of treatment with lapatinib and capecitabine, when circulating 
concentrations of octreotide should already be within the clinically effective range.  
Subjects who report constipation with a severity of NCI CTCAE Grade 2 and above
(Table 9) following the first dose of octreotide LAR must not receive the second dose of 
octreotide LAR, but will continue to receive treatment with lapatinib and capecitabine as 
scheduled.  
Table 9
National Cancer Institute common terminology criteria for grading 
constipation adverse events
Adverse 
Event Grade
Constipation
1
Occasional or intermittent symptoms; occasional use of stool softeners, laxatives, 
dietary modification, or enema
2
Persistent symptoms with regular use of laxatives or enemas; limiting instrumental ADL
3
Obstipation with manual evacuation indicated; limiting self care ADL
4
Life-threatening consequences; urgent intervention indicated
5
Death
ADL=Activities of daily living


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Dose reductions and dose delays are permitted during treatment with lapatinib and 
capecitabine.  The procedures to be followed are described in Section 5.10 for lapatinib 
and in Section 5.11 for capecitabine.
Study completion will be the end of 24 weeks treatment with lapatinib and capecitabine,
or disease progression, unacceptable toxicity or subject withdrawal if this is sooner.  
Serious AEs and other safety data will be reported beyond 24 weeks in subjects who 
continue treatment with lapatinib and capecitabine until disease progression in countries 
where the Sponsor is supplying lapatinib and capecitabine.  Serious AEs will be followed 
up until resolution or stabilization of the event or until the subject is lost to follow-up.  
The efficacy of prophylactic octreotide in reducing the frequency and severity of 
diarrhoea is the primary endpoint of this study.  Each episode of diarrhoea will be 
recorded by the investigator as an AE in the eCRF in accordance with the standard AE 
reporting procedure.  Actions associated with the management of diarrhoea (use of anti-
diarrhoeal medication, unscheduled visits to healthcare professionals, treatment 
interruption, rehydration) will be recorded in the eCRF.  
Subjects will complete the DMD every week and the FACIT-D every 3 weeks during 
treatment with lapatinib and capecitabine to provide an additional perspective on the 
effects of treatment-associated diarrhoea.
Diarrhoea, nausea and vomiting, dermatological events, hepatobiliary, cardiovascular and 
respiratory events have been identified as events of special interest relating to lapatinib.  
Management of dermatological events, gastrointestinal events, and cardiovascular and 
respiratory events is described in Section 5.12.1, Section 5.12.2, and Section 5.12.3, 
respectively.  Dose delay and dose reduction guidance for lapatinib related to these events 
and to hepatobiliary events is described in Section 5.10. If future changes are made to 
this guidance, 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 the 
revised version of the AE management or dose modification guidelines will be included 
in the SPM.
Hand and foot syndrome has been identified as an event of special interest relating to 
capecitabine.  Management of this event is described in further detail in Section 5.12.4.  
Dose delay and dose reduction guidance for capecitabine related to this event is described 
in Section 5.11. If future changes are made to this guidance, 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 the revised version of the AE management or 
dose modification guidelines will be included in the SPM.
There are no events of special interest relating to octreotide [Octreotide SPC].
The GSK SRT will review safety data from this study on an ongoing basis.  A formal 
review of safety data will be conducted after the first 60 subjects (approximately 30 in 
each treatment arm) have received at least 9 weeks of treatment with lapatinib and 
capecitabine; subsequent reviews will be conducted at least every 12 weeks, or more 
frequently if required.  It is anticipated that the SRT will meet at least three times during 
the course of the study.  There are no pre-defined stopping rules for this study.


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3.2.
Discussion of Design
All subjects in this study will receive treatment with lapatinib and capecitabine consistent 
with the approved indication for this treatment combination.  Diarrhoea is a recognised 
side effect of cancer treatment, and all subjects will be recommended to follow the 
standardised guidelines for diarrhoea management (Appendix 1).  The use of octreotide 
in the s.c. formulation for the management of diarrhoea refractory to treatment with 
loperamide is not excluded, and investigators should use their clinical judgement 
concerning the use of octreotide s.c. in subjects randomised to receive treatment with 
octreotide LAR.
Subjects will be randomised in a 1:1 ratio to receive octreotide prophylaxis 7 days prior 
to starting treatment with lapatinib and capecitabine, or to start treatment with lapatinib 
and capecitabine immediately after enrolment.  Treatment with octreotide is the key 
difference between the two groups of subjects with respect to the management of adverse 
events associated with cancer treatment.  Therefore, any differences noted between the 
two groups of subjects with respect to efficacy or safety outcomes should be attributable 
to prophylactic treatment with octreotide.  
This is an open label study, and no placebo for octreotide treatment will be used.  It is 
possible that delaying treatment with lapatinib and capecitabine in subjects randomised to 
receive octreotide treatment may have a negative impact on disease outcome.  The extent 
of risk associated with this delay is unknown, but it is considered to be a reasonable 
approach to disease management within the constraints of this study.  Treatment with 
lapatinib and capecitabine would also need to be delayed in subjects who receive no 
octreotide if a placebo control was included, exposing subjects to an increased risk with 
no potential benefit.  In addition, it is uncertain to what extent AEs associated with 
octreotide treatment will confound the assessment of AEs associated with treatment with 
lapatinib and capecitabine, and it is therefore uncertain to what extent the use of a 
placebo control for octreotide treatment would mitigate this complicating factor.
There are several common AEs associated with octreotide treatment, including diarrhoea, 
abdominal pain, nausea and constipation,  Gastrointestinal AEs associated with octreotide 
treatment are generally mild and short lasting [McKeage, 2003], but there are no 
published data to provide information on the expected incidence, severity, time to onset 
or duration of gastrointestinal AEs following the first dose of octreotide LAR.  In most 
patients, circulating concentrations of octreotide are below clinically relevant levels for 
the first 7 days after receiving the first dose of the LAR formulation, and plateau 
concentrations are achieved after about 14 days [Octreotide LAR SPC].  It is possible that 
circulating concentrations of octreotide will be below the levels required to elicit AEs 
during the first 7 days after the first dose of octreotide LAR in LAP117314.  
It is also possible that the subjects’ perception of the tolerability of lapatinib and 
capecitabine may be influenced by whether or not they receive octreotide, and by their 
expectations concerning the potential efficacy and tolerability of octreotide.  This issue 
will be resolved at least in part by the information provided in the Informed Consent, to 
the effect that octreotide is an effective anti-diarrhoeal agent in other clinical settings, but 
that diarrhoea and other gastrointestinal AEs may also be associated with octreotide 


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treatment.  In LAP117314 it is uncertain to what extent the predicted gastrointestinal AE 
profile associated with octreotide treatment will compromise the potentially beneficial 
effects of the prevention of diarrhoea associated with treatment with lapatinib and 
capecitabine.  While it is recognised that the inclusion of a placebo control for octreotide 
would provide a more robust study design, it is uncertain to what extent this would 
resolve the complications associated with the efficacy and tolerability profile of 
octreotide.
The recommended dose for initiating treatment with octreotide LAR is 20mg, to be 
repeated every 28 days.  There is a recognised delay of several days required for 
circulating concentrations of octreotide to achieve therapeutically relevant levels 
following the first dose of the LAR formulation [Octreotide LAR SPC].  During this 
period patients receiving octreotide LAR in clinical practice may also be treated with 
octreotide in the formulation for s.c. administration to manage episodes of diarrhoea.  In 
this study, octreotide in the formulation for s.c. administration will not be provided 
prophylactically to prevent episodes of diarrhoea in subjects during the first 7 to 14 days 
after the first dose of octreotide LAR.  This is primarily due to concerns that subjects are 
unlikely to be compliant with a regimen which requires self-administration of octreotide 
by s.c. injection three times daily, and uncertainty regarding the required duration of this 
treatment regimen.  The dose of octreotide LAR to be used in this study is 40mg, and it is 
anticipated that this higher dose will reduce the time required for circulating 
concentrations of octreotide to achieve therapeutically relevant levels.
It is also acknowledged that a significant proportion of subjects who receive treatment 
with lapatinib and capecitabine do not report diarrhoea as an adverse event.  There will, 
therefore, be a proportion of subjects randomised to receive treatment with octreotide 
who would not have reported diarrhoea as an adverse event and would not have required 
treatment with anti-diarrhoeal medication.  The safety profile of octreotide is well 
established.  Subjects randomised to receive octreotide LAR will first receive octreotide 
by s.c. administration to assess short term tolerability.  Subsequently, subjects who report 
clinically significant constipation or other AEs which are considered likely to be related 
to octreotide treatment will not receive the second dose of octreotide LAR.  This 
approach will minimise the risk associated with treatment with octreotide in this study.
Overall, 140 subjects will be enrolled.  LAP117314 is an exploratory Phase II study, and 
the sample size is not based on the number of subjects required to achieve a pre-specified 
reduction in the control incidence of diarrhoea.  While it is predicted that octreotide 
prophylaxis will reduce the frequency and severity of diarrhoea, the degree of benefit and 
the impact this might have on treatment compliance and on the subjects’ quality of life 
are uncertain.  The study should be of sufficient size to provide clinically meaningful data 
within a reasonable enrollment timeframe.
The primary endpoint of the study is the proportion of subjects reporting diarrhoea with a 
severity of Grade 2 or more.  This represents an increase of at least four stools per day 
relative to baseline, and is considered to be sufficiently severe to have an impact on the 
subjects’ sense of wellbeing.  The recommended management of Grade 2 diarrhoea 
includes maintaining treatment with lapatinib on the first and second occurrence, with 
interruption of lapatinib treatment on subsequent occurrences (Table 10), and interruption 


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of treatment with capecitabine at the first occurrence, with restart at a reduced dose after 
the first occurrence if clinically indicated, restart at a reduced dose after the second and 
third occurrences, and treatment withdrawal after the fourth occurrence (Table 11).  In 
addition to the diarrhoea management related dose interruptions, Grade 2 diarrhoea may 
also adversely affect the acceptability of subsequent cycles of treatment.
Secondary endpoints of the study provide a broader assessment of the incidence and 
severity of diarrhoea of all grades.  It is possible that octreotide prophylaxis may not 
reduce the overall incidence of diarrhoea, but may reduce the severity of these incidences 
of diarrhoea.  The proportion of subjects who report diarrhoea with a severity of Grade 3 
or more will be summarised separately, as this represents diarrhoea which requires a 
significant clinical intervention.
The frequency and severity of diarrhoea will be recorded by the investigator in 
accordance with the standard process for AE reporting in the eCRF.  In addition, actions 
associated with the management of diarrhoea (use of anti-diarrhoeal medication, 
unscheduled visits to healthcare professionals, treatment interruption, rehydration) will be 
recorded in the eCRF.  This methodology is broadly consistent with that used in clinical 
studies EGF100151 and EGF111438. 
Further information concerning the frequency of diarrhoea and the consequences of 
diarrhoea will be recorded by the subjects in the DMD.  The DMD, together with the 
FACIT-D, provides an alternative and complementary approach to recording the 
frequency of diarrhoea and to evaluating the impact of diarrhoea.  The DMD is
considered to be an independent source of study data, and investigators must not use 
information collected in the DMD to supplement data entry into the eCRF.  The PROs 
recorded by completion of the DMD and the FACIT-D will provide an additional 
perspective on the impact of diarrhoea associated with treatment with lapatinib and 
capecitabine.
The management of the subjects’ cancer will be conducted in accordance with local 
clinical practice, rather than according to a predefined schedule within the protocol.  It is 
assumed that visits to the clinic will occur in three weekly cycles consistent with the 
cycles of treatment with lapatinib and capecitabine, and that the clinical management of 
subjects enrolled at different study sites will be broadly comparable.
3.3.
Recruitment Plan
The interim analysis will be triggered when approximately 40% (n=60) of the subjects 
that have completed 3 cycles of study treatment.  In order to protect subjects from 
unnecessary exposure to octreotide, once 60 patients have been enrolled, recruitment will 
be temporarily halted to minimise potentially unnecessary further subjects being enrolled, 
whilst review of the interim analysis is being conducted.  Therefore, once 60 patients 
have been recruited, investigator sites will receive communication from the sponsor to 
suspend any further recruitment and screening activities until the outcome of the interim 
analysis has been communicated to investigator sites.  Subjects that are in screening 
during this period will still be considered for randomisation into the study.


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4.
SUBJECT SELECTION AND DISCONTINUATION/ 
COMPLETION CRITERIA
4.1.
Subject Selection Criteria
All subjects enrolled in LAP117314 will receive treatment with lapatinib and 
capecitabine in accordance with the approved indication for the use of this treatment 
combination as described in the Lapatinib SPC.  It is the responsibility of the investigator 
to ensure all subjects enrolled in LAP117314 are eligible to receive treatment with 
lapatinib and capecitabine in accordance with the criteria described in the Lapatinib SPC.  
The investigator must also ensure that other factors have been considered, such as 
concurrent medications and medical conditions, which might affect the efficacy or safety 
of treatment with lapatinib, capecitabine or octreotide.  Specific information regarding 
warnings, precautions, contraindications, AEs, and other pertinent information that may 
affect subject eligibility is provided in the Lapatinib, Capecitabine and Octreotide SPCs.  
Subject selection criteria are based on the Lapatinib, Capecitabine and Octreotide SPCs 
current at the effective date for this protocol.  Investigators will be informed of any 
changes to the SPCs which affect subject selection criteria, and formal documentation 
will be created and stored with the study file.
4.1.1.
Number of Subjects
Approximately 140 subjects will be randomised, 70 will receive octreotide and 70 will 
receive no octreotide. See Section 9.2.1 for sample size assumptions.
4.1.2.
Inclusion Criteria
Deviations from the 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 enrolment in the study must meet all of the following criteria:
1. Signed written informed consent.
2. Histologically or cytologically confirmed HER2-positive advanced or metastatic 
breast cancer which has progressed following prior therapy, which must have 
included anthracyclines and taxanes and therapy with trastuzumab in the 
metastatic setting.
3. Females age 18 years old.
4. Eastern Cooperative Oncology Group (ECOG) performance status 0-2 (Appendix 
4).
5. Life expectancy of at least 12 weeks.  
6. Able to swallow and retain oral medications.


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7. Incapable of becoming pregnant, or not pregnant and using an adequate form of 
contraception, i.e. a female who is of:  
a.
non-childbearing potential (physiologically incapable of becoming 
pregnant), including any female who has had hysterectomy, bilateral 
oophorectomy, bilateral tubular ligation or is post-menopausal (total 
cessation of menses for at least 1 year);
b. childbearing potential must have a negative serum pregnancy test within 7 
days prior to treatment with octreotide if randomised to receive octreotide 
or the first dose of lapatinib with capecitabine if randomised to receive no 
octreotide, preferably as close to the first dose as possible, and must agree
to use adequate contraception (intrauterine device, birth control pills 
unless clinically contraindicated, or barrier device) during the study and 
continuing for at least 4 weeks after the final dose of treatment with 
lapatinib and capecitabine.  Acceptable contraceptive methods are 
described in Section 7.5.1.
8. Subjects must complete all screening assessments as outlined in the protocol.  
9. Subjects must complete the FACIT-D and diarrhoea diary before receiving the 
first dose of octreotide if randomised to receive octreotide.  All subjects must 
complete the FACIT-D and diarrhoea diary before receiving the first dose of 
lapatinib with capecitabine. 
10. Prior treatment with other chemotherapeutic agents or endocrine therapy is 
permitted.  All prior treatment related toxicities, except diarrhoea and alopecia, 
must be NCI CTCAE (version 4.03) ≤ Grade 1 at the time of randomisation.  
Subjects with diarrhoea with any grade of severity within 14 days prior to 
randomisation are excluded from LAP117314.
11. Prior treatment with radiation therapy is permitted provided that at least 2 weeks 
have elapsed since the last fraction of radiation therapy prior to treatment with 
octreotide if randomised to receive octreotide or the first dose of lapatinib with 
capecitabine if randomised to receive no octreotide, and all radiation therapy 
related AEs are ≤ Grade 1 at the time of randomisation.
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.  Other country-specific 
criteria are included in Appendix 5.
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. Concurrent treatment with an investigational agent or concurrent participation in 
another clinical study.  


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2. Administration of an investigational drug within 30 days or 5 half-lives, 
whichever is longer, prior to treatment with octreotide for subjects randomised to 
receive octreotide or the first dose of lapatinib and capecitabine for subjects 
randomised to receive no octreotide.  
3. Treatment with octreotide within the 3 months prior to randomisation.  
4. Concurrent chemotherapy, radiation therapy, immunotherapy, biologic therapy 
(including an EGFR and/or HER2 inhibitor), or hormonal therapy for treatment of 
cancer.  
5. Dementia, altered mental status, or any psychiatric condition that would prohibit 
the understanding or rendering of informed consent, unless a legally acceptable 
representative could provide informed consent (if in accordance with the policies
of the local Ethics Committee).  
6. Concurrent disease or condition that would make the subject inappropriate for 
study participation or any serious medical or psychiatric disorder that would 
interfere with the subject's safety or compliance with study procedures.
7. Diarrhoea with any grade of severity within 14 days prior to treatment with 
octreotide for subjects randomised to receive octreotide or within 14 days prior to 
the first dose of lapatinib and capecitabine for subjects randomised to receive no 
octreotide.  
8. Malabsorption syndrome, inflammatory bowel disease (ulcerative colitis, 
Chrohn’s disease), irritable bowel syndrome, disease significantly affecting 
gastrointestinal function, or resection of the stomach or small bowel.  
9. Pregnant or lactating subjects.  
10. Prior treatment with lapatinib.
French subjects: the French subject has participated in any study using an 
investigational drug during the previous 30 days or 5 half-lives, whichever is longer, 
preceding the first dose of protocol treatment.
4.2.
Other Eligibility Criteria Considerations
It is the responsibility of the investigator to ensure all subjects enrolled in LAP117314 are 
eligible to receive treatment with lapatinib and capecitabine, and meet other criteria 
described in the Lapatinib, Capecitabine and Octreotide SPCs.  In addition to the 
inclusion criteria (Section 4.1.2) and exclusion criteria (Section 4.1.3), the 
contraindications, special warnings and precautions for use, and other information 
included in the Lapatinib, Capecitabine and Octreotide SPCs should be taken into 
consideration.
Lapatinib, capecitabine and octreotide are contraindicated in subjects with a history of 
allergic reactions to these drugs, compounds with a similar chemical composition, or 
excipients associated with these drug formulations.  Capecitabine is contraindicated in 


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subjects with severe leucopenia, neutropenia or thrombocytopenia, or dihydropyrimidine 
dehydrogenase deficiency.
Caution should be taken in subjects with moderate or severe hepatic impairment.  
Investigators should consider the subjects hepatic function measures relative to the 
guidance provided for the management of hepatobiliary AEs in Section 5.13.  It is 
recommended that hepatic function measures prior to randomisation should meet the 
following criteria:

Albumin ≥2.5 g/dL

Serum bilirubin ≤1.5 x the upper limit of the normal range (ULN) or ≤2.5 x 
ULN with Gilbert's Syndrome

AST and ALT ≤3 × ULN
Caution should be taken in subjects with severe renal impairment.  
Caution should be taken in subjects with conditions that could impair cardiac function, 
including conditions that could result in prolongation of QTc, arrhythmias and angina 
pectoris.  Subjects with hypertension who are randomised to receive octreotide must be 
monitored to manage the potential risk of bradycardia associated with octreotide use.
Information on potential interactions with other medicinal products is presented in the 
Lapatinib, Capecitabine and Octreotide SPCs and in Section 6.2.
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.
4.3.
Permanent Discontinuation from Study Treatment and 
Subject Completion Criteria
4.3.1.
Discontinuation from Treatment with Octreotide
Subjects randomised to receive octreotide must be given one 0.1mg dose of the standard 
formulation of octreotide s.c. to assess tolerability at least one hour before the first dose 
of the LAR formulation is administered.  Subjects who show any evidence of 
intolerability to octreotide administered s.c. must not receive treatment with the LAR 
formulation; these subjects should receive treatment with lapatinib and capecitabine and 
should not be withdrawn from the study.  
Subjects randomised to receive octreotide will be given prophylactic octreotide 
(Sandostatin LAR) 40mg 7 days before the start of treatment with lapatinib and 
capecitabine and again 28 days later.  Episodes of mild diarrhoea which occur following 
treatment with octreotide LAR should be managed in accordance with the diarrhoea 
management guidelines (Appendix 1).  The use of octreotide in the s.c. formulation for 
the management of diarrhoea refractory to treatment with loperamide is not excluded.  
Investigators should use their clinical judgement concerning the use of octreotide s.c. in 


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subjects randomised to receive treatment with octreotide LAR, particularly during Week 
2 through to Week 12 of treatment with lapatinib and capecitabine, when circulating 
concentrations of octreotide should already be within the clinically effective range.  
Subjects who report constipation with a severity of NCI CTCAE Grade 2 and above
(Table 9) or other adverse events which are considered likely to be related to octreotide 
treatment following the first dose of octreotide LAR must not receive the second dose of 
octreotide LAR, but should continue to receive lapatinib and capecitabine and should not 
be withdrawn from the study.  
4.3.2.
Discontinuation from Treatment with Lapatinib and Capecitabine
Subjects may withdraw from the study at any time.
Study treatment may be permanently discontinued for any of the following reasons:

liver chemistry meeting the stopping criteria described in Section 5.13.1

deviation(s) from the protocol

disease progression

request of the subject or proxy

investigator’s discretion

subject is lost to follow-up

study is closed or terminated.
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and the study eCRF. If the subject voluntarily 
discontinues treatment due to toxicity, ‘AE’ will be recorded as the primary reason for 
permanent discontinuation in the eCRF.
Subjects who require permanent discontinuation of either lapatinib or capecitabine must 
permanently discontinue both treatments in that combination and the reason for 
discontinuation must be recorded.  Once a subject has permanently discontinued
treatment with lapatinib and capecitabine, the subject will not be allowed to be re-treated
and must be withdrawn from the study. 
All subjects who discontinue treatment with lapatinib and capecitabine will have safety 
assessments at the time of discontinuation as specified in the Time and Events Schedule 
(Table 16 and Table 17) and in Section 7.1.8.  
4.3.3.
Subject Completion
A subject will be considered to have completed the study if the subject completes 24 
weeks of treatment with lapatinib and capecitabine, or if cancer progresses or the subject 
dies during treatment, whichever is sooner.  The cause of death must be recorded in the 
eCRF.  A subject will be considered to have withdrawn from the study prematurely if 


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treatment is permanently stopped due to toxicity, or the subject has withdrawn consent, or 
the subject is no longer being followed at the investigator’s discretion.
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.
The mechanism for providing lapatinib and capecitabine will vary by centre and by 
country, depending on drug reimbursement status.  Lapatinib and capecitabine will be 
provided locally by each centre, and if this is not possible lapatinib and capecitabine will 
be provided by GSK.  Only subjects enrolled in the study may receive study-related 
treatment, in accordance with all applicable regulatory requirements.  Only the site 
pharmacist or authorized site personnel may supply or administer study-related treatment.  
Octreotide will be provided by GSK for all sites.
Prescribing information and patient information documents for lapatinib, capecitabine 
and octreotide will be sourced locally, in the local language.
The content of the treatment labels will be in accordance with all applicable regulatory 
requirements.  A Material Safety Data Sheet describing the occupational hazards and 
recommended handling precautions will be provided to site staff if required by local laws 
or will otherwise be available from GSK upon request.  Under normal conditions of 
handling and administration, study-related treatment is not expected to pose significant 
safety risks to site staff.  
5.1.
Lapatinib
Lapatinib is indicated in combination with capecitabine for the treatment of patients with 
advanced or metastatic breast cancer whose tumours overexpress HER2 and who have 
received prior therapy including an anthracycline, a taxane, and trastuzumab in the 
metastatic setting.  The approved dose of the combination is lapatinib 1250mg once daily
and capecitabine 1000mg/m2 twice daily.  
Lapatinib is supplied as 250mg tablets that are oval, biconvex, and orange film-coated 
with one side plain and the opposite side debossed with FG HLS, or as 250mg tablets that 
are oval, biconvex, and yellow film-coated with one side plain and the opposite side 
debossed with GS XJG.  Each tablet contains 405mg of lapatinib ditosylate monohydrate, 
equivalent to 250mg lapatinib free base.  For more information regarding the physical 
and chemical properties of the drug substance and the list of excipients refer to the 
Lapatinib SPC.


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5.1.1.
Lapatinib Dosage and Administration
Lapatinib will be dispensed to the subject after it has been confirmed that the subject 
meets all eligibility criteria and all 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.  Subjects are to receive 1250 mg per day of lapatinib, so will be instructed to take 5 
x 250 mg tablets per day.  Subjects will be instructed to take lapatinib therapy either 1 
hour (or more) before breakfast or 1 hour (or more) after breakfast.  Lapatinib is taken 
every day, including during the week that capecitabine is not taken.  A record of therapy 
administered to each subject must be maintained in the source documents.
Lapatinib dose modification guidelines are outlined in Section 5.10 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 dose of lapatinib therapy as scheduled.  If vomiting 
persists then the subject should contact the investigator.  
5.2.
Capecitabine
Capecitabine (Xeloda) is indicated for the treatment of patients with metastatic breast 
cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen. 
Capecitabine is supplied as a biconvex, oblong, light peach or peach colored film-coated 
tablet for oral administration.  Each light peach colored tablet contains 150mg 
capecitabine and each peach colored tablet contains 500mg capecitabine.  For more 
information regarding the physical and chemical properties of the drug substance and the 
list of excipients refer to the Capecitabine SPC.
Capecitabine is also available in generic form.  The characteristics of generic 
capecitabine tablets may differ from those as described for capecitabine (Xeloda).  
Generic capecitabine may be used in LAP117314 if capecitabine (Xeloda) cannot be 
provided.
5.2.1.
Capecitabine Dosage and Administration
The capecitabine dose schedule is an intermittent regimen consisting of 2 weeks of 
treatment followed by a 1 week drug-free period.  The starting dose of capecitabine in 
combination with lapatinib will be 2000mg/m2/day.  This is to be divided to 1000 mg/m2 
per dose and given twice daily orally, 12 hours apart, for 14 days, every 21 days.  Study 
staff will carefully instruct subjects on how to take capecitabine and the correct dose to 
be taken.  


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The capecitabine morning dose must be taken with food or within 30 minutes after a 
breakfast meal with approximately 200ml of water.  The capecitabine evening dose 
should be taken approximately 12 hours after the morning dose and should be taken with 
food, or within 30 minutes after food, with approximately 200ml of water.
5.3.
Octreotide
Octreotide is the acetate salt of a cyclic octapeptide. It has pharmacologic properties 
mimicking those of the natural hormone somatostatin, but has a longer duration of action 
than somatostatin. Octreotide is not an anti-tumour agent. 
Octreotide is indicated for the relief of symptoms associated with gastroenteropancreatic 
tumours, including carcinoid tumours with features of carcinoid syndrome, VIP-secreting 
tumours and glucagonomas.  Octreotide is provided as a 0.1mg/mL solution for s.c. 
injection.
Octreotide is also available as a depot formulation (Sandostatin LAR), which is indicated 
in patients in whom initial treatment with octreotide injection has been shown to be 
effective and tolerated, for the long-term treatment of the severe diarrhoea and flushing 
episodes associated with metastatic carcinoid tumors and the long-term treatment of the 
profuse watery diarrhoea associated with VIP-secreting tumors. Sandostatin LAR may 
only be administered by deep intragluteal injection. 
Sandostatin LAR is available as sterile 5mL vials delivering 10mg, 20mg or 30mg 
octreotide as the free peptide.  When mixed with diluent (approximately 2mL or 2.5 mL) 
it becomes a suspension that is given as an intramuscular injection. The octreotide is 
uniformly distributed within the microspheres which are made of a biodegradable glucose 
star polymer, D,L-lactic and glycolic acids copolymer.  Sterile mannitol is added to the 
microspheres to improve suspendability.
For more information regarding the physical and chemical properties of the drug 
substance and the list of excipients refer to the Octreotide and Octreotide LAR SPCs.  
5.3.1.
Octreotide Dosage and Administration
Octreotide in the formulation for s.c. injection will be administered as a 0.1mg dose 
(1mL) at the study site to assess tolerability at least one hour before the first 40mg dose 
of the LAR formulation is administered.  The LAR formulation must not be administered 
to any subjects who show signs or symptoms of intolerance to octreotide following 
administration of the 0.1mg s.c. dose.
The 40mg dose of the LAR formulation will be given as two 20mg doses, each of 
approximately 2.5mL.  The mixing instructions for this formulation should be followed 
carefully to ensure the suspension is properly prepared.  Octreotide in the LAR 
formulation will be administered at the study site 7 days prior to starting the first cycle of 
treatment with lapatinib and capecitabine, and repeated 28 days later.  


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5.4.
Handling and Storage of Study Treatment
Study-related treatment must be stored in a secure area under the appropriate physical 
conditions for the product. Access to and administration of study-related treatment will 
be limited to the investigator and authorized site staff. Study-related treatment must be 
dispensed or administered only to subjects enrolled in the study and in accordance with 
the protocol.
5.5.
Treatment Assignment
Subjects will be identified by a unique subject number that will remain constant for the 
duration of the study.  Investigators or designated staff will telephone the GSK interactive 
voice response (IVR) system called RAMOS (Registration and Medication Ordering 
System) to register and record subject activity.  To randomize the subject, the study staff 
will enter the subject number to obtain a randomisation number and treatment group 
assignment.  All calls to RAMOS are confirmed with a fax, which will be sent to the site 
on the completion of each call.  Study-specific instructional worksheets will be provided 
for the use of the IVR system.
5.6.
Blinding
This is an open label study; however, effort will be made to maintain the blind for key
internal sponsor personnel working on the study.
To preserve the integrity of the study at the interim analysis (Section 9.3.4), the treatment 
assignment will be obtained by an independent statistician, (who has access to the 
randomisation system RandAll NG), and provided to an external statistics group (to be 
appointed) to allow the required pre-defined analyses and data summaries to be produced.   
These analyses and data tables will be clearly documented in the Reporting Analysis plan.   
These data tables will then be provided to the independent review committee for their 
review.  The results of the interim analyses will only be known by the independent 
review committee and not disclosed to the study team.   There will be a secure firewall 
put in place to ensure that the study team remain blinded to the interim data and results.   
The recommendation from the independent review committee will be communicated to 
the study team and, in the event of a recommendation to halt the trial early, also to the 
appropriate regulatory agencies.  If the independent review committee recommends the 
study continue, the study team will continue to remain blinded to interim results and 
treatment assignments until final analysis.
5.7.
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 
octreotide, lapatinib and capecitabine dispensed and/or administered to study subjects, the 
amount of lapatinib and capecitabine returned by study subjects, and the amount received 
from and returned to GSK, when applicable. Recording of drug accountability is 


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required regardless of whether the Institution or GSK are providing lapatinib and 
capecitabine.  Product accountability records must be maintained throughout the course 
of the study.  Further detailed instructions on product accountability are included in the 
SPM.
5.8.
Treatment Compliance
Compliance with treatment with lapatinib and capecitabine will be assessed through 
querying the subject during the site visits and will be recorded in the source documents 
and in the eCRF. 
A record of the number of lapatinib and capecitabine tablets dispensed to and returned by 
each subject must be maintained and reconciled with 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.
Treatment delays and/or dose reductions will also be recorded by subjects in the DMD.  
The eCRF and the DMD are considered to be independent source data, and information 
recorded in the DMD should not be used to supplement information recorded in the eCRF.
Octreotide will be administered to subjects at the study site.  Administration will be 
recorded in the source documents and in the eCRF.
5.9.
Dose Adjustment
Dose adjustment will be considered for lapatinib (Section 5.10) and capecitabine (Section 
5.11), and the dose of either agent may be adjusted independently of the other.  All 
subjects who may require discontinuation of either lapatinib or capecitabine must 
discontinue both treatments.  Subjects should be carefully instructed when any dose 
modifications occur.
Treatment with lapatinib and capecitabine may be delayed up to 2 weeks, to allow for 
resolution of toxicity except in the event of a ≥ Grade 3 relative decrease in left 
ventricular ejection fraction, interstitial pneumonitis or hepatotoxicity. Guidelines for the 
management of these events are presented in Section 5.12.3 (cardiovascular and 
respiratory) and Section 5.13 (hepatobiliary).
No dose reduction or dose delay is permitted for octreotide.  Subjects who show 
intolerance to the s.c. injection of octreotide must not receive treatment with octreotide 
LAR.  Episodes of mild diarrhoea which occur following the first dose of octreotide LAR 
and prior to the first dose of lapatinib and capecitabine should be managed in accordance 
with the diarrhoea management guidelines (Appendix 1).  The use of octreotide in the s.c. 
formulation for the management of diarrhoea refractory to treatment with loperamide is 
not excluded.  Investigators should use their clinical judgement concerning the use of 
octreotide s.c. in subjects randomised to receive treatment with octreotide LAR, 
particularly during Week 2 through to Week 12 of treatment with lapatinib and 
capecitabine, when circulating concentrations of octreotide should already be within the 
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Subjects who report constipation with a severity of NCI CTCAE Grade 2 and above
(Table 9) or other adverse events which are considered likely to be related to octreotide 
treatment following the first dose of octreotide LAR must not receive the second dose of 
octreotide LAR.
5.10.
Dose Delays and Reductions for Lapatinib
Dose modification guidelines for lapatinib have been developed for the management of 
selected AEs (Table 10). The investigator must consult the Medical Monitor prior to 
continuing therapy for any subject requiring a delay of treatment of more than two weeks 
for any reason, but in general in these circumstances subjects should be withdrawn from
treatment permanently. 


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Table 10
Dose modification rules for lapatinib
Toxicity NCI-CTCAE Grade
During Course of Therapy
Lapatinib Dose Change
Grade 1
Maintain dose
No change
Specific Events of Grade 2/3
Haematology 
Absolute Neutrophil Count (ANC) 1.5 
109/L
Platelet count is 100.0 109/L
Haemoglobin is 9.0 g/dL (after transfusion 
if needed)
Chemistry
For liver AE refer to Section 5.13
Serum Creatinine-1.5 mg/dL Calculated 
Creatinine Clearance <40mL/mins 
(Appendix 6)
Interrupt treatment until resolved to 
Grade 0-1, up to 14 days.
If toxicity does not resolve, consult 
GSK Medical Monitor to determine 
if it is in the best interest of the 
subject to continue in the study
1st appearance Resume 100%
2nd appearance Resume 100%
or dose reduce to 1000mg/day.
3rd appearance-Resume 100%
or dose reduce to 1000mg/day.
Grade 2-Any other event
For Cardiac Ejection Fraction and 
interstitial pneumonitis AEs, refer to 
Section 5.12.3.
For liver AE refer to Section 5.13. 
For rash refer to Section 5.12.1.
For diarrhoea refer to Section 5.12.2 and to 
Appendix 1
Maintain dose for 1st and 2nd
appearance
Interrupt treatment until resolves to 
Grade 0-1, up to 14 days for 3rd
and 4th appearance
1st appearance-Maintain dose-
No change
2nd appearance- Maintain dose 
No change
3rd appearance – Resume 100% 
or dose reduce to 1000mg/day
4th appearance – Resume with a 
dose reduction to 1000mg/day.
Grade 3 – Any other event
For Cardiac Ejection Fraction and 
interstitial pneumonitis AEs, refer to 
Section 5.12.3.
For liver AE refer to Section 5.13. 
For rash refer to Section 5.12.1.
For diarrhoea refer to Section 5.12.2and to 
Appendix 1
Interrupt treatment until resolves to 
Grade 0-1, up to 14 days.
Any appearance-Resume 100% 
or Reduce dose to 1000mg 
permitted in consultation with 
GSK Medical Monitor.
Grade 4
For Cardiac Ejection Fraction and 
interstitial pneumonitis AEs, refer to 
Section 5.12.3
For liver AE refer to Section 5.13. 
For rash refer to Section 5.12.1.
For diarrhoea refer to Section 5.12.2 and to 
Appendix 1
Interrupt treatment until resolves to 
Grade 0-1, up to 14 days.
Consult with GSK Medical 
Monitor to determine if in the best 
interest of the subject to continue 
at a dose reduction.
Toxicity grading system according to NCI-CTCAE V4.03
5.11.
Dose Delays and Reductions for Capecitabine
Dose modification guidelines for capecitabine have been developed for the management 
of selected AEs (Table 11).


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Table 11
Dose modification rules for capecitabine
Toxicity NCI-CTCAE Grade
During Course of Therapy
Capecitabine Dose Change
Grade 1
Maintain dose
No change
Specific Events of Grade 2/3
Haematology 
ANCs 1.5 109/L
Platelet count is 100.0 109/L
Haemoglobin is 9.0 g/dL (after 
transfusion if needed)
Chemistry
For liver AE refer to Section 5.13. 
Serum Creatinine-1.5 mg/dL Calculated 
Creatinine Clearance <40mL/mins 
(Appendix 6)
Interrupt treatment until resolved to 
Grade 0-1, up to 14 days.
If toxicity does not resolve, consult 
GSK Medical Monitor to determine 
if it is in the best interest of the 
subject to continue in the study.
1st appearance -Resume at 
100% or Resume at 75% 
(rounded to nearest 150mg) as 
clinically indicated 
2nd appearance Resume at 75% 
(rounded to nearest 150mg)
3rd appearance-Resume at 50% 
of starting dose rounded to 
nearest 150mg) 
4th appearance-Discontinue 
permanently
Grade 2-Any other event
For liver AE refer to Section 5.13. 
For diarrhoea refer to Section 5.12.2and to 
Appendix 1
Interrupt treatment until resolved to 
Grade 0-1, up to 14 days. 
1st appearance -Resume at 
100% or Resume at 75% 
(rounded to nearest 150mg) as 
clinically indicated 
2nd appearance Resume at 75% 
(rounded to nearest 150mg)
3rd appearance-Resume at 50% 
of starting dose rounded to 
nearest 150mg) 
4th appearance-Discontinue 
permanently
Grade 3 – Any other event
For liver AE refer to Section 5.13. 
For diarrhoea refer to Section 5.12.2and to 
Appendix 1
Interrupt until resolves to Grade 0-
1, up to 14 days.
1st appearance-Resume 75% of 
starting dose (rounded to nearest 
150mg) 
2nd appearance- Resume 50% of 
starting dose (rounded to 
nearest150 mg)
3rd appearance- Discontinue 
treatment permanently
Grade 4
For liver AE refer to Section 5.13. 
For diarrhoea refer to Section 5.12.2and to 
Appendix 1
Interrupt until resolves to Grade 0-
1, up to 14 days.
Consult GSK Medical Monitor to 
determine if it is in the best 
interest of the subject to continue 
at a dose level lower than the 
original capecitabine dose
Toxicity grading system according to NCI-CTCAE V4.03
5.12.
Guidelines for Events of Special Interest and Dose 
Modifications
The severity of AEs will be graded in accordance with the NCI CTCAE version 4.03.  
Guidelines for dose modifications and interruptions for management of common 
toxicities associated with the treatment with lapatinib and capecitabine are provided in 
this section. Any future changes made to this guidance will be communicated to the 
investigative sites in the form of a letter and the revised version will be included in the 
SPM.


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5.12.1.
Dermatological Events
5.12.1.1.
Dermatological Monitoring
As part of their physical examination, subjects must have a thorough skin examination 
prior to the start of study treatment or randomisation. The examination may include the 
scalp, previously irradiated areas, hair, and nails.  In addition, if clinically indicated an 
examination of the oral/genital mucosa may also be included.
Subsequent dermatological evaluations should be performed as clinically indicated.  Any 
serious and/or clinically relevant dermatological AEs must be followed until resolution to 
grade one (or better), or until there is no further improvement.
Subjects must also have a skin examination as part of the physical examination at the end 
of 24 weeks of treatment with lapatinib and capecitabine, or disease progression, 
treatment discontinuation due to unacceptable toxicity or subject withdrawal, whichever 
is sooner.
The purpose of dermatological monitoring is:

to facilitate dermatological safety throughout the trial in all subjects receiving 
lapatinib;

to assess whether a holding/stopping rule imposed during the course of 
treatment leads to less dermatological toxicity;

to identify the incidence of dermatological adverse events (AEs) for lapatinib, or 
the combination of lapatinib with other agents.
5.12.1.2.
Frequency Evaluation and Grading Guide of Dermatological AEs
The frequency of dermatological adverse events occurring in 2,093 patients with locally 
advanced or metastatic cancer who participated in nine completed phase II and III 
lapatinib clinical trials is shown in Table 12.  This patient population included 1,413 
patients with breast cancer and 680 patients with other cancers. Patients were treated 
with lapatinib as monotherapy (n = 926) or in combination with paclitaxel (n=293) or 
capecitabine (n = 491).  Patients who were not exposed to lapatinib but received 
paclitaxel, capecitabine, or hormonal agents served as controls (n = 676).


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Table 12
Most Common Dermatological AEs Occurring in Patients Receiving 
Lapatinib (NCI-CTCAE versions 2.0 and 3.0)
The NCI CTCAE descriptions and grades of severity of dermatological AEs is presented 
in Table 13.
Table 13
NCI-CTCAE dermatological reactions
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Rash maculo-papular
Macules/papules 
covering <10% 
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 super infection 
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
super infection 
with IV
antibiotics 
indicated; life-
threatening
consequences
Death


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Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
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
-
-
-
Nail ridging
Asymptomatic; 
clinical or
diagnostic 
observations only;
intervention not 
indicated
-
-
-
-
Paronychia
Nail fold edema or 
erythema;
disruption of the 
cuticle
Localised 
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 localised; 
topical intervention 
indicated
Intense 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
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
Hair loss of 
>50% normal for
that individual 
-
-


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Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
is not obvious 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
that is readily
apparent to 
others; a wig or
hair piece is 
necessary if the
patient desires to 
completely
camouflage the 
hair loss;
associated with 
psychosocial
impact
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
Lapatinib-related severe dermatological events (Grade 3) are infrequent (1-3%).  
Despite the rarity of lapatinib associated severe dermatological events, it is recommended 
that subjects who present with a severe dermatological event be assessed for the 
following: shortness of breath, angioedema, or generalised mucosal/cutaneous affectation 
with blisters or ulcers, suggestive of Type I hypersensitivity and/or NCI-CTCAE Grade 4 
dermatological event, manifested as toxic epidermal necrolysis or Stevens-Johnson 
Syndrome etc.  If a Grade 4 dermatological event occurs, lapatinib must be permanently 
discontinued.
5.12.1.3.
Stopping and holding rules
If any Grade 4 dermatological event occurs, lapatinib must be permanently discontinued.
5.12.1.3.1. Holding rule
Lapatinib should be held for 14 days, in all patients who experience either a grade 3 
dermatological reaction or a grade 2 dermatological reaction, which is unimproved after 
two-weeks of medical management.  After the 14 day interruption, and provided the 
dermatological reaction improves to grade 1 or better, lapatinib may be restarted at the 
previous dose.
If the investigator considers continuation of lapatinib without interruption, it is required 
that he/she discusses the individual case with the GSK medical monitor before taking any 
decision on study treatment.  In some cases, resolution of grade 2 or greater 
dermatological reactions occurred without interruption of lapatinib.  For those subjects 


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that interrupted lapatinib, many were able to resume lapatinib therapy at the same dose 
after resolution of the dermatological event.
5.12.1.3.2. 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 dermatological events which recover to 
NCI-CTCAE Grade 1 or better (within 14 days) after holding lapatinib.
5.12.1.3.3. Stopping rules
Lapatinib must be permanently discontinued for:

Recurrent Grade 3 dermatological reactions

All Grade 4 dermatological reactions, including Stevens-Johnson Syndrome and 
Toxic Epidermal Necrolysis.
5.12.1.4.
Treatment
There is no standard treatment proven to be effective for lapatinib-induced 
dermatological reactions.  Therefore it is recommended that subjects who develop Grade 
2 dermatological reactions that are unresponsive to initial treatment may be referred to a 
dermatologist for evaluation and management.  For subjects with Grade 3 or 4 
dermatologic events, or chronic, persistent or recurring lower grade skin events, a 
dermatology consultation is strongly encouraged.
There are some general precautions for subjects receiving lapatinib therapy. Subjects are 
recommended to avoid exposure to bright sunlight.  When going out into bright sunlight, 
a broad spectrum sunscreen (containing titanium dioxide or zinc oxide) with an SPF of at 
least 30 should be applied.
A variety of agents may be used to manage dermatological reactions.  These include 
mild-to-moderate strength steroid creams, topical or systemic antibiotics, topical or 
systemic antihistamines, immunomodulators, hypoallergenic moisturisers, and emollients.
The need for oral or topical antibiotics and topical steroids is a clinical decision.  For 
pruritic lesions oral antihistamine agents may be effective.  For paronychia antiseptic 
bath and local potent corticosteroids in addition to tetracycline therapy is recommended.
If no improvement occurs, a dermatology or surgery consultation is recommended.  For 
infected lesions appropriate, culture driven treatment with systemic or topical antibiotics 
is recommended as clinically indicated.
Oral retinoids are not recommended because of theoretical concerns about negative 
effects on lapatinib’s mechanism of action. Topical steroids may result in skin irritation
and severe xerodermia (dryness).  Oral steroids may be used for a short treatment course 
(maximum of 14 days).


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5.12.2.
Gastrointestinal Events
If gastrointestinal AEs are not appropriately managed, they may be associated with the 
development of dehydration.
5.12.2.1.
Nausea and vomiting
In subjects who vomit and are unable to retain lapatinib and/or capecitabine, every 
attempt should be made to control nausea and vomiting. If a subject vomits after 
administration of study drug, the subject should be instructed not to retake the dose. 
Subjects should take the next dose as scheduled. If vomiting persists, then the subject 
should contact the investigator.
5.12.2.2.
Diarrhoea
Diarrhoea is the primary efficacy endpoint of this study.  It is essential that the 
investigator understands fully the classification of diarrhoea and the definitions of 
severity used in this study (Table 8).  For each diarrhoea AE report, the investigator 
should assess the change in stool form and frequency relative to the normal form and 
frequency for the subject to accurately ascertain the grade of the diarrhoea AE.
In rare cases, diarrhoea can be debilitating, and potentially life threatening if 
accompanied by dehydration, renal insufficiency, and/or electrolyte imbalances. 
Diarrhoea should be managed proactively to avoid complications such as dehydration, 
renal insufficiency, and electrolyte imbalances or worsening of the subject’s condition. 
Standardised guidelines for treating chemotherapy-associated diarrhoea have been 
developed by ASCO [Benson, 2004], and these have been used to develop specific 
guidelines for the management of diarrhoea associated with lapatinib use (Appendix 1).  
These guidelines should be used in combination with the treatment delay and dose 
reduction rules described in Section 5.10 and in Section 5.11.
5.12.3.
Cardiac and Respiratory Events
Asymptomatic Cardiac Events
Subjects who have a ≥20% decrease in left ventricular cardiac ejection fraction relative to 
baseline, and an ejection fraction below the institution's lower limit of the normal range 
(LLN), should have a repeat evaluation of ejection fraction 1-2 weeks later while still 
receiving treatment with lapatinib and capecitabine.
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 LLN, then 
treatment with lapatinib and capecitabine should be temporarily discontinued.


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If the left ventricular ejection fraction recovers during the next 3 weeks, after consultation 
and approval of the medical monitor, the subject may be restarted on treatment with 
lapatinib and capecitabine at a reduced dose of lapatinib.  For such subjects, monitoring 
of left ventricular ejection fraction will then be performed 2 weeks and 4 weeks after 
rechallenge, and then every 4 weeks thereafter.
If repeat ejection fraction evaluation still shows a ≥20% decrease in left ventricular 
ejection fraction relative to baseline, and the value is below the institution's LLN, then 
the subject should be withdrawn from treatment with lapatinib and capecitabine.
Symptomatic Respiratory and Cardiac Events
Subjects should be monitored for symptoms of pulmonary toxicity (dyspnoea, cough, 
fever, interstitial pneumonitis) or cardiotoxicity, and subjects who experience pulmonary 
symptoms or left ventricular systolic dysfunction which are NCI CTCAE Grade 3 or 
greater must be withdrawn from treatment with lapatinib and capecitabine.
5.12.4.
Hand and Foot Syndrome
The frequency of hand and foot syndrome among patients receiving capecitabine has led 
the US regulatory agency, in conjunction with the manufacturer, to arrive at the 
capecitabine- specific toxicity rating scale shown in Table 14.  
Table 14
Hand and Foot toxicity rating scale
Criteria for grading palmar-plantar erythrodysthesia (hand and foot) syndrome
Toxicity 
Grade
Manifestations
Grade 1
Numbness, dysesthesia/paresthesia, tingling, painless swelling, or 
erythema of the hands and/or feet that causes discomfort but does not 
disrupt normal activities of daily living
Grade 2
Painful erythema and swelling of the hands and/or feet that results in 
discomfort affecting normal activities of daily living
Grade 3
Moist desquamation, ulceration, blistering, and severe pain of the 
hands and/or feet and/or severe discomfort that causes inability to 
work or perform activities of daily living
Source: Capecitabine SPC
In the event the subject presents with hand-foot syndrome, follow the recommended dose 
modification guidelines for capecitabine described in Section 5.11.  If Grade 2 or 3 hand-
foot syndrome occurs, administration of lapatinib and capecitabine should be stopped 
until resolution to Grade 0-1.


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5.13.
Monitoring, Interruption, and Stopping Criteria for 
Hepatobiliary Events
If alanine aminotransferase (ALT) is 3xULN and bilirubin 2xULN, and serum 
bilirubin fractionation is not immediately available, the subject must discontinue study 
treatment.  Serum bilirubin fractionation should be performed if testing is available.
If serum bilirubin testing is unavailable, the presence of detectable urinary bilirubin on a 
dipstick test is indicative of direct bilirubin elevations and suggests liver injury may be 
present.
A safety algorithm detailing stopping and follow up criteria for hepatobiliary AEs is 
presented in Appendix 7.
5.13.1.
Liver Chemistry Stopping Criteria
Phase II study liver chemistry stopping and follow up criteria have been designed to 
assure subject safety and to evaluate liver event etiology in alignment with the FDA 
Guidance for Industry – Drug-Induced Liver Injury: Premarketing Clinical Evaluation 
(July 2009, www.fda.gov).
Phase II liver chemistry stopping criteria 1-5 are defined as follows and are presented in a 
Figure in Appendix 7:
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 to GSK within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE  


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
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).

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.

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 5.13.1.1), 
and close monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, Aspartate 
aminotransferase [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 
5.13.1.1)

Monitor subjects weekly until liver chemistries (ALT, aspartate aminotransferase 
(AST), alkaline phosphatase, bilirubin) resolve, stabilize or return to within baseline 
values; 

Subjects meeting criterion 5 should be monitored as frequently as possible.
All subjects who meet the liver chemistry criteria requiring permanent discontinuation of 
treatment with lapatinib and capecitabine must complete the study assessments and 
procedures as defined in the Time and Events Schedule (Table 16 and Table 17).


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5.13.1.1.
Liver event follow up assessments
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 immunoglobulin M (IgM) antibody;

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM);

Hepatitis C RNA;

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 one week 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 eCRF.  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 and lactate dehydrogenase;

Fractionate bilirubin if total bilirubin ≥2xULN.

Complete blood count with differential to assess eosinophilia;

Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, decreased appetite, nausea, vomiting, right upper 
quadrant pain or tenderness, jaundice, 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, and Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG) or gamma 
globulins)

Liver imaging (ultrasound, magnetic resonance, or computerised tomography) to 
evaluate liver disease.


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
Serum acetaminophen adduct high performance liquid chromatography 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].
5.13.2.
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 GSK Medical Monitor within 24 hours of learning of the abnormality to 
discuss subject safety

Continue treatment with lapatinib and capecitabine

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 (Section 
5.13.1), 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. 
An algorithm of liver chemistry monitoring, interruption stopping and follow up criteria
is presented in Appendix 7.
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 treatment with 
octreotide for subjects randomised to receive octreotide or within two weeks prior to 
the first dose of lapatinib and capecitabine for subjects randomised to receive no 
octreotide.


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
All treatments related to supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, anti-emetics, anti-
diarrhoeal medications and analgesics.  

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 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 15 for a list of CYP3A4 Inducers and 
Inhibitors that are prohibited during this study. 
Concurrent treatment with bisphosphonates is permitted; however treatment must be 
initiated prior to the first dose of study treatment. Prophylactic use of bisphosphonates in 
subjects without bone disease is not permitted, except for the treatment of osteoporosis.
6.2.
Prohibited Medications and Non-Drug Therapies
The following medications are prohibited:

Anti-cancer therapy should not be given until disease progression or withdrawal 
from investigational treatment.  Subjects who receive concurrent anti-cancer therapy 
(i.e. cytotoxic or biologic) will not be allowed to continue treatment with lapatinib 
and capecitabine.  Subjects who require an alternative anti-cancer therapy may 
withdraw from the study at any time;

Concurrent radiation therapy and surgery for metastatic breast cancer, including 
resection of non-dominant metastases.  Radiotherapy will ONLY be allowed for 
palliation of pain for bone metastases and for spinal cord decompressions;

Hormonal therapy(ies), other than physiologic replacement;

Any other investigational drug;

All herbal supplements, because the composition, pharmacokinetics and metabolism 
of many herbal supplements are unknown;

Inducers and inhibitors of CYP3A4, because they may alter the metabolism of 
lapatinib.  The list of CYP3A4 inducers and inhibitors that are prohibited from 
screening through to discontinuation from study treatment is presented in Table 15. 

allopurinol, dipyridamole, folinic acid, trimethoprim, leucovorin, sorivudine and 
its’analogues, because they are contraindicated with capecitabine or associated with 
5-FU interactions.
Pre-treatment with a proton pump inhibitor (esomeprazole) decreased lapatinib exposure 
by an average of 27% (range: 6% to 49 %).  This effect decreases with increasing age 
from approximately 40 to 60 years.  Therefore, caution should be used when lapatinib is 
used in subjects pre-treated with a proton pump inhibitor.


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Anticoagulation with coumarin or derivatives other than in low doses (e.g. ≤1mg 
coumarin daily) for catheter prophylaxis is prohibited.  Subjects taking coumarin at doses 
≤1mg daily should be monitored regularly for alteration in their coagulation parameters 
(prothrombin time or international normalized ratio [INR]).  
Concomitant administration of octreotide and bromocriptine increases the bioavailability 
of bromocriptine.
Octreotide reduces the intestinal absorption of cyclosporin and delays that of cimetidine.  
Cimetidine is a prohibited medication due to its known effect on liver enzymes, and the 
potential for interaction with lapatinib.
Information on potential interactions with other medicinal products is presented in the 
Lapatinib, Capecitabine and Octreotide SPCs.


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Table 15
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 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 a GSK Medical Monitor 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 the SPM.
6.3.
Treatment after Discontinuation of the 24 Week 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 whether or not GSK is providing 
specific post-study treatment.
In countries and centres where lapatinib and capecitabine are reimbursed and have been 
sourced locally, lapatinib and capecitabine should also be sourced locally for continuation 


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of treatment post-study.  These subjects are considered to have completed the study after 
24 weeks of treatment with lapatinib and capecitabine, and post-study care should be 
conducted in accordance with local best practice.
In countries and centres where lapatinib and capecitabine are provided by GSK, these 
drugs will also be provided by GSK for continuation of treatment post-study. After 
completing 24 weeks of treatment with lapatinib and capecitabine, these subjects will 
enter the long term follow up (LTFU) phase of the study and will continue to receive 
treatment with lapatinib and capecitabine until disease progression, unacceptable toxicity 
or death.  
Upon discontinuation from treatment with lapatinib and capecitabine, subjects may 
receive additional (non protocol) anti-cancer therapy at the discretion of the treating 
physician.  Every effort should be made to complete the required withdrawal evaluations 
and follow up evaluations relating to resolution or stabilization of SAEs prior to initiating 
further anti-cancer therapy or dosing of an investigational agent (see Table 16 and Table 
17 for end of study and follow-up assessments and procedures).  
6.4.
Treatment of Study Treatment Overdose
There is no specific antidote for the inhibition of EGFR and/or HER2 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.
Lapatinib is not significantly renally excreted and is highly bound to plasma proteins, 
therefore haemodialysis would not be expected to be an effective method to enhance the 
elimination of lapatinib.  Further management should be as clinically indicated or as 
recommended by the national poisons centre, where available.
If an overdose with octreotide should occur, the investigator, site pharmacist or 
authorized site personnel should refer to the Sandostatin SPC for instruction.
Any SAEs that occur as a result of an overdose of treatment with lapatinib or 
capecitabine should be reported to the GSK Medical Monitor and through the usual SAE 
reporting process as described in Section 7.4.9.


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7.
STUDY ASSESSMENTS AND PROCEDURES
A signed, written informed consent form must be obtained from the subject prior to any 
study-specific procedures or assessments.  
The schedule of all assessments is presented in Table 16 and Table 17.  Details of the 
efficacy and safety assessments are presented in Section 7.2 and Section 7.3, respectively.  
Details of health outcomes 
 are presented in 
Section 7.7 and Section 7.8, respectively.  Further details of study procedures and 
assessments can be found in the SPM.
Procedures conducted as part of the subject’s routine clinical management (e.g., liver 
function) and obtained prior to the signing of informed consent may be utilized for 
screening or baseline purposed provided the procedure meets the protocol-defined criteria 
and has been performed within the timeframe of the study.
Investigators may be requested to perform additional safety tests during the course of the 
study based on newly available data to ensure appropriate safety monitoring.  
Appropriate local regulatory and ethical approvals should be obtained before any 
additional testing is performed.
Table 16
Time and events schedule; Subjects who receive octreotide
Screen1
Octreotide 
Dose 1
(Week -1)
Lapatinib and Capecitabine Cycle10
Withdrawal 
from Study 
Treatment or 
End of Study15
Cycle 1
Cycle 213
(Octreotide 
Dose 2)
Cycles 
3 to 813
Procedures
Informed Consent
x
Inclusion/Exclusion 
Criteria
x2
x2
Demographics
x
Breast Cancer 
Medical/Surgical and 
Treatment History
x
Efficacy and Safety Assessments
AE/Toxicity Assessment
x
x
x
x
x16
Disease Assessment
x3
(x)5
(x)5
(x)5
(x)5
x
PROs6
x7
x11
x
x
x
Concurrent Medications
x
x
x
x
x
x
Physical Exam
x
x
Dermatological Exam
x
(x)8
(x)8
(x)8
(x)8
x
Weight, Height, Vital 
Signs (Temp, BP, pulse)
x
x
ECOG Performance 
Status
x4
x
Cardiac function
x
x17
ECG
x
(x)8
Lab Assessments


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Screen1
Octreotide 
Dose 1
(Week -1)
Lapatinib and Capecitabine Cycle10
Withdrawal 
from Study 
Treatment or 
End of Study15
Cycle 1
Cycle 213
(Octreotide 
Dose 2)
Cycles 
3 to 813
Procedures
Liver function
x
(x)5
(x)5
(x)5
(x)5
x
Pregnancy Test
x
x
Study Treatments
Administer Octreotide
x9
x14
Dispense Lapatinib and 
Capecitabine
x
x
x
Assess Lapatinib and 
Capecitabine Returned
x
x
x
1.
Schedules for screening assessments are presented in Section 7.1.1 and Section 7.1.2.  All screening and 
baseline assessments must be completed prior to administration of the octreotide 0.1mg s.c. tolerability 
assessment dose.
2.
Inclusion and exclusion criteria are presented in Section 4.1.2 and Section 4.1.3, and other considerations are 
presented in Section 4.2.  Investigators must ensure all subjects are eligible to receive treatment with lapatinib 
and capecitabine in accordance with the Lapatinib SPC and Capecitabine SPC, including evaluation of cardiac 
function.
3.
Disease assessment criteria are described in Section 7.1.11.
4.
ECOG status may be assessed more than once prior to randomisation, but only the assessment within 3 days 
prior to randomisation will be recorded in the eCRF.
5.
Not mandatory at these visits, but should be conducted in accordance with local clinical practice, at the time of 
a scheduled 3 weekly visits when possible.
6.
PROs are the FACIT-D and the DMD.
7.
Week -1 baseline PROs to be completed prior to randomisation, before the octreotide 0.1mg s.c. tolerability 
assessment dose. 
8.
If clinically indicated, in accordance with the Lapatinib SPC. 
9.
First dose of octreotide LAR to be given 7 days before start of Cycle 1 treatment with lapatinib and 
capecitabine.  Subjects must receive octreotide 0.1mg s.c. at least one hour before the first dose of octreotide 
LAR to assess tolerability.
10. Visits at the start of Cycle 2 and Cycle 4 are mandatory. Visits at the start of Cycle 3, 5, 6, 7 and 8 are not 
mandatory; visits every 3 weeks would be preferred, but may be adapted to match local practice. 
11. Week 0 baseline PROs to be completed before the first dose of lapatinib and capecitabine is administered.  
12.
 
13. Cycle 2 to be started 21 days (2 days) after the start of Cycle 1.  Other cycles should be started within 4 
days of the 3 weekly treatment cycle intervals.
14. Second dose of octreotide LAR to be given 28 days (2 days) after first dose of octreotide LAR.
15. After 24 weeks treatment with lapatinib and capecitabine.  Investigators should continue to treat subjects with 
lapatinib and capecitabine beyond 24 weeks in accordance with local clinical practice. 
16. Serious adverse events and other safety data as described in Section 7.4 should be reported for all subjects 
who continue treatment with lapatinib and capecitabine beyond the 24 week end of study assessment.
17. If more than 12 weeks since the screening cardiac function assessment.


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Table 17
Time and events schedule; Subjects who receive no octreotide
Screen1
Lapatinib and Capecitabine Cycle
Withdrawal from 
Study Treatment or 
End of Study Visit12
Cycle 1
Cycle 210,11 to 8
Procedures
Informed Consent
x
Inclusion/Exclusion Criteria
x2
x
Demographics
x
Medical/Surgical and 
Treatment History
x
Efficacy and Safety Assessments
AE/Toxicity Assessment
x
x
x13
Disease Assessment
x3
(x)5
(x)5
x
PROs6
x7
x
x
Concurrent Medications
x
x
x
x
Physical Exam
x
x
Dermatological Exam
x
(x)8
(x)8
x
Weight, Height, Vital Signs 
(Temp, BP, pulse)
x
x
ECOG Performance Status
x4
x
Cardiac function
x
x14
ECG
x
(x)8
Lab Assessments
Liver function
x
(x)5
(x)5
x
Pregnancy Test
x
x
Study Treatments
Dispense Lapatinib and 
Capecitabine
x
x
Assess Lapatinib and 
Capecitabine Returned
x
x
1.
Schedules for screening assessments are presented in Section 7.1.1 and Section 7.1.2.  All screening and 
baseline assessments must be completed prior to the start of Cycle 1 of treatment with lapatinib and capecitabine.
2.
Inclusion and exclusion criteria are presented in Section 4.1.2 and Section 4.1.3, and other considerations are 
presented in Section 4.2.  Investigators must ensure all subjects are eligible to receive treatment with lapatinib 
and capecitabine in accordance with the Lapatinib SPC and Capecitabine SPC, including evaluation of cardiac 
function.
3.
Disease assessment criteria are described in Section 7.1.11. 
4.
ECOG status may be assessed more than once prior to randomisation, but only the assessment within 3 days 
prior to randomisation will be recorded in the eCRF.
5.
Not mandatory at these visits, but should be conducted in accordance with local clinical practice, at the time of a 
scheduled 3 weekly visits when possible.
6.
PROs are the FACIT-D and the DMD. 
7.
Week 0 baseline PROs to be completed prior to randomisation, before the first dose of lapatinib and capecitabine 
is administered.
8.
If clinically indicated, in accordance with the Lapatinib SPC.
9.
 
 
10. Cycle 2 to be started 21 days (2 days) after the start of Cycle 1.  Other cycles should be started within 4 days 
of the 3 weekly treatment cycle intervals.
11. Visits at the start of Cycle 2 and Cycle 4 are mandatory.  Visits at the start of Cycle 3, 5, 6, 7 and 8 are not 
mandatory; visits every 3 weeks would be preferred, but may be adapted to match local practice.
12. After 24 weeks treatment with lapatinib and capecitabine.  Investigators should continue to treat subjects with 
lapatinib and capecitabine beyond 24 weeks in accordance with local clinical practice. 


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13. Serious adverse events and other safety data as described in Section 7.4 should be reported for all subjects who 
continue treatment with lapatinib and capecitabine beyond the 24 week end of study assessment.
14. If more than 12 weeks since the screening cardiac function assessment.
7.1.
Assessments and Procedures
Following randomisation subjects will be followed according to the Time and Events 
Schedules (Table 16 and Table 17).  Under exceptional circumstances and with prior 
documented agreement between the principal investigator and the medical monitor, the 
timing of assessments may be adjusted to ensure subject safety or scientific integrity.
7.1.1.
Critical Baseline Assessments
All subjects enrolled in LAP117314 must be eligible to receive treatment with lapatinib 
and capecitabine.  The investigator must confirm that all subjects have histologically or 
cytologically confirmed HER2-positive breast cancer which has progressed following 
prior therapy, which must have included anthracyclines and taxanes and trastuzumab in 
the metastatic setting.
Cardiovascular medical history/risk factors will be assessed at baseline.
7.1.2.
Screening and Baseline Assessments and Procedures
Baseline and screening assessments should be completed prior to the first dose of 
octreotide for subjects randomised to receive octreotide and prior to the first dose 
of lapatinib and capecitabine for subjects randomised to receive no octreotide.
Subjects who meet the inclusion and exclusion criteria for the study must complete the 
Informed Consent Form before any study-specific procedures are conducted.  
Within 4 Weeks prior to First Dose of Study Treatment

Disease assessment, in accordance with RECIST version 1.1 [Eisenhauer, 2009]:
o Lymph nodes that have a short axis of <10mm are considered non-pathological 
and should not be recorded or followed.    
o Pathological lymph nodes with <15mm and but 10mm short axis are considered 
non measurable.    
o Pathological lymph nodes with 15mm 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.    
o 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).       


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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.        
o Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by computerized tomography (CT) or 
magnetic resonance imaging (MRI) can be considered measurable. Bone scans, 
fluorodeoxyglucose-positron emission tomography scans or X-rays are not 
considered adequate imaging techniques to measure bone lesions.  
o 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 group by organ. 
Measurements of these lesions are not required, but the presence or absence of 
each should be noted throughout follow-up. 

Disease characteristics and breast cancer history:
o
Details of the primary tumor: oestrogen and progesterone receptor status 
(performed by immunohistochemical [IHC] methods), and HER2 status, including 
IHC and /or fluorescence in-situ hybridization (FISH) analysis;
o
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, lines of therapy completed;
o
Prior treatment history: adjuvant or neoadjuvant chemotherapy received (agent(s), 
date of last dose), biologic therapy, immunotherapy or hormonal therapy received.

Current medical conditions.

ECOG performance status (as defined in Appendix 4).  This should not be recorded 
in the eCRF.

Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin).  Other 
haematology and clinical chemistry tests should be conducted in accordance with 
local clinical practice, but should only be recorded in the eCRF if associated with an 
AE or SAE.

Electrocardiogram (12-lead ECG).

Cardiac function: left ventricular ejection fraction (LVEF) measurement by 
echocardiogram or Multiple Gated Acquisition Scan (MUGA).
Within 7 days prior to First Dose of Study Treatment

Pregnancy test: serum human chorionic gonadotrophin (-hCG) pregnancy test for 
women of childbearing potential.  Test to be performed within 7 days prior to 
treatment with octreotide if randomised to receive octreotide or within 7 days prior to 
the first dose of lapatinib with capecitabine if randomised to receive no octreotide, 
but preferably as close to the start of treatment as possible.  The results must be 
reviewed prior to initiating treatment.


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7.1.3.
Prior to Randomisation
These assessments are to be performed within 3 days prior to treatment with octreotide if 
randomised to receive octreotide or within 3 days prior to the first dose of lapatinib with 
capecitabine if randomised to receive no octreotide:

Demographic data: year of birth, race, ethnicity, gender.

Physical examination.

Dermatological examination.

Vital signs (body temperature, blood pressure and pulse rate).

Height and weight.

Review Current Medical Conditions.

Review of screening liver function test results.  If any result is outside the normal 
range the laboratory screening will be repeated (prior to the first dose of study 
medication) at the discretion of the Principal Investigator.

Evaluation of diarrhoea occurring within the previous 2 weeks.

Concomitant Medication: Record all medication(s) received within 2 weeks prior to 
the first dose of study treatment and note if the medication is continuing.

ECOG performance status, as defined in Appendix 4  This must be recorded in the 
eCRF.
Note: if the subject's performance status score is >2, the subject will be excluded 
from the study.

FACIT-D questionnaire and the baseline DMD. These must be completed before the 
first dose of any study treatment.
After all screening and baseline evaluations have been completed, determine if the 
subject is eligible for the study by reviewing the inclusion and exclusion criteria (Section 
4.1.2 and Section 4.1.3). Any changes in the subject's mental or physical condition since 
the time of screening that would make the subject ineligible for the study should be 
considered.  
7.1.4.
Post-Randomisation
Subjects will be randomised to receive octreotide or to receive no octreotide.
For subjects randomised to receive octreotide:

Administer the octreotide 0.1mg s.c. tolerability assessment dose, monitor for at least 
one hour and record any AEs associated with this dose.  

Administer first dose of octreotide 40mg LAR (only in subjects who have not shown 
intolerance to the octreotide 0.1mg s.c. tolerability assessment dose).
For subjects randomised to receive no octreotide:


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
Dispense lapatinib and capecitabine to the subject with instructions for taking 
therapy.
All subjects will be given advice concerning the management of diarrhoea.  It is 
recommended that subjects should be provided with loperamide for the prompt 
management of diarrhoea.
7.1.5.
One Week after the First Dose of Octreotide LAR (Subjects 
Randomised to Receive Octreotide only)
These assessments and procedures are to be performed 7 days after the first dose of 
octreotide LAR in subjects randomised to receive octreotide only.

Record any AEs and SAEs and assign appropriate toxicity grade (NCI CTCAE, 
version 4.03).

Dermatological examination, if clinically indicated.

FACIT-D questionnaire and the baseline DMD. These must be completed before the 
first dose of lapatinib and capecitabine.

Record all concomitant medications added and/or changed.

Record visits to/contact with healthcare professionals associated with diarrhoea AEs.

Record intravenous rehydration associated with diarrhoea AEs.

Dispense lapatinib and capecitabine to the subject with instructions for taking 
therapy.
Other assessments, such as haematology, clinical chemistry, liver function tests and 
change in disease status should be conducted in accordance with the local standard of 
care.  Liver function tests and change in disease status should be recorded as required in 
the relevant modules of the eCRF.  Haematology and other clinical chemistry tests should 
be recorded in the eCRF only if associated with an AE or SAE.
7.1.6.
Assessments Every 3 Weeks
These assessments are to be performed every 3 weeks or as close to these intervals as 
possible.  Assessments at the start of Cycle 2 and Cycle 4 of treatment with lapatinib 
and capecitabine are mandatory; assessments at the start of Cycles 3, 5, 6, 7 and 8 
should be performed in accordance with local clinical practice.  Assessments at the end of 
the 24 week study treatment period (i.e. Cycle 8 of treatment with lapatinib and 
capecitabine) or at withdrawal from study treatment before the end of the 24 week study 
treatment period are described in ‘Assessments at Study Completion or Early Withdrawal 
from Study and/or Study Treatment’ (Section 7.1.8). 

Record any AEs and SAEs and assign appropriate toxicity grade (NCI CTCAE, 
version 4.03).

Dermatological examination if clinically indicated.

Record all concomitant medications added and/or changed.


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
Record visits to/contact with healthcare professionals associated with diarrhoea AEs.

Record intravenous rehydration associated with diarrhoea AEs.

Record treatment delays or dose reductions associated with diarrhoea AEs.

Assess compliance of taking lapatinib and capecitabine since the previous study 
visit; the importance of compliance should be reviewed and emphasised.

Dispense lapatinib and capecitabine to the subject with instructions for taking 
therapy.

Confirm completion of FACIT-D questionnaire and DMDs.
Subjects randomised to receive octreotide only, start of Cycle 2 only: 

Administer octreotide 40mg LAR dose 2.
Other assessments, such as haematology, clinical chemistry, liver function tests and 
change in disease status should be conducted in accordance with the local standard of 
care.  Liver function tests and change in disease status should be recorded as required in 
the relevant modules of the eCRF.  Haematology and other clinical chemistry tests should 
be recorded in the eCRF only if associated with an AE or SAE.
7.1.7.
Unscheduled Visits
Unscheduled visits must be recorded in the eCRF.  There are no formal requirements for 
assessments and procedures to be conducted at unscheduled visits.  All data relevant to 
this study must be recorded, such as reason for the visit and actions taken as a 
consequence of the visit.
7.1.8.
Study Completion (24 weeks) or Early Withdrawal from Study 
and/or Study Treatment

Record any AEs and SAEs and assign appropriate toxicity grade (NCI CTCAE, 
version 4.03).

Record all concomitant medications added and/or changed.

Record visits to/contact with healthcare professionals associated with diarrhoea AEs.

Record intravenous rehydration associated with diarrhoea AEs.

Assess compliance of taking lapatinib and capecitabine since the previous study 
visit; the importance of compliance should be reviewed and emphasised.

Record treatment delays or dose reductions associated with diarrhoea AEs.

Confirm completion of FACIT-D questionnaires and DMDs.

Liver function tests; ALT, AST, alkaline phosphatase, total bilirubin, fractionated 
bilirubin (if total bilirubin ≥2 x ULN).

Echocardiogram or MUGA scan if the last cardiac assessment was >12 weeks
previously.


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
Physical examination.

Dermatological examination.

Vital signs; blood pressure, pulse rate.

Body weight.

ECOG performance status, as defined in Appendix 4.

Disease assessment, in accordance with RECIST version 1.1 [Eisenhauer, 
2009].

Pregnancy test: serum human chorionic gonadotrophin (-hCG) pregnancy 
test for women of childbearing potential.  
7.1.9.
Assessments after Study Completion: Long Term Follow Up
Following completion of the 24 week study treatment period subjects may continue to 
receive treatment with lapatinib and capecitabine until disease progression or the 
occurrence of AEs leading to treatment discontinuation.  
In countries and centres where lapatinib and capecitabine are provided by the study 
centre, subjects will continue to receive treatment with lapatinib and capecitabine in 
accordance with local practice.  Post-study assessments of efficacy and safety will be 
performed in accordance with the local standard of medical care and the Lapatinib and 
Capecitabine SPCs.  
In countries and centres where lapatinib and capecitabine are provided by GSK subjects 
will enter the LTFU phase of the study. Investigators will be required to collect and 
report the following safety information until lapatinib discontinuation:

Adverse events (AEs) leading to lapatinib discontinuation.

Other reasons leading to lapatinib discontinuation.

Date of lapatinib discontinuation.
Additionally, investigators will be required to collect and report the following safety 
information, until 30 days following lapatinib discontinuation:

Serious adverse events (SAEs) including AEs of special interested defined as 
SAEs will continue to be collected (as defined in Section 7.1.8 per protocol 
specific SAEs: cardiac, hepatic and pneumonitis).

Pregnancies.

Other AEs the investigator deems medically necessary to report.
Subjects with abnormal clinical or laboratory findings believed to be treatment-related 
will be followed until the condition resolves or until laboratory findings are not 
considered to be clinically significant.


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7.1.10.
Procedures and Assessments: Additional Information
At mandated visits laboratory assessments may be performed 3 days from the date of
actual visit to the site in order to allow for flexibility in scheduling.  Procedures, 
examinations, and laboratory assessments may be performed more frequently, if 
clinically indicated or part of routine clinical practice.  GSK recommend that all 
laboratory tests with values that become significantly abnormal while the subject is 
participating in the study or within 5 days after the last dose of study-related treatment
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 medical monitor notified.
Severity of diarrhoea will be determined according to the NCI CTCAE version 4.03 
definitions (Table 8) and each episode will be recorded as an AE in the eCRF.  It is 
essential that the frequency and form of stools are assessed relative to baseline to ensure 
accurate assessment of the severity of each episode of diarrhoea.  
7.1.11.
Disease Assessments
Disease assessments and response evaluations will be determined according to the 
definitions established in RECIST version 1.1 [Eisenhauer, 2009].  The frequency and 
methodology of disease assessments will be in accordance with local clinical practice 
during treatment with lapatinib and capecitabine, but disease assessments in accordance 
with RECIST version 1.1 must be conducted at the early withdrawal or study completion 
visit.
Overall response will be determined at the end of study treatment or at early withdrawal.  
The possible combinations of tumour responses are described in Table 18 and in Table 19.
Table 18
Evaluation of overall response for subjects with measurable disease 
at screening
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


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Table 19
Evaluation of overall response for subjects with non-measurable 
only disease at screening
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
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.  
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.
7.2.
Efficacy Endpoints
The primary efficacy endpoint is the proportion of subjects experiencing diarrhoea with a 
severity of Grade 2 and above, as defined by the NCI CTCAE, version 4.03.  Other 
aspects of the frequency and severity of diarrhoea and of the consequences of diarrhoea 
are secondary endpoints.
Overall response rate and clinical benefit response are secondary endpoints.  Disease 
status will be defined in accordance with RECIST version 1.1 [Eisenhauer, 2009], and 
will be categorized in accordance with the definitions outlined in Table 18 and Table 19.  
7.3.
Safety Endpoints
LAP117314 will evaluate the effect of prophylactic treatment with octreotide on the 
tolerability of treatment with lapatinib and capecitabine.  Reduction of the frequency and 
severity of diarrhoea are efficacy endpoints.  Changes in the frequency and severity of 
other AEs will be used to evaluate the effects of prophylactic treatment with octreotide on 
the safety and tolerability of treatment with lapatinib and capecitabine.
7.4.
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.


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7.4.1.
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.
Definition of a SAE
A SAE 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 eCRF 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, diarrhoea, 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 hyperbilirubinaemia 
defined as ALT 3xULN and bilirubin 2xULN with >35% direct (or ALT 


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3xULN and INR>1.5, if INR measured) termed ‘Hy’s Law’ events. (INR 
measurement is not required and the threshold value stated will not apply to 
subjects 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 2xULN, 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, and interstitial 
pneumonitis has been reported in subjects taking compounds that inhibit ErbB1.  As a 
precaution, the following will be reported as an SAE:

Cardiac dysfunction, defined as any signs or symptoms of deterioration in left 
ventricular cardiac function that are Grade 3 (NCI CTCAE) or a ≥20% decrease 
in left ventricular cardiac ejection fraction relative to baseline which is below 
the institution's lower limit of normal.  

Any signs or symptoms of pneumonitis that are Grade 3 (NCI CTCAE) (defined 
as radiographic changes and requiring oxygen). 

Hepatobiliary event leading to permanent discontinuation of study-related 
treatment.
7.4.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements) 
including those that worsen from baseline, and events felt to be clinically significant in 
the medical and scientific judgement 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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7.4.4.
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

Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.
7.4.5.
Death Events
A specific death data collection tool is to be completed for all deaths, whether or not they 
are considered SAEs.  The death data collection tool includes questions regarding 
cardiovascular (including sudden cardiac death) and non-cardiovascular death.
This information should be recorded within one week of when the death is first reported.
7.4.6.
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 eCRF 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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7.4.7.
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 of treatment with the first dose of octreotide for 
subjects randomised to receive octreotide and treatment with the first dose of lapatinib 
and capecitabine for subjects randomised to receive no octreotide until 30 days following 
the end of the 24 week study period or discontinuation of study-related treatment, 
whichever is sooner, regardless of initiation of a new cancer therapy or transfer to 
hospice. 
Serious AEs 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 7.4.9.   
Serious AEs, AEs of special interest, AEs leading to treatment discontinuation and 
pregnancies will be collected for all subjects who enter the LTFU phase of the study 
(Section 7.1.9).
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 AE that they 
believe possibly related to study treatment.   
7.4.8.
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?”
7.4.9.
Prompt Reporting of SAEs and Other Events to GSK
SAEs, pregnancies, and liver function abnormalities and any other events meeting pre-
defined criteria will be reported promptly by the investigator to GSK as described in 
Table 20 once the investigator determines the event meets the protocol definition for that 
event.


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Table 20
Adverse events to be reported promptly to the study sponsor
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 Phase II:
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.
GSK to be notified at onset of liver chemistry elevations 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.
Liver chemistry stopping criteria are described in Section 5.13.1.  


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Methods for detecting, recording, evaluating, and following up on AEs and SAEs and 
procedures for completing and transmitting SAE reports to GSK are provided in the SPM.  
Procedures for post-study AEs and SAEs are provided in the SPM.
7.4.10.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK 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 GSK policy 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) from GSK will file it with 
the Investigator Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements.
7.5.
Pregnancy Testing, Prevention and Reporting
7.5.1.
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 with total cessation of 
menses for at least 1 year.
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.  In questionable cases, the subject must have a follicle stimulating hormone
value >40 mIU/mL and an oestradiol value < 40pg/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 -hCG pregnancy 
test performed within 7 days prior to treatment with octreotide if randomised to receive 
octreotide or the first dose of lapatinib with capecitabine if randomised to receive no 
octreotide, but preferably as close to the start of treatment as possible. Subjects with a 


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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 end of the 24 week study period or 
until 30 days following the last dose of lapatinib and capecitabine for subjects who enter 
the LTFU phase of the study.  Subjects who continue treatment with lapatinib and 
capecitabine beyond the 24 week study period but do not enter the LTFU phase of the 
study should continue to use an acceptable contraceptive method in accordance with the 
Lapatinib and Capecitabine SPCs.
GSK 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.

Vasectomised partner who is sterile prior to the female subject’s entry and is the sole 
sexual partner for that female.

Complete abstinence from sexual intercourse for 14 days prior to first dose of study-
related treatment, through the dosing period, and for at least 30 days following the 
end of the 24 week study period or until 30 days following the last dose of lapatinib 
and capecitabine for subjects who enter the LTFU phase of the study.
UK subjects: In the UK, sexual inactivity by abstinence must be consistent with the 
preferred and usual lifestyle of the subject.  Periodic abstinence (e.g. calendar, 
ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable 
methods of contraception.

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 subject population or 
per local practice.  

Injectable progesterone where not contraindicated for this subject population or per 
local practice. 

Oral contraceptives (either combined or progesterone only) where not
contraindicated for this subject 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 30 days 
following the end of the 24 week study period or until 30 days following the last dose of 
lapatinib and capecitabine for subjects who enter the LTFU phase of the study.  Subjects 
who continue treatment with lapatinib and capecitabine beyond the 24 week study period 
but do not enter the LTFU phase of the study should discontinue nursing in accordance 
with the Lapatinib and Capecitabine SPCs.


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7.5.2.
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.
7.6.
Laboratory Assessments
All laboratory assessments will be performed by a local laboratory.  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 may be repeated 
(prior to the first dose) at the discretion of the investigator.  A subject with a laboratory 
value outside the reference range(s) or ranges for tests which relate to inclusion criteria 
(Section 4.1.2) and exclusion criteria (Section 4.1.3), the contraindications, special 
warnings and precautions for use, and other information included in the Lapatinib, 
Capecitabine and Octreotide SPCs may be included only if the investigator and GSK 
Medical Monitor agree that it is unlikely to introduce additional risk factors and will not 
interfere with study procedures.  
All laboratory tests with values that are significantly abnormal during participation in the 
study or within 30 days following the end of the 24 week study period or until 30 days 
following the last dose of lapatinib and capecitabine for subjects who enter the LTFU 
phase of the studyshould 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.
7.7.
Health Outcomes
7.7.1.
Health Outcomes Endpoints
The health outcome endpoint of this study is subject-reported quality of life.
7.7.2.
Health Outcomes Assessments
Quality of life will be assessed using the FACIT-D (Appendix 2).  Detail concerning the 
methods of collecting and returning FACIT-D data are included in the SPM.
All subjects will complete the baseline FACIT-D prior to randomisation, before any 
study related treatment is administered.  Subjects randomised to receive treatment with 
octreotide will also complete the FACIT-D immediately before receiving the first dose of 


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lapatinib and capecitabine.  All subjects will complete the FACIT-D every three weeks 
during treatment with lapatinib plus capecitabine through to withdrawal from the study or 
the end of the 24 week period of treatment with lapatinib and capecitabine, whichever is 
sooner.  
The FACIT-D (version 4; Appendix 2) consists of the FACT-G [Webster, 2003] and a 
diarrhoea-specific subscale, and measures multidimensional quality of life in subjects 
with cancer. FACT-G includes 27 general questions relating to four subscales, PWB, 
SWB, EWB and FWB, and the DSS includes 11 questions. Subjects assess how true 
each statement has been for them in the previous 7 days on a 5-point scale ranging from 0 
(not at all) to 4 (very much). Higher scores on the FACIT-D scales indicate a better 
quality of life. In psychometric testing, the FACT/FACIT system has shown good test-
retest reliability and sensitivity to change when compared with ECOG performance status. 
The FACIT-D has been translated and validated in many languages, and the translations 
have been shown to have cross-cultural acceptability. 
8.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system.  
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.  AEs and concomitant medications terms will be 
coded using MedDRA and an internal validated medication dictionary, GSKDrug.  
Electronic CRFs (including queries and audit trails) will be retained by GSK, and copies 
will be sent to the investigator to maintain as the investigator copy.  
The PRO data (FACIT-D and DMD) will be entered in a non-GSK database.  This 
database will be used for the sole purpose of the LAP117314 study.  Only authorised 
personnel will have access to the PRO database, and all personnel are obliged to fully 
comply with The Data Protection Act 1998.  All electronic PRO data will be kept in a 
dedicated database in a secure data vault, on a dedicated database server.  Access to the 
database will be password and access right controlled.  
In all cases, subject initials will not be collected or transmitted to GSK in accordance
with GSK policy.


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9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
9.1.
Hypotheses
The primary objective of this study is to evaluate and compare whether administering 
prophylactic octreotide vs. no prophylactic octreotide reduces the incidence of cancer 
treatment-associated diarrhoea in subjects taking lapatinib plus capecitabine. 
The study is designed to provide evidence to support the null hypothesis H0: δ >= 0 or to 
reject it in favour of the alternative hypothesis HA: δ < 0, where δ is the difference in the 
incidence of Grade 2 or higher diarrhoea between prophylactic octreotide vs. no 
prophylactic octreotide.
9.2.
Study Design Considerations
9.2.1.
Sample Size Assumptions
It is planned that a total of 140 subjects will be randomised in a 1:1 ratio i.e. 70 subjects 
in each treatment arm.  LAP117314 is an exploratory Phase II study, and the sample size 
is not based on the number of subjects required to achieve a statistically significant pre-
specified reduction in the control incidence of diarrhoea.  
The overall incidence of diarrhoea associated with treatment with lapatinib and 
capecitabine ranges from less than 40% to more than 80% across a number of studies 
(Section 1.1).  Only limited data are available on the incidence of diarrhoea with a 
severity of Grade 2 or more which can be used as a basis for sample size estimation.  It is 
likely that the implementation of active diarrhoea management guidelines will limit the 
incidence of more severe diarrhoea which develops as a progression from inadequately 
treated mild diarrhoea.  Therefore, a conservative approach has been taken in LAP117314, 
and data from study EGF111438, which shows the lowest incidence of diarrhoea with a 
severity of Grade 2 or more (20%), has been used as the basis for the power calculations.  
In addition, power calculations have been conducted based on a less conservative 
approach using data from EGF100151, in which diarrhoea management guidelines were 
not implemented and in which the incidence of diarrhoea with a severity of Grade 2 or 
more was 32%.
9.2.2.
Sample Size Sensitivity
Based on the results of EGF111438, an incidence of 20% of Grade 2 or higher diarrhoea
is assumed for subjects who receive lapatinib and capecitabine with no prophylactic 
octreotide.  The power for the analysis to detect a reduction in the incidence of Grade 2 or 
higher diarrhoea from 14% to 8% ranges from 69% to 25%, if the assumed incidence in 
the control arm is 20%, using a one-sided test with an alpha level of 0.025 (Table 21).


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Table 21
Sensitivity of sample size based on 20% control incidence of Grade 
2 or more diarrhoea
Incidence, placebo
20%
20%
20%
20%
20%
Incidence, prophylactic octreotide
6%
7%
8%
10%
12%
Power
69%
61%
53%
37%
25%
Subjects per Treatment Arm
70
70
70
70
70
Based on the results of EGF100151, an incidence of 32% of Grade 2 or higher diarrhoea
is assumed for subjects who receive lapatinib and capecitabine with no prophylactic 
octreotide.  The power for the analysis to detect a reduction in the incidence of Grade 2 or 
higher diarrhoea  from 20% to 12% ranges from 82% to 36%, if the assumed incidence in 
the control arm is 32%, using a one-sided test with an alpha level of 0.025 (Table 22).
Table 22
Sensitivity of sample size based on 32% control incidence of Grade 
2 or more diarrhoea
Incidence, placebo
32%
32%
32%
32%
32%
Incidence, prophylactic octreotide
12%
14%
16%
18%
20%
Power
82%
72%
60%
48%
36%
Subjects per Treatment Arm
70
70
70
70
70
Power calculations were performed using nQuery software version 7.0.
9.2.3.
Sample Size Re-estimation
Sample size re-estimation is not planned for this study.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The Intent-to-Treat (ITT) population will comprise all randomised subjects regardless of 
whether or not treatment was administered.  This population will be based on the 
treatment to which the subject was randomised.  Any subject who receives a treatment 
randomisation number will be considered to have been randomised.  The primary 
analysis of disease efficacy and all diarrhoea-related efficacy endpoints will be conducted 
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The modified ITT (m-ITT) population will comprise all subjects in the ITT population 
who do not show intolerance to octreotide in the s.c. formulation and who do not have 
diarrhoea recorded as an AE after the first dose of octreotide LAR and prior to the start of 
treatment with lapatinib and capecitabine.  The supplementary analysis of all diarrhoea-
related efficacy endpoints will be conducted using the m-ITT population. 
The Per-Protocol (PP) population will comprise all randomised subjects who receive at 
least one dose of study treatment and who comply closely with the protocol.  Major 
protocol violations that would exclude subjects from the PP population will be defined 
and documented in the Reporting and Analysis Plan (RAP) prior to database release.  The 
PP population will not be analysed if this population comprises more than 95% of the 
ITT population.
The Safety population will comprise all randomised subjects who receive at least one 
dose of study treatment and will be based on the actual treatment received if this differs 
from that to which the subject was randomised.  This population will be used for the 
analysis of clinical safety data.
9.3.2.
Analysis Data Sets
The primary data set for assessing disease efficacy will be the ITT population as defined 
in Section 9.3.1. 
The primary data set for assessing diarrhoea-related efficacy will be the ITT population 
as defined in Section 9.3.1.
The primary data set for assessing safety will be the Safety population as defined in 
Section 9.3.1.
9.3.3.
Treatment Comparisons
9.3.3.1.
Primary comparison of interest
The primary objective will be supported through the test for superiority of prophylactic 
octreotide vs. no prophylactic octreotide in relation to reducing the incidence of Grade 2
or higher diarrhoea in subjects after 9 weeks of treatment with lapatinib plus capecitabine, 
using the ITT population.  
9.3.3.2.
Other comparisons of interest
This is an exploratory study, and the sample size may be insufficient to demonstrate 
statistical significance for the primary objective.  The diarrhoea-related secondary 
objectives of the study will provide additional perspective to support the primary 
objective.
Assessment of disease progression in accordance with RECIST version 1.1 is required 
only at the end of study visit.  Disease assessments during the course of treatment with 
lapatinib and capecitabine may be conducted in accordance with local practice, and there 


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will be some inconsistency between the data provided by different sites at these visits.  
The assessment of disease progression in LAP117314 will be limited by the sample size 
and by the variability in response assessments prior to the end of study visit, and may not 
be comparable with that reported in other studies.
9.3.4.
Interim Analysis
An interim analysis will be conducted to assess the futility of octreotide in relation to 
reducing the incidence of Grade 2 diarrhoea after 9 weeks of treatment. This analysis will 
take place when at least 60 subjects have been randomised to treatment and completed 
their 9 week assessment. At this analysis a review of both the accumulating safety and 
efficacy data will be conducted by an independent review committee to assure the safety 
of the patients in the trial and to provide an opportunity to terminate the study if:-

There is overwhelming clinical evidence of a negative imbalance in the safety
profile of either treatment group

There is not sufficient evidence of an effect of efficacy in the reduction of Grade 
2 diarrhoea as described by the stopping rules in Section 9.3.4.2.
The independent review committee will review the accumulating safety data and also the 
analysis of the primary endpoint, the incidence of Grade 2 diarrhoea.  There will be full 
treatment disclosure at the interim analysis to the Senior Management team, but the study 
team will remain blinded to treatment assignment and the results of the interim analysis.
9.3.4.1.
Interim Review of Safety Profile
The data to be reviewed by the independent review committee will be the accumulated 
safety and diarrhoea response data. These safety data will include, at minimum, all AEs, 
SAEs and any deaths. The safety review committee will evaluate these data and make a 
clinical judgement as whether the study can progress as planned based on the welfare of 
the subjects. At least one interim review of this safety data will occur.
9.3.4.2.
Futility Analysis of Primary Endpoint
A futility analysis of the incidence of Grade 2 diarrhoea, the primary endpoint, 
comparing this incidence between the group of subjects who receive lapatinib and 
capecitabine to the group of subjects who receive no prophylactic octreotide will be 
performed. This will take place at a single interim analysis after approximately 40% of 
subjects (60 subjects) have had at least 9 weeks of study treatment.   
Early termination of the study will be considered by the independent review committee.   
Their recommendation will be based on the following points:-

Whether it would be possible to draw any meaningful conclusions if the study 
were to continue to planned completion given the:-


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o
The clinical relevance of the observed incidence of Grade 2 diarrhoea. 
o
The conditional power based on data from approximately 40% of the 
patients   
o
The totality of the evidence observed.
For example:

If the diarrhoea rate is 30% in the control arm, in order for the conditional power 
(under the current trend) to be around 50% to see a positive result at the end of the 
trial, we would need to see a diarrhoea rate of 16% or lower in the octreotide arm. 
(Equating to a difference in 14% in incidence between treatment arms)

If the diarrhoea rate is 20% in the control arm, in order for the conditional power 
(under the current trend) to be around 70% to see a positive result at the end of the 
trial, we would need to see a diarrhoea rate of 6% or lower in the octreotide arm. 
(Equating to a difference of 14% in incidence between treatment arms)
The conditional power will need to be re-calculated based on the actual incidence and
actual percentage of patients evaluated at the time of the interim analyses.  
It is envisaged that if at least a modest improvement in the diarrhoea rate in the octreotide 
arm is not seen with a conditional power of at least 50% at the interim analysis, it is 
unlikely that the trial would justify octreotide use in clinical practice. Further confidence 
intervals around the estimate of the observed difference in incidence of Grade 3 diarrhoea 
will be provided to aid clinical judgement.
9.3.5.
Key Elements of Analysis Plan
The final analysis will take place when all subjects have completed the study. 
Data will be listed and summarised according to the GSK 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 (24 weeks or early withdrawal from the 
study) will be included in the summaries, regardless of the duration of treatment.  
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of treatment will vary between subjects.  Non-responder imputation will be 
used in the case of missing data for the analysis of the primary endpoint based on the ITT 
population.  Subjects who withdraw from the study prior to the Week 9 visit without 
experiencing Grade 2 diarrhoea or above will be assumed to have experienced Grade 2 
diarrhoea or above for the purpose of the analysis. Similar imputation techniques will be 


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used for the m-ITT population analysis of the primary endpoint.  No imputation will be 
performed for the Per Protocol analyses.  Imputation methods for the secondary 
endpoints will be considered and detailed as appropriate in the RAP.  
Demographic and screening characteristics will be summarised.
Details on the determination of tumour response are given in Section 7.1.11.  There will 
be no adjustments for multiplicity.
Details on efficacy summaries are provided in Section 9.3.5.1 and details on safety 
summaries are provided in Section 9.3.5.2.
9.3.5.1.
Efficacy analyses
The ITT population will be used for the analyses of diarrhoea-related endpoints and for 
the analysis of disease efficacy.  The m-ITT population will be used for the 
supplementary analysis of diarrhoea-related endpoints.  The primary analysis of 
diarrhoea-related endpoints will be based on data recorded in the eCRF.  Secondary 
analyses of diarrhoea-related endpoints will be based on data recorded in the eCRF and in 
the DMD.  
9.3.5.1.1.
Primary endpoint analysis
The primary efficacy endpoint is the proportion of subjects experiencing at least one 
episode of diarrhoea with a severity of Grade 2 or higher during the first 9 weeks of 
treatment with lapatinib and capecitabine in the ITT population.  The AE terms diarrhoea
and frequent bowel movements will be aggregated to form the term diarrhoea in 
accordance with the Aggregation Guidelines for AE Terms in Lapatinib Studies.  The 
superiority of prophylactic octreotide compared to no prophylactic octreotide will be 
assessed using a chi-square test.  The proportion of subjects experiencing at least one 
episode of diarrhoea with a severity of Grade 2 or higher in each treatment arm, the 
reduction in proportions between the treatment arms, the corresponding 95% confidence 
interval for the reduction and the two-sided p-value from the chi-square test will be 
presented. 
Secondary analyses of the primary endpoint will be conducted based on the proportion of 
subjects experiencing at least one episode of diarrhoea with a severity of Grade 2 or 
higher during the period of treatment with lapatinib and capecitabine after 9 weeks and 
up to 24 weeks (nominally weeks 12-24), and also for the entire 24 week treatment period 
(nominally weeks 0-24).
Supplementary analyses of the primary endpoint will be conducted in the m-ITT and PP 
populations, using the same lapatinib and capecitabine treatment intervals as described 
for the m-ITT population.


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9.3.5.1.2.
Secondary endpoint analysis: Investigator-reported endpoints
These analyses will be based on data reported by the investigator in the eCRF.  Analyses 
of secondary diarrhoea-related endpoints will be conducted for the ITT and m-ITT 
populations using the same lapatinib and capecitabine treatment intervals as described for 
the analysis of the primary endpoint in Section 9.3.5.1.1.  Disease efficacy will be 
assessed in the ITT and m-ITT populations over the total 24 week treatment period. For 
the secondary endpoints, 95% confidence intervals and two-sided tests will be presented.
Diarrhoea of Grade 3 and above
The proportion of subjects experiencing at least one episode of diarrhoea of Grade 3 and 
above will be summarised and analysed using the same methods as described in Section 
9.3.5.1.1 for the primary endpoint.
Diarrhoea of any grade
The proportion of subjects experiencing at least one episode of diarrhoea of any grade of 
severity will be summarised and analysed using the same methods as described in Section 
9.3.5.1.1 for the primary endpoint.  
Duration of diarrhoea of any grade of severity
The maximum duration of episodes of diarrhoea of any grade of severity will be 
calculated for each subject and will be summarised by treatment arm using descriptive 
statistics (including lower quartile, median and upper quartile) and the treatment arms 
will be compared using the Wilcoxon Rank Sum test.  The median maximum duration of 
episodes in each treatment arm, the Hodges-Lehmann estimate for the difference between 
treatment arms, corresponding 95% confidence interval for the Hodges-Lehmann 
estimate and the p-value from the Wilcoxon Rank Sum test will be presented.  It should 
be noted that if episodes of diarrhoea are ongoing at the time of study completion or 
premature withdrawal from the study, the duration of these episodes will be censored at 
that point, and therefore the resulting summary statistics and analyses may be subject to 
bias.
Time to onset of the first episode of diarrhoea
The time to onset of the first episode of diarrhoea of any grade of severity will be 
summarised by treatment arm using Kaplan-Meier methods.  Subjects who complete the 
study or withdraw prematurely without experiencing an episode of diarrhoea will be 
censored at the date of withdrawal or study completion.  The Kaplan-Meier estimate of 
the proportion of patients experiencing an episode of diarrhoea will be presented for each
3-week time interval by treatment group. Estimates and 95% confidence intervals for the 
25th percentile, median and 75th percentile will be provided by treatment group.  
Treatment groups will be compared using the log-rank test, or the Wilcoxon test in the
case of non-proportional hazards.


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Anti-diarrhoeal medication
The proportion of subjects taking medication at least once as a result of diarrhoea will be 
summarised and analysed using the same methods as described in Section 9.3.5.1.1 for 
the primary endpoint.
Unscheduled visits to/contact with healthcare professionals
The proportion of subjects requiring an unscheduled visit to or contact with a healthcare 
professional at least once as a result of diarrhoea will be summarised and analysed using 
the same method as described in Section 9.3.5.1.1 for the primary endpoint.
Changes in study treatment
The proportion of subjects requiring changes in study treatment (lapatinib or
capecitabine) as a result of diarrhoea will be summarised and analysed using the same 
methods as described in Section 9.3.5.1.1 for the primary endpoint.  Summaries will be 
performed separately for each type of change in study treatment (i.e. dose delays, dose 
reductions and treatment withdrawal) as well as overall. 
Dose intensity of study treatment (lapatinib or capecitabine) will be calculated daily (i.e. 
total dose of lapatinib or capecitabine divided by the number of days on lapatinib or 
capecitabine).  Dose intensity will be summarised and analysed using the same methods 
as described above for frequency of diarrhoea of any grade of severity.  


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Intravenous fluids
The proportion of subjects requiring treatment with intravenous fluids at least once as a 
result of diarrhoea will be summarised and analysed using the same methods as described 
in Section 9.3.5.1.1 for the primary endpoint. 
Study treatment compliance
Inference of the efficacy of prophylactic octreotide will be made by summarising overall 
compliance to the study treatment (lapatinib plus capecitabine) by treatment arm.
A summary of compliance with prophylactic octreotide will be presented for the ITT and 
m-ITT populations.
Overall Response Rate
Overall response rate (ORR) is defined as the percentage of subjects achieving either a 
confirmed complete (CR) or partial (PR) tumour response.  The ORR will be calculated 
from the investigator’s assessment of response.  Subjects who do not have measurable 
disease or have an unknown or a missing response will be treated as non-responders 
when calculating the percentages and will contribute to the response rate-based analyses 
for the evaluation of CR, PR, stable disease (SD) and progressive disease.  The ORR in 
each treatment arm and corresponding 95% confidence interval will be presented.
Clinical Benefit Response
Clinical benefit response (CBR) is defined as the percentage of subjects with a CR, PR or 
SD for at least 24 weeks.  The CBR will be calculated using the same methods as 
described for the ORR, i.e. from the investigators assessment of response, subjects who 
do not have measurable disease, missing or unknown will be treated as non-responders.
The CBR in each treatment arm and corresponding 95% confidence interval will be 
presented.
9.3.5.1.3.
Secondary analyses: Patient-reported endpoints
These analyses will be based on data reported in the DMD.  Analyses of secondary 
diarrhoea-related endpoints will be presented for the ITT and m-ITT populations for 
patients completing the baseline and at least one post-baseline DMD.
Diarrhoea
The proportion of patients reporting an increase in the frequency and/or worsening in 
consistency of bowel movements will be summarised and analysed using Generalised 
Estimating Equations (GEE), using a repeated statement, the binary response is the 
patient reported increase in frequency or worsening in consistency, as defined in the RAP, 
in addition individual patient data will be plotted.    


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Time to onset of first patient-reported increase in frequency and/or worsening in 
consistency of bowel movements
The time to onset of the first patient-reported increase in frequency and/or worsening of 
consistency of bowel movements will be summarised by treatment arm using Kaplan-
Meier methods.  Patients who complete the study or withdraw prematurely without 
experiencing an increase in the frequency and/or worsening in consistency of bowel 
movements will be censored at the date of withdrawal or study completion.  The Kaplan-
Meier estimate of the proportion of patients reporting an increase in the frequency and/or 
worsening of consistency of bowel movements will be presented for each weekly time
interval by treatment group. Estimates and 95% confidence intervals for the 25th
percentile, median and 75th percentile will be provided by treatment group.  Treatment 
groups will be compared using the log-rank test, or the Wilcoxon test in the case of non-
proportional hazards. 
Additional anti-diarrhoeal medication
The proportion of patients taking any extra medication not prescribed by the hospital-
doctor to help with diarrhoea will be summarised and analysed using the same GEE 
analysis and plots as described for patient-reported diarrhoea.
Impact of dietary changes
The proportion of patients making dietary changes to help with the diarrhoea will be 
summarised and analysed using the same GEE analysis and plots as described for patient-
reported diarrhoea.
Contact with any other healthcare professionals
The proportion of patients contacting a health care professional other than the hospital 
doctors/nurses to discuss diarrhoea will be summarised and analysed using the same GEE 
analysis as and plots as described for patient-reported diarrhoea..
Reduction / stopping of anti-cancer treatment
The proportion of patients reducing or completely stopping the number of anti-cancer 
tablets to help with diarrhoea will be summarised and analysed using the same GEE 
analysis and plots as described for patient-reported diarrhoea. Summaries will be 
performed separately for each type of change in anti-cancer tablets (i.e. reducing tablets 
and stopping completely) as well as overall. 
9.3.5.2.
Safety analyses
The Safety population will be used for the analysis of safety data. Complete details of 
the safety analyses will be provided in the RAP.  Summaries will be presented by 
treatment arm and overall unless specified otherwise.  Safety endpoints are described in 
Section 2 and Section 7.3.


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9.3.5.2.1.
Extent of exposure
The number of subjects administered prophylactic octreotide will be summarised 
according to the duration of therapy. The extent of exposure to prophylactic octreotide 
will be presented.  
The extent of exposure to treatment with lapatinib and capecitabine may be increased if 
prophylactic octreotide is effective in reducing the incidence of Grade 2 or higher 
diarrhoea.  Exposure to lapatinib and capecitabine will be summarised by treatment arm.
9.3.5.2.2.
Adverse events
Adverse events (AEs) will be coded using the standard GSK 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 4.03).  
The AE terms diarrhoea and frequent bowel movements will be aggregated to form the 
term diarrhoea in accordance with the Aggregation Guidelines for AE Terms in Lapatinib 
Studies.
The number and percentage of subjects experiencing adverse events will be summarised 
by system organ class and preferred term. Separate summaries will be given for all AEs, 
drug-related AEs, SAEs and AEs leading to discontinuation of study treatment.
If the AE is listed in the NCI CTCAE (version 4.03) table, the maximum grade will be 
summarised.
Characteristics (e.g. number of occurrences, action taken, grade and severity) of the 
following AEs of special interest will be summarised separately: diarrhoea, rash, nausea, 
vomiting, hepatobiliary events, cardiac events, and pneumonitis.  
The incidence of deaths and the primary cause of death will be summarised.
9.3.5.2.3.
Clinical laboratory evaluations
Haematology and clinical chemistry data will be summarised at each scheduled 
assessment according to NCI CTCAE grade (version 4.03). 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 it was 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 physical examination, body height and weight, 
vital signs, (temperature, blood pressure, pulse), 12-lead ECG, echocardiogram (or 


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MUGA scan) and ECOG performance status will be summarised.  Summaries will 
include data from scheduled assessments only.  All data will be reported according to the 
nominal visit date for which it was 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.
Health Outcomes analyses
The primary endpoint for the FACIT-D will be the Trial Outcome Index (TOI) comprised 
of the PWB, FWB and the DSS.  Secondary endpoints will be: 

Total FACT-G (i.e. PWB, SWB, EWB and FWB subscales); 

Total FACIT-D (i.e. PWB, SWB, EWB and FWB subscales and the DSS); 

Each individual subscale score.
Scores will be summarised by visit and treatment arm.  Changes from baseline (prior to 
randomisation) and changes from baseline (prior to start of lapatinib and capecitabine) 
will also be summarised at each post-baseline visit as appropriate.  Proportions of 
subjects in each treatment arm who achieve a clinically meaningful improvement or 
decline will be compared at each time point using the chi-square test.  A responder 
criterion can be defined as a 6 or more point change from baseline on the TOI, a 7 or 
more point change from baseline for the Total FACT-G, a 7 or more point change from 
baseline for the Total FACIT-D, a 3 or more point change from baseline for the 
individual subscales (PWB, EWB, SWB, FWB), and a 4 or more point change from 
baseline for the DSS.  For the total scores and each of the subscale scores, the difference 
between the treatment arms in terms of the change from baseline at each study visit will 
be analysed using a two sample t-test.  Treatment effect over time will be evaluated.  
Further details will be provided in the RAP.
The calculation of scores and methods to deal with missing data will be handled 
according to the standard scoring guidelines.  Full details of all the FACIT-D analyses 
will be provided in the RAP.  


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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.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK 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 GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:

IRB/IEC review and favourable opinion/approval of study protocol and any 
subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
GSK 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 
 
described in Appendix 3, 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.


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10.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK 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 GSK 
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the eCRF 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:

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, GSK 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 end of the study will occur when the last subject has completed the last visit, and all 
SAEs have been followed up as required.
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 GSK Standard Operating Procedures (SOPs).
GSK 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 GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.


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If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK 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.
GSK also reserves the right to close sites which fail to enroll subjects within a predefined 
timeframe, as described in the SPM.
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 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.
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.


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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.
Upon completion of the clinical study report, GSK will ensure public disclosure of the 
clinical trial research results via the GSK Clinical Study Register. GSK will also publish 
the results of the study to be searchable on the internet according to the GSK policy and 
SOP. 
The results summary will be posted to the GSK Clinical Study Register no later than 8 
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 will be submitted to a peer-reviewed journal 
for publication no later than 18 months after the last subject’s last visit. 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. 
10.8.
Safety Review Team
The SRT includes GSK representatives from Biostatistics, Clinical and Global Clinical 
Safety and Pharmacovigilance.  Representatives from other disciplines may be involved 
in the SRT meetings on an ad hoc basis as required to provide additional expertise.  All 
members of the SRT must be independent of the LAP117314 study team, and must have 
no other role or responsibility within the broader scope of the study.  The primary role of 
the SRT is to provide an internal and independent review of safety data to protect the 
interests of subjects and to ensure their safety.  
The SRT will review safety data on an ongoing basis.  The first formal review of safety 
data will be conducted after the first 60 subjects have received at least 9 weeks of 
treatment with lapatinib and capecitabine.  Subsequent formal review will be conducted 
at least every 12 weeks, or more frequently if required.  It is anticipated that the SRT will 
meet to conduct formal review of the safety data at least three times during the course of 
the study.  Unblinded study data will be provided to the SRT by a statistician independent 
of the LAP117314 study team.  All efforts will be made to maintain the study integrity 
and validity of study data.  


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11.
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Basch E.  The Missing Voice of Patients in Drug-Safety Reporting.  N Engl J Med 2010; 
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Benson A, Jaffer A, Catalano R, et al.  Recommended Guidelines for the Treatment of 
Cancer Treatment-Inducted Diarrhoea.  Journal of Clinical Oncology 2004; 22: 2918-
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Cameron D, Casey M, Press M, et al. A phase III randomised comparison of lapatinib 
plus capecitabine versus capecitabine alone in women with advanced breast cancer that 
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Cascinu S, Fedeli A, Fedeli S, et al.  Control of chemotherapy-induced diarrhea with 
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Cascinu S, Fedeli A, Fedeli S, et al.  Octreotide versus loperamide in the treatment of 
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Cella D, Hahn E, Dineen K.  Meaningful change in cancer-specific quality of life scores: 
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Cooper J, Williams N, King R, et al.  Effects of a long-acting somatostatin analogue in 
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Crown J, Burris H, Boyle F, et al.  Pooled analysis of diarrhea events in patients with 
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Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, et al.  Cancer incidence and mortality 
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the treatment of diarrhea following chemotherapy. Anticancer Drugs 1993; 4: 443-445.
Geyer C, Forster J, Lindquis D, et al.  Lapatinib plus Capecitabine for HER2-Positive 
Advanced Breast Cancer.  N Engl J Med. 2006; 355: 2733-43.
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Capecitabine versus Trastuzumab plus Capecitabine in Patients with Anthracycline- or 
Taxane-Exposed ErbB2-Positive Metastatic Breast Cancer Effective date 16 October 
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Le Gal F, Gordien E, Affolabi D, et al.  Quantification of Hepatitis Delta Virus RNA in 
Serum by Consensus Real-Time PCR Indicates Different Patterns of Virological 
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Rosenhoff S, Gabrail N, Conklin R, et al.  A Multicenter, Randomized Trial of Long-
Acting Octreotide for the Optimum Prevention of Chemotherapy-Induced Diarrhea: 
Results of the STOP Trial.  J Support Oncol 2006; 4: 289–294.
Rosenhoff S.  Resolution of refractory chemotherapy-induced diarrhea (CID) with 
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2002: 54: 195-202.
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chemoradiation-induced diarrhea in anorectal cancer: Randomized RTOG trial 0315.  
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severe chemotherapy-induced diarrhea.  Annals of Oncology 2001; 12: 227-229.


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12.
APPENDICES
12.1.
Appendix 1
Diarrhoea Management Guidelines
Experience thus far suggests that when lapatinib is used as monotherapy most diarrhoea
presents as uncomplicated NCI CTCAE Grade 1 or 2 (G1 54%, G2 20%, G3 15%, 
G4<1%). 
In rare cases, diarrhoea can be debilitating, and potentially life threatening if 
accompanied by dehydration, renal insufficiency, and/or electrolyte imbalances. 
Standardised and universal guidelines have been developed by an American Society of 
Clinical Oncology (ASCO) panel for treating chemotherapy-induced diarrhoea [Benson, 
2004]. Presented in the sections below are the recommended guidelines for the 
management of diarrhoea 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 diarrhoea.  
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 
diarrhoea as per the recommendations outlined below.  
Subjects should be instructed to first notify their physician/healthcare provider at 
onset of diarrhoea 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 diarrhoea can be identified.  
Subjects should be educated on signs and symptoms of diarrhoea 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 diarrhoea 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 diarrhoea history. 
If subjects present with diarrhoea 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.


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Definitions
National Cancer Institute (NCI) guidelines define diarrhoea compared to baseline 
(Appendix 1 Table 1)
Appendix 1 Table 1
NCI Common terminology criteria for grading diarrhoea 
adverse events (version 4.03)
Adverse 
Event Grade
Diarrhoea
1
Increase of <4 stools/day over baseline; mild increase in ostomy output compared to 
baseline
2
Increase of 4-6 stools/day over baseline; moderate increase in ostomy output 
compared to baseline;
3
Increase of ≥7 stools/day over baseline; incontinence; hospitalisation indicated; severe 
increase in ostomy output compared to baseline; limiting self care activities of daily 
living (ADL)
4
Life-threatening consequences; urgent intervention indicated
5
Death
Uncomplicated diarrhoea is considered mild-to-moderate and defined as CTCAE 
Grade 1 or 2 with no complicating signs or symptoms.
Complicated diarrhoea is severe and defined as any CTCAE Grade 3 or 4 diarrhoea, 
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 Diarrhoea
I.
CTCAE Grade 1  
NOTE:  Subject should be instructed to: start supportive care immediately at the 
first episode of diarrhoea (i.e., unformed stool) and call their physician. 
1. Administer loperamide 


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a.
Initial dose 4mg followed by 2mg after every unformed stool. Re-evaluate after
24 hours, if:
i.
Diarrhoea is resolving:

Continue loperamide treatment at 2mg dose after every unformed 
stool until diarrhoea free (i.e., <Grade 1/bowel patterns returned to 
baseline) for 12 hours.

If diarrhoea recurs, re-initiate loperamide treatment as needed to 
maintain normal bowel patterns
ii.
Diarrhoea is not resolving:

Administer loperamide at 2mg every 4 hours for the next 24 hour.  
Re-evaluate after 24 hours.  If diarrhoea is resolving, administer 
loperamide at 2mg after every unformed stool until diarrhoea free (i.e., 
<Grade 1/bowel patterns returned to baseline) for 12 hours.  If 
diarrhoea is not resolving continue loperamide treatment at 2mg every 
4 hours and re-evaluate every 24 hours.
b.
If Grade 1 diarrhoea persists for more than 1 week with loperamide treatment, 
consider treatment with second-line agents (octreotide, budesonide or tincture 
of opium).
2. Dietary modifications which are essential in the management of diarrhoea  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
i.
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).
i.
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 diarrhoea due to the fiber content (e.g., 
apricots)
1. Continue with study treatment (i.e., lapatinib-based treatment)
Continue with supportive care until diarrhoea has resolved (diarrhoea free for 12 
hours/bowel pattern return to baseline). Once diarrhoea has resolved, the subject can 
begin to gradually re-introduce foods from their normal diet.  
If diarrhoea 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 diarrhoea persists for ≥2 weeks, refer to the management guidelines for 
Persistent Grade 2 Diarrhoea.
II.
CTCAE Grade 2
NOTE:  Subject should be instructed to call physician at first episode of diarrhoea
and start supportive care immediately
1. Administer loperamide 
a.
Initial dose 4mg followed by 2mg every 4 hours or after every unformed stool. 
Re-evaluate after 24 hours. If:
i.
Diarrhoea is resolving, continue loperamide treatment at 2mg dose after 
every unformed stool until diarrhoea free (i.e., <Grade 1/bowel patterns 
returned to baseline) for 12 hours

If diarrhoea recurs, re-initiate loperamide treatment as needed to 
maintain normal bowel patterns
ii.
Diarrhoea is not resolving, consider loperamide dose of 2mg every 2 
hours for 24 hours. If Grade 2 diarrhoea persists after total of 48 hours of 
loperamide treatment, start second-line agents (octreotide, budesonide or 
tincture of opium).

Consider performing stool work-up, CBC, electrolytes and other 
tests as appropriate
2. Dietary modifications which are essential in the management of diarrhoea 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
i.
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).
ii.
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 diarrhoea due to the fiber content (e.g., 
apricots)
2. Continue with study treatment (i.e., lapatinib-based treatment)
Continue with supportive care until diarrhoea has resolved (diarrhoea free for 12 
hours/bowel pattern return to baseline). Once diarrhoea has resolved, the subject can 
begin to gradually re-introduce foods from their normal diet.  Refer to Section IV 
“Recurrent Diarrhoea” for study treatment guidelines.


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If diarrhoea 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 Diarrhoea: hold lapatinib and 
chemotherapy (if applicable) until diarrhoea resolves (<Grade 1/return to 
baseline bowl pattern).  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 diarrhoea, perform stool work-up, CBC, 
electrolytes and other tests as appropriate, consider consulting with a 
gastrointestinal specialist. 
After diarrhoea resolves (≤Grade 1), resume treatment with lapatinib and 
chemotherapy (if applicable). 
IV.
Recurrent Diarrhoea (more than 1 occurrence of Grade 2 diarrhoea): once 
the 2nd occurrence of Grade 2 diarrhoea resolves to ≤Grade 1, consider reducing 
the dose of lapatinib by 250mg or 1 tablet, unless the lapatinib dose already had 
been reduced to 750mg.  No further dose reduction is recommended for subjects 
taking lapatinib at 750mg.
3. Consider a dose reduction for chemotherapy (if applicable)
B) Complicated Diarrhoea
1. 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)
a.
Subject must call physician immediately for any complicated severe 
diarrhoea event
b. If loperamide has not been initiated, initiate loperamide immediately:  
Initial dose 4mg followed by 2mg every 2 hours or after every 
unformed stool 
c.
Refer to the dietary modification recommendations for Grade 1 and 
Grade 2 uncomplicated diarrhoea
d. For dehydration use intravenous fluids as appropriate, if subject 
presents with severe dehydration administer octreotide
e.
Perform stool work-up, CBC, electrolytes and other tests as 
appropriate
f.
Administer antibiotics as needed (example fluoroquinolones), 
especially if diarrhoea is persistent beyond 24 hours or there is fever or 
Grade 3-4 neutropenia
g. Hold lapatinib and chemotherapy (if applicable) until symptoms 
resolve to ≤Grade 1 and reintroduce lapatinib at a reduced dose (unless 
dose had been reduced to 750mg, contact medical monitor for further 
guidance)


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i. Consider a dose reduction for chemotherapy (if applicable)
4. Supportive care and other interventions should be continued until 
diarrhoea free (i.e., <Grade 1/bowel patterns returned to baseline) for 24 
hours
5. Intervention may require hospitalisation for subjects most at risk for life 
threatening complications
II
CTCAE Grade 4
Subject must call physician immediately for any Grade 4 diarrhoea event
1. Discontinue treatment with lapatinib, hold chemotherapy (if applicable)
2. If loperamide has not been initiated, initiate loperamide immediately:  Initial dose 
4mg followed by 2mg every 2 hours or after every unformed stool
3. For dehydration use intravenous fluids as appropriate, if subject presents with 
severe dehydration administer octreotide
4. Perform stool work-up, CBC, electrolyte and other tests as appropriate
5. Recommend consulting with gastrointestinal specialist
6. Administer antibiotics as needed (example fluoroquinolones), especially if 
diarrhoea is persistent beyond 24 hours or there is fever or Grade 3/4 neutropenia
7. Supportive care and other intervention should be continued until diarrhoea free 
(i.e., <Grade 1/bowel patterns returned to baseline) for 24 hours
8. Intervention may require hospitalisation for subjects most at risk for life 
threatening complications 
Refer to and follow the recommended supportive care guidelines in the previous sections 
and as depicted in Appendix 1 Figure 1.


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Appendix 1 Figure 1 Algorithm for the management of diarrhoea in subjects 
treated with lapatinib-based therapy
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)

Assess subject for fever, dizziness, abdominal pain/cramping or weakness

Medications (Prescription; OTC; herbal supplements) and dietary profile
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
•
Frank bleeding
•
Dehydration
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 
•
Continue with lapatinib-based treatment
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:discontinue lapatinib
•
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
1.
For Grade 1 diarrhoea that persists for 2 weeks or longer, refer to Section III
2.
For Grade 2 diarrhoea that persists longer than 3 days/72 hours, refer to Section III
3.
For recurrent diarrhoea, refer to Section IV for further management guidelines


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References
American Cancer Society. Coping with physical and emotional changes: Diarrhoea: what 
the subject can do.  
Diahttp://www.cancer.org/docroot/MBC/content/MBC_2_3X_Diarrhoea.asp
Benson A, Jaffer AA, Catalano RB, et al.  Recommended Guidelines for the Treatment of 
Cancer Treatment-Inducted Diarrhoea.  Journal of Clinical Oncology 2004; 22:2918-
2926.
Charma R, Tobin P, Clarke SJ.  Management of chemotherapy-induced nausea, vomiting, 
oral mucositis, and diarrhoea.  Lancet/Oncology 2005; 6:93-102
National Cancer Institute. Nutrition in cancer care (PDQ®). 
http://www.cancer.gov/cancertopics/pdq/supportivecare/nutrition/Subject
Saltz LB.  Understanding and Managing Chemotherapy-Induced Diarrhoea.  Journal of 
Supportive Oncology 2003; 1:35-46. 


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12.2.
Appendix 2
FACIT-D Questionnaire
The FACIT-D questionnaire (version 4, English original) is available in two forms with 
different dates: ’16 Nov 2007’ and ’09 June 2013’. These two forms have minor 
differences in question phrasing and format.  Both forms are fully validated and the 
minor differences between two forms do not affect the quality of data collection and 
analysis.  In this study, the languages translated based on ‘English FACIT-D version 4 
(dated 16 Nov 2007)’ are Arabic, French, Hebrew, Italian and Polish.  The languages 
translated based on ‘English FACIT-D version 4 (dated 09 June 2013)’ are Czech, Greek, 
Russian and Traditional Chinese. 
This appendix provides an example of the questionnaire ‘English FACIT-D version 4 
(dated 09 June 2013)’.
Below is a list of statements that other people with your illness have said are important. 
Please circle or mark one number per line to indicate your response as it applies to 
the past 7 days.


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s 
s 
 
r 


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References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-46.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-2.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-40.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  Lancet. 
2002; 359:727-32.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-78
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-66.


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12.4.
Appendix 4
Eastern Cooperative Oncology Group 
Performance Status
The scale and criteria summarised Appendix 4 Table 1 are designed to assess how a 
subject’s disease is progressing and to assess how the disease affects activities of daily 
living of the subject. 
Appendix 4 Table 1
Eastern Cooperative Oncology Group performance status 
grading criteria
Grade Criteria
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
Eastern Cooperative Oncology Group, Robert Comis M.D., Group Chair.
Abbreviations:  ECOG = Eastern Cooperative Oncology Group 
References
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, E.T., 
Carbone, P.P.: Toxicity And Response Criteria Of The Eastern Cooperative Oncology 
Group. Am J Clin Oncol 5:649-655, 1982


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12.5.
Appendix 5
Country Specific Requirements
No country-specific requirements exist.


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12.6.
Appendix 6
Cockcroft-Gault Equation for Calculating 
Creatinine Clearance
Creatinine clearance can be calculated from serum creatinine values by two formulas.
To calculate as mg/dL:
Calculated creatinine
clearance (mL/min)  =
(140 age [years] ) weight (kg)
72 serum creatinine (mg/dL)
Female subjects: multiply by 0.85
To calculate as mol/L:
Calculated creatinine
clearance (mL/min)  =
(140 age [years] ) weight (kg) x 88.4
72 × 1 × serum creatinine (mol/L))
Female subjects: multiply by 0.85
References
Cockcroft DW, Gault MH. Prediction of Creatinine Clearance from Serum Creatinine. 
Nephron 16: 31-41, 1976


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12.7.
Appendix 7
Liver Chemistry Monitoring, Interruption 
Stopping and Follow-up Criteria
Appendix 7 Figure 1 Liver safety algorithm
•Instruct subject to stop investigational product (IP)
•Notify GSK and arrange clinical followup 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 followup
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, stabilised 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 or bilrubin >2xULN?
Yes
*INR value not applicable to subjects on anticoagulants


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12.8.
Appendix 8
Protocol Changes
Amendment 1
Protocol Amendment 01 applies to all site(s) participating in the conduct of the 
study
Summary of changes and rationale:
Change
Rationale
Prior treatment with lapatinib was 
added as an exclusion criterion.
It is possible that prior treatment with lapatinib 
might influence the subjects’ perception of the 
tolerability of lapatinib, or the subjects’ 
susceptibility to lapatinib-associated diarrhoea.
Additional detail was provided for 
dermatological monitoring.
The protocol was updated to include the GSK 
lapatinib dermatological assessment guidelines 
(version 4.0, 10 March 2014). The frequency of 
skin examination was modified to be consistent 
with recommendations in the lapatinib SPC.
Secondary endpoints related to patient 
reported outcomes were updated.
The Diarrhoea Management Diary was revised 
after the LAP117314 protocol was finalised (17 
February 2014).  The patient-reported endpoints 
and objectives were amended to be consistent 
with the revised Diarrhoea Management Diary.
The schedule for completion of the 
Diarrhoea Management Diary and 
FACIT-D was clarified.
Information has been provided to describe and 
clarify the schedule for completion of the 
Diarrhoea Management Diary and FACIT-D at 
the baseline visits and during treatment with 
lapatinib and capecitabine.
The schedule of study visits relative to 
the week numbers and cycles of 
treatment with lapatinib and 
capecitabine was clarified
The Diarrhoea Management Diary and FACIT-
D refer to ‘Week’ of treatment and the protocol 
Time and Events table refers to ‘Cycle’ of 
treatment.  Information has been provided to 
describe and clarify the relationship between 
‘Week’ and ‘Cycle’ of treatment.
The use of octreotide s.c. within the 
diarrhoea management guidelines was 
clarified
The protocol includes the GSK diarrhoea 
management guidelines, which recommend the 
use of octreotide as a second line treatment 
option for diarrhoea refractory to treatment with 
loperamide.  Additional guidance has been 
provided concerning the use of octreotide s.c. in 
subjects randomised to receive treatment with 
octreotide LAR.


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Change
Rationale
Typographical errors have been 
corrected; Time and Events table 
content has been update; format 
changes have been made.
These changes have been made to improve the 
quality of the protocol, and are listed in detail in 
this appendix.
Detail of changes

The detail of changes is presented in the order in which the change appears in the 
protocol.  

‘Original’ refers to content of the protocol dated 17 February 2014.  

‘Amended’ refers to the content of the protocol as updated in Amendment 01.  

Text deleted from the original protocol is presented as a strikethrough font.  

The location of the changes in the text of the protocol is identified by section number 
and title, followed by paragraph number and sentence number if required.  

Minor changes to table content are identified by table number, followed by row 
number and column number.

More extensive changes to tables are presented as ‘Original’ table content, followed 
by ‘Amended’ table content.

Changes to section numbers and table numbers subsequent to amendment changes 
are not recorded in the appendix, unless this clarifies the location of the change.
Title page 
 were added as authors.
Sponsor Information page  
Item
Original
Amended
 position 
updated
Tykerb/Tyverb 
 
 position 
updated
Tykerb/Tyverb 
 
Tykerb/Tyverb 
 
 address 
updated
 telephone 
number updated
 fax number 
deleted
n/a


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Item
Original
Amended
 added as 
Principal Investigator
n/a
 
 
 
 added 
as Principal Investigator
n/a
 
 
 
 
Table of contents
The Table of Contents was updated.
List of abbreviations
Added:
DMD
Diarrhoea Management Diary
DSS
Diarrhoea symptom subscale
Deleted:
IWR
Interactive web response
NG
Next generation
Minor Typographical changes
These changes may also occur in sections of text which have been more extensively 
modified, summarised in other sections of this appendix. 
‘Diarrhoea diary’ has been changed to ‘Diarrhoea Management Diary’ or ‘DMD’ in the 
following locations:
Location
Paragraph
Line
Protocol Summary: Rationale
7
15/16


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Location
Paragraph
Line
Protocol Summary: Objectives
3
2, 4
Section 1.2 Study rationale
6
1
Section 1.2 Study rationale
7
1, 2
Section 2 Objectives and Endpoints
3
2, 4, 5
Section 3.1 Study design
14
1
Section 3.2 Discussion of design
12
2, 4, 6, 7
Section 5.8 Treatment compliance
3
2, 3
Time and Events Table 16
Footnote
6
Time and Events Table 17
Footnote
6
Section 7.1.6 Assessments every 3 weeks
Bullet list
Bullet point 9
Section 7.1.8 Study completion or early 
withdrawal
Bullet list
Bullet point 7
Section 8 Data Management
3
1
Section 9.3.5.1 Efficacy analyses
1
6
The term ‘every week’ was added to clarify the frequency for completing the DMD in the 
following locations:
Location
Paragraph
Line
Protocol Summary: Objectives
3
2
Section 2 Objectives and Endpoints
3
2
Section 3.1 Study design
14
1


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The term ‘every 3 weeks’ was added to clarify the frequency for completing the FACIT-
D in the following locations:
Location
Paragraph
Line
Protocol Summary: Objectives
3
2
Section 2 Objectives and Endpoints
3
2
Section 3.1 Study design
14
1
Protocol Summary: Study design  
Original text, paragraph 3: 
All subjects with episodes of diarrhoea will be encouraged to follow the GSK diarrhoea 
management guidelines for subjects receiving lapatinib.
Protocol Summary: Study assessments  
Original text, paragraph 2: 
Subjects randomised to receive octreotide will complete the diarrhoea diary and FACIT-
D before receiving the first dose of octreotide.  All subjects will complete the diarrhoea 
diary and FACIT-D immediately before starting the first cycle of treatment with lapatinib 
and capecitabine.  Subjects will then complete a diarrhoea diary and the FACIT-D at 
regular intervals until the end of 24 weeks of treatment or subject withdrawal, whichever 
is sooner.  PROs will not be collected beyond 24 weeks of treatment.
Amended text, paragraph 2:
All subjects will complete the baseline DMD and FACIT-D during the 3 days prior to 
randomisation, before any study-related treatment is administered.  Subjects randomised 
to receive octreotide will complete a second baseline DMD and FACIT-D before starting 
the first cycle of treatment with lapatinib and capecitabine.  Subjects will then complete 
the DMD every week and the FACIT-D every 3 weeks until the end of 24 weeks of 
treatment with lapatinib and capecitabine or subject withdrawal, whichever is sooner.  
The DMD and FACIT-D will not be completed beyond 24 weeks of treatment.
New text inserted, paragraph 5:
All subjects with episodes of diarrhoea will be encouraged to follow the GSK diarrhoea 
management guidelines for subjects receiving lapatinib.  The use of octreotide in the s.c. 
formulation for the management of diarrhoea refractory to treatment with loperamide is 
not excluded.  Investigators should use their clinical judgement concerning the use of 
octreotide s.c. in subjects randomised to receive treatment with octreotide LAR, 
particularly during Week 2 through to Week 12 of treatment with lapatinib and 


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capecitabine, when circulating concentrations of octreotide should already be within the 
clinically effective range.
New text inserted, last sentence of original paragraph 5, amended paragraph 6:
Dermatological monitoring and assessment will be conducted in accordance with the 
guidance provided in the Lapatinib SPC.
Section 1.3.1 Risk assessment
Original text, paragraph 4, sentence 4:
Diarrhoea will be managed in accordance with the GSK guidelines (Appendix 1), with 
the exception that subjects with severe diarrhoea unresponsive to loperamide who have 
received octreotide LAR should not receive further treatment with octreotide, but should 
receive supportive care as second-line management of diarrhoea.  
Amended text, paragraph 4, sentence 4:
Diarrhoea will be managed in accordance with the GSK guidelines (Appendix 1); 
subjects with severe diarrhoea unresponsive to loperamide who have received octreotide 
LAR may receive further treatment with octreotide s.c. at the investigators discretion,
Section 2 Objectives and Endpoints, Table 7
Original text, Row 2 ‘Primary: Investigator reported’
Amended text, Row 2 ‘Primary: Investigator reported (eCRF)’.
Original text Row 3, Endpoints column, ‘Proportion of subjects experiencing diarrhoea 
with a severity of Grade 2 and above, as defined by the NCI CTCAE, version 4.03’.
Amended text Row 3, Endpoints column ‘Proportion of subjects experiencing diarrhoea 
with a severity of Grade 2 and above, as defined by the NCI CTCAE, version 4.03, 
recorded as AEs in the eCRF.’
Original text Row 4, ‘Secondary: Investigator reported’, 
Amended text Row 4 ‘Secondary: Investigator reported (eCRF)’.
Original text, Rows relating to Secondary: Subject-reported endpoints and objectives.


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Secondary: Subject reported
To determine the efficacy of prophylactic octreotide 
in reducing the proportion of subjects experiencing 
diarrhoea of any grade of severity.
To determine the efficacy of prophylactic octreotide 
in increasing the time to onset of the first episode 
of diarrhoea of any grade of severity.
To determine the efficacy of prophylactic octreotide 
in reducing the proportion of subjects taking anti-
diarrhoeal medication. 
To determine the efficacy of prophylactic octreotide 
in reducing the proportion of subjects making 
dietary changes as a result of diarrhoea.
To determine the effect of prophylactic octreotide 
on the proportion of subjects making unscheduled 
visits to healthcare professionals as a result of 
diarrhoea.
To determine the efficacy of prophylactic octreotide 
in reducing the proportion of subjects making 
changes to cancer therapy as a result of diarrhoea.
Proportion of subjects experiencing 
diarrhoea of any grade of severity, recorded 
in the diarrhoea diary.
Time to onset of the first episode of 
diarrhoea of any grade of severity, recorded 
in the diarrhoea diary.
Proportion of subjects taking anti-diarrhoeal 
medication, recorded in the diarrhoea diary.
Proportion of subjects making dietary 
changes due to diarrhoea, recorded in the 
diarrhoea diary.
Proportion of subjects making unscheduled 
visits to healthcare professionals due to 
diarrhoea, recorded in the diarrhoea diary.
Proportion of subjects missing doses of 
lapatinib and capecitabine due to diarrhoea, 
recorded in the diarrhoea diary.
Quality of Life
To determine the effect of prophylactic octreotide 
on quality of life.
Proportion of subjects with improvement in 
quality of life, recorded by FACIT-D.  
Trial Outcomes Index will be the primary 
measure; sub-scales will be secondary 
measures.
Amended text, Rows relating to Secondary: Patient-reported endpoints and objectives. 


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Secondary: Patient1 reported (DMD)
To determine the effect of prophylactic octreotide 
on patient-reported diarrhoea.
To determine the effect of prophylactic octreotide in 
delaying patient reported diarrhoea.
To determine the effect of prophylactic octreotide in 
reducing the proportion of patients taking anti-
diarrhoeal medication. 
To determine the effect of prophylactic octreotide in 
reducing the proportion of patients making dietary 
changes to control diarrhoea.
To determine the effect of prophylactic octreotide 
on the proportion of patients contacting other non-
hospital healthcare professionals to discuss
diarrhoea.
To determine the effect of prophylactic octreotide in 
reducing the proportion of patients reporting non-
adherence due to diarrhoea.
Proportion of patients reporting changes in 
bowel movements from baseline (frequency 
and/or consistency), recorded in the DMD.
Time to the first patient reported change in 
frequency and/or consistency of bowel 
movements from baseline, recorded in the 
DMD.
Proportion of patients taking anti-diarrhoeal 
medication, recorded in the DMD.
Proportion of patients making dietary 
changes due to diarrhoea, recorded in the 
DMD.
Proportion of patients contacting other non-
hospital healthcare professionals to discuss
diarrhoea, recorded in the DMD.
Proportion of patients reporting stopping 
completely or missing doses of anti-cancer 
tablets due to diarrhoea, recorded in the 
DMD.
Quality of Life (FACIT-D)
To determine the effect of prophylactic octreotide 
on health-related quality of life.
Proportion of patients with changes in 
health-related quality of life, recorded by 
FACIT-D.  
Trial Outcomes Index will be the primary 
endpoint; FACT-G total, FACIT-D total, and 
sub-scales will be secondary endpoints..
1.
The term ‘patient’ refers to study subject in the context of DMD- and FACIT-D-related objectives 
and endpoints.
Section 2 Objectives and endpoints
Amended text, new paragraphs inserted after paragraph 3:
All subjects will complete the baseline DMD and the FACIT-D during the 3 days prior to 
randomisation, before any study-related treatment is administered.  Subjects randomised 
to receive octreotide will complete a second baseline DMD and the FACIT-D before 
starting the first cycle of treatment with lapatinib and capecitabine.  Hence, subjects 
randomised to receive octreotide will complete the baseline DMD and the FACIT-D 
(Week -1) prior to receiving the first dose of octreotide (0.1mg subcutaneous tolerability 


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test dose), and all subjects will complete the baseline DMD and the FACIT-D prior to 
receiving the first dose of lapatinib and capecitabine (Week 0).  
The DMD will be completed every week after the first dose of lapatinib and capecitabine 
is administered (Week 1, Week 2, Week 3, etc), until the end of study visit (Week 24,
disease progression, unacceptable toxicity or subject withdrawal if this is sooner).  The 
FACIT-D will be completed every 3 weeks during treatment with lapatinib and 
capecitabine (Week 3, Week 6, Week 9, etc), until the end of study visit (Week 24,
disease progression, unacceptable toxicity or subject withdrawal if this is sooner). The 
DMD and FACIT-D will not be completed beyond 24 weeks of treatment.  
The baseline DMD comprises 3 questions to record stool form and consistency.  The 
DMD to be completed throughout the rest of the study comprises the 3 questions in the 
baseline DMD and a further 5 questions and 6 sub-questions to evaluate the 
consequences and management of diarrhoea.  A copy of the baseline DMD and the DMD 
is included in the Study Procedures Manual (SPM).
Original text, paragraph 4:
The FACIT-D (Appendix 2) comprises the 27 item Functional Assessment of Cancer 
Therapy-General (FACT-G) questionnaire which has physical (PWB), social (SWB), 
emotional (EWB) and functional wellbeing (FWB) subscales and an 11 item subscale 
which measures quality of life specific to diarrhoea.  The primary PRO endpoint will be 
the Trial Outcome Index, which is a summation of the PWB, FWB and diarrhoea 
subscales.  Secondary PRO endpoints will be overall quality of life (total FACT-G), total 
FACIT-D and scores from each of the individual subscales.  The FACIT-D will be 
completed every 3 weeks. 
Amended text, paragraph 7 (replaces original paragraph 4):
The FACIT-D (Appendix 2) comprises the 27 item Functional Assessment of Cancer 
Therapy-General (FACT-G) questionnaire which has physical (PWB), social (SWB), 
emotional (EWB) and functional wellbeing (FWB) subscales and an 11 item diarrhoea 
symptom subscale (DSS) which measures quality of life specific to diarrhoea.  The 
primary endpoint derived from the FACIT-D will be the Trial Outcome Index, which is a 
summation of the PWB, FWB and diarrhoea symptom subscales.  Secondary endpoints 
will be overall quality of life (total FACT-G), total FACIT-D and scores from each of the 
individual subscales.  
Original text, paragraph 5 (amended text paragraph 8), line 5, mis-spell ‘efficiacy’ 
corrected to ‘efficacy’.
Section 3.1 Study design: 
Original text paragraph 3, sentence 1, Study Procedures Manual (SPM)
Amended text ‘paragraph 3, sentence 1, SPM.


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Original text: paragraph 5, sentence 3, ‘All subjects with episodes of diarrhoea will be 
encouraged to follow the diarrhoea management guidelines for subjects receiving 
lapatinib (Appendix 1).
Original text: paragraph 9
Episodes of mild diarrhoea which occur following the first dose of octreotide LAR and 
prior to the first dose of lapatinib and capecitabine should be managed in accordance with 
the diarrhoea management guidelines (Appendix 1).  Episodes of severe diarrhoea which 
occur following any dose of octreotide should be managed by taking supportive measures, 
but should not include further use of octreotide.  
Amended text (new paragraph):
All subjects with episodes of diarrhoea will be encouraged to follow the GSK diarrhoea 
management guidelines for subjects receiving lapatinib (Appendix 1).  In subjects 
randomised to receive octreotide, episodes of mild diarrhoea which occur following the 
first dose of octreotide LAR should be managed in accordance with the diarrhoea 
management guidelines.  The use of octreotide in the s.c. formulation for the management 
of diarrhoea refractory to treatment with loperamide is not excluded.  Investigators 
should use their clinical judgement concerning the use of octreotide s.c. in subjects 
randomised to receive treatment with octreotide LAR, particularly during Week 2 
through to Week 12 of treatment with lapatinib and capecitabine, when circulating 
concentrations of octreotide should already be within the clinically effective range.  
Original text, paragraph 14:
Subjects will complete diarrhoea diaries and the FACIT-D to provide an additional 
perspective on the effects of treatment-associated diarrhoea.
Amended text, paragraph 15 (replaces original paragraph 14)
Subjects will complete the DMD every week and the FACIT-D every 3 weeks during 
treatment with lapatinib and capecitabine to provide an additional perspective on the 
effects of treatment-associated diarrhoea.
Original text, paragraph 15, sentence 5
Any changes will be communicated to the investigative sites in the form of a letter and 
revised version will be included in the SPM.
Amended text, paragraph 16, sentence 5 (replaces original paragraph 15, sentence 5)
Any changes will be communicated to the investigative sites in the form of a letter and 
the revised version of the AE management or dose modification guidelines will be 
included in the SPM.
Original text, paragraph 16, sentence 5


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Any changes will be communicated to the investigative sites in the form of a letter and 
revised version will be included in the SPM.
Amended text, paragraph 17, sentence 5 (replaces original paragraph 16, sentence 5)
Any changes will be communicated to the investigative sites in the form of a letter and 
the revised version of the AE management or dose modification guidelines will be 
included in the SPM.
Section 3.2 Discussion of design
Original text, paragraph 1
All subjects in this study will receive treatment with lapatinib and capecitabine consistent 
with the approved indication for this treatment combination.  Diarrhoea is a recognised 
side effect of cancer treatment, and all subjects will be recommended to follow the 
standardised guidelines for diarrhoea management (Appendix 1).  
Amended text, paragraph 1
All subjects in this study will receive treatment with lapatinib and capecitabine consistent 
with the approved indication for this treatment combination.  Diarrhoea is a recognised 
side effect of cancer treatment, and all subjects will be recommended to follow the 
standardised guidelines for diarrhoea management (Appendix 1).  The use of octreotide
in the s.c. formulation for the management of diarrhoea refractory to treatment with 
loperamide is not excluded, and investigators should use their clinical judgement 
concerning the use of octreotide s.c. in subjects randomised to receive treatment with 
octreotide LAR.
Original text, paragraph 6, sentence 4
In this study, all subjects will be recommended to follow the standardised guidelines for 
management of diarrhoea associated with lapatinib use, and octreotide in the formulation 
for s.c. administration will not be provided to manage episodes of diarrhoea in subjects 
randomised to receive octreotide LAR. 
Amended text, paragraph 6, sentence 4
In this study, octreotide in the formulation for s.c. administration will not be provided 
prophylactically to prevent episodes of diarrhoea in subjects during the first 7 to 14 days 
after the first dose of octreotide LAR.
Section 4.1.2 Inclusion criteria
Amended text, bullet 7b, ‘Acceptable contraceptive methods are described in Section 
7.5.1.’ was added.
Section 4.1.3 Exclusion criteria
Amended text, bullet point 10, ‘Prior treatment with lapatinib’ was added.


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Section 4.2 Other eligibility criteria considerations
Original text, paragraph 3
Caution should be taken in subjects with moderate or severe hepatic impairment or severe 
renal impairment.  Caution should be taken in subjects with conditions that could impair 
cardiac function, including conditions that could result in prolongation of QTc, 
arrhythmias and angina pectoris.  Subjects with hypertension who are randomised to 
receive octreotide must be monitored to manage the potential risk of bradycardia 
associated with octreotide use.
Amended text, paragraph 3
Caution should be taken in subjects with moderate or severe hepatic impairment.  
Investigators should consider the subjects hepatic function measures relative to the 
guidance provided for the management of hepatobiliary AEs in Section 5.13.  It is 
recommended that hepatic function measures prior to randomisation should meet the 
following criteria:

Albumin ≥2.5 g/dL

Serum bilirubin ≤1.5 x the upper limit of the normal range (ULN) or ≤2.5 x 
ULN with Gilbert's Syndrome

AST and ALT ≤3 × ULN
Caution should be taken in subjects with severe renal impairment.  
Caution should be taken in subjects with conditions that could impair cardiac function, 
including conditions that could result in prolongation of QTc, arrhythmias and angina 
pectoris.  Subjects with hypertension who are randomised to receive octreotide must be 
monitored to manage the potential risk of bradycardia associated with octreotide use.
Section 4.3.1 Discontinuation from treatment with octreotide
Original text, paragraph 2, sentence 2 and sentence 3
Episodes of mild diarrhoea which occur following the first dose of octreotide LAR and 
prior to the first dose of lapatinib and capecitabine should be managed in accordance with 
the diarrhoea management guidelines (Appendix 1).  Episodes of severe diarrhoea 
occurring at any time during the first three cycles of treatment with lapatinib and 
capecitabine should be managed by taking supportive measures, but should not include 
further use of octreotide.  
Amended text, paragraph 2, sentence 2 and sentence 3
Episodes of mild diarrhoea which occur following treatment with octreotide LAR should 
be managed in accordance with the diarrhoea management guidelines (Appendix 1).  The 
use of octreotide in the s.c. formulation for the management of diarrhoea refractory to 
treatment with loperamide is not excluded.  Investigators should use their clinical 
judgement concerning the use of octreotide s.c. in subjects randomised to receive 


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treatment with octreotide LAR, particularly during Week 2 through to Week 12 of 
treatment with lapatinib and capecitabine, when circulating concentrations of octreotide 
should already be within the clinically effective range.  
Section 4.3.2 Discontinuation from treatment with lapatinib and capecitabine
Amended text, inserted before original text sentence 1
Subjects may withdraw from the study at any time.
Section 5.3 Octreotide
Original text, paragraph 2, sentence 2
Octreotide is provided as a 0.1mg/mL solution for s.c. injection, which may be diluted for 
intravenous infusion.
Amended text, paragraph 2, sentence 2
Octreotide is provided as a 0.1mg/mL solution for s.c. injection.
Section 5.3.1 Octreotide dosage and administration
Original text, paragraph 3
Episodes of mild diarrhoea which occur following the first dose of octreotide LAR and 
prior to the first dose of lapatinib and capecitabine should be managed in accordance with 
the diarrhoea management guidelines (Appendix 1).  Episodes of severe diarrhoea should 
be managed by taking supportive measures, but should not include further use of 
octreotide.  Subjects who report constipation with a severity of NCI CTCAE Grade 2 and 
above (Table 9) or other adverse events which are considered likely to be related to 
octreotide treatment following the first dose of octreotide LAR must not receive the 
second dose.
There is no amended text for this deletion.
Section 5.5 Treatment assignment
Original text, sentence 2
Investigators or designated staff will telephone the GSK interactive voice response (IVR) 
system called RAMOS (Registration and Medication Ordering System) or will contact 
the GSK interactive web response (IWR) system called RAMOS NG (Next Generation) 
to register and record subject activity.
Amended text, sentence 2
Investigators or designated staff will telephone the GSK interactive voice response (IVR) 
system called RAMOS (Registration and Medication Ordering System) to register and 
record subject activity.


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Original text, sentence 5
Study-specific instructional worksheets will be provided for the use of the IVR and IWR 
systems.
Amended text, sentence 5
Study-specific instructional worksheets will be provided for the use of the IVR system.
Section 5.7, Product accountability
Amended text, inserted after sentence 1.
Recording of drug accountability is required regardless of whether the Institution or GSK 
are providing lapatinib and capecitabine.
Section 5.9, Dose adjustment
Original text, paragraph 3, sentence 3.
Episodes of severe diarrhoea should be managed by taking supportive measures, but 
should not include further use of octreotide.  
Amended text, paragraph 3, sentence 3.
The use of octreotide in the s.c. formulation for the management of diarrhoea refractory 
to treatment with loperamide is not excluded.  Investigators should use their clinical 
judgement concerning the use of octreotide s.c. in subjects randomised to receive 
treatment with octreotide LAR, particularly during Week 2 through to Week 12 of 
treatment with lapatinib and capecitabine, when circulating concentrations of octreotide 
should already be within the clinically effective range.
Section 5.12.1 Dermatological events
Original text
The NCI CTCAE descriptions and grades of severity of dermatological AEs is presented 
in Table 12.


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Table 12
NCI-CTCAE dermatological reactions
Adverse Event
(Short name)
Grade 1
Grade 2
Grade 3
Grade 4
Rash / desquamation*
(Rash)
Macular or papular 
eruption or erythema 
without associated 
symptoms
Macular or papular 
eruption or 
erythema with 
pruritus or  other 
associated 
symptoms; 
localized 
desquamation* or 
other lesions 
covering <50% of 
body surface area 
(BSA)
Severe, 
generalized 
erythroderma or 
macular, papular 
or vesicular 
eruption; 
desquamation* 
covering 50% 
BSA.
Generalized 
exfoliative, 
ulcerative, or 
bullous 
dermatitis.
Rash:
Acne/acneiform
(Acne)
Intervention not 
indicated
Intervention 
indicated
Associated with 
pain, 
disfigurement, 
ulceration or 
desquamation
-
Nail changes
(Nail changes)
Discoloration; ridging 
(koilonychias; pitting)
Paronychia: no 
intervention indicated
Partial or complete 
loss of nail(s); pain 
in nailbed(s)
Paronychia: 
intervention 
indicated
Interfering with 
Activities of Daily 
Living (ADL)
-
Pruritus/itching 
(Pruritus)
Mild or localized
Intense or 
widespread
Intense or 
widespread and 
interfering  with 
ADL
-
Dry skin
(Dry skin)
Asymptomatic
Symptomatic, not 
interfering with 
ADL
Symptomatic, 
interfering with 
ADL
-
Hair loss/alopecia
(scalp or body)
Thinning or patchy
Complete
-
-
Photosensitivity
(Photosensitivity)
Painless erythema
Painful erythema
Erythema with 
desquamation
Life-threatening; 
disabling
Significant skin AEs (Grade 3 or more) resulting from lapatinib are rare, occurring in 
only 1-3% of subjects.
For NCI-CTCAE Grade 4 rash manifested as toxic epidermal necrolysis (i.e.Stevens-
Johnson’s Syndrome, etc) lapatinib must be permanently discontinued.
Subjects with poorly tolerated skin AEs may be successfully managed by providing a 
brief (up to 14 days) therapy interruption.  However, the rash may improve without the 
need for interrupting therapy with lapatinib.
A variety of agents can be used to manage skin rashes.  These agents include mild-to-
moderate strength steroid creams, topical or systemic antibiotics, topical or systemic 
antihistamines, and occasionally, retinoid creams. 


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Amended text
5.12.1.1
Dermatological Monitoring
As part of their physical examination, subjects must have a thorough skin examination 
prior to the start of study treatment or randomisation. The examination may include the 
scalp, previously irradiated areas, hair, and nails.  In addition, if clinically indicated an 
examination of the oral/genital mucosa may also be included.
Subsequent dermatological evaluations should be performed as clinically indicated.  Any 
serious and/or clinically relevant dermatological AEs must be followed until resolution to 
grade one (or better), or until there is no further improvement.
Subjects must also have a skin examination as part of the physical examination at the end 
of 24 weeks of treatment with lapatinib and capecitabine, or disease progression, 
treatment discontinuation due to unacceptable toxicity or subject withdrawal, whichever 
is sooner.
The purpose of dermatological monitoring is:

to facilitate dermatological safety throughout the trial in all subjects receiving 
lapatinib;

to assess whether a holding/stopping rule imposed during the course of 
treatment leads to less dermatological toxicity;

to identify the incidence of dermatological adverse events (AEs) for lapatinib, or 
the combination of lapatinib with other agents.
5.12.1.2
Frequency Evaluation and Grading Guide of Dermatological AEs
The frequency of dermatological adverse events occurring in 2,093 patients with locally 
advanced or metastatic cancer who participated in nine completed phase II and III 
lapatinib clinical trials is shown in Table 12.  This patient population included 1,413 
patients with breast cancer and 680 patients with other cancers. Patients were treated 
with lapatinib as monotherapy (n = 926) or in combination with paclitaxel (n=293) or 
capecitabine (n = 491).  Patients who were not exposed to lapatinib but received 
paclitaxel, capecitabine, or hormonal agents served as controls (n = 676).


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Table 12
Most Common Dermatological AEs Occurring in Patients Receiving 
Lapatinib (NCI-CTCAE versions 2.0 and 3.0)
The NCI CTCAE descriptions and grades of severity of dermatological AEs is presented 
in Table 13.
Table 13
NCI-CTCAE dermatological reactions
Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Rash maculo-papular
Macules/papules 
covering <10% 
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 super infection 
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
super infection 
with IV
antibiotics 
indicated; life-
threatening
consequences
Death
Nail discoloration
Asymptomatic; 
clinical or 
-
-
-
-


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Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
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
-
-
-
Nail ridging
Asymptomatic; 
clinical or
diagnostic 
observations only;
intervention not 
indicated
-
-
-
-
Paronychia
Nail fold edema or 
erythema;
disruption of the 
cuticle
Localised 
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 localised; 
topical intervention 
indicated
Intense 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
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 from 
a distance but only 
Hair loss of 
>50% normal for
that individual 
that is readily
apparent to 
-
-


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Adverse Event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
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
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
Lapatinib-related severe dermatological events (Grade 3) are infrequent (1-3%).  
Despite the rarity of lapatinib associated severe dermatological events, it is recommended 
that subjects who present with a severe dermatological event be assessed for the 
following: shortness of breath, angioedema, or generalised mucosal/cutaneous affectation 
with blisters or ulcers, suggestive of Type I hypersensitivity and/or NCI-CTCAE Grade 4 
dermatological event, manifested as toxic epidermal necrolysis or Stevens-Johnson 
Syndrome etc.  If a Grade 4 dermatological event occurs, lapatinib must be permanently 
discontinued.
5.12.1.3
Stopping and holding rules
If any Grade 4 dermatological event occurs, lapatinib must be permanently discontinued.
5.12.1.3.1
Holding rule
Lapatinib should be held for 14 days, in all patients who experience either a grade 3 
dermatological reaction or a grade 2 dermatological reaction, which is unimproved after 
two-weeks of medical management.  After the 14 day interruption, and provided the 
dermatological reaction improves to grade 1 or better, lapatinib may be restarted at the 
previous dose.
If the investigator considers continuation of lapatinib without interruption, it is required 
that he/she discusses the individual case with the GSK medical monitor before taking any 
decision on study treatment.  In some cases, resolution of grade 2 or greater 
dermatological reactions occurred without interruption of lapatinib.  For those subjects 
that interrupted lapatinib, many were able to resume lapatinib therapy at the same dose 
after resolution of the dermatological event.


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5.12.1.3.2
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 dermatological events which recover to 
NCI-CTCAE Grade 1 or better (within 14 days) after holding lapatinib.
5.12.1.3.3
Stopping rules
Lapatinib must be permanently discontinued for:

Recurrent Grade 3 dermatological reactions

All Grade 4 dermatological reactions, including Stevens-Johnson Syndrome and 
Toxic Epidermal Necrolysis.
5.12.1.4
Treatment
There is no standard treatment proven to be effective for lapatinib-induced 
dermatological reactions.  Therefore it is recommended that subjects who develop Grade 
2 dermatological reactions that are unresponsive to initial treatment may be referred to a 
dermatologist for evaluation and management.  For subjects with Grade 3 or 4 
dermatologic events, or chronic, persistent or recurring lower grade skin events, a 
dermatology consultation is strongly encouraged.
There are some general precautions for subjects receiving lapatinib therapy. Subjects are 
recommended to avoid exposure to bright sunlight.  When going out into bright sunlight, 
a broad spectrum sunscreen (containing titanium dioxide or zinc oxide) with an SPF of at 
least 30 should be applied.
A variety of agents may be used to manage dermatological reactions.  These include 
mild-to-moderate strength steroid creams, topical or systemic antibiotics, topical or 
systemic antihistamines, immunomodulators, hypoallergenic moisturisers, and emollients.
The need for oral or topical antibiotics and topical steroids is a clinical decision.  For 
pruritic lesions oral antihistamine agents may be effective.  For paronychia antiseptic 
bath and local potent corticosteroids in addition to tetracycline therapy is recommended.
If no improvement occurs, a dermatology or surgery consultation is recommended.  For 
infected lesions appropriate, culture driven treatment with systemic or topical antibiotics 
is recommended as clinically indicated.
Oral retinoids are not recommended because of theoretical concerns about negative 
effects on lapatinib’s mechanism of action. Topical steroids may result in skin irritation
and severe xerodermia (dryness).  Oral steroids may be used for a short treatment course 
(maximum of 14 days).
Section 5.13. Monitoring, Interruption, and Stopping Criteria for Hepatobiliary 
Events
Original text, paragraph 1, sentence 1
the upper limit of the normal range (ULN)


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Amended text, paragraph 1, sentence 1
ULN
Section 6.2.
Prohibited Medications and Non-Drug Therapies
Amended text, added after bullet point 1, sentence 2
Subjects who require an alternative anti-cancer therapy may withdraw from the study at 
any time.
Amended text, paragraph added after paragraph 5
Information on potential interactions with other medicinal products is presented in the 
Lapatinib, Capecitabine and Octreotide SPCs.
Section 7, Study Assessments and Procedures.  Original Table 15, Amended Table 16.
Column 3, row 1-2, inserted text ‘Week -1’.
Below row 13 (Physical Exam) insert new row, Dermatological Exam, with ‘x’ and ‘(x)8’ 
in relevant columns to show schedule of assessment.
Original text Table footnote 7
To be completed before the octreotide 0.1mg s.c. tolerability assessment dose.
Amended text Table footnote 7
Week -1 baseline PROs to be completed prior to randomisation, before the octreotide 
0.1mg s.c. tolerability assessment dose.
New footnote inserted, Table footnote 8
If clinically indicated, in accordance with the Lapatinib SPC.
Original Table footnotes 8 and 9 were renumbered as Table footnotes 9 and 10.
Original text Table footnote 9 
Cycle 2 and Cycle 4 visits are mandatory. Cycle 3, 5, 6, 7 and 8 visits are not mandatory; 
visits every 3 weeks would be preferred, but may be adapted to match local practice.
Amended text Table footnote 10
Visits at the start of Cycle 2 and Cycle 4 visits are mandatory. Visits at the start of Cycle 
3, 5, 6, 7 and 8 visits are not mandatory; visits every 3 weeks would be preferred, but 
may be adapted to match local practice.
Original text Table footnote 10 


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Cycle 2 to be started 21 days (+/- 2 days) after the start of Cycle 1.  Other cycles should 
be started within +/- 4 days of the 3 weekly treatment cycle intervals.
Original text Table footnote 11 
To be completed before the first dose of lapatinib and capecitabine is administered.  
Amended text Table footnote 11
Week 0 baseline PROs to be completed  before the first dose of lapatinib and 
capecitabine is administered.  
Amended text inserted, new Table footnote 13
Cycle 2 to be started 21 days (2 days) after the start of Cycle 1.  Other cycles should be 
started within 4 days of the 3 weekly treatment cycle intervals.
Original Table footnotes 13, 14, 15 and 16 were renumbered as Table footnotes 14, 15, 
16 and 17.
Original Table footnote 17
If clinically indicated.
Superscript numbers linking table cells to table footnotes were updated in accordance 
with the updated footnote numbers.
Section 7, Study Assessments and Procedures.  Original Table 16, Amended Table 17.
Column 3, row 2, inserted text ‘Cycle’.
Column 4, row 2, inserted text ‘Cycle’.
Below row 13 (Physical Exam) insert new row, Dermatological Exam, with ‘x’ and ‘(x)8’ 
in relevant columns to show schedule of assessment.
Original text Table footnote 7
To be completed before the first dose of lapatinib and capecitabine is administered.
Amended text Table footnote 7
Week 0 baseline PROs to be completed prior to randomisation, before the first dose of 
lapatinib and capecitabine is administered.
New footnote inserted, Table footnote 8
If clinically indicated, in accordance with the Lapatinib SPC.
Original Table footnotes 8 and 9 were renumbered as Table footnotes 9 and 10.


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Original text Table footnote 10 
Cycle 2 and Cycle 4 visits are mandatory. Cycle 3, 5, 6, 7 and 8 visits are not mandatory; 
visits every 3 weeks would be preferred, but may be adapted to match local practice.
Amended text Table footnote 11
Visits at the start of Cycle 2 and Cycle 4 visits are mandatory. Visits at the start of Cycle 
3, 5, 6, 7 and 8 visits are not mandatory; visits every 3 weeks would be preferred, but 
may be adapted to match local practice.
Original Table footnote 14
If clinically indicated.
Superscript numbers linking table cells to table footnotes were updated in accordance 
with the updated footnote numbers.
Section 7.1.3 Prior to randomisation
Paragraph 1, new bullet point inserted after bullet point 2 
Dermatological examination.
Original text, paragraph 1, original bullet point 10, amended bullet point 11
diarrhoea diary
Amended text, paragraph 1, original bullet point 10, amended bullet point 11
baseline DMD
Section 7.1.5, One Week after the First Dose of Octreotide LAR (Subjects 
Randomised to Receive Octreotide only).
Paragraph 1, new bullet point inserted after bullet point 1
Dermatological examination, if clinically indicated.
Original text, paragraph 1, original bullet point 2, amended bullet point 3
diarrhoea diary
Amended text, paragraph 1, original bullet point 2, amended bullet point 3
baseline DMD
Original text, paragraph 1, original bullet point 4, amended bullet point 5
Record visits to healthcare professionals associated with diarrhoea AEs.


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Amended text, paragraph 1, original bullet point 4, amended bullet point 5
Record visits to/contact with healthcare professionals associated with diarrhoea AEs.
Section 7.1.6 Assessments every 3 weeks
Paragraph 1, new bullet point inserted after bullet point 1
Dermatological examination, if clinically indicated.
Original text, paragraph 1, original bullet point 3, amended bullet point 4
Record visits to healthcare professionals associated with diarrhoea AEs.
Amended text, paragraph 1, original bullet point 3, amended bullet point 4
Record visits to/contact with healthcare professionals associated with diarrhoea AEs.
Section 7.1.8 Study Completion (24 weeks) or Early Withdrawal from Study and/or 
Study Treatment
Original text, paragraph 1, bullet point 3
Record visits to healthcare professionals associated with diarrhoea AEs.
Amended text, paragraph 1, bullet point 3
Record visits to/contact with healthcare professionals associated with diarrhoea AEs.
Paragraph 1, new bullet point inserted after bullet point 10
Dermatological examination.
Section 7.4.2 Definition of a SAE
Format change, bullet point g, sub-bullet point 4, beginning ‘Cardiovascular events have 
been seen...’; bullet point removed and text changed to ‘Normal’ format.
Section 7.5.1 Pregnancy test and prevention
Paragraph 6, new text inserted at the end of bullet point 3
UK subjects: In the UK, sexual inactivity by abstinence must be consistent with the 
preferred and usual lifestyle of the subject.  Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, postovulation methods) and withdrawal are not acceptable methods of 
contraception.
Section 7.7.2 Health outcomes assessments
Original text, paragraph 2


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Subjects randomised to receive treatment with octreotide will complete the FACIT-D 
immediately before receiving the first dose of octreotide.  All subjects will complete the 
FACIT-D immediately before the start of treatment with lapatinib plus capecitabine, then 
every three weeks through to withdrawal from the study or the end of the 24 week period 
of treatment with lapatinib and capecitabine, whichever is sooner.  
Amended text, paragraph 2
All subjects will complete the baseline FACIT-D prior to randomisation, before any 
study related treatment is administered.  Subjects randomised to receive treatment with 
octreotide will also complete the FACIT-D immediately before receiving the first dose of 
lapatinib and capecitabine.  All subjects will complete the FACIT-D every three weeks 
during treatment with lapatinib plus capecitabine through to withdrawal from the study or 
the end of the 24 week period of treatment with lapatinib and capecitabine, whichever is 
sooner.  
Original text, paragraph 3, sentences 1 and 2
The FACIT-D (version 4;Appendix 2) consists of the FACT-G [Webster, 2003] and a 
diarrhoea-specific subscale, and measures multidimensional quality of life in subjects 
with cancer.  FACT-G includes 27 general questions relating to four subscales: physical 
wellbeing, social/family wellbeing, emotional wellbeing, functional wellbeing, and the 
diarrhoea-specific subscale includes 11 questions. 
Amended text, paragraph 3, sentences 1 and 2
The FACIT-D (version 4;Appendix 2) consists of the FACT-G [Webster, 2003] and a 
diarrhoea-specific subscale, and measures multidimensional quality of life in subjects 
with cancer. FACT-G includes 27 general questions relating to four subscales, PWB,
SWB, EWB and FWB, and the DSS includes 11 questions. 
Section 9.3.5.1.2. Secondary endpoint analysis: Investigator-reported endpoints
Original bold heading 6 and paragraph 7
Unscheduled visits to healthcare professionals
The proportion of subjects requiring an unscheduled visit to a health care professional at 
least once as a result of diarrhoea will be summarised and analysed using the same 
method as described in Section 9.3.5.1.1 for the primary endpoint. 
Amended bold heading 6 and paragraph 7
Unscheduled visits to/contact with healthcare professionals
The proportion of subjects requiring an unscheduled visit to or contact with a healthcare 
professional at least once as a result of diarrhoea will be summarised and analysed using 
the same method as described in Section 9.3.5.1.1 for the primary endpoint.
Section 9.3.5.1.3. 


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Original section title
Secondary analyses: Subject-reported endpoints
Original text
These analyses will be based on data reported by the subject in the diarrhoea diary.  
Analyses of secondary diarrhoea-related endpoints will be presented for the ITT and m-
ITT populations using the same lapatinib and capecitabine treatment intervals as 
described for the summaries of the primary endpoint in Section 9.3.5.1.1.  
Diarrhoea at any grade
The proportion of subjects experiencing at least one episode of diarrhoea, of any grade of 
severity, will be summarised and analysed using the same methods as described in 
Section 9.3.5.1.1 for the primary endpoint.  
Time to onset of diarrhoea of any grade of severity
The time to onset of the first episode of diarrhoea of any grade of severity will be 
summarised by treatment arm using Kaplan-Meier methods.  Subjects who complete the 
study or withdraw prematurely without experiencing an episode of diarrhoea will be 
censored at the date of withdrawal or study completion.  The Kaplan-Meier estimate of 
the proportion of patients experiencing an episode of diarrhoea will be presented for each 
weekly time interval by treatment group.  Estimates and 95% confidence intervals for the 
25th percentile, median and 75th percentile will be provided by treatment group.  
Treatment groups will be compared using the log-rank test, or the Wilcoxon test in the 
case of non-proportional hazards. 
Anti-diarrhoeal medication
The proportion of subjects taking medication at least once as a result of diarrhoea will be 
summarised and analysed using the same methods as described in Section 9.3.5.1.1 for 
the primary endpoint. 
Dietary changes
The proportion of subjects making dietary changes at least once as a result of diarrhoea 
will be summarised and analysed using the same methods as described in Section 
9.3.5.1.1 for the primary endpoint. 
Unscheduled visits to healthcare professionals
The proportion of subjects making an unscheduled visit to a health care professional at 
least once as a result of diarrhoea will be summarised and analysed using the same 
method as described in Section 9.3.5.1.1 for the primary endpoint. 
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The proportion of subjects making changes to study treatment (lapatinib or capecitabine) 
as a result of diarrhoea will be summarised and analysed using the same methods as 
described in Section 9.3.5.1.1 for the primary endpoint.  Summaries will be performed 
separately for each type of change in study treatment (i.e. dose delays, dose reductions 
and treatment withdrawal) as well as overall. 
Amended section title
Secondary analyses: Patient-reported endpoints
Amended text
T hese analyses will be based on data reported in the DMD.  Analyses of secondary 
diarrhoea-related endpoints will be presented for the ITT and m-ITT populations for 
patients completing the baseline and at least one post-baseline DMD.
Diarrhoea
The proportion of patients reporting an increase in the frequency and/or worsening in 
consistency of bowel movements will be summarised and analysed using Generalised 
Estimating Equations (GEE), using a repeated statement, the binary response is the 
patient reported increase in frequency or worsening in consistency, as defined in the RAP, 
in addition individual patient data will be plotted.    
Time to onset of first patient-reported increase in frequency and/or worsening in 
consistency of bowel movements
The time to onset of the first patient-reported increase in frequency and/or worsening of 
consistency of bowel movements will be summarised by treatment arm using Kaplan-
Meier methods.  Patients who complete the study or withdraw prematurely without 
experiencing an increase in the frequency and/or worsening in consistency of bowel 
movements will be censored at the date of withdrawal or study completion.  The Kaplan-
Meier estimate of the proportion of patients reporting an increase in the frequency and/or 
worsening of consistency of bowel movements will be presented for each weekly time
interval by treatment group. Estimates and 95% confidence intervals for the 25th
percentile, median and 75th percentile will be provided by treatment group.  Treatment 
groups will be compared using the log-rank test, or the Wilcoxon test in the case of non-
proportional hazards. 
Additional anti-diarrhoeal medication
The proportion of patients taking any extra medication not prescribed by the hospital-
doctor to help with diarrhoea will be summarised and analysed using the same GEE 
analysis and plots as described for patient-reported diarrhoea.
Impact of dietary changes


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The proportion of patients making dietary changes to help with the diarrhoea will be 
summarised and analysed using the same GEE analysis and plots as described for patient-
reported diarrhoea.
Contact with any other healthcare professionals
The proportion of patients contacting a health care professional other than the hospital 
doctors/nurses to discuss diarrhoea will be summarised and analysed using the same GEE 
analysis as and plots as described for patient-reported diarrhoea..
Reduction / stopping of anti-cancer treatment
The proportion of patients reducing or completely stopping the number of anti-cancer 
tablets to help with diarrhoea will be summarised and analysed using the same GEE 
analysis and plots as described for patient-reported diarrhoea. Summaries will be 
performed separately for each type of change in anti-cancer tablets (i.e. reducing tablets 
and stopping completely) as well as overall.
Section 9.3.5.3 Health Outcomes analyses
Original text
The following scores will be calculated: Total diarrhoea subscale, individual Physical, 
Social/Family, Emotional and Functional Wellbeing subscales, FACT-G total and 
FACIT-D total.  Each score will be summarized by visit and treatment arm.  Changes 
from baseline (prior to randomisation) and changes from baseline (prior to start of 
lapatinib and capecitabine) will also be summarized at each post-baseline visit as 
appropriate.  Proportions of subjects in each treatment arm who achieve a clinically 
meaningful improvement or decline will be compared at each time point using the chi-
square test.  A responder criterion can be defined as a 5 or more point change from 
baseline on the FACT-G and FACIT-D and a 2 or more change from baseline for the 
individual subscales [Cella, 2002;Eton, 2004].  For the total scores and each of the 4 
subscale scores, the difference between the treatment arms in terms of the change from 
baseline at each study visit will be analysed using a two sample t-test.  Treatment effect 
over time will be evaluated.  Further details will be provided in the RAP.
The calculation of scores and methods to deal with missing data will be handled 
according to the standard scoring guidelines.  Full details of all the health outcomes 
analyses will be provided in the RAP.  
Amended text
The primary endpoint for the FACIT-D will be the Trial Outcome Index (TOI) comprised 
of the PWB, FWB and the DSS.  Secondary endpoints will be: 

Total FACT-G (i.e. PWB, SWB, EWB and FWB subscales); 

Total FACIT-D (i.e. PWB, SWB, EWB and FWB subscales and the DSS); 

Each individual subscale score.


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Scores will be summarised by visit and treatment arm.  Changes from baseline (prior to 
randomisation) and changes from baseline (prior to start of lapatinib and capecitabine) 
will also be summarised at each post-baseline visit as appropriate.  Proportions of 
subjects in each treatment arm who achieve a clinically meaningful improvement or 
decline will be compared at each time point using the chi-square test.  A responder 
criterion can be defined as a 6 or more point change from baseline on the TOI, a 7 or 
more point change from baseline for the Total FACT-G, a 7 or more point change from 
baseline for the Total FACIT-D, a 3 or more point change from baseline for the 
individual subscales (PWB, EWB, SWB, FWB), and a 4 or more point change from 
baseline for the DSS.  For the total scores and each of the subscale scores, the difference 
between the treatment arms in terms of the change from baseline at each study visit will 
be analysed using a two sample t-test.  Treatment effect over time will be evaluated.  
Further details will be provided in the RAP.
The calculation of scores and methods to deal with missing data will be handled 
according to the standard scoring guidelines.  Full details of all the FACIT-D analyses 
will be provided in the RAP.  
Appendix 2 FACIT-D
New text inserted
The FACIT-D questionnaire (version 4, English original) is available in two forms with 
different dates: ’16 Nov 2007’ and ’09 June 2013’.  These two forms have minor 
differences in question phrasing and format.  Both forms are fully validated and the 
minor differences between two forms do not affect the quality of data collection and 
analysis.  In this study, the languages translated based on ‘English FACIT-D version 4 
(dated 16 Nov 2007)’ are Arabic, French, Hebrew, Italian and Polish.  The languages 
translated based on ‘English FACIT-D version 4 (dated 09 June 2013)’ are Czech, Greek, 
Russian and Traditional Chinese. 
This appendix provides an example of the questionnaire ‘English FACIT-D version 4 
(dated 09 June 2013)’.
Original FACIT-D copy was deleted.
Amended FACIT-D copy was inserted.
End of Amendment 01 record of changes.


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Amendment 2
Protocol Changes for Amendment 2 (DD-MMM-YYYY) from the Protocol 
Amendment 1 (23-Aug-2014)
Protocol Amendment 02 applies to all site(s) participating in the conduct of the 
study
Summary of changes and rationale:
Change
Rationale
Incorporation of a planned Interim 
Analysis
An interim analysis for futility is being 
incorporated into this study to allow an early 
assessment of the primary endpoint, that is the 
proportion of subjects experiencing diarrhoea 
with a severity of Grade 2 and above, as defined 
by the NCI CTCAE, version 4.03, recorded as 
AEs in the eCRF.  The diarrhoea data from the 
eCRF will be summarised / analysed and 
reviewed by an independent review committee.
Number of subjects undergoing 
formal review of safety data was 
updated in Section Study Design and 
Section Safety Review Team.
An interim analysis and first safety review is 
planned when approximately 40% (n=60) of the 
patients have been recruited, change made for
consistency and practicality.  
Recruitment Plan Section included.
To include a recruitment plan as an interim 
analysis is being incorporated.
Blinding Section updated. 
The addition of an interim analysis requires 
further clarification to preserve the integrity of 
the study.
Details of tertiary Sponsor Medical 
Monitor Contact Information was 
added, Author list, Sponsor Signatory, 
address and telephone numbers of 
medical monitors updated
Details have been added based on administrative 
change.
Appendix for Country Specific 
Requirements was updated
Instructive text presented was deleted to 
improve the quality of the protocol.
Appendix for Protocol Changes was 
updated
Statement regarding application of amendment 
01 to all participating sites added to improve the 
quality of the protocol.


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Detail of changes

The detail of changes is presented in the order in which the change appears in the 
protocol.  

‘Original’ refers to content of the protocol dated 23-Aug-2014.  

‘Amended’ refers to the content of the protocol as updated in Amendment 02.  

Text deleted from the original protocol is presented as a strikethrough font and 
underlining to identify Amended text.

The location of the changes in the text of the protocol is identified by section number 
and title, followed by paragraph and sentence number if required.  
List of Specific Changes
Title Page
Added:
 
 
Sponsor Signatory
Original text:
,MD
Tykerb/Tyverb 
Amended text:
 ,DO, 
Sponsor Information page  
Original text:
Sponsor Medical Monitor Contact Information
, MD
Tykerb/Tyverb 
GlaxoSmithKline SA 
C/ Severo Ochoa, 2
28760
Tres Cantos, 


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Madrid
Spain
Office:
Mobile:
Fax:
e mail:
 
Sponsor Secondary Medical Monitor Contact Information: 
, MD
Tykerb/Tyverb 
GlaxoSmithKline 
Office:
Mobile:
e mail:
Amended text:
Sponsor Medical Monitor Contact Information
, MD
Novartis Farmaceutica S. A., Madrid Site 
Office:
Mobile:
e mail:
Sponsor Secondary Medical Monitor Contact Information: 
, MD
Novartis Farma S. p. A.
Office:
Mobile:
e mail:


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Added:
Sponsor Tertiary Medical Monitor Contact Information: 
Novartis Pharmaceuticals
Office: 
Mobile: 
Email:
Protocol Summary, Study Assessments
Added, last paragraph :
An interim analysis is planned when approximately 40% of the patients have been 
recruited and when those subjects have received 3 cycles of study treatment (lapatinib 
plus capecitabine), i.e. after 9 weeks of study treatment.   The first safety review will take 
place at the same time as the interim analysis.
Section 3 Investigational Plan
Section 3.1 Study Design
Original text, last paragraph, Sentence 2:
A formal review of safety data will be conducted after the first 50 subjects 
(approximately 25 in each treatment arm) have received at least 9 weeks of treatment 
with lapatinib and capecitabine; subsequent reviews will be conducted at least every 12 
weeks, or more frequently if required.
Amended text, last paragraph, Sentence 2:
A formal review of safety data will be conducted after the first 60 subjects 
(approximately 30 in each treatment arm) have received at least 9 weeks of treatment 
with lapatinib and capecitabine; subsequent reviews will be conducted at least every 12 
weeks, or more frequently if required.


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Added:
Section 3.3 Recruitment Plan
The interim analysis will be triggered when approximately 40% (n=60) of the subjects 
that have completed 3 cycles of study treatment.  In order to protect subjects from 
unnecessary exposure to octreotide, once 60 patients have been enrolled, recruitment will 
be temporarily halted to minimise potentially unnecessary further subjects being enrolled, 
whilst review of the interim analysis is being conducted.  Therefore, once 60 patients 
have been recruited, investigator sites will receive communication from the sponsor to 
suspend any further recruitment and screening activities until the outcome of the interim 
analysis has been communicated to investigator sites.  Subjects that are in screening 
during this period will still be considered for randomisation into the study.
Section 5.6 Blinding
Added, Paragraph 2:
To preserve the integrity of the study at the interim analysis (Section 9.3.4), the treatment 
assignment will be obtained by an independent statistician, (who has access to the 
randomisation system RandAll NG), and provided to an external statistics group (to be 
appointed) to allow the required pre-defined analyses and data summaries to be produced.   
These analyses and data tables will be clearly documented in the Reporting Analysis plan. 
These data tables will then be provided to the independent review committee for their 
review. The results of the interim analyses will only be known by the independent review 
committee and not disclosed to the study team.   There will be a secure firewall put in 
place to ensure that the study team remain blinded to the interim data and results.   The 
recommendation from the independent review committee will be communicated to the 
study team and, in the event of a recommendation to halt the trial early, also to the 
appropriate regulatory agencies.  If the independent review committee recommends the 
study continue, the study team will continue to remain blinded to interim results and 
treatment assignments until final analysis.
Section 9.3.4 Interim Analysis
Original text:
No interim efficacy analyses are planned for this study.
The GSK Safety Review Team (SRT) will review safety data on an ongoing basis.  The 
first formal review of safety data will be conducted after the first 50 subjects have 
received at least 9 weeks of treatment with lapatinib and capecitabine.  Subsequent 
formal review will be conducted at least every 12 weeks, or more frequently if required.  
There are no formal stopping criteria for this study, and in the absence of significant 
unexpected safety findings the SRT review of the study data should have no effect on 
study conduct or data integrity. 


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Amended text:
An interim analysis will be conducted to assess the futility of octreotide in relation to 
reducing the incidence of Grade 2 diarrhoea after 9 weeks of treatment. This analysis will 
take place when at least 60 subjects have been randomised to treatment and completed 
their 9 week assessment. At this analysis a review of both the accumulating safety and 
efficacy data will be conducted by an independent review committee to assure the safety 
of the patients in the trial and to provide an opportunity to terminate the study if:-

There is overwhelming clinical evidence of a negative imbalance in the safety
profile of either treatment group

There is not sufficient evidence of an effect of efficacy in the reduction of Grade 
2 diarrhoea as described by the stopping rules in section 9.3.4.2.
The independent review committee will review the accumulating safety data and also the 
analysis of the primary endpoint, the incidence of Grade 2 diarrhoea. There will be full 
treatment disclosure at the interim analysis to the Senior Management team, but the study 
team will remain blinded to treatment assignment and the results of the interim analysis.
Section 9.3.4.1 Interim Review of Safety Profile
The data to be reviewed by the independent review committee will be the accumulated 
safety and diarrhoea response data.   These safety data will include, at minimum, all AEs, 
SAEs and any deaths. The safety review committee will evaluate these data and make a 
clinical judgement as whether the study can progress as planned based on the welfare of 
the subjects. At least one interim review of this safety data will occur.
Section 9.3.4.2 Futility Analysis of Primary Endpoint
A futility analysis of the incidence of Grade 2 diarrhoea, the primary endpoint, 
comparing this incidence between the group of subjects who receive lapatinib and 
capecitabine to the group of subjects who receive no prophylactic octreotide will be 
performed. This will take place at a single interim analysis after approximately 40% of 
subjects (60 subjects) have had at least 9 weeks of study treatment.   
Early termination of the study will be considered by the independent review committee.   
Their recommendation will be based on the following points:-

Whether it would be possible to draw any meaningful conclusions if the study 
were to continue to planned completion given the:-
o
The clinical relevance of the observed incidence of Grade 2 diarrhoea. 
o
The conditional power based on data from approximately 40% of the 
patients   
o
The totality of the evidence observed.
For example:


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
If the diarrhoea rate is 30% in the control arm, in order for the conditional power 
(under the current trend) to be around 50% to see a positive result at the end of the 
trial, we would need to see a diarrhoea rate of 16% or lower in the octreotide arm. 
(Equating to a difference in 14% in incidence between treatment arms)

If the diarrhoea rate is 20% in the control arm, in order for the conditional power 
(under the current trend) to be around 70% to see a positive result at the end of the 
trial, we would need to see a diarrhoea rate of 6% or lower in the octreotide arm. 
(Equating to a difference of 14% in incidence between treatment arms)
The conditional power will need to be re-calculated based on the actual incidence and 
actual percentage of patients evaluated at the time of the interim analyses.  
It is envisaged that if at least a modest improvement in the diarrhoea rate in the octreotide 
arm is not seen with a conditional power of at least 50% at the interim analysis, it is 
unlikely that the trial would justify octreotide use in clinical practice. Further confidence 
intervals around the estimate of the observed difference in incidence of Grade 3 diarrhoea 
will be provided to aid clinical judgement.
Section 10.8 Safety Review Team
Original text, paragraph 2, Sentence 2:
The first formal review of safety data will be conducted after the first 50 subjects have 
received at least 9 weeks of treatment with lapatinib and capecitabine.
Amended text, paragraph 2, Sentence 2:
The first formal review of safety data will be conducted after the first 60 subjects have 
received at least 9 weeks of treatment with lapatinib and capecitabine.
Section 12.5 Appendix 5 Country Specific Requirements
Original text: 
This blank appendix is handled modularly by each participating CMD and serves as a
place holder for CMD to add standard text authorized for that country prior to distribution 
within that country.  If standard authorized text for that country does not exist, then use 
the following wording:  
Section 12.8 Appendix 8 Protocol Changes
Added, paragraph 1 and paragraph 2:
Amendment 1 
Protocol Amendment 01 applies to all site(s) participating in the conduct of the study
End of Amendment 02 record of changes.

SAP_001.pdf: 
Clinical Development
LAP016A/ Lapatinib/Tykerb
Clinical Trial Protocol CLAP016A2410 / NCT02294786
A Randomised, Multicentre, Open Label, Phase II study 
of Prophylactic Octreotide to Prevent or Reduce the 
Frequency and Severity of Diarrhoea in Subjects 
Receiving Lapatinib with Capecitabine for the Treatment 
of Metastatic Breast Cancer
Statistical Analysis Plan (SAP)
Author:
 Trial Statistician
Document type:
SAP Documentation
Document status:
Final 1.0
Release date:
28-Nov-2017
Number of pages:
41
Property of Novartis
Confidential
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)
28-
Nov-
2017
First Final 
version
NA
NA


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Table of contents
Table of contents...................................................................................................3
List of abbreviations .............................................................................................5
1.
Introduction...........................................................................................................6
1.1
Study design..............................................................................................6
Table 1-3 Objectives and endpoints........................................................10
2
Statistical methods..............................................................................................12
2.1
Data analysis general information...........................................................12
2.1.1
Data included in the analysis..................................................12
2.1.2
General analysis conventions .................................................13
2.1.3
General definitions .................................................................13
2.2
Analysis Populations...............................................................................17
2.3
Patient disposition, demographics and other baseline characteristics.....18
2.3.1
Patient disposition ..................................................................18
2.3.2
Protocol deviations.................................................................19
2.3.3
Basic demographic and background data...............................19
2.3.4
Disease history and medical history.......................................20
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance).............................................................................................20
2.4.1
Study treatment and compliance ............................................20
2.4.2
Concomitant medications.......................................................20
2.5
Analysis of the primary objective...........................................................21
2.5.1
Primary endpoint ....................................................................21
2.5.2
Statistical hypothesis, model, and method of analysis ...........21
2.5.3
Handling of missing values/censoring/discontinuations ........22
2.5.4
Supportive analyse..................................................................22
2.5.5
Subgroup analyses for the primary endpoint..........................22
2.6
Analysis of the secondary objective........................................................22
2.6.1
Investigator-reported endpoints..............................................22
2.6.2
Patient-reported outcomes......................................................24
2.7
Safety analyses........................................................................................24
2.7.1
Extent of Exposure .................................................................24
2.7.2
Adverse events (AEs).............................................................25
2.7.3
Adverse Events of Special Interest.........................................26
2.7.4
Deaths and Serious Adverse Events.......................................26
2.7.5
Adverse Events Leading to Discontinuation of Study 
Treatment and/or Withdrawal from the Study........................27
2.7.6
Clinical Trial Safety Disclosure .............................................27


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2.7.7
Pregnancies.............................................................................27
2.7.8
Clinical Laboratory Evaluations.............................................28
2.7.9
Other Safety Measures ...........................................................30
2.8
Health outcomes analyses.......................................................................32
2.8.1
Health Outcomes Assessments...............................................32
2.9
Interim analysis.......................................................................................33
3
Sample size calculation.......................................................................................33
3.1
Sample size assumptions.........................................................................33
3.2
Sample Size Sensitivity...........................................................................33
3.3
Sample Size Re-estimation .....................................................................34
4
Change to protocol specified analyses................................................................34
5
Appendix.............................................................................................................34
5.1
Imputation rules ......................................................................................34
5.1.1
AE date imputation.................................................................35
5.1.2
Concomitant medication and blood and blood supportive care 
products ..................................................................................36
5.1.3
Other imputations...................................................................38
5.2
AEs coding/grading.................................................................................38
5.3
Statistical models ....................................................................................39
5.3.1
Analysis of binary data...........................................................39
5.3.2
Analysis of time to events data...............................................40
6
Reference ............................................................................................................40


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee 
DMD
Diarrhoea Management Diary
eCRF
Electronic Case Report Form
FACIT-D
Functional Assessement of Chronic Illness therapy-Diarrhoea
FACT-G
Functional Assessment of Cancer Therapy-General
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
PRO
Patient-reported Outcomes
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP
Statistical Analysis Plan
SOC
System Organ Class


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1. Introduction
This statistical analysis plan (SAP) describes analyses required for a Clinical Study Report 
(CSR) to support a publication of study LAP016A2410, a randomised, multicentre, open 
label, phase II study of Prophylactic Octreotide to prevent or reduce the frequency and 
severity of diarrhoea in subjects receiving Lapatinib with Capecitabine for the treatment of 
metastatic breast cancer. This is a phase II study to evaluate the efficacy, safety 
 
 of prophylactic octreotide compared to no octreotide using a 
parallel group, open label, randomised study design.
As first interim analysis results showed study is futile and no patients will be recruted in 
the study. For final analysis abbreviated CSR will be done and it will include reduced 
analyses as compared to planned analyses in the protocol.  
As planned in the protocol an interim analysis was performed after 62 patients enrolled 
using a cut-off date (30-Mar-2016) and an interim database lock on 16-Aug-2016. As the 
interim analysis results showed study was futile the DMC recommended to stop the study. 
Per protocol no further patients were enrolled in the study per IA cut-off. 
For final analysis an abbreviated CSR will be done and it will include reduced analyses as 
compared to planned analyses in the protocol.  
The content of this SAP is based on protocol CLAP016A2410 Amendment 02 dated 11 
September 2015 (2012N152651_03). 
The SAP was written by Novartis Statistician. The execution of the SAP will be undertaken 
by staff of 
and the GSK layout standard will be used to generate all tables, 
figures, and listings.
All decisions regarding final analysis, as defined in the SAP document, have been made 
prior to database lock of the study data.
1.1
Study design
This is a randomised, parallel group, multi-centre, open-label Phase II study in subjects 
with HER2-positive metastatic breast cancer which has progressed following prior therapy, 
which must have included anthracyclines and taxanes and therapy with trastuzumab in the 
metastatic setting.  This study is not placebo controlled, and there is no active comparator.
Subjects must be screened for eligibility and informed consent must be given before any 
study-related procedures are conducted.  
All subjects will receive treatment with lapatinib 1250mg once daily and capecitabine 
1000mg/m2 twice daily until disease progression. Lapatinib will be given every day; 
capecitabine will be given in 3 week cycles of two weeks treatment followed by one week 
off treatment. All subjects with episodes of diarrhoea will be encouraged to follow the 
diarrhoea management guidelines for subjects receiving lapatinib. One cycle of lapatinib 
and capecitabine equates to three study weeks.  
Subjects will be randomised in a 1:1 ratio to receive either: 

Octreotide (Sandostatin long acting release (LAR)) 40mg 7 days before the start of 
treatment with lapatinib and capecitabine and again 28 days later, or


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
No octreotide treatment.
For subjects randomised to receive octreotide, treatment with lapatinib and capecitabine 
will be initiated 7 days after the first dose of octreotide given as the LAR formulation.  For 
subjects randomised to receive no octreotide, treatment with lapatinib and capecitabine will 
be initiated immediately following enrolment.  
Subjects randomised to receive octreotide LAR must be given one 0.1mg dose of the 
standard formulation of octreotide subcutaneous (s.c.) to assess tolerability at least one 
hour before the first dose of the LAR formulation is administered. Subjects with significant 
intolerance to octreotide 0.1mg s.c. will not receive treatment with octreotide LAR, but 
will receive treatment with lapatinib and capecitabine as scheduled.  
Study completion will be at the end of 24 weeks treatment with lapatinib and capecitabine, 
or disease progression, unacceptable toxicity or subject withdrawal if this is sooner.  SAEs 
and other safety data will be reported beyond 24 weeks in subjects who continue treatment 
with lapatinib and capecitabine until disease progression in countries where the Sponsor is 
supplying lapatinib and capecitabine. SAEs will be followed up until resolution or 
stabilization of the event or until the subject is lost to follow-up.  
The efficacy of prophylactic octreotide in reducing the frequency and severity of diarrhoea 
is the primary endpoint of this study. Each episode of diarrhoea will be recorded by the 
investigator as an AE in the eCRF in accordance with the standard AE reporting procedure.  
Actions associated with the management of diarrhoea (use of anti-diarrhoeal medication, 
unscheduled visits to healthcare professionals, treatment interruption, rehydration) will be 
recorded in the eCRF.  
Subjects will complete the DMD and the FACIT-D to provide an additional perspective 
on the effects of treatment-associated diarrhoea.
Diarrhoea, nausea and vomiting, dermatological events, hepatobiliary, cardiovascular and 
respiratory events have been identified as events of special interest relating to lapatinib.  
Hand and foot syndrome has been identified as an event of special interest relating to 
capecitabine.  There are no events of special interest relating to octreotide.
The schedule of all assessments is presented in Table 1-1 for subjects who receive 
octreotide and Table 1-2 for subjects who do not receive octreotide.  
Table 1-1
Time and events schedule; Subjects who receive octreotide.
Screen1
Octreotide 
Dose 1
Lapatinib and Capecitabine Cycle9,10
Withdrawal 
from Study 
Treatment or 
End of Study14
Cycle 1
Cycle 2
(Octreotide 
Dose 2)
Cycles 
3 to 8
Procedures
Informed Consent
X
Inclusion/Exclusion 
Criteria
x2
x2
Demographics
X
Breast Cancer 
Medical/Surgical and
Treatment History
X
Efficacy and Safety Assessments


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AE/Toxicity Assessment
x
x
x
x
x15
Disease Assessment
x3
(x)5
(x)5
(x)5
(x)5
x
PROs6
x7
x11
x
x
x
Concurrent Medications
X
x
x
x
x
x
Physical Exam
X
x
Weight, Height, Vital 
Signs (Temp, BP, pulse)
X
x
ECOG Performance 
Status
x4
x
Cardiac function
X
x16
ECG
X
(x)17
Lab Assessments
Liver function
X
(x)5
(x)5
(x)5
(x)5
x
Pregnancy Test
X
x
Study Treatments
Administer Octreotide
x8
x13
Dispense Lapatinib and 
Capecitabine
x
x
x
Assess Lapatinib and 
Capecitabine Returned
x
x
x
1.
Schedules for screening assessments are presented in Section [7.1.1] and Section [7.1.2] of the Study 
Protocol.  All screening and baseline assessments must be completed prior to administration of the octreotide 
0.1mg s.c. tolerability assessment dose.
2.
Inclusion and exclusion criteria are presented in Section [4.1.2] and Section [4.1.3] of the Study Protocol, and 
other considerations are presented in Section [4.2] of the Study Protocol.  Investigators must ensure all 
subjects are eligible to receive treatment with lapatinib and capecitabine in accordance with the Lapatinib SPC 
and Capecitabine SPC, including evaluation of cardiac function.
3.
Disease assessment criteria are described in Section [7.1.11] of the Study Protocol.
4.
ECOG status may be assessed more than once prior to randomisation, but only the assessment within 3 days 
prior to randomisation will be recorded in the eCRF.
5.
Not mandatory at these visits, but should be conducted in accordance with local clinical practice, at the time of 
a scheduled 3 weekly visits when possible.
6.
PROs are the FACIT-D and the diarrhoea diary.
7.
To be completed before the octreotide 0.1mg s.c. tolerability assessment dose. 
8.
First dose of octreotide LAR to be given 7 days before start of Cycle 1 treatment with lapatinib and 
capecitabine.  Subjects must receive octreotide 0.1mg s.c. at least one hour before the first dose of octreotide 
LAR to assess tolerability.
9.
Cycle 2 and Cycle 4 visits are mandatory. Cycle 3, 5, 6, 7 and 8 visits are not mandatory; visits every 3 
weeks would be preferred, but may be adapted to match local practice. 
10. Cycle 2 to be started 21 days (2 days) after the start of Cycle 1.  Other cycles should be started within +/- 4 
days of the 3 weekly treatment cycle intervals.
11. To be completed before the first dose of lapatinib and capecitabine is administered.
 
 
13. Second dose of octreotide LAR to be given 28 days (+/- 2 days) after first dose of octreotide LAR.
14. After 24 weeks treatment with lapatinib and capecitabine.  Investigators should continue to treat subjects with 
lapatinib and capecitabine beyond 24 weeks in accordance with local clinical practice. 
15. Serious adverse events and other safety data as described in Section [7.4 ] of the Study Protocol should be 
reported for all subjects who continue treatment with lapatinib and capecitabine beyond the 24 week end of 
study assessment.
16. If more than 12 weeks since the screening cardiac function assessment.


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17. If clinically indicated.
Table 1-2
Time and events schedule; Subjects who receive no octreotide
Screen1
Lapatinib and Capecitabine Cycle9,10
Withdrawal from 
Study Treatment or 
End of Study Visit11
1
2 to 8
Procedures
Informed Consent
x
Inclusion/Exclusion Criteria
x2
x
Demographics
x
Medical/Surgical and 
Treatment History
x
Efficacy and Safety Assessments
AE/Toxicity Assessment
x
x
x12
Disease Assessment
x3
(x)5
(x)5
x
PROs6
x7
x
x
Concurrent Medications
x
x
x
x
Physical Exam
x
x
Weight, Height, Vital Signs 
(Temp, BP, pulse)
x
x
ECOG Performance Status
x4
x
Cardiac function
x
x13
ECG
x
(x)14
Lab Assessments
Liver function
x
(x)5
(x)5
x
Pregnancy Test
x
x
Study Treatments
Dispense Lapatinib and 
Capecitabine
x
x
Assess Lapatinib and 
Capecitabine Returned
x
x
1.
Schedules for screening assessments are presented in Section [7.1.1] and Section [7.1.2] of the Study Protocol.  
All screening and baseline assessments must be completed prior to the start of Cycle 1 of treatment with lapatinib 
and capecitabine.
2.
Inclusion and exclusion criteria are presented in Section [4.1.2] and Section [4.1.3] of the Study Protocol, and 
other considerations are presented in Section [4.2] of the Study Protocol.  Investigators must ensure all subjects 
are eligible to receive treatment with lapatinib and capecitabine in accordance with the Lapatinib SPC and 
Capecitabine SPC, including evaluation of cardiac function.
3.
Disease assessment criteria are described in Section [7.1.11] of the Study Protocol. 
4.
ECOG status may be assessed more than once prior to randomisation, but only the assessment within 3 days 
prior to randomisation will be recorded in the eCRF.
5.
Not mandatory at these visits, but should be conducted in accordance with local clinical practice, at the time of a 
scheduled 3 weekly visits when possible.
6.
PROs are the FACIT-D and the diarrhoea diary. 
7.
To be completed before the first dose of lapatinib and capecitabine is administered.
8.
 
 
9.
Cycle 2 to be started 21 days (+/- 2 days) after the start of Cycle 1.  Other cycles should be started within +/- 4 
days of the 3 weekly treatment cycle intervals.
10. Cycle 2 and Cycle 4 visits are mandatory. Cycle 3, 5, 6, 7 and 8 visits are not mandatory; visits every 3 weeks 
would be preferred, but may be adapted to match local practice.


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Screen1
Lapatinib and Capecitabine Cycle9,10
Withdrawal from 
Study Treatment or 
End of Study Visit11
1
2 to 8
11. After 24 weeks treatment with lapatinib and capecitabine.  Investigators should continue to treat subjects with 
lapatinib and capecitabine beyond 24 weeks in accordance with local clinical practice. 
12. Serious adverse events and other safety data as described in Section [7.4 ] of the Study Protocol should be 
reported for all subjects who continue treatment with lapatinib and capecitabine beyond the 24 week end of study 
assessment.
13. If more than 12 weeks since the screening cardiac function assessment.
14. If clinically indicated.
One interim analysis was planned when at least 60 subjects have been randomised to 
treatment and completed their 9 week assessment or discontinued from study. The interim 
analysis allowed stopping the study early for lack of efficacy (futility) or safety. Table 1-3
described the objectives and endpoints for final analysis. Since study was futile based on 
the interim analysis results, team decided to create abbreviated CSR for final analysis and 
hence removed some of the endpoints from final analysis. 
The objectives and endpoints of the study are summarized in Table 1-3. 
Table 1-3
Objectives and endpoints
Objectives
Endpoints
Primary: Investigator reported
To determine the efficacy of prophylactic 
octreotide in reducing the proportion of 
subjects experiencing diarrhoea with a 
severity of National Cancer Institute 
Common Terminology Criteria for Adverse 
Events (NCI-CTCAE) Grade 2 and above.
Proportion of subjects experiencing 
diarrhoea with a severity of Grade 2 
and above, as defined by the NCI-
CTCAE, version 4.03.


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Secondary: Investigator reported
To determine the efficacy of prophylactic 
octreotide in reducing the proportion of 
subjects experiencing diarrhoea with a 
severity of NCI-CTCAE Grade 3 and above. 
To determine the efficacy of prophylactic 
octreotide in reducing the proportion of 
subjects experiencing diarrhoea of any grade 
of severity.
To determine the efficacy of prophylactic 
octreotide in increasing the time to onset of 
the first episode of diarrhoea of any grade of 
severity.
Proportion of subjects experiencing 
diarrhoea with a severity of Grade 3 
and above, as defined by the NCI-
CTCAE, version 4.03, recorded as 
adverse events (AEs) in the electronic 
Case Report Form (eCRF).
Proportion of subjects experiencing 
diarrhoea of any grade of severity as 
defined by the NCI-CTCAE, version 
4.03, recorded as AEs in the eCRF.
Time to onset of the first episode of 
diarrhoea of any grade of severity, 
recorded as an AE in the eCRF.


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Objectives
Endpoints
Secondary: Investigator reported
To determine the effect of prophylactic 
octreotide on compliance with lapatinib and 
capecitabine treatment.
To determine the effect of prophylactic 
octreotide on the efficacy of treatment with 
lapatinib and capecitabine.
To determine the effect of prophylactic 
octreotide on the safety and tolerability of 
cancer treatment.
Number of lapatinib and capecitabine
tablets dispensed and returned, recorded 
in the eCRF.
Overall response rate and clinical benefit 
response measured in accordance with 
the Response Evaluation Criteria In Solid 
Tumours (RECIST) version 1.1.
Proportion of subjects with AEs and 
SAEs, recorded in the eCRF.
Secondary: Patient reported Diarrhoea Management Diary (DMD)
To determine the effect of prophylactic 
octreotide on patient reported diarrhoea.
Patients reporting changes in bowel 
movements from baseline (frequency 
and/or consistency), recorded in the 
DMD.
Quality of Life – FACIT-D
To determine the effect of prophylactic 
octreotide on health-related quality of life.
Trial Outcomes Index will be the primary 
measure; the sub-scales, Total FACT-G 
score and Total FACIT-D score will be 
secondary measures.
2
Statistical methods
2.1
Data analysis general information
Data will be listed and summarized according to GSK Integrated Data Standards Library (IDSL) 
reporting standards. Formatting for dates, times, and decimal places will follow GSK standards 
except where specified.
The final analyses will be performed by 
 The currently supported version of 
Statistical Analysis System (SAS®) will be used to perform all data analyses, and generate tables, 
figures, and listings. 
2.1.1 Data included in the analysis
All data up to the time of study completion (i.e. 24 weeks of lapatinib and capecitabine treatment) 
or withdrawal from the study will be included in the final analysis, regardless of duration of 
treatment.
All data with an assessment date or event start date (e.g. vital sign assessment date or start date 
of an adverse event) prior to or on the cut-off date will be included in the analysis. Any data 


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collected beyond the cut-off date will not be included in the analysis and will not be used for
any derivations. For the final analysis the database lock date will be used as cut-off date.
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘continuing at the cut-off date’. The same rule will be applied to events starting 
before or on the cut-off date and not having documented end date. This approach applies, in 
particular, to adverse event and concomitant medication reports. For these events, the end date 
will not be imputed and therefore will not appear in the listings.
2.1.2 General analysis conventions
Unless specified otherwise, categorical data (e.g., gender, race, etc.) will be summarized by 
means of contingency tables by treatment group; a missing category will be included as 
applicable. Percentages will be calculated using the number of subjects in the relevant 
population as the denominator. Continuous data (e.g., age, body weight, etc.) will be 
summarized by appropriate descriptive statistics (i.e. mean, standard deviation, minimum, 
median, and maximum) by treatment group.
Unless specified otherwise, all listings will be sorted by treatment group, center, subject number, 
and then by visit date and time, if applicable. Only visits at Cycle 2 and 4 are mandated, other 
visits are as per clinical practice.  All available data will be included in listings, including data 
from unscheduled visits.
All laboratory data will be presented in GSK’s standard units for reporting.
Planned (nominal) assessment times relative to study drug dosing will be used in all summaries 
and analyses.
Assessment windows will not be defined for the purpose of classifying measurements obtained 
outside scheduled assessment times.
Note: although octreotide is administered twice, once 7 days before the first cycle of lapatinib 
and capecitabine and then 28 days later, assessments will be entered as cycles to correspond to 
the lapatinb plus capecitabine assessments. For this purpose a cycle corresponds to 3 weeks of 
lapatinib and capecitabine.
Deviations from the analyses in the SAP will be identified in the CSR.
2.1.3 General definitions
2.1.3.1 Investigational drug and study treatment
Investigational drug, will refer to the Octreotide only. Whereas, study treatment will refer to 
Octreotide + Lapatinib + Capecitabine and Lapatinib + Capecitabine. 
The following treatment descriptors will be used on all applicable displays:
Table 2-1
Treatment descriptors of investigational drug
Treatment Group Description
Data Display
Order of Treatment 
Groups
Octreotide+Lapatinib+Capecitabine
Octreotide+Lap+Cap
1


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Lapatinib+ Capecitabine
Lap+Cap 
2
2.1.3.2 Reference start date
There are three reference start dates:

Age is an eligibility requirement and therefore the reference start date for age is the date of 
screening.

The safety reference start date is the date of a subject receiving the first dose of study 
treatment (i.e., octreotide, lapatinib or capecitabine).

The efficacy reference start date is the date of randomization and will be used to calculate 
study day for efficacy measures and baseline characteristics.
The reference start date for all other, non-safety assessments (i.e., tumor assessment, death, 
disease progression, tumor response, ECOG performance status, and patient reported outcomes 
(PRO)) is the date of randomization. 
2.1.3.3 Date of first/last administration of study drug/study treatment

Date of first administration of study drug
The date of first administration of investigational drug is defined as the first date when a nonzero 
dose of investigational drug is administered and recorded on the Dosage Administration Record 
(DAR) (e)CRF. The date of first administration of study drug will also be referred as start of 
investigational drug.

Date of last administration of study drug
The date of last administration of investigational drug is defined as is the last date when a 
nonzero dose of investigational drug is administered and recorded on DAR eCRF. The date of 
last administration of investigational drug will also be referred as end of investigational drug.

Date of first administration of study treatment 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment was administered as per the Dosage Administration 
(e)CRF. (Example: if 1st dose of Octreotide is administered on 05-Jan-2015, and 1st dose of 
combination partner is administered on 03-Jan-2015, then the date of first administration of 
study treatment is on 03-Jan-2015).

Date of last administration of study treatment 
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment was administered as per Dose Administration 
(e)CRF. (Example: if the last Octreotide dose is administered on 15-Apr-2014, and the last 
dose of a combination partner is administered on 17-May-2014, then the date of last 
administration of study treatment is on 17-May-2014).
2.1.3.4 Study day
The study day, describes the day of the event or assessment date, relative to the reference start
date. There is no study day 0.


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The study day is defined as:

The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − reference 
start date if event precedes the reference start date.
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.
2.1.3.5 Duration/Elapsed Time/Time unit
Durations (e.g., the duration of an adverse event, duration of exposure, duration of episodes of 
diarrhoea) are calculated as the stop date minus the start date +1.   
For elapsed time (e.g., the time since initial diagnosis):

If the reference start date is on or after the event date, then the elapsed time is the reference
start date minus the event date + 1.

If the reference start date is before the event date then the elapsed time is the reference start 
date minus the event date.
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375. If duration is  reported in 
years, duration in days will be divided by 365.25.
2.1.3.6 Baseline
Baseline is defined as the most recent, non-missing value prior to receiving the first dose of 
study treatment (octreotide, lapatinib or capecitabine).   
For subjects who did not receive any study treatment (i.e. octreotide, lapatinib or capecitabine) 
during the study, baseline will be defined as the latest, non-missing collected value.
If patients have no value as defined above, the baseline result will be missing.
2.1.3.7 Change from baseline
Change from baseline will be presented for safety data as described in the relevant sections. 
Change from baseline is calculated as:

visit value - baseline value, if records occurr after baseline, or

missing, if either the baseline or visit value is missing.
2.1.3.8 Multiple assessments 
All data will be analysed according to the nominal visit date for which it was reported (that is, 
no visit windows will be applied during dataset creation). Unscheduled data will only be 
included in the display sections that report worst-case post-baseline. 


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If multiple assessments on different days are reported for the same scheduled assessment, then 
the latest assessment for that scheduled assessment will be analysed.
If multiple assessments are reported on the same date for the same scheduled planned time, then 
the mean of the multiple measurements reported for the same date will be analysed. For example, 
for ECG data where 3 assessments are collected for each scheduled planned time, the first 3 
measures will be used to compute the mean values for ECG intervals at each scheduled planned 
time.
Data from all assessments (scheduled and unscheduled), including multiple assessments, will 
be included in listings.
2.1.3.9 Last contact date 
The last contact date will be derived for subjects not known to have died at the analysis cut-off 
using the last complete date among the following:

“When was subject last seen or heard alive?” collected on the ‘DEATH’ eCRF.

All assessment dates (e.g.  tumor  assessment,  laboratory collection  dates,  vital signs 
assessment, performance status/PRO assessment, ECG assessment). Note, only a true 
on study assessment date or patient contact date will be used. If there is a visit date 
without evidence of any actual assessment performed that date will not be used. 

Medication dates including study medications, concomitant medications, and anti-
neoplastic therapies administered after study treatment discontinuation (with non-
missing medication/procedure term).

Adverse event dates (with non-missing verbatim AE term present).

Randomization date.

Date of subject discontinuation from ‘Conclusion Details’ eCRF.
The last contact date is defined as the latest complete date from the above list or the cut-off date 
whichever comes first. The cut-off date will not be used for last contact date, unless the patient 
was seen or contacted on that date. No date post cut-off date will be used. Completely imputed 
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date 
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring is coming from ‘Death’ eCRF. 
The last contact date will be used for censoring of subjects in the analysis of overall survival.
2.1.3.10
On-treatment assessment/event
All on-treatment assessments/events are any assessments/events obtained in the time interval:
[date of first administration of study treatment, date of last administration of study 
treatment +28 days], i.e., inclusive lower and upper limit.
2.1.3.11
Study Time Periods for Concomitant Medications and Blood and 
Blood Supportive Care Products
Concomitant Medication and Blood and Blood Supportive Care Product start and end dates 
will be assigned to study time periods in relation to first dose of study treatment (octreotide, 
lapatinib or capecitabine as applicable).  The start date reference time flag variables and end 


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date reference time flag variables will be added to the concomitant medications and blood and 
blood supportive products datasets, respectively.

Start relative to treatment: Assign to 'BEFORE' if start date is prior to first dose of 
study treatment start date, if subject has not taken any study treatment, or start date is 
missing and end date is before study treatment start date. Else assign to 'DURING' if the 
start date falls into the on-therapy period (defined as the time from first dose of study 
treatment to the last dose date of study treatment) or if subject is ongoing (not all study 
treatment discontinuation records completed) or start date is missing. Else assign to 
'AFTER' if start date is after the on-therapy period.

End relative to treatment: Assign to 'BEFORE' if end date is prior to study treatment 
start date or if subject has not taken any study treatment. Else assign to 'DURING' if start 
date falls into the on-therapy period or if subject is ongoing (not all study treatment 
discontinuation records completed) or end date is missing and start relative to treatment 
not 'AFTER'. Else assign to 'AFTER' if start date is after the on-therapy period or end 
date is missing and start relative to treatment='AFTER'.
Only on-therapy blood and blood supportive care products that start after the start of study 
treatment are included in the Blood Products and Blood Supportive Care Product summaries. 
Therefore, for summary tables, include blood and blood supportive care product records where 
start relative to treatment in ('DURING') and end relative to treatment in ('DURING','AFTER'). 
All data will be reported in listings. 
Concomitant medication start relative to treatment and end relative to treatment flags are used 
to select data to include in the Concomitant Medication summaries as follows:

Summary of Concomitant Medications: This summary will contain medications including 
those with start date prior to study treatment start date and which continue (missing end 
date or end date after study treatment start date) on therapy. Note that any medications 
with start date and end date prior to study treatment start date will be excluded. In 
addition, any medication that was started during post-therapy will be excluded. Include 
concomitant medication records where start relative to treatment in 
('BEFORE','DURING') and end relative to treatment in ('DURING','AFTER').
2.2
Analysis Populations
Intent-to-Treat Population
The Intent-to-Treat (ITT) population will comprise all randomised subjects regardless of 
whether or not treatment was administered. This population will be based on the treatment to 
which the subject was randomised. Any subject who receives a treatment randomization number 
will be considered to have been randomised. The primary analysis of disease efficacy and all 
diarrhoea-related efficacy endpoints will be analysed using the ITT population.
Modified ITT
The modified ITT (m-ITT) population will comprise all subjects in the ITT population and 
under Octreotide arm this population will include subjects who do not show intolerance to 
octreotide in the s.c. formulation and who do not have non treatment related diarrhoea recorded 


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as an AE after the first dose of octreotide LAR and prior to the start of treatment with lapatinib 
and capecitabine. A sensitivity analysis of diarrhoea-related primary efficacy endpoint will be 
conducted using the m-ITT population. 
Per Protocol Population
The Per-Protocol (PP) population will comprise all randomised subjects who receive at least 
one dose of study treatment and who comply closely with the protocol (that is subjects who are 
not excluded from PP set as per PDMP). The PP population will not be analysed if this 
population comprises more than 95% or less than 50% of the ITT population. The analysis of 
primary efficacy endpoint will be repeated using the PP population.  
Subjects with potential PDs will be excluded from PP population based on Protocol Deviation 
Management Plan (PDMP).
Safety Population
The Safety population will comprise all randomised subjects who receive at least one dose of 
study treatment and will be based on the actual treatment received if this differs from that to 
which the subject was randomised. This population will be used for the analysis of clinical 
safety data. Moreover, if a subject who was randomised to Octreotide arm, showed intolerance 
to octreotide in the s.c. formulation, and took at least one dose of lapatinib or capecitabine, then 
subject will be included in no Octreotide arm for safety analysis.
2.3
Patient disposition, demographics and other baseline 
characteristics
The Intent-to-Treat (ITT) population will be used for all baseline and demographic summaries 
and listings unless otherwise specified. Summaries will be reported by treatment group labeled
as specified in Table 2-1 and for all subjects and listings will be reported by treatment group to 
assess baseline comparability.  No inferential statistics will be provided.
2.3.1 Patient disposition
A summary of the number of subjects in each of the analysis populations described in Section 
2.2 will be provided. A listing of analysis populations in which each subject will be included or 
excluded will be provided as well. 
A summary of study treatment status (octreotide, lapatinib and capecitabine) will be provided.
This display will show the number and percentage of subjects who completed all doses of 
Octreotide, completed 24 weeks of treatment with lapatinib and capecitabine and a summary of 
the primary reason for discontinuation of study treatment. Reasons for study treatment 
discontinuation will be presented in the order they are displayed in the eCRF.
A seperate table of a summary of study status will be provided with frequency and percenteges
for patients died and withdrawn from study will be provided. Reasons for withdrawal will be 
presented in the order they are displayed in the eCRF.
Listing of patient disposition will be provided including details on study treatment
discontiuation and study discontinuation.


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2.3.2 Protocol deviations
The number (%) of patients in the ITT population with any important protocol deviation will
be tabulated by deviation category, total, and by treatment group for the ITT population. All 
important protocol deviations will be listed and devaitions leading to exclusion from per
protocol population will be flagged in the listing. The important protocol deviation will be 
categorized as below as per GSK SOP:

those who entered the study even though they did not satisfy the entry criteria; 

those who developed withdrawal criteria during the study but were not withdrawn; 

those who received the wrong treatment or incorrect dose; 

those who received an excluded concomitant treatment 

Any study specific procedure or assessment deviation, which the study team determines 
may compromise subject rights, safety, or well being, or has a significant impact on 
study donclusions
Protocol deviations are listed / described in the Protocol Deviation Management Plan, (PDMP).
All protocol deviations will be summarized and listed. Protocol deviations will be classified by 
criteria - Deviations are/aren’t important or/and Deviations that do/don’t require exclusion from 
per-protocol population.
2.3.3 Basic demographic and background data
Demographics data and background data at baseline (including key efficacy variables) will be 
summarized by treatment for all Intent-to-Treat subjects (ITT).
Categorical variables will be summarized by frequency counts and percentages.
The category “Missing” will be displayed if data is missing 
Continuous variables will be summarized by n (number of subjects with a non-missing value), 
mean, standard deviation, minimum (Min.), median, and maximum (Max.).  
Demographics data summary includes the following variables:

(continuous)
Age (years) at Screening

(categorical)
Age group at Screening:
<18 years
                                     >= 18 years - <65 years
>= 65 years - <75 years
>=75 years

(categorical)
Sex

(categorical)
Ethnicity: 

(categorical)       Geographic Ancestry

(continuous)
Baseline Height (cm) at Screening

(continuous)
Baseline weight (kg) at Screening


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
(categorical)
Baseline ECOG performance status at Screening
A by-subject listing of all demographic characteristics will be produced.
2.3.4 Disease history and medical history
Cardiovascular medical history / risk factors assessed at screening, disease characteristic for the
primary tumor type under study at screening and biomarker assessment at screening will be
summarized and listed.
In addition, prior anti-cancer therapies are summarized.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1 Study treatment and compliance
A listing of percentage overall compliance for octreotide, lapatinib and capecitabine based on
the exposure data will be produced. Overall compliance (octreotide) is calculated as:  
Overall compliance (%) =
total cumulative actual dose
total cumulative planned dose × 100.
where total cumulative planned dose of octreotide will be 80mg if the subject is continuing in 
the study at the Cycle 2 visit or 40mg otherwise.
Overall compliance (lapatinib) is calculated as:
Overall compliance (%) =
total cumulative actual dose
total cumulative planned dose × 100.
where total cumulative actual (or planned) dose is the summation of all actual (or planned)
daily doses (mg) of lapatinib in the duration of lapatinib which is last dose date-first dose date
+1. 
Overall compliance (capecitabine) is calculated as:
Overall compliance (%) =
total cumulative actual dose
total cumulative planned dose × 100.
where total cumulative actual (or planned) dose is the summation of all actual (or planned)
daily doses (mg/m2) of capecitabine in the duration of lapatinib which is last dose date-first 
dose date +1. 
In addition, summaries of exposure to study medication (octreotide, lapatinib and capecitabine) 
and dose modifications (e.g., number of dose reductions, escalations, and interruptions) will 
further characterize compliance. These analyses are described in Section 2.7.1 ‘Extent of
Exposure’.
2.4.2 Concomitant medications
Concomitant medications will be coded using GSK Drug coding dictionary, summarized, and 
listed. The summary of concomitant medications will show the number and percentage of 
subjects taking concomitant medications by Ingredient. Multi-ingredient products will be 


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summarized by their separate ingredients rather than as a combination of ingredients. 
Anatomical Therapeutic Chemical (ATC) classification Level 1 (Body System) information 
will be included in the dataset created but will not appear on the listing or summary.
In the summary of concomitant medications, each subject is counted once within each unique 
ingredient. For example, if a subject takes Amoxycillin on two separate occasions, the subject 
is counted only once under the ingredient “Amoxycillin”.
2.5
Analysis of the primary objective
The primary objective of the study is to determine the efficacy of prophylactic octreotide in 
reducing the proportion of subjects experiencing diarrhoea with a severity of National Cancer 
Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Grade 2 and above
during the first 3 cycles of treatment with lapatinib and capecitabine. 
2.5.1 Primary endpoint
The primary efficacy endpoint is proportion of subjects experiencing diarrhoea with a severity 
of Grade 2 and above during the first 3 cycles of treatment with lapatinib and capecitabine, as 
defined by the NCI-CTCAE, version 4.03 (see Appendix 1 Table 1 of the study protocol).
2.5.2 Statistical hypothesis, model, and method of analysis
2.5.2.1 Diarrhoea of Grade 2 and above during the first 3 cycles treatment
This study is designed to test the superiority of prophylactic octreotide vs. no prophylactic 
octreotide in reducing the proportion of subjects experiencing diarrhoea with a severity of 2 or 
higher during the first 9 weeks (i.e., 3 cycles treatment) of lapatinib and capecitabine. 
Superiority will be assessed using data from the Intent-to-Treat population. The following 
statistical hypothesis will be tested to address the primary efficacy objective:
H: δ = 0 vs. H : δ < 0,
where δ is the difference in the incidence of Grade 2 or higher diarrhoea between prophylactic 
vs. no prophylactic octreotide during the first 3 cycles of lapatinib and capecitabine.  
The AE term ‘diarrhoea’ will be used to select episodes of diarrhoea.
Episodes of diarrhoea ‘during the first 3 cycles of treatment’ are defined as those with an onset 
date on or after the efficacy reference start date as defined in Section 2.1.3.2 and before the 
Cycle 4 visit date.
Subjects who withdraw from the study on or prior to the Cycle 4 visit date will be assumed to 
have experienced diarrhoea (non-responder imputation) of grade 2 or higher.
The superiority of prophylactic octreotide compared to no prophylactic octreotide will be 
assessed using a Pearson chi-square test in ITT population. The implementation of the Pearson 
chi-square test is specified in Section 5.3.1.  The proportion of subjects experiencing at least 
one episode of diarrhoea with a severity of Grade 2 or higher in each treatment group, the 
difference in proportions between the treatment groups, the corresponding 95% confidence 
interval and the two-sided p-value from the chi-square test will be presented.


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2.5.2.2 Diarrhoea of Grade 2 and above during the entire treatment period
The proportion of subjects experiencing at least one episode of diarrhoea with a severity of 
Grade 2 or higher during the entire treatment period will be summarised using the same methods 
as described for Section 2.5.2.1. There wll not be any statistical test performed for this endpoint.
Episodes of diarrhoea ‘during the entire treatment period’ are defined as those with an onset 
date on or after the efficacy reference start date as defined in Section 2.1.3.2 and on or before 
the End of Study/Withdrawal visit date.
2.5.3 Handling of missing values/censoring/discontinuations
Diarrhoea with a severity of 2 or higher during the first 9 weeks (i.e., 3 cycles treatment): 
Subjects who withdraw from the study on or prior to the Cycle 4 visit date will be assumed to 
have experienced diarrhoea (non-responder imputation) of grade 2 or higher. Such an
imputation techniques will be used for the ITT and m-ITT population analysis of the primary 
endpoint. No imputation will be performed for the Per Protocol analyses.
Diarrhoea with a severity of 2 or higher during the entire treatment period: Subjects who do 
not have diarrhea event prior to the End of Study/Withdrawal visit date will be considered as 
non-responders and no imputation will be done in such cases. 
2.5.4 Supportive analyse
Supportive analyses of the primary endpoint will be conducted using the m-ITT and PP 
populations, using the same methods as defined for the primary analysis. The primary endpoint 
will be summarized using the m-ITT and PP populations, but there wll not be any statistical test
performed for these populations.
No imputation will be used for the PP analysis, i.e., patients without any diarrhea event on or 
before desired timepoint will not be imputed and considered as non-responders. 
2.5.5 Subgroup analyses for the primary endpoint
Not Applicable.
2.6
Analysis of the secondary objective
2.6.1 Investigator-reported endpoints
These analyses will be based on data reported by the investigator in the eCRF.  Analyses of 
secondary diarrhoea-related endpoints and disease efficacy will be conducted for the ITT 
population.
2.6.1.1 Diarrhoea of Grade 3 and above
The proportion of subjects experiencing at least one episode of diarrhoea with a severity of 
Grade 3 or higher during the entire treatment period will be summarised using the same methods 
as described for Section 2.5.2, diarrhoea of Grade 2 and above.


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2.6.1.2 Diarrhoea of any grade
The proportion of subjects experiencing at least one episode of diarrhoea of any grade of 
severity during the entire treatment period will be summarised using the same methods as 
described for Section 2.5.2 diarrhoea of Grade 2 and above.
A by-subject listing of all diarrhoea events will be presented in the form of an adverse event 
listing, including the duration and time to onset of each event. 
2.6.1.3 Time to onset of the first episode of diarrhoea
The time to onset (in days) of the first episode of diarrhoea of any grade of severity will be 
derived as ((date of first episode of diarrhoea – date of first dose of lapatinib and capecitabine) 
+ 1) and it will be summarised by treatment group using Kaplan-Meier methods.  Subjects who 
complete the study or withdraw prematurely without experiencing an episode of diarrhoea will 
be censored at the date of withdrawal or study completion.  
The Kaplan-Meier estimate of the proportion of subjects experiencing an episode of diarrhoea 
will be presented for each 3 week cycle of lapatinib and capecitabine by treatment group.  
Estimates and 95% confidence intervals for the 25th percentile, median and 75th percentile will 
be provided by treatment group.  
2.6.1.4 Study treatment compliance
Inference of the efficacy of prophylactic octreotide will be made by summarising compliance 
to lapatinib and capecitabine separately by treatment group. Compliance will be derived as 
described in Section 2.4.1.
A summary of compliance with prophylactic octreotide will be presented. Compliance will be 
derived as described in Section 2.4.1.
2.6.1.5 Response
Response is a secondary aim of this study, as the sample size is relatively small and the study 
is not powered to detect a statistically significant difference in the response rate or the efficacy 
of lapatinib and capecitabine for octreotide vs. no octreotide subjects. However, overall 
response rate and clinical benefit response rate will be presented for interest. RECIST data to 
assess tumour size and new tumours will be collected as per clinical practice throughout the 
study. Data will be collected at baseline (screening) and end of 24 weeks of lapatinib and 
capecitabine treatment. Therefore overall response rate will be presented as response following 
24 weeks of treatment, as subjects will not be followed up to progression or death.  Therefore, 
the results of this analysis should be treated with caution and are for interest and exploratory 
purposes.
Overall response rate (ORR)
Overall response rate (ORR) is defined as the percentage of subjects achieving either a 
confirmed complete (CR) or partial (PR) tumour response at the end of the study (End of 
Study/Withdrawal visit). This will be based on the investigator’s assessment of overall response.    


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Subjects with a not evaluable (NE) or missing response will be treated as non-responders; i.e. 
they will be included in the denominator when calculating the percentage.
The 95% CI for response rates in each group will be provided for the difference in response 
rates, as for the primary endpoint. 
Clinical benefit response
Clinical benefit response (CBR) is defined as the percentage of subjects with a CR, PR or stable 
disease (SD) for at least 24 weeks.  The CBR will be calculated using the investigator’s 
assessment of response. Subjects who do not have measurable disease, or who have a missing 
or NE response will be treated as non-responders. The CBR in each treatment group and 
corresponding 95% confidence interval will be presented. 
2.6.2 Patient-reported outcomes
These analyses will be based on data reported by the patient in the DMD and FACIT-D (see
Section 2.6.2.1 and Section 2.8.1). Analyses of secondary patient-reported diarrhoea-related 
endpoints will be presented for the ITT populations for patients completing the baseline and at 
least one post-baseline assessments. Missing data will be treated as missing, i.e. there will be 
no imputation of missing data.
2.6.2.1 DMD
A by-patient listing of all DMD data will be presented. 
2.7
Safety analyses
Unless otherwise specified, all the safety analyses will be based on the Safety population and 
summaries will include all events or assessments collected during the study. All the summaries 
will be presented by treatment group.
2.7.1 Extent of Exposure
Extent of exposure to octrotide, lapatinib and capecitabine will be summarized separately.
2.7.1.1 Octreotide
The number and percentage of subjects who received a given number of infusions of octreotide 
(an infusion is defined as one dose of 20mg, patients should have two 20 mg infusions per dose) 
(0, 1, 2, 3, 4, >4 20mg infusions) will be reported. The duration of exposure to study treatment 
in days, calculated as (last dose of octreotide – first dose of octreotide +1), will also be 
summarised. 
Dose intensity (total dose delivered i.e. two 20 mg infusions per dose) will be summarized using 
mean, median, standard deviation, minimum, and maximum.
The number of subjects with dose reductions, dose escalation, dose delays or missed doses will 
be summarized using frequency and percentages.


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2.7.1.2 Lapatanib and capecitabine
The duration of exposure to lapatinib and capecitabine in weeks will be derived as described in
Section 2.1.3.5
and will be summarised. Descriptive statistics including mean, median, 
standard deviation, minimum, and maximum will be calculated for weeks on study treatment.  
Moreover, time on study treatment will be categorized in different time periods: <=3 weeks, >3-
6 weeks, >6-9 weeks, >9-12 weeks, >12-24 weeks, >24 weeks. 
The subject’s average daily dose, defined as the cumulative dose divided by the duration of 
exposure for each subject, will be summarized. In addition, summary of the population level 
daily dose will also be provided. In this analysis, a dose on each day for each subject will be 
treated as an observation and the summary will be based on the dose on each individual day for 
all subjects.
Dose reductions will be summarised by number of reductions and reasons for reductions. Dose 
escalations will be summarised by number of escalations and reasons for escalation. Dose
interruptions will be summarised by number of interruptions and reasons for the interruptions. 
The mean, standard deviation, median, minimum, and maximum will be computed for the 
duration of interruptions. The summaries of dose modifications will be provided only if there 
is sufficient data.
All the dose reductions, dose escalations, missed doses and dose delays will be listed separately 
for octreotide, lapatinib and capecitabine.
2.7.2 Adverse events (AEs)
AEs will be graded by the investigator according to the NCI-CTCAE, Version 4.03. Adverse 
events will be coded to the PT level using Medical Dictionary for Regulatory Activities 
(MedDRA). 
The following adverse event summaries will be produced by treatment group: overview of 
adverse events and deaths (number and % of subjects who died, any AE, any SAE, any dose 
reductions/interruptions, AEs related to study treatment, SAEs related to study treatment, AEs 
leading to treatment discontinuation, AEs requiring additional therapy, AEs leading to 
withdrawal), AEs by SOC and PT summarized by relationship (all AEs and AEs related to study 
treatment), SAEs by SOC and PT.
A summary of all AEs that occurred in strictly 5% or higher of all the subjects will be provided 
(no rounding for the percentage will be used in terms of 5% threshold, e.g., event with 4.9% 
incidence rate should not be included in this table). The summary will be displayed by preferred 
term (PT) and maximum grade.
The summary will use the following algorithms for counting the subject:

Preferred term row: Subjects experiencing the same AE preferred term several times with 
different grades will only be counted once with the maximum grade.

Any event row: Each subject with at least one adverse event will be counted only once at 
the maximum grade no matter how many events they have.


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These summaries are displayed in descending order of Octreotide+Lap+Cap group by SOC and 
PT. In the SOC row, the number of subjects with multiple events under the same system organ 
class will be counted once. 
A study treatment-related AE is defined as an AE for which the investigator classifies the 
relationship to study treatment as “Yes”. A worst case scenario approach will be taken to handle 
missing relatedness data, i.e., the summary table will include events with the relationship to 
study treatment as ‘Yes’ or missing. The summary table will be displayed in descending order 
of Octreotide+Lap+Cap group by SOC and PT
A listing for all AEs will be provided including seriousness, relatedness, action taken. 
2.7.3 Adverse Events of Special Interest
Adverse events of special interest are:  

diarrhoea, 

hepatobiliary events 

cardiac events 
A comprehensive list of MedDRA terms based on clinical review will be used to identify each 
type of event.  Changes to the MedDRA dictionary may occur between the start of the study 
and the time of reporting and/or emerging data from on-going studies may highlight additional 
adverse events of special interest, therefore the list of terms to be used for each event of interest 
and the specific events of interest will be based on the SRT agreements in place at the time of 
reporting. 
Summaries of the number and percentage of subjects with these events of special interest will 
be provided for each type of event separately by SOC and PT. 
The worst case approach will be applied at subject level for the event outcome and maximum 
grade, i.e. a subject will only be counted once as the worst case from all the events experienced 
by the subject. 
In addition, AEs of special interest will be listed separately.
2.7.4 Deaths and Serious Adverse Events
In the event that a subject has withdrawn consent, no data after the withdrawal of consent date 
from this subject including death is supposed to appear in the database, which should be part of 
the data cleaning process. 
Separate summaries for on-treatment and all deaths (on-treatment and post-treatment) will be 
produced. All deaths will be summarized by treatment arm and primary cause of death. All 
deaths  will be listed, post treatment deaths will be flagged.
All SAEs will be tabulated based on the number and percentage of subjects who experienced 
the event. Separate summaries will also be provided for study treatment-related SAEs. The 
summary tables will be displayed in descending order of Octreotide+Lap+Cap group by SOC 
and PT.


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A study treatment-related SAE is defined as an SAE for which the investigator classifies the 
relationship to study treatment as “Yes”. A worst case scenario approach will be taken to handle 
missing data, i.e. the summary table will include events with the relationship to study treatment 
as ‘Yes’ or missing. 
SAEs are included in the listing of all adverse events with flag for fatal AEs. 
2.7.5 Adverse Events Leading to Discontinuation of Study Treatment and/or 
Withdrawal from the Study 
The following categories of AEs will be summarized separately in descending order of 
Octreotide+Lap+Cap group by SOC and PT and separate supportive listings will be generated 
with subject level details for those subjects:

AEs leading to discontinuation of octreotide

AEs leading to discontinuation of lapatinib

AEs leading to discontinuation of capecitabine 

AEs leading to withdrawal from the study
2.7.6 Clinical Trial Safety Disclosure
For the legal requirements of ClinicalTrials.gov and EudraCT, two required tables on treatment 
emergent adverse events which are not serious adverse events with an incidence greater than 5% 
and on treatment emergent serious adverse events and SAE suspected to be related to study 
treatment will be provided by system organ class and preferred term on the safety set population.
If for a 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 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
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 AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
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.
2.7.7 Pregnancies 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be recorded as an AE or SAE as 
described in the protocol. If subjects become pregnant while on the study, the information will 
be included in the narratives and no separate table or listing will be produced.


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2.7.8 Clinical Laboratory Evaluations
The assessment of laboratory toxicities will examine the following laboratory tests: 
Hematology: 

Hemoglobin (HGB), 

Hematocrit (HCT),

Red Blood Cell (RBC) count, 

White Blood Cell (WBC) count, 

Total Neutrophils, 

Lymphocyte count 

Monocytes

Eosinophils

Basophils

Platelet count. 
Hematocrit, monocytes, eosinophils, basophils and RBC are not gradable by NCI-CTCAE 
v4.03.
Clinical Chemistry:

Sodium, 

Potassium, 

Ionised Calcium, 

Glucose, 

Urea/Blood Urea Nitrogen (BUN)

Creatinine, 

Estimated Creatinine Clearance, 

Albumin, 

Total Protien 
Estimated Creatinine Clearance and Total Protien are not gradable by CTCAE v4.03. For 
Sodium, Potassium, Inonised Calcium and Glucose there will be two bi-directional parameters 
(hyper and hypo) created, and the tests will be graded by NCI-CTCAE v4.03 in both directions.
Liver Function Tests (LFT):

Aspartateaminotransferase (AST)

Alanine aminotransferase (ALT)

Alkaline phosphatase

Total bilirubin (total)


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
Direct bilirubin. 
All these tests are gradable by NCI-CTCAE v4.03.
Coagulation Tests: 

Prothrombin time (PT) 

International Normalized Ratio (INR)

Activated partial thromboplastin time (APTT). 
INR and APTT are gradable by NCI-CTCAE v4.03 and PT is not.
Urinalysis:
Dipstick urinalysis; if dipstick urinalysis showed ≥2+ urine protein, then a 24-hour urine protein 
must be assessed. It is not gradable by NCI-CTCAE v4.03.
Laboratory grades will be reported using NCI-CTCAE v4.03.
Summaries of lab data by maximum toxicity grade will be provided.
Summaries of worst case grade increase from baseline grade will be provided for all the lab 
tests that are gradable by NCI-CTCAE v4.03. These summaries will display the number and 
percentage of subjects 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 labeled by direction, e.g., sodium will be summarized as hyponatremia and 
hypernatremia.
For lab tests that are not gradable by NCI-CTCAE v4.03, 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 subject has a decrease to low and an increase to high during the same 
time interval, then the subject is counted in both the “Decrease to Low” categories and the 
“Increase to High” categories. In addition, the summary will include worst case changes from 
baseline with respect to normal range by scheduled visits.
Separate summary tables for hematology, chemistry and liver function laboratory tests will be 
produced.
A supporting listing of laboratory data for subjects with abnormalities of potential clinical 
concern will be provided.  A separate listing of laboratory data with character values will also 
be provided.
Detailed derivation of baseline assessment is specified in Section 2.1.3.6.
Unless otherwise specified, the denominator in percentage calculation will be based on the 
number of subjects with non-missing value at each particular visit.


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2.7.8.1 Analyses of Liver Function Tests
Summaries of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided. 
Possible Hy’s law cases are defined as any elevated ALT>3×ULN, total bilirubin≥2×ULN and 
ALP<3×ULN/missing. Total bilirubin≥2×ULN can be within 28 days following the ALT 
elevation and if direct bilirubin is available on the same day, it must be ≥ 35% of total bilirubin. 
ALP<3×ULN/missing means the criteria is satisfied unless the ALP is ≥3×ULN at any time of 
bilirubin elevation within the 28 days window.
2.7.8.2 Lab values of Potential Clinical Importance
Reference ranges for all laboratory parameters collected throughout the study are provided by 
the laboratory. A laboratory value that is outside the reference range is considered either high 
abnormal (value above the upper limit of the reference range) or low abnormal (value below 
the lower limit of the reference range). Note: a high abnormal or low abnormal laboratory value 
is not necessarily of clinical concern. The laboratory reference ranges will be provided on the 
listings of laboratory data. Clinical laboratory test results outside of the reference range will be 
flagged in the listings.
To identify laboratory values of potential clinical importance, NCI-CTCAE v4.03 will be used 
to assign grades to the relevant laboratory parameters.
For laboratory data which are not listed in the NCI-CTCAE v4.03, a summary of values outside 
the normal range will be provided.
2.7.9 Other Safety Measures
Unless otherwise specified, the denominator in percentage calculation will be based on the 
number of subjects in safety set.
Vital Signs
In addition vital signs values will be categorized as follows:

Systolic BP (mmHg): Grade 0 (<120), Grade 1 (≥120-<140), Grade 2 (≥140-<160) and 
Grade 3 (≥160)

Diastolic BP (mmHg): Grade 0 (<80), Grade 1 (≥80-<90), Grade 2 (≥90-<100), and Grade 
3 (≥100)

Heart rate (beats/min): <60, 60-100, and >100
Summaries of increase in vital signs from the baseline with respect to the categories defined 
above will be performed. These summaries will display the number and percentage of subjects 
with any grade increase, increase to grade 2 and increase to grade 3 at the worst case post-
baseline. 
The following criteria will be used to flag vital sign values that are values of potential clinical 
importance:


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To identify heart rate values of potential clinical importance, NCI-CTCAE v4.03 will be used 
to assign categories that align with the grades for ‘Sinus bradycardia’, ‘Sinus tachycardia’, 
‘Supraventricular tachycardia’, and ‘Ventricular tachycardia’.
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Decrease from baseline 
Heart Rate
Decrease to <60
bpm
Increase from baseline 
Heart Rate
Increase to >100
bpm
To identify blood pressure values of potential clinical importance, NCI-CTCAE v4.03 will be 
used to assign categories that align with the grades for ‘Hypertension’.
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Increase from baseline 
Systolic Blood Pressure
120 to <140 (Grade 1)
140 to <160 (Grade 2)
160 (Grade 3)
mmHg
Increase from baseline 
Diastolic Blood Pressure
80 to <90 (Grade 1)
90 to <100 (Grade 2)
100 (Grade 3)
mmHg
ECG
A summary of the number and percentage of subjects who had normal and abnormal (clinically 
significant and not clinically significant) ECG findings will be displayed overall at baseline and 
at 24 week end. 
Listings of abnormal ECG findings will be provided.
LVEF
Absolute and relative change from baseline in LVEF will be summarized at 24 week end. 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 baseline. 
LVEF results will also be listed with subject level details including absolute/relative change 
from baseline and abnormal ECHO / MUGA findings.
To identify LVEF values of potential clinical importance, NCI-CTCAE v4.03 will be used to 
assign categories that align with the grades for ‘Ejection fraction decreased’.
LVEF Parameter
Potential Clinical Importance (PCI) Range
Unit
Relative change from 
baseline LVEF
20 decrease and below LLN
%


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Liver Events 
For any liver events that occur during the study, the liver event information will be summarized, 
including 

whether the subject was age 55 or over, 

whether the subject became pregnant, 

whether a liver imaging was normal or not, 

whether a biopsy was taken or not, 

whether there was fasting or significant dietary change, 

whether the subject took any unconventional medications, if yes, timing when the 
unconventional medications taken (on treatment or after stopping treatment)

summary statistics for time from first dose to start of liver event 

summary statistics for time from last dose to start of liver event. 
If the number of events does not support a summary, then only listings will be produced.
For subjects with multiple events, the first event will be used for the summary tables. All events 
with subject level details will be displayed in a supporting listing.
2.8
Health outcomes analyses
The health outcome endpoint of this study is subject-reported quality of life.
2.8.1 Health Outcomes Assessments
Quality of life will be assessed using the FACIT-D questionnaire. Patients randomised to 
receive treatment with octreotide will complete the FACIT-D immediately before receiving the 
first dose of octreotide. All patients will complete the FACIT-D immediately before the start of 
treatment with lapatinib and capecitabine, then every three weeks through to withdrawal from 
the study or the end of the 24 week period of treatment with lapatinib and capecitabine, 
whichever is sooner.  
The FACIT-D (version 4) consists of the FACT-G and a diarrhoea-specific subscale, and 
measures multidimensional quality of life in patients with cancer. FACT-G includes 27 general 
questions relating to four subscales: physical wellbeing, social/family wellbeing, emotional 
wellbeing, functional wellbeing, and the diarrhoea-specific subscale includes 11 questions.
Patients assess how true each statement has been for them in the previous 7 days on a 5-point 
scale ranging from 0 (not at all) to 4 (very much).  Higher scores on the FACIT-D scales indicate 
a better quality of life. In psychometric testing, the FACT/FACIT system has shown good test-
retest reliability and sensitivity to change when compared with ECOG performance status.  
The following scores will be calculated, using the standard scoring algorithms and methods to 
deal with missing data: 
-
Trial Outcome Index (includes diarrhoea subscale)
-
Physical subscale, 


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-
Social/Family subscale, 
-
Emotional subscale
-
Functional Wellbeing subscale, 
-
FACT-G total,
-
FACIT-D total.  
A by-patient listing of total scores and each of the 4 subscales will be presented. Each of these 
7 scores will be listed by visit and treatment group.    
2.9
Interim analysis
It was planned to have one formal interim analysis. The results were reviewed by the 
independent DMC. Based on the interim analysis DMC meeting (09-Sep-2016) it was 
recommended to stop the trial for futility. 
3
Sample size calculation
3.1
Sample size assumptions
It is planned that a total of 140 subjects will be randomised in a 1:1 ratio i.e. 70 subjects in each 
treatment group.  LAP117314 is an exploratory Phase II study, and the sample size is not based 
on the number of subjects required to achieve a statistically significant pre-specified reduction 
in the control incidence of diarrhoea. The sample size for this study was based on considerations 
of cost and feasibility of completing the trial in a timely manner.
The overall incidence of diarrhoea associated with treatment with lapatinib and capecitabine 
ranges from less than 40% to more than 80% across a number of studies (see Protocol).  Only 
limited data are available on the incidence of diarrhoea with a severity of Grade 2 or more which 
can be used as a basis for sample size estimation.  It is likely that the implementation of active 
diarrhoea management guidelines will limit the incidence of more severe diarrhoea which 
develops as a progression from inadequately treated mild diarrhoea.  Therefore, a conservative 
approach has been taken in LAP117314, and data from study EGF111438, which shows the 
lowest incidence of diarrhoea with a severity of Grade 2 or more (20%), has been used as the 
basis for the power calculations.  In addition, power calculations have been conducted based on 
a less conservative approach using data from EGF100151, in which diarrhoea management 
guidelines were not implemented and in which the incidence of diarrhoea with a severity of 
Grade 2 or more was 32%.
3.2
Sample Size Sensitivity
Based on the results of EGF111438, an incidence of 20% of Grade 2 or higher diarrhoea is 
assumed for subjects who receive lapatinib and capecitabine with no prophylactic octreotide.  
The power for the analysis to detect a reduction in the incidence of Grade 2 or higher diarrhoea 
from 14% to 8% ranges from 69% to 25%, if the assumed incidence in the control group is 20%, 
using a one-sided test with an alpha level of 0.025 (Table 3-1).


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Table 3-1
Sensitivity of sample size based on 20% control incidence of Grade 2 or 
more diarrhoea
Incidence, no prophylactic octreotide
20%
20%
20%
20%
20%
Incidence, prophylactic octreotide
6%
7%
8%
10%
12%
Estimated Statistical Power
69%
61%
53%
37%
25%
Subjects per Treatment group
70
70
70
70
70
Based on the results of EGF100151, an incidence of 32% of Grade 2 or higher diarrhoea is 
assumed for subjects who receive lapatinib and capecitabine with no prophylactic octreotide.  
The power for the analysis to detect a reduction in the incidence of Grade 2 or higher diarrhoea  
from 20% to 12% ranges from 82% to 36%, if the assumed incidence in the control group is 
32%, using a one-sided test with an alpha level of 0.025 (Table 3-2) Table 3-2.
Table 3-2
Sensitivity of sample size based on 32% control incidence of Grade 2 or 
more diarrhoea
Incidence, no prophylactic octreotide
32%
32%
32%
32%
32%
Incidence, prophylactic octreotide
12%
14%
16%
18%
20%
Estimated Statistical Power
82%
72%
60%
48%
36%
Subjects per Treatment group
70
70
70
70
70
Power calculations were performed using nQuery software version 7.0.
3.3
Sample Size Re-estimation
Sample size re-estimation is not planned for this study.
4
Change to protocol specified analyses
Since final CSR will be an abbreviated CSR, not all endpoints will be analysed. Table 1-3
contains reduced list of endpoints as compared to protocol. 
Secondary endpoint Patient reported Diarrhoea Management Diary (DMD) is reported using a 
listing of patients reporting changes in bowel movements from baseline (frequency and/or 
consistency), recorded in the DMD. 
5
Appendix
5.1
Imputation rules
Octreotide will be administered 7 days before the start of treatment with lapatinib and 
capecitabine and again 28 days later.  The primary endpoint is the reduction of treatment-
induced diarrhoea for subjects taking lapatinib and capecitabine over 3 cycles. Subjects 
withdrawing prior to the end of Cycle 3 of lapatinib and capecitabine will be considered to be 
non-responders. For responder endpoints, subjects withdrawing before the Cycle 4 assessment, 
i.e. before completing 3 cycles of treatment with lapatinib and capecitabine, will be assumed to 
be non-responders, and will be included in the denominator when calculating the percentages. 


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In the event that the study is terminated, all available data will be listed and a review carried 
out by the study team to assess which statistical analyses are still considered appropriate.
Missing data occurs when any requested data is not provided, leading to blank fields on the 
collection instrument. These data will be indicated by the use of a “blank” in subject listing 
displays. Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
Subjects with the designation of treatment relationship for AEs and SAEs missing will have the 
worst case assumed to impute the relationship: if relationship to study treatment is missing it 
will be assumed to be “Yes”.
Imputed partial dates will not be used to derive study day, duration (e.g., duration of adverse 
events), or elapsed time variables.
With the exception of date of birth on the Demography analysis dataset and exposure end date 
on the Exposure analysis dataset, imputed dates will also not be stored on datasets. 
Imputed dates will not be displayed in listings. However, where necessary, display macros may 
impute dates as temporary variables for the purpose of sorting data in listings only. In addition 
partial dates may be imputed for ‘slotting’ data to study time periods or for specific analysis 
purposes as outlined below. 
The partial date imputation will follow ADaM conventions. The ADaM approach is to populate 
the numeric date variables with the imputed date and add a flag variable to the dataset that 
indicates the level of imputation. 
The flag variable can contain the values: blank, 'D', 'M', 'Y'. 
blank: indicates that no imputation was done
D='Day': indicates that the day portion of the date is imputed
M='Month': indicates that the month and day portions of the date are imputed
Y='Year': indicates that the entire date (year, month, and day) is imputed
Example of Date Variables: 
XYZD_ - character date variable
XYZDT - numeric date variable
XYZDTFL - flag variable
5.1.1 AE date imputation
Imputations in the adverse events dataset are used for slotting events to the appropriate study 
time periods and for sorting in data listings.
Dataset
Date
Missing 
Element
Rule
Adverse 
Events 
(AE)
Start 
Date
day, 
month, 
No Imputation for completely missing dates


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Dataset
Date
Missing 
Element
Rule
and 
year
day, 
month

If study treatment start date is missing (i.e. subject did not 
start study treatment), then set start date = January 1.

Else if study treatment start date is not missing: 

If year of start date = year of study treatment start date
then 
-
If stop date contains a full date and stop date is 
earlier than study treatment start date then set start 
date = January 1. 
-
Else set start date = study treatment start date. 

Else set start date = January 1.
day

If study treatment start date is missing (i.e. subject did not 
start study treatment), then set start date = 1st of month. 

Else if study treatment start date is not missing: 

If month and year of start date = month and year of 
study treatment start date then 
-
If stop date contains a full date and stop date is 
earlier than study treatment start date then set start 
date= 1st of month. 
-
Else set start date = study treatment start date.

Else set start date = 1st of month.
End 
Date
No imputation for partial end dates will be performed
5.1.2 Concomitant medication and blood and blood supportive care products
Concomitant medication and blood and blood supportive care products are defined as any 
medications taken 2 weeks prior to the start of octreotide for subjects randomised to octreotide 
and 2 weeks prior to the start of lapatinib and capecitabine for subjects randomised to no 
octreotide. 
Impute start and end dates for use in derivation of the reference variables concomitant 
medication start and end relative to treatment and blood and blood supportive care start and end 
relative to treatment, but do not permanently store the imputed start and end dates in the analysis 
datasets. The reference variables will be used to differentiate before, during and after for the 
concomitant medication or blood or blood supportive care start and end dates. The derived time 
in relation to treatment variables are not needed for reporting of these data.


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Dataset
Date
Missing 
Element
Rule
Concomitant 
Medication
Blood and 
Blood 
Supportive 
Care 
Products 
Start 
Date
day, 
month, 
and year
No Imputation for completely missing dates
day, 
month

If study treatment start date is missing (i.e. subject 
did not start study treatment), then set start date = 
January 1. 

Else if study treatment start date is not missing: 

If year of start date = year of study treatment 
start date then 
-
If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date = January 1. 
-
Else set start date = study treatment start 
date. 

Else set start date = January 1.
day

If study treatment start date is missing (i.e. subject 
did not start study treatment), then set start date = 
1st of month. 

Else if study treatment start date is not missing: 

If month and year of start date = month and 
year of study treatment start date then 
-
If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date= 1st of month. 
-
Else set start date = study treatment start 
date.

Else set start date = 1st of month.
End 
Date
day, 
month, 
and year

No Imputation for completely missing dates
day, 
month

If partial end date contains year only, set end date 
= earliest of December 31 or date of last contact. 
day

If partial end date contains month and year, set end 
date = earliest of last day of the month or date of 
last contact (MSTONE.LCONTDT).


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5.1.3 Other imputations
5.1.3.1 Date of birth
Due to data protection rules, only a subject’s year of birth (YOB) can be collected, therefore 
date of birth (DOB) will be imputed as, 30th June YOB, for the calculation of age in the 
demography dataset
5.1.3.2 Missing exposure end date imputation
In general, completely missing dates are not imputed. However, subjects completing 24 weeks 
of lapatinib and capecitabine may still be on lapatinib and capecitabine and so may have missing 
exposure end dates in their last dosing record. Missing exposure end dates for subjects who are 
still on lapatinib and capecitabine at the time of analysis will be imputed as the date of the End 
of Study/Withdrawal visit. 
For subjects with missing exposure end dates at the time of data cut-off, i.e. for SRT summaries, 
the exposure end date will be imputed to be the earliest of: the date of the data cut-off, the date 
of End of Study/Withdrawal visit, or the death date. The imputed exposure end date will be 
used to calculate cumulative dose and exposure duration. The imputed exposure end date will 
be stored in the exposure analysis dataset and an exposure end date imputation flag variable 
will be derived indicating which exposure end date records are imputed. Imputed exposure end 
dates will also be stored on the study treatment end date variable.
For subjects who have missing end dates in their last exposure record because they are still on 
lapatinib and capecitabine, the on-therapy indicator variables (time in relation to lapatinib and 
capecitabine) are assigned to on-therapy for all records where the 'dataset'.'date' is after or on 
the lapatinib and capecitabine start date.
5.1.3.3 Missing death date
For cases when either day is missing or both month and day are missing for the date of death, 
the following imputation rules will be implemented:

If only day is missing, then impute max [(1 mmm-yyyy), min(last contact date+1 , cutoff 
date)]. 

If both day and month are missing, then impute max [(1 Jan-yyyy, min (last contact date +1, 
cutoff date)].
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
AEs will be assessed according to the National Cancer Institute Common Terminology Criteria 
for Adverse Events (NCI-CTCAE) version 4.03. 
The NCI-CTCAE represents a comprehensive grading system for reporting the acute and late 
effects of cancer treatments. NCI-CTCAE grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 


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proportionality among grades (a grade 2 is not necessarily twice as bad as a grade 1). The NCI-
CTCAE grade of 5 (death) is not used; rather, ‘fatal’ is collected as AE outcome and death 
information is also collected on a separate (e)CRF page.
5.3
Statistical models
5.3.1 Analysis of binary data
Analysis of the proportion difference
The null hypothesis of equal proportion of subjects who have a specific event (e.g., the Grade 
2 or higher diarrhoea) in the two treatment group will be tested against one-sided alternative.
The statistical hypotheses are:
H: δ = 0 vs. H : δ < 0,
where δ is the difference in proportions of subjects who have a specific event (e.g., the Grade 2 
or higher diarrhoea) between two treatment groups, i.e., δ = π$ −π&, where π$ and π& are 
proportions of subjects who have a specific event in prophylactic octreotide and no prophylactic
octreotide group respectively.  
The Pearson chi-square test (implemented via SAS procedure FREQ with CHISQ option in the 
TABLES statement) will be used to test the difference in proportions of subjects who have a 
specific event between the treatment groups. The two-sided p-value corresponding to the chi-
square test will be used which follows a Chi-square distribution with one degree of freedom.
The difference in proportions and its corresponding 95% confidence interval will be estimated 
by using the Wald method (implemented via SAS procedure FREQ with RISKDIFF option in 
the TABLES statement).
If the sampling assumptions for chi-square test is not met (i.e., the expected values should
exceed 5 for all of the table cells.), the exact Pearson chi-square test will be used (implemented 
via SAS procedure FREQ with the TABLES statement and a CHISQ option in the EXACT
statement) for the estiamtion of the two-sided p-value. The corresponding 95% confidence 
interval of the difference of propotions between two groups will be estimated by the exact 
unconditional confidence limits which will be implemented via SAS procedure FREQ with the 
TABLES statement and RISKDIFF option in the EXACT statement. The approach of exact 
unconditional confidence limits estimation eliminates nuisance parameters by maximizing the 
p-vlaue over all possible values of the nuisance parameters [Santner and Snell 1980].
The SAS syntax is specified as follows:
PROC FREQ DATA = <input_dataset>;
  TABLES <treat_var> * <response>/CHISQ RISKDIFF;
EXACT CHISQ RISKDIFF;
RUN;
Confidence interval for response rate
Response rate is defined as the percentage of subjects who have a specific event (e.g., 
experiencing diarrhoea). The 100(1 − α)% confidence interval of a response rate will be 


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estimated by using exact binomial confidence interval (implemented using SAS procedure 
FREQ with EXACT statement for one-way table [Clopper and Pearson 1934].
The SAS syntax is specified as follows:
PROC FREQ DATA = <input_dataset>;
  BY <treat_var>;
  TABLES <response>/BINOMIAL(EXACT);
RUN;
where treat_var
= treatment group
            response          = response (e.g., diarrhoea)
5.3.2 Analysis of time to events data
Kaplan-Meier estimates
An estimate of the survival function in each treatment group will be constructed using Kaplan-
Meier (product-limit) method as implemented in PROC LIFETEST with METHOD=KM 
option. The PROC LIFETEST statement will use the option CONFTYPE=LOGLOG.
25th, 50th, and 75th percentile survivals for each treatment group will be obtained along with 95% 
confidence intervals calculated from PROC LIFETEST output using the method of 
[Brookmeyer and Crowley 1982]. Kaplan-Meier estimates of the survival function with 95% 
confidence intervals at specific time points will be summarized.
Treatment of ties
The STRATA statement in LIFETEST procedure will be used to analyze time to event data 
with ties. 
6
Reference
1. Agresti, A. A Survey of Exact Inference for Contingency Tables. Statistical Science, 
1992; 7(1),131–177.
2. Bernstein L, Anderson J, Pike M. Estimation of the proportional hazard in two-treatment-
group clinical trials. Biometrics, 1981; 37:513-519.
3. Berry G, Kitchen R, Mock P. A Comparison of two simple hazard ratio estimators based 
on the Logrank Test. Statistics in Medicine, 1991; 10:749-755.
4. Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics, 1982; 38:29-41.
5. Carroll KJ. Back to basics: Explaining sample size in outcome trials, are statisticians 
doing a thorough job? Pharmaceutical Statistics, 2009; 8(4):333-345.
6. Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrical, 26, 404-413.
7. Santner, T. J. and Snell, M. K., Small-Sample Confidence Intervals for p1-p2 and p1/p2 in
2 X 2 Contingency Tables. Journal of the American Statistical Association, (1980; 75, 
386–394.


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8. Schuirmann DJ. A comparison of the two one-sided tests procedure and the power 
approach for assessing the equivalence of average bioavailability. Journal of 
Pharmacokinetics and Biopharmaceutics, 1987; 15(6):657-80.
9. Hollander M, Wolfe DA. Nonparametric Statistical Methods. 2nd ed. New York: John 
Wiley & Sons; 1999.