Clinical trial NCT01953913
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim
Start date: 2013-09-30; Completion date: 2018-07-06
Enrollment: 542 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Primary objective of the trial is to evaluate the safety of afatinib in patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR (Epidermal growth factor receptor) mutation(s) and have never been treated with an EGFR-TKI (tyrosine kinase inhibitor). Secondary objective is to assess the time to symptomatic progression (as judged by investigator).

Detailed description:

Arms: arm 1: Patient will receive afatinib once daily
Interventions: intervention 1: Afatinib
Intervention descriptions: intervention 1: Patient will receive afatinib once daily

Protocol documents:
Prot_001.pdf: 
TITLE PAGE
Clinical Trial Protocol
Doc. No.: c14890504-01
BI Trial No.:
1200.66
BI Investigational
Product:
Giotrif®/ Gilotrif™(afatinib) 
Title:
An open label, multicentre, single-arm trial to assess the safety of 
afatinib for patients with locally advanced or metastatic non-small cell 
lung cancer (NSCLC) harboring EGFR mutation(s)
Clinical Phase:
IIIb
Trial Clinical 
Monitor:
Co-ordinating 
Investigator:
 
Status:
Final Protocol (Revised Protocol based on global amendment 4)
   Version and Date:
   Version:  5.0
Date: 3 Feb 2017
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Giotrif®/ Gilotrif™
Name of active ingredient:
afatinib (BIBW 2992)
Protocol date:
Trial number:
Revision date:
3 Feb 2017
29 Mar 2013
1200.66
Title of trial:
An open label, multicentre, single-arm trial to assess safety of afatinib for patients 
with locally advanced or metastatic non-small cell lung cancer (NSCLC) harboring 
EGFR mutation(s)
Co-ordinating 
Investigator :
Trial sites:
Multi-center trial conducted at approximately 40 sites within Asia countries (China 
Hong Kong, India, Singapore, Taiwan)
Clinical phase:
IIIb
Objective:
To evaluate the safety, tolerability and efficacy of afatinib in patients with locally 
advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR 
mutation(s) and have never been treated with an EGFR-Tyrosine Kinase Inhibitor 
(TKI)
Methodology:
Open-label, multi-center, single-arm trial
No. of patients: 
total entered:
Approximately 500 patients
each treatment:
All entered patients will receive afatinib
Diagnosis :
Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC)
harboring EGFR mutation(s) and have never been treated with an EGFR-TKI
Main criteria
for inclusion:
All patients should have locally advanced or metastatic non-small cell lung cancer 
(NSCLC) harboring EGFR mutation(s) and have never been treated with an EGFR-
TKI
Test products:
Afatinib as 40, 30, and 20 mg film-coated tablets
Patients will receive starting dose of 40 mg afatinib once daily with an option to 
reduce the dose based on individual tolerability.
dose:
40 mg/day or 30 mg/day or 20 mg/day
mode of admin.:
Oral, once daily, continuous


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Giotrif®/ Gilotrif™
Name of active ingredient:
afatinib (BIBW 2992)
Protocol date:
Trial number:
Revision date:
3 Feb 2017
29 Mar 2013
1200.66
Comparator products:
None.
dose:
NA
mode of admin.:
NA
Duration of treatment: Continuous treatment in the absence of progressive disease and trial withdrawal 
criteria specified in Section 3.3.4.
In this trial, progression is determined by investigator. Afatinib must be permanently 
discontinued when investigator judges that patient is no longer benefiting from 
treatment with afatinib. 
.
Criteria for efficacy:
Time to symptomatic progression (TTSP) as determined by investigator
Criteria for safety:
Adverse events according to Common Terminology Criteria (CTCAE Version 3)
Statistical methods:
Exploratory descriptive statistics of demographic, efficacy and safety data will be 
presented as appropriate.


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FLOW CHART
Procedure
Screening 
Baseline
Treatment and Safety 
evaluation
End of 
Treatment
Follow-
up
Visits (V)
V1*
V2, V3, V4,
V5, V6. 
Onwards
V4, V7, V10, 
V13, V16... 
Onwards
EOT**
FU#
Days
Day -1           
(-28 to -1)
Day 
1
Day 15 
(±3) 
(phone 
call)
Day 28 (-7/+2 
days) of every 
treatment 
cycle 
Day 28 (-
7/+2) of every 
3rd treatment 
cycle
0-14 Days 
after last trial 
drug intake 
EOT+ 
28 (+7)
Informed 
consent1
X
Demographics
X
Medical history
X
In/Exclusion 
criteria
X
Physical 
examination2
X
X
X
Tumour clinical 
assessment 3
X
X
X
ECOG 
X
X
X
Safety 
laboratory 
testing5
X
X
X
Urine 
examination6
X
X
Pregnancy test7
X
X
Adverse events
X
X
X8
X
X
X9
Dispense trial 
medication
X
X
Compliance
X
X
Termination of 
trial medication
X
Patient Status
X
Diarrhoea diary 
completion10
X
X11
*
Afatinib will be dispensed only after verification that all trial requirements are met.
1
Written informed consent must be obtained before any screening/baseline assessments are performed. All 
screening procedures conducted as per site standard of care prior to ICF and within the screening period of 28 days 
prior to first dose can be used for the study.
2
Includes vital signs (pulse, blood pressure), temperature, weight (kg) and an ECOG performance score.  Height is 
only captured at screening visit only.
3. 
Tumour assessment should be performed by investigator according to local standard at the time of screening. 
During treatment period, tumour assessment should be conducted according to local standard of care or recorded 
every 3 cycles.  Diagnosis of progression is at the discretion of the investigator. Investigator should confirm there 
is clinical benefit before patient continues on next cycle of afatinib. See definition of PD in Section 5.1


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4             
 
5
Safety laboratory testing: haematology and biochemistry examinations (see Section 5.2.3). All laboratory tests 
mentioned in Table 5.2.3: 1 are required to be performed at screening, every 12 weeks following first dose.  Also
recommended to be performed at the discretion of the investigator and in accordance to the current standard of 
care.
6
Urine examinations (see Table 5.2.3: 1) are required to be performed at screening and EOT; are recommended to 
be performed at the discretion of the investigator and in accordance to the current standard of care.
7
Beta-Human Chorionic Gonadotropin (β-HCG) testing in urine or serum in women of childbearing potential. A 
negative result is required for inclusion in the trial.
8
A phone call is required 15 (±3) days after the patient’s first dose to assess AEs and dose reductions.
9
Within 28 days after last trial drug administration all AEs will be collected and documented. SAEs must always be 
collected, documented, and reported within this 28 day time period. In addition, only SAE that are considered 
related to the trial medication or trial design must be reported after the FU visit (end of residual effect phase).
10
Provide a diarrhoea diary with drug supply see sample on in Appendix 10.4. Data on diaries should be checked by 
the study staff against AEs and Appendix 10.1.1.
11           Diarrhoea diary will only be dispensed for the first 2 cycles of Afatinib treatment.
**
EOT (V): end of treatment (visit) with trial medication. Patients without clinical progression at EOT will be
followed as per site standard practice until appearance of clinical progression or start of other anti-cancer treatment 
whichever occurs earlier. 
#
FU (V): Follow-up visit which should occur 28 days after the end of treatment (EOT) visit – this visit can be 
conducted by a phone call. 


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 12
1.1
MEDICAL BACKGROUND............................................................................12
1.2
DRUG PROFILE...............................................................................................13
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 15
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................15
2.2
TRIAL OBJECTIVES.......................................................................................15
2.3
BENEFIT - RISK ASSESSMENT ...................................................................15
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 20
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................20
3.1.1
Administrative structure of the trial...................................................20
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................21
3.3
SELECTION OF TRIAL POPULATION ......................................................21
3.3.1
Main diagnosis for study entry............................................................22
3.3.2
Inclusion criteria...................................................................................22
3.3.3
Exclusion criteria ..................................................................................22
3.3.4
Removal of patients from therapy or assessments.............................24
3.3.4.1
Removal of individual patients .............................................24
3.3.4.1.1   Patient discontinuation of trial participation...................25
3.3.4.2
Discontinuation of the trial by the sponsor..........................25
4.
TREATMENTS........................................................................................ 26
4.1
TREATMENTS TO BE ADMINISTERED....................................................26
4.1.1
Identity of BI investigational product and comparator product......26
4.1.2
Method of assigning patients to treatment groups ............................26
4.1.3
Selection of doses in the trial................................................................26
4.1.4
Drug assignment and administration of doses for each patient .......27
4.1.4.1
Dose reduction scheme ..........................................................27
4.1.5
Blinding and procedures for unblinding ............................................29


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4.1.6
Packaging, labelling, and re-supply ....................................................29
4.1.7
Storage conditions.................................................................................29
4.1.8
Drug accountability ..............................................................................30
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................30
4.2.1
Rescue medication, emergency procedures, and additional 
treatment................................................................................................30
4.2.2
Restrictions............................................................................................31
4.2.2.1
Restrictions regarding concomitant treatment ...................31
4.2.2.2
Restrictions on diet and life style..........................................32
4.2.3
Contraception and pregnancy .............................................................32
4.3
TREATMENT COMPLIANCE.......................................................................34
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 35
5.1
EFFICACY.........................................................................................................35
5.1.1
Endpoints of efficacy.............................................................................35
5.1.2
Assessment of efficacy...........................................................................35
5.2
SAFETY..............................................................................................................36
5.2.1
Endpoints of safety................................................................................36
5.2.2
Assessment of adverse events...............................................................36
5.2.2.1
Definitions of adverse events.................................................36
5.2.2.2
Adverse event and serious adverse event reporting............38
5.2.3
Assessment of safety laboratory parameters......................................39
5.2.4
Electrocardiogram................................................................................39
5.2.5
Assessment of other safety parameters...............................................40
5.2.5.1
Physical examination .............................................................40
5.2.5.2
Vital signs................................................................................40
5.2.5.3
Left ventricular function.......................................................40
5.3
OTHER...............................................................................................................40
5.3.1
Documentation of diarrhoea.................................................40
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................41
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................41
5.6
BIOMARKER....................................................................................................41
5.6.1
Endpoint based on biomarker .............................................................41
5.6.2
Methods of sample collection...............................................................41
5.6.3
Analytical determinations ....................................................................41
5.7
PHARMACODYNAMICS................................................................................41
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP......41


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6.
INVESTIGATIONAL PLAN.................................................................. 42
6.1
VISIT SCHEDULE............................................................................................42
6.1.1
Screening visit (Visit 1).........................................................................42
6.1.2
Baseline visit (Visit 1)............................................................................42
6.1.3
Treatment and safety evaluation visits ...............................................42
6.1.4
End of Treatment (EOT) visit..............................................................42
6.1.5
Follow-Up (FU) visit .............................................................................42
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................42
6.2.1
Screening and baseline periods............................................................43
6.2.2
Treatment periods.................................................................................45
6.2.3
End of Treatment and follow-up period.............................................47
6.2.4
Follow-Up...............................................................................................48
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 50
7.1
STATISTICAL DESIGN - MODEL................................................................50
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................50
7.3
PLANNED ANALYSES....................................................................................50
7.3.1
Primary analyses...................................................................................50
7.3.2
Secondary analyses ...............................................................................50
7.3.3
Safety analyses.......................................................................................51
7.3.4
Interim analyses ....................................................................................52
7.5
RANDOMISATION ..........................................................................................52
7.6
DETERMINATION OF SAMPLE SIZE ........................................................52
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS ................................................................................................ 53
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................53
8.2
DATA QUALITY ASSURANCE .....................................................................54
8.3
RECORDS..........................................................................................................54
8.3.1
Source documents .................................................................................54
8.3.2
Direct access to source data and documents.......................................54
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................54
8.4.1
Listedness...............................................................................................54
8.4.2
Expedited reporting to health authorities and IECs/IRBs................55
8.5
STATEMENT OF CONFIDENTIALITY.......................................................55
9.
REFERENCES......................................................................................... 56
9.1
PUBLISHED REFERENCES...........................................................................56


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9.2
UNPUBLISHED REFERENCES.....................................................................58
10. APPENDICES .......................................................................................... 60
10.1 MANAGEMENT OF EXPECTED ADVERSE EVENTS.............................60
10.1.1 Management of diarrhoea and hydration status following 
treatment with afatinib.........................................................................60
10.1.2 Management recommendations for dermatological AEs 
following treatment with afatinib........................................................61
10.1.3 Management of mucositis/stomatitis...................................................65
10.1.4 Management of interstitial lung disease (ILD) and keratitis............66
10.2
NEW YORK HEART ASSOCIATION CLASSIFICATION OF HEART 
FAILURE............................................................................................................67
10.3
ADVERSE EVENT/SERIOUS ADVERSE EVENT REPORTING.............68
10.4
SAMPLE DIARRHOEA DIARY.....................................................................69
11. DESCRIPTION OF GLOBAL AMENDMENTS................................. 71


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ABBREVIATIONS
ADL
Activities of Daily Living
AE
Adverse Event
ALT (SGPT)
Alanine Amino Transferase (Serum Glutamate Pyruvate Transaminase)
ANC
Absolute Neutrophil Count
ASCO
The American Society of Clinical Oncology
AST (SGOT)
Aspartate Amino Transferase (Serum Glutamic Oxaloacetic Transaminase)
ß-HCG
Beta-Human Chorionic Gonadotropin
BI
Boehringer Ingelheim
BSC
Best Supportive Care
BUN
Blood Urea Nitrogen
CA
Competent Authority
CML
Clinical Monitor Local
CRA
Clinical Research Associate
CR
Complete Response
CRO
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DCR
Disease Control Rate
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ECHO
Echocardiography
ECOG
Eastern Cooperative Oncology Group
EC
Ethics Committee
eCRFs
Electronic Case Report Forms
EGFR
Epidermal Growth Factor Receptor
EOT
End of Treatment
erbB
Epidermal Growth Factor family of receptors (erB1/EGFR/HER1, 
erB2/HER2, erB3/HER3, erB4/HER4)
FDA
Food and Drug Administration
FU
Follow-up Visit
GCP
Good Clinical Practice
GGT
y-glutamyltransferase
HDPE
High-Density Polyethylene
HEPB
Hepatitis B
HEP C
Hepatitis C
HER2
Human Epidermal Growth Factor Receptor 2
HIV
Human Immunodeficiency Virus
IB
Investigator Brochure
ICH
International Conference on Harmonisation
ILD
Interstitial Lung Disease
IEC
Independent Ethics Committee
IRB
Institutional Review Board


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ISF
Investigator Site File
IUD
Intrauterine Device
LDH
Lactic Dehydrogenase
LVEF
Left Ventricular Ejection Fraction
mL
Milliliter
MTD
Maximum Tolerated Dose
MUGA
Multiple Gated Acquisition scan
NYHA
New York Heart Association
NSCLC
Non-Small Cell Lung Cancer
OPU
Operating Unit
ORR
Overall Response Rate
PC
Pemetrexed/Cisplatin
PCR
Polymerase Chain Reaction
P-gp
P-glycoprotein (P-gp)
PK
Pharmacokinetics
SAE(s)
Serious Adverse Event
SOPs
Standard Operating Procedures
SUSARs
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TDM
Trial Data Manager
TKI
Tyrosine Kinase Inhibitor
tmax
Time of Occurrence for Maximum Peak Drug Concentration
TS
Treated Set
WBC
White Blood Cell Count
WOCBP
Women of Child -Bearing Potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer-related deaths in many 
countries. The prognosis for advanced stage disease has improved modestly in the past 20
years. With an overall 5-year survival rate of only 15% the treatment of this disease clearly 
remains a major clinical challenge (R05-0876). 
While systemic chemotherapy has demonstrated modest activity in advanced NSCLC, novel 
targeted therapies based on specific molecular and biological characteristics of lung cancer 
have emerged as a new treatment paradigm. Among the targeted therapies most extensively 
studied are the inhibitors of Epidermal Growth Factor Receptors (EGFR) or the Subclass I of 
the superfamily of transmembrane tyrosine kinase receptors (R06-1301, R06-1302). 
Aberrant activation of EGFR frequently observed in a variety of malignant tumours can be 
induced by different molecular mechanisms including receptor overexpression, mutation, 
ligand-dependent receptor dimerization, and ligand-independent activation. Overexpression 
of EGFR has been detected in 40% to 80% of NSCLC patients (R06-1301, R06-1393, 
R06-1394). However, recent clinical experiences with specific EGFR-Tyrosine Kinase 
Inhibitors (TKI) have demonstrated tumour regression in only 10% to 15% of unselected 
NSCLC patients (R05-0867, R06-1301, R06-1306). The frequency of EGFR somatic 
mutations was found to be approximately 10% in NSCLC patients from the US, Europe or 
Australia compared to a mutation rate of up to 30% in patients from Japan and Taiwan 
(R06-1262, R06-1306, R06-1393). 
This is in general agreement with composite data from three retrospective analyses, in which 
the response rates for NSCLC patients harboring EGFR mutations ranged from 65% to 94% 
(R06-1306).
The pre-clinical and clinical data support the clinical testing of irreversible inhibitors of 
EGFR in NSCLC patients who are naïve to previous EGFR-TKI treatment as well as in 
patients who have progressed after treatment with a reversible EGFR-TKIs such as gefitinib 
and erlotinib (R06-1307, R07-1162), for which the only remaining standard treatment option 
is currently Best Supportive Care (BSC).
In preclinical disease models with Epidermal Growth Factor Family of Receptors (ErbB)
pathway deregulation, afatinib (an irreversible TKI) effectively inhibits ErbB receptor 
signaling resulting in tumour growth inhibition or tumour regression.[U02-1391, U02-1702, 
U02-1703, U02-1660, U02-1614, U07-1338, P08-06904] As a single agent it retains 
significant anti- tumour activity in NSCLC cell lines (in vitro) and tumour models (in vivo, 
xenografts or transgenic models) driven by mutant EGFR isoforms known to be resistant to 
the reversible EGFR TKIs erlotinib and gefitinib.[P08-06904]
A number of clinical trials with afatinib have evaluated treatment of NSCLC patients, both 
those who are EGFR TKI naïve as well as those previously treated with a reversible EGFR 
TKI (see Section 2.3).


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First line EGFR TKI naïve patients with EGFR mutation positive tumours showed significant 
and clinically meaningful improvements in Progression Free Survival (PFS) and Overall 
Response Rate (ORR) accompanied by significant delays in time to deterioration of the 
cancer-related symptoms of cough and dyspnoea as compared to patients receiving up to six 
cycles of pemetrexed/cisplatin (LUX-Lung 3/1200.32). In a separate single arm trial, (LUX-
Lung 2/1200.22) [U11-3644-01] enrolling both first and second line TKI naïve patients, high 
ORRs and disease control rates (DCRs) were seen in both groups (61%, and 82%, 
respectively) and were confirmed by independent review.  
1.2
DRUG PROFILE
Afatinib is a potent, selective, and irreversible ErbB Family Blocker. In preclinical models, it 
covalently binds to and irreversibly blocks signaling from all homo- and heterodimers formed 
by the ErbB family members EGFR (ErbB1), HER 2(ErbB2), ErbB3, and ErbB4 resulting in 
tumour growth inhibition and regression of established subcutaneous tumours derived from 
four human cell-lines known to co-express ErbB receptors. [U02-1083, U03-1086, 
U11-2645-01].
For the latest information on the drug profile of afatinib, please refer to the current 
Investigator’s Brochure (IB) (c01617169-04) and/or local product label information. All 
references in this protocol concerning afatinib refer to the free base compound of afatinib.
Afatinib is moderately rapidly absorbed after oral administration, with maximum plasma 
concentrations of afatinib achieved mainly at 2 to 5 hours after drug oral administration. 
Afatinib maximum plasma concentrations and area under the curve increased slightly 
overproportional with increasing doses in the therapeutic range of 20-50mg.. However, 
moderate to high inter- and intra-individual differences in plasma concentration were seen. 
Afatinib is highly distributed out of the blood and has a moderate to high clearance. The 
overall gMean terminal half-life at steady state was 37.2 hours in cancer patients. Steady state 
was reached no later than 8 days after the first administration. The major route of elimination 
of afatinib was via feces. After food intake, a decreased systemic exposure was observed 
compared to administration under fasted conditions. The Pharmacokinetics (PK)
characteristics in Caucasian cancer patients were comparable to those observed in Japanese 
cancer patients.
Afatinib is bound covalently to proteins to a variable extent and covalent protein adducts 
were the major circulating metabolites in the plasma. Afatinib did not show relevant 
inhibition or induction of cytochrome P450 isoenzymes, and it appears unlikely that 
drug-drug interactions based on this mechanism will occur. 
Afatinib is a substrate of the P-glycoprotein (P-gp) transporter. Concomitant administration 
of the potent P-gp inhibitor ritonavir did not relevantly change the exposure to 40 mg afatinib
when taken simultaneously with or 6 h after afatinib but increased the bioavailability of 
afatinib (single dose of 20 mg) by 48% and 39% for AUC0-∞and Cmax when given 1 h 
before afatinib, respectively. Pretreatment with the potent P-gp inducer rifampicin decreased 
the plasma exposure of 40 mg afatinib by 34 % afatinib (AUC0-∞) and 22 % (Cmax), 


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respectively. If P-gp inhibitors need to be taken, they should be administered simultaneously 
with afatinib (see Section 4.2.2.1) [U12-1170-01].
In pre-clinical trials s afatinib is not irritant to intact skin but an ocular irritant. Afatinib is 
mutagenic in a single bacteria strain, but did not show genotoxic potential in vivo when tested 
up to overt toxic/lethal doses. Studies on embryo-foetal development in rats and rabbits up to 
life-threatening doses have revealed no indication of teratogenicity.
Two phase I open label dose-escalation trials (U07-3128-02, U08-1023-03) each determined 
a Maximum Tolerated Dose (MTD) with continuous dosing of afatinib as 40 mg and 50 mg 
daily, respectively. Both daily doses (40mg and 50mg) have been used in
Phase II and Phase III trials depending on the patient population evaluated. Adverse Events 
(AEs) observed with afatinib are consistent with those reported for EGFR and dual EGFR/
Human Epidermal Growth Factor Receptor 2 (HER2) inhibitors. The most common AEs in 
Afatinib monotherapy trials were associated with gastrointestinal disorders (including 
diarrhoea, and stomatitis), skin and subcutaneous tissue disorders (rash/acne, dry skin, 
pruritus), nail effects, fatigue and decreased appetite. Early and proactive management of 
diarrhoea, skin rash, mucositis and stomatitis together with treatment interruptions and dose 
reductions is recommended in line with recent guidelines in the management of common 
toxicities of EGFR and EGFR/HER2 TKIs and monoclonal antibodies (R07-4077, P07-
11507, R07-4078, R11-0826).
At the time of this amendment, afatinib is an approved medicine in most countries for use in 
patients with EGFR mutation positive NSCLC and is approved in the EU for the treatment of 
patients with locally advanced or metastatic NSCLC of squamous histology progressing on or 
after platinum-based chemotherapy and by the FDA for the treatment of patients with 
metastatic squamous NSCLC progressing after platinum-based chemotherapy.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
This trial will assess the safety of afatinib in patients with locally advanced or metastatic non-
small cell lung cancer (NSCLC) harbouring EGFR mutation(s) and have never been treated 
with an EGFR-TKI. The trial will also obtain additional data on clinical benefit of afatinib in 
this patient population.
2.2
TRIAL OBJECTIVES
Primary objective of the trial is to evaluate the safety of afatinib in patients with locally 
advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutation(s)
and have never been treated with an EGFR-TKI.
Secondary objective is to assess the efficacy of afatinib in patients with locally advanced or 
metastatic NSCLC harbouring EGFR mutation(s) and treated with afatinib.
See Section 5 for trial endpoints.
2.3
BENEFIT - RISK ASSESSMENT
The benefits of providing afatinib to patients in this trial are based on the results obtained in 
two prior trials in patients with pathologic confirmation of stage IIIB or stage IV NSCLC. 
These trials were afatinib monotherapy trials and were either Phase III or large 
(>100 patients) Phase II trials with particular relevance for the proposed population for this
trial in that they included NSCLC patients with confirmed EGFR mutations. Both trials
enrolled EGFR TKI-naïve patients (1200.32 and 1200.22). In addition, data from a third 
study, a Phase III open label, randomized trial in Asian patients with EGFR mutation-positive 
advanced adenocarcinoma of the lung, confirmed these results.
An overview of the characteristics of these trials is provided in Table 2.3: 1. 
Table 2.3: 1
Study characteristics of LUX-Lung 2 and 3 and 6
Trial
Regions
EGFR 
mutation 
status
Line of 
treatment
Prior 
EGFR 
TKI
Afatinib
starting 
dose
Comparator Patients per 
treatment group 
1200.32
LUX-Lung 3
Asia, Europe, 
North America, 
South America
Positive
First
No
40 mg
Chemo 1
Afatinib:230
Chemo: 115
1200.22
LUX-Lung 2
Taiwan, USA
Positive
First or 
second
No
40 mg or 
50 mg
None
129 (40 mg: 30; 
50 mg: 99)
1200.34
LUX-Lung 6
China, South 
Korea, Thailand
Positive
First
No
40 mg 
Chemo2
Afatinib: 242
Chemo: 122
1 Chemotherapy with pemetrexed/cisplatin


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2 Chemotherapy with gemcitabine/cisplatin
In study 1200.32 (LUX-Lung 3) treatment with afatinib resulted in a significantly prolonged 
PFS as compared to treatment with chemotherapy by independent review (median 11.1 vs 6.9 
months, HR 0.58; 0.43–0.78; p=0.0004). In patients with common EGFR mutations 
(Del19/L858R), the median PFS for afatinib treated patients was 13.6 months as compared to 
6.9 months for patients receiving PC (HR=0.47; 0.34-0.65; p<0.0001). The ORR for patients 
treated with afatinib (56%) was significantly higher than that for patients treated with PC 
(23%) (p<0.0001). The prolonged PFS and higher ORR observed in patients treated with 
afatinib were accompanied by significant delays (as compared to patients treated with PC) in 
time to deterioration of the cancer-related symptoms of cough (HR=0.60, p=0.0072) and 
dyspnoea (HR=0.68, p=0.0145). The pre-specified number of events necessary to evaluate 
Overall Survival (OS) has not yet been reached.
In the afatinib arm, the highest CTCAE Grade of AEs was Grade 3 in 51.1%, Grade 4 in 
3.9%, and Grade 5 in 5.7% of patients. In the chemotherapy arm, the highest CTCAE Grade 
of AEs was Grade 3 in 44.1%, Grade 4 in 9.9%, and Grade 5 in 2.7% of patients. The 
incidence of patients with AEs leading to dose reduction was 57.2% (afatinib) and 16.2% 
(chemotherapy). The incidence of AEs leading to treatment discontinuation was 14.0% 
(afatinib) and 15.3% (chemotherapy). Drug-related AEs leading to treatment discontinuation 
were experienced by 7.9% (afatinib) and 11.7% of patients (chemotherapy).  SAEs were 
reported in 28.8% (afatinib) and 22.5% (chemotherapy) of patients, 14.4% of patients in each 
treatment arm experienced drug-related SAEs. The most frequent SAEs related to treatment 
with afatinib were diarrhoea (6.6%) and vomiting (3.5%). The most frequent SAEs related to 
chemotherapy were vomiting (2.7%) and fatigue (2.7%). There were 13 deaths (5.7%) 
reported due to on-treatment AEs in the afatinib arm, with 4 of them (sepsis, dyspnoea, acute 
respiratory distress syndrome, and death) considered related to afatinib by the investigator. 
Three deaths (2.7%) were reported due to on-treatment AEs in the chemotherapy group; none 
of them were considered related to chemotherapy by the investigator. [U12-1199-01]
In study 1200.22 (LUX-Lung 2) confirmed objective responses in the first line setting were 
noted in 66% of 61 patients with a median PFS of 12.0 months (and of 13.7 months in 
patients with common EGFR mutation(s) by independent review. Median OS was not 
reached in the first line population. 
1200.34 (LUX-Lung 6)
More recent evidence of the benefits of afatinib versus chemotherapy in EGFR TKI-naïve 
asian patients with NSCLC was obtained in trial 1200.34, an open-label, randomized,  
Phase III trial of afatinib versus chemotherapy as first-line treatment for patients with Stage 
IIIB or IV adenocarcinoma of the lung harboring an EGFR activating mutation who had 
received no prior chemotherapy or EGFR-targeting drugs for  advanced NSCLC. The 
primary objective of the study was to assess the efficacy of afatinib as defined by 
progression-free survival (PFS) by central independent review and determined by Response 
Evaluation Criteria in Solid Tumors (RECIST). Secondary endpoints included ORR, disease 
control rate (DCR), duration of response, tumor shrinkage, overall survival (OS), patient-


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reported outcomes (PRO), and safety and pharmacokinetics of afatinib. A central test for 
EGFR mutations was carried out using the companion diagnostic TheraScreen® EGFR RGQ 
PCR kit. Three hundred and sixty four (364) patients were randomised in a 2:1 ratio to 
receive either afatinib (n=242) 40 mg daily continuous treatment in the absence of disease 
progression or adverse events, or Gemcitabine/Cisplatin (GC) (n=122), with Gemcitabine 
1000 mg/m2 on Day 1 and Day 8, with cycplatin 75 mg/m2 every 21 days up to 6 cycles. 
Baseline characteristics were well balanced between arms: overall the median age was 58 
years, 65% of patients were female, 77% were never-smokers and 94% had Stage IV disease. 
Regarding EGFR mutation status, 51% had deletions in exon 19 (Del19), 38% had the L858R 
mutation and 11% had a variety of other less common mutations.
As assessed by central independent review, treatment with afatinib resulted in a significantly 
prolonged PFS as compared to treatment with GC (median 11.0 vs. 5.6 months, HR 0.28, 
p<0.0001). The ORR for patients treated with afatinib (66.9%) was significantly higher than 
that for patients treated with GC (23%) (p<0.0001). The prolonged PFS and higher ORR 
observed in patients treated with afatinib were accompanied by significant delays (as 
compared to patients treated with GC) in time to deterioration of the cancer-related symptoms 
of cough (HR=0.45, p=0.0001) and dyspnoea (HR=0.54, p<0.0001). The pre-specified 
number of events necessary to Overall Survival (OS) has not yet been reached.
The incidence of patients with AEs leading to dose reduction was 32.2% in the afatinib arm 
and 26.5% in the chemotherapy arm. In the afatinib arm, drug-related AEs leading to 
treatment discontinuation were experienced by 5.9% of the patients as compared to 39.8% of 
the patients in the chemotherapy arm.  The most frequent reported afatinib-related AEs were 
diarrhoea, rash/acne and stomatitis. The most frequent reported chemotherapy-related AEs 
were nausea/vomiting, fatigue, and bone-marrow suppression. There were 14 deaths (5.9%) 
reported due to on-treatment AEs in the afatinib arm, and three deaths (2.7%) were reported 
due to on-treatment AEs in the chemotherapy group.  
Significant differences between the proportion of patients with improvements in lung cancer 
symptoms of cough, dyspnoea, and pain were observed with patient in afatinib arm compared 
to chemotherapy ( P13-06250). Taken together, these results support the efficacy data and 
conclusions of LUX-Lung 3.
Risks
Adverse events observed in the 359 patients treated with afatinib in the clinical studies 
described above plus 1544 patients treated in two other studies which were clinically 
enriched for EGFR mutations (1200.23 [U10-3048-01] and 1200.42 [U12-1167-01]) have 
been of a nature and severity expected for EGFR inhibitors. Diarrhoea, rash/acne, stomatitis, 
and lip, nail, and ocular effects represent the mechanistic effect of the inhibition of EGFR by 
afatinib. As such, diarrhoea and rash/acne were the most frequently reported AEs. Nearly all 
patients developed diarrhoea with an onset within 2 weeks of treatment exposure. Rash/acne 
occurred at a high incidence, beginning within 4 weeks of afatinib exposure for about half of 
cases. These events were mainly of Common Terminology Criteria for Adverse Events 
(CTCAE) Grade 1 or 2 with an incidence of CTCAE Grade 3 diarrhoea in the studies 


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described above of 14-20% and that for rash/acne 9-23%. The occurrence of CTCAE Grade 4 
diarrhoea or rash/acne was infrequent, <0.5% overall in these studies.
Most diarrhoea and rash/acne was adequately managed by a combination of pausing 
treatment, reducing the dose, and supportive treatment with loperamide for diarrhoea and 
topical antibiotics for rash. Dose reduction was required to manage common AEs in 
approximately half of patients treated with afatinib. Treatment related AEs that led to 
discontinuation occurred in 8% of afatinib treated patients in study 1200.32, and 9% in study 
1200.22. The frequency of discontinuation due to diarrhoea was <5% for afatinib treated 
patients in each of the aforementioned studies.
The low rates of discontinuation due to diarrhoea and rash/acne compared with the incidence 
of these events suggested that the protocol-defined dose reduction scheme and recommended 
medical management were effective and allowed patients to continue treatment with afatinib
for as long as there was clinical benefit. In study 1200.32 in which patients were randomised 
between treatment with afatinib and chemotherapy, overall treatment-related AEs led to 
discontinuation of therapy in 8% of patients receiving afatinib as compared to 12% of 
patients receiving pemetrexed/cisplatin in spite of the fact that the afatinib treatment patients 
remained on treatment for a significantly longer period.
In a pooled analysis of patients taking the 40 mg dose in monotherapy trials, the frequency of 
patients with serious adverse events were: diarrhoea (3.2%), vomiting (2.6%), dyspnoea 
(1.6%), metastases to central nervous system (1.4%), fatigue (1.0), pneumonia (1.0), and 
respiratory failure; all others occurred at a rate less than 1% (U12-1482-01).
Interstitial Lung Disease (ILD) or ILD-like events are a known and infrequent risk associated 
with EGFR inhibitor therapy and encompass a variety of clinical entities. Diagnosis is often 
made on clinical and/or radiographic findings and at times is difficult to distinguish from 
pulmonary processes, such as infection or malignancy. In afatinib monotherapy and 
combination therapy trials, adverse events identified as potential ILD or ILD-like, were 
reported infrequently (unadjudicated frequency 1.5%; investigator assigned drug related 
frequency 0.7%). The frequency of these events is similar to that observed with other EGFR 
inhibitors. [c01617169-04] As this is a known class effect of other EGFR/HER2 inhibitors, 
patients with known ILD will be excluded from this trial and careful monitoring of 
pulmonary symptoms with sudden onset is warranted in patients treated with afatinib.
Overall these findings demonstrate that for patients with EGFR mutation positive NSCLC the 
benefits of treatment with afatinib outweigh the associated risks. These patients experienced 
significant improvements in time to disease progression that were accompanied by significant 
and clinically meaningful improvements in disease related symptoms. Adverse events 
observed following treatment with afatinib have been of a nature and severity expected for 
EGFR inhibitors. Dose reduction was frequently required to manage common AEs, but the 
dose reduction scheme and the proposed supportive care described for common AEs allowed 
the vast majority of patients to remain on treatment for as long as there was clinical benefit.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is an open-label, multicentre, single arm trial, designed to evaluate the safety and 
efficacy of the investigational drug afatinib in patients with locally advanced or metastatic 
non-small cell lung cancer (NSCLC) harboring EGFR mutation(s) and have never been 
treated with an EGFR-TKI. EGFR mutation positivity of all patients needs to be established 
and documented prior to enrolment into the trial. Treated patients will visit the investigator at 
regular intervals as specified in the Flow chart.
All entered patients (i.e., patients that have been treated with the trial medication) will receive 
continuous treatment of afatinib in the absence of disease progression or meeting any other 
trial withdrawal criteria (see Section 3.3.4). In this trial, disease progression is determined by 
the investigator. Afatinib must be permanently discontinued when investigator judges that 
patient is no longer benefiting from treatment with afatinib. Enrolment of new patients into 
the trial will end once enrolment goal in the trial has been met and/or if any of the criteria in 
Section 3.3.4.2 are met.
All patients will visit the investigator at regular intervals for assessment of safety as outlined 
in the Flow Chart. The investigator will assess the patient at each visit and record adverse 
events.  Investigator can perform radiological assessment according to local standard of care
at his discretion. Clinical benefit will be assessed at each visit (i.e., every 28 days) based on 
change in cancer-related symptoms. 
Patients meeting withdrawal criteria will stop treatment with afatinib and undergo End of 
Treatment (EOT) visit. After end of treatment, all AEs, including those persisting are 
followed-up for up to 28 days and it should be confirmed if they have resolved or sufficiently 
characterised. The end of the trial is defined as “last patient out”, ie. Follow-up (refer to 
Section 3.3.4.1) completed by last patient.
Investigators in this trial will be physicians experienced in treating patients with NSCLC and 
who can complete the site qualification and initiation process.
3.1.1
Administrative structure of the trial
This trial is sponsored by Boehringer Ingelheim (BI).
Boehringer Ingelheim (BI) will appoint a Trial Clinical Monitor (TCM), responsible for 
coordinating the activities required in order to manage the trial in accordance with applicable 
regulations and internal Standard Operating Procedures (SOPs), directing the clinical trial 
team in the preparation, conduct, and reporting of the trial, ordering the materials as needed 
for the trial, ensuring appropriate training and information of a local Clinical Monitor Local 
(CML), Clinical Research Associates (CRAs), and investigator.


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Data Management and Statistical evaluation will be performed by BI and/or a Contract 
Research Organization (CRO) according to BI SOPs. A BI: Trial Data Manager (TDM), Trial
Statistician (TSTAT) and Trial Programmer will provide oversight for these activities.
Tasks and functions assigned in order to organize, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons will be provided in the Clinical 
Trial Master File (CTMF) document.
The organization of the trial will be done by the respective local BI-organization Operating 
Unit (OPU) or by a CRO with which the responsibilities and tasks will have been agreed and 
a written contract filed before initiation of the clinical trial. A CML will be appointed and 
will be responsible for coordinating the activities required in order to manage the trial in 
accordance with applicable regulations and internal SOPs.
The coordinating investigator is an investigator participating in the trial that has experience of 
this type of trial and investigations. The coordinating investigator has been designated by BI 
and will sign the Clinical Trial Report (CTR). 
The trial will be performed by investigators specialized in the treatment of lung cancer.
Documents on the coordinating investigator and other important participants, especially their 
curricula vitae, will be filed in the CTMF. 
Details on handling of the trial supplies including responsible institutions are given in Section 
4 of this protocol.
All relevant trial documentation will be stored in the CTMF at BI. In addition each site will 
have an Investigator Site File (ISF) containing all trial documents relevant for the site, as 
required by local regulation and BI SOP.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
The primary objective of this trial is to assess the safety of afatinib in patients with NSCLC. 
This trial is a single-arm, open-labeled study. 
3.3
SELECTION OF TRIAL POPULATION
A log of all patients screened/enrolled into the trial (i.e., patients who provided consent) will 
be maintained in the ISF at the investigator’s site regardless of whether they have been 
treated with the investigational drug or not. This trial will recruit approximately 500 patients 
at approximately 40 sites within China, Hong Kong, India, Singapore and Taiwan.
Participation in this trial will be available to patients with advanced NSCLC who meet all the 
eligibility requirements specified in Sections 3.3.2 and 3.3.3 (i.e., inclusion and exclusion 
criteria).


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3.3.1
Main diagnosis for study entry 
All patients should have locally advanced or metastatic NSCLC harboring EGFR mutation(s)
and have never been treated with an EGFR-TKI.
3.3.2
Inclusion criteria
Patients with:
1) locally advanced or metastatic Non-Small Cell Lung Cancer (NSCLC)
2) presence of Epidermal Growth Factor Receptor (EGFR) mutation in tumour biopsy. 
Results of EGFR mutation must be available before enrolment in this trial. No 
rebiopsy is required for purpose of this trial. 
3) male or female patients age ≥18 years (For India only, male or female patients age ≥18 
years and ≤75 years)
4) adequate organ function, defined as all of the following:
a.
Absolute Neutrophil Count (ANC) > 1500/mm3. (ANC >1000/mm3 may be     
considered in special circumstances such as benign cyclical neutropenia as 
judged by the investigator and in discussion with the sponsor).
b. Platelet count >75,000/mm3
c.
Serum creatinine 1.5 times of the upper limit of normal
d. Total Bilirubin < 1.5 times upper limit of (institutional) normal (Patients with
Gilbert’s syndrome total bilirubin must be <4 times institutional upper limit of 
normal).
e.
Aspartate Amino Transferase (AST) and Alanine Amino Transferase (ALT) < 
three times the upper limit of (institutional) normal (ULN) (if related to liver 
metastases < five times ULN). 
5) ECOG score between 0 – 2
6) written informed consent by patient or guardian prior to admission into the trial that is 
consistent with International Conference on Harmonisation (ICH)- Good Clinical 
Practice (GCP) guidelines and local law.
3.3.3
Exclusion criteria
Patients who or with:
1) prior treatment with an EGFR tyrosine kinase inhibitor (TKI)


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2) use of anti-cancer treatment within 2 weeks prior to start of trial treatment (continued 
use of anti-androgens and/or gonadorelin analogues for treatment of prostate cancer 
permitted) 
3) radiotherapy within 4 weeks prior to drug administration, except as follows:
a.
Palliative radiation to organs other than chest may be allowed up to 2 weeks 
prior to drug administration, and
b. Single dose palliative treatment for symptomatic metastasis outside above 
allowance to be discussed with sponsor prior to enrolling.  
4) major surgery within 4 weeks from day 1 of first dose of afatinib. At least 7 days 
should have elapsed since minor surgical procedure including placement of an access 
device or fine needle aspiration and at least 14 days for diagnostic or palliative video-
assisted thoracoscopic surgery (VATS).
5) known hypersensitivity to afatinib or any of its excipients (see Section 4.1.1)
6) history or presence of clinically relevant cardiovascular abnormalities such as 
uncontrolled hypertension, congestive heart failure New York Heart Association
(NYHA) classification of >3 (Refer to Appendix 10.2), unstable angina or poorly 
controlled arrhythmia as determined by the investigator. Myocardial infarction within 
6 months prior to starting trial treatment.
7) Women of Child-Bearing Potential (WOCBP) and men who are able to father a child, 
unwilling to be abstinent or use medically acceptable method of contraception during 
the trial entry and for at least 4 weeks after treatment has ended. Adequate methods of 
contraception and Women of Child-Bearing Potential described in Section 4.2.3.  
Perimenopausal women must be amenorrhoeic for at least 24 months to be considered 
for non-childbearing potential.
8) childbearing potential (see Section 4.2.3) who:
a.
are nursing or
b. are pregnant or
c.
are not using an acceptable method of birth control, or do not plan to continue 
using this method throughout the trial and/or do not agree to submit to 
pregnancy testing required by this protocol
9) history of or co-existing condition that, in the opinion of the investigator, would 
compromise the patient’s ability to comply with the trial or interfere with the 
evaluation of safety for the trial drug
10) previous or concomitant malignancies at other sites, except effectively treated non-
melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or 


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effectively treated malignancy that has been in remission for more than 3 years and is 
considered to be cured.
11) requiring treatment with any of the prohibited concomitant medications listed in 
Section 4.2.2 that cannot be stopped for the duration of trial participation
12) known pre-existing interstitial lung disease
13) presence of poorly controlled gastrointestinal disorders that could affect the 
absorption of the trial drug (e.g. Crohn’s disease, ulcerative colitis, malabsorption, or 
CTC grade ≥2 diarrhoea of any aetiology) based on investigator assessment.
14) Known active hepatitis B infection (defined as presence of Hepatitis B (HepB) sAg 
and/or HepB DNA), active Hepatitis C (HEP C) infection (defined as presence of Hep 
C RNA) and/or known Human Immunodeficiency Virus (HIV) carrier.
15) meningeal carcinomatosis
16) symptomatic brain metastases (patients with brain metastases, who were previously 
treated, are eligible provided they have asymptomatic brain metastasis for at least 4 
weeks on stable doses of medication) 
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
The investigator or patient themselves may stop trial treatment at any time for safety or 
personal reasons.
If a patient is entered in violation of inclusion/exclusion criteria, the sponsor, in discussion 
with the investigator, will determine the medical risk/benefit on a patient-by-patient basis and 
can require such a patient be discontinued from the trial treatment.
The investigator or the sponsor may permanently discontinue a patient’s participation at any 
time for any of the following reasons:

patient withdraws consent, without the need to justify the decision

patient fails to follow protocol requirements/directions and represent a safety issue for 
the patient

eligibility criteria are violated and represent a safety issue for the patient

patient requires concomitant medication which may interfere with the trial medication 
(see Section 4.2.2)

patient is no longer able to participate for other medical reasons (e.g., surgery, adverse 
events or other diseases)

adverse events that cannot be managed by dose reduction

further dose reductions considered necessary but not allowed according to the 
protocol (see Section 4.1.4.1)


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
patient is found to be pregnant during trial participation (please refer to Table 4.2.3: 1) 

is diagnosed with interstitial lung disease (ILD)

change in patient’s status creating an unfavourable risk/benefit in favour to stop trial
treatment. 

termination of the trial

Start of any other anti-cancer treatment
When discontinuation is due to a AE/SAE the investigator must follow the event until it is 
resolved, becomes chronic, or remains stable with no resolution expected. Data on these 
events must be collected in the electronic case report form (eCRF). For guidelines in the 
management of class expected adverse events, refer to Appendix 10.1.
The sponsor may remove patients from the study after completion of the primary analysis if 
the patient has access to afatinib through marketed product, an expanded-access program, 
named patient use program, or compassionate use protocol or other means based on local 
regulation. The cost of any ongoing supply of afatinib will be incurred by the sponsor. If a 
patient is removed from the study treatment, an end of treatment and follow-up visit will be 
performed to ensure all adverse events are reported and followed up.
3.3.4.1.1    Patient discontinuation of trial participation
Patients who discontinues from the treatmentl, will complete an End of Treatment (EOT) 
visit (see Section 6.2.3) and then a Follow Up (FU) visit 28 days later (see Section 6.2.4). 
If a patient withdraws consent for any further trial procedures and follow-up activities, no 
additional trial assessments will be completed. This will be documented in the eCRF.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Emergence of any efficacy/safety information that could significantly affect continuation 
of the trial
2. Violation of GCP, the Clinical Trial Protocol (CTP), or the contract by a trial site staff or 
investigator, disturbing the appropriate conduct of the trial.
3. Discontinuation or modification of the clinical development program with afatinib for any 
reason.
4. At the discretion of the sponsor (BI).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
Boehringer Ingelheim will provide the investigational product afatinib. 
4.1.1
Identity of BI investigational product and comparator product
Substance (INN):
afatinib (BIBW 2992)
Pharmaceutical form:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
40, 30, and 20 mg film-coated tablets (the dose of afatinib in 
the film-coated tablets is related to the free base equivalent of 
afatinib)
Daily dose:
40 mg with an option to reduce the dose based on individual 
tolerability (see Section 4.1.4.1). 
Duration of use:
Continuous daily dosing, one cycle consists of 28 days. 
Patients are eligible for repeated treatment cycles in the 
absence of symptomatic disease progression or other trial
withdrawal criteria.
Route of administration:
Oral (swallowed)
Posology:
Once daily
Excipients
Core Tablet: Lactose monohydrate, Microcrystalline 
cellulose, Colloidal silicon dioxide, Crospovidone, and 
Magnesium stearate. Film-coat: Hypromellose 2910, 
Polyethylene glycol 400, Titanium dioxide, Talc, FD&C 
Blue No. 2 11-14% (may not be included in 20 mg tablet), 
and Polysorbate 80.
4.1.2
Method of assigning patients to treatment groups
An enrolment form should be faxed to the sponsor, or designee, as soon as written informed 
consent has been obtained. The form and instructions will be provided in the ISF. Patients 
who meet all eligibility criteria will be entered into the trial. Enrolment of new patients into 
the trial will end once enrollment goal, (500 patients) in the trial has been met and/or if any of 
the criteria in Section 3.3.4.2 are met. 
There is no comparator group in this trial. All eligible patients will receive afatinib.
4.1.3
Selection of doses in the trial
The starting dose for patients is 40 mg once daily, continuously. This dose was selected based 
on the results from the LUX-Lung 2/1200.22 (P12-03681) [U11-3644-01] study (see Section 
1.1 and the current version of the Investigator's Brochure, (c01617169-04) as well as the 
results of the LUX-Lung 3 (1200.32) study.


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4.1.4
Drug assignment and administration of doses for each patient
Medication will be dispensed in bottles containing 30 tablets at the beginning of each
treatment cycle. For administrative purposes treatment will be divided into treatment cycles, 
which are each 4 weeks (28 days) in duration. Patients will take a single oral dose of afatinib
each day. Treatment will stop when the patient meets withdrawal criteria listed in Section 
3.3.4.1. Trial drug will be prescribed by the investigator and may be dispensed either by the 
investigator or designee.
The dose of afatinib for this trial is 40 mg. All dose reductions will be based on individual 
tolerability (see Section 4.1.4.1). Each dose reduction will be by 10 mg and no reduction is 
allowed less than 20 mg dose. Patients who are unable to tolerate 20 mg dose must be 
permanently discontinued from trial. 
The medication should be taken at approximately the same time each day. Food should not be 
ingested for at least three hours before and at least one hour after taking afatinib film-coated 
tablets.
If the patient does not meet any of the criteria on Table 4.1.4.1: 1 then the dose of afatinib
should remain on the 40 mg dose (unless dose reduction is necessary - see Section 4.1.4.1). 
Dose escalation is prohibited.
Patients will take a single oral dose of afatinib daily. The tablet should be swallowed with a 
glass of water (~250 Milliliter (mL)). Afatinib tablets are film-coated and therefore should 
not be chewed or crushed, but may be administered after dispersing the afatinib tablets 
according to the following procedure: 
If dosing of whole tablets is not possible, afatinib tablets can also be dispersed in 
approximately 100 ml of non-carbonated drinking water. No other liquids should be used. 
The tablet should be dropped in the water, without crushing it, and occasionally stirred for up 
to 15 Minutes (min) until the tablet is broken up into very small particles. The dispersion 
should be drunk immediately. The glass should be rinsed with approximately 100 ml of water 
which should also be drunk. The dispersion can also be administered through a gastronomy 
tube (G-tube).
If a dose of afatinib is missed, it should be taken during the same day as soon as the patient 
remembers. However, if the next scheduled dose is due within eight hours then the missed 
dose must be skipped.
4.1.4.1
Dose reduction scheme
Treatment related adverse events will be managed by treatment pauses and subsequent dose 
reductions of afatinib according to the schedule described in Table 4.1.4.1: 1. Dose 
reductions will apply to individual patients only. Once the dose has been reduced, it cannot 
be increased later.


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The investigator is responsible for determining the necessity and frequency of any 
additional/unscheduled visits as well as the extent of the evaluation (e.g., physical
examination, laboratory testing, adverse events, etc.) performed at these visits. At a minimum 
the investigator should note in the patient’s chart when an additional/unscheduled visit occurs 
and make relevant entries on the AE and medication dispensing eCRFs. 
To prevent the development of more severe adverse events, treatment related diarrhoea, 
nausea and vomiting or rash should be managed early and proactively as described in 
Appendix 10.1.
Table 4.1.4.1: 1
Dose reduction scheme
AE type and CTC-AE*Grade
Action
Dose Reduction Scheme
Events related to trial drug:
Diarrhoea
Grade 2 persisting for 2 or more 
consecutive days (48 hours) 
despite adequate anti-diarrhoeal 
medication/hydration 
Reduced renal function
to ≥ Grade 2 as measured by serum 
creatinine, proteinuria or decrease 
in glomerular filtration rate of more 
than 50% from baseline
Any drug related AE Grade ≥3
Pause treatment until 
patient has recovered 
to Grade ≤1 or 
baseline1.
Resume treatment at a 
reduced dose 
according to the Dose 
Reduction Column.
If patient has not 
recovered to Grade ≤1 
or baseline1 within 6 
weeks trial treatment 
must be permanently 
discontinued2.
Resume with dose reduction by 10mg 
decrements.
If patient cannot tolerate 20mg/day, 
permanent discontinuation of afatinib
should be considered.
Acute onset and/or unexplained 
worsening of pulmonary systems 
(dyspnoea, cough, fever)
Pause afatinib while 
clinical assessment to 
exclude ILD is 
completed.
If ILD is ruled out as a cause of 
symptoms, grade symptoms and 
relatedness and report as AEs. If AEs 
are not related, resume afatinib at current 
dose. If AEs are drug related, follow 
directions in row above. 
If ILD is confirmed, discontinue 
afatinib.
* The intensity of clinical adverse events graded by the Common Terminology Criteria for Adverse Events v 3.0 
(CTC-AE)
1 Baseline is defined as the CTCAE Grade at the start of treatment
2 In the event that the patient is deriving obvious clinical benefit according to the investigator’s judgment, further 
treatment with afatinib will be decided by the investigator.
After treatment pause due to drug related adverse events, treatment with afatinib can be 
resumed after patient recovers to < Grade 1 or baseline. Dose reduction should always follow 
a treatment pause for drug related AE more than grade 1. In the event of any unrelated 
adverse events, the investigator may choose to pause the medication to allow the patient to 
recover, but no dose reduction is required.
Patients will discontinue treatment if they experience deterioration in left ventricular cardiac 
function (LVEF) to CTCAE Grade ≥3.


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In the event of any unrelated adverse events, the investigator may choose to interrupt the 
medication for up to 14 days, but no dose reduction is required and is at the discretion of the 
investigator. If the medication is continuously interrupted for more than 14 days, the decision 
to continue with afatinib will be made by the investigator following discussion with the 
sponsor. Investigator can consider permanently discontinue the patient from the trial if they 
have been off trial medication for more than 6 weeks.
4.1.5
Blinding and procedures for unblinding
Not applicable since this is an open-label trial.
4.1.6
Packaging, labelling, and re-supply
Afatinib will be supplied by BI (or a designated 3rd party drug distribution vendor) as film-
coated tablets in High-Density Polyethylene (HDPE) or Polypropylene (PP), child-resistant, 
tamper-evident bottles. Available dosage strengths will be 40 mg, 30 mg and 20 mg. Each 
plastic bottle will contain 30 tablets of identical dosage strength. Each bottle will be labelled 
according to dosage strength and will also include the trial number, medication number, 
expiry (‘use by’) dates, and instructions for use. Examples of the labelling of the bottles are 
found in the ISF.
Adequate supply of afatinib bottles will be dispensed at each visit to last until the next 
scheduled visit. Afatinib must be dispensed in the original bottles. Patients should be 
instructed to keep the bottles tightly closed to protect from moisture.
4.1.7
Storage conditions
Afatinib bottles must be kept in a secure, limited access storage area (to authorized people)
under storage conditions defined on bottle label until supplied/administered to patient. 
Temperature logs must be maintained to make certain that the afatinib supplies are stored at 
the correct temperature. Facilities that have a central temperature alarm do not have to 
maintain a log; however, a note to file should be kept in the ISF describing the system and the 
procedure in the event of an alarm. If a site does not have an acceptable central temperature 
alarm system then the Min/Max temperatures will be documented using a calibrated 
thermometer with a valid calibration certificate to ensure storage conditions per label. In the 
event that the temperature would be out of range, this has to be documented in the ISF and 
reported to the sponsor according the Storage conditions for Trial Medications (STORM) in 
the ISF.
Afatinib must be stored in the original package in order to protect from light. Film-coated 
tablets are humidity sensitive, therefore bottles must be kept tightly closed to protect from 
moisture. Tablets must be stored according to the storage instructions on the bottle label and 
in the ISF.


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4.1.8
Drug accountability
Drug supplies, which will be provided by the sponsor, must be kept in a secure, limited 
access storage area under the storage conditions defined by the sponsor.  Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature.
The investigator, pharmacist, or investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor or designee when the following requirements 
are provided / fulfilled:

approval of the clinical trial protocol by the Institutional Review Board (IRB)/Ethics 
Committee (EC), 

availability of a signed and dated clinical trial contract between the sponsor and the 
investigator /institution,

approval/notification of the regulatory authority, e.g. competent authority,

availability of the curriculum vitae of the principal investigator,

availability of a signed and dated clinical trial protocol, or immediately imminent signing 
of the clinical trial protocol

proof of a medical license for the principal investigator, 
The investigator, pharmacist, or investigational drug storage manager must maintain records 
of the product’s delivery to the trial site, the inventory at the site, the use by each patient, and 
the return to the sponsor or alternative disposition of unused product(s). 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers (i.e., medication numbers) assigned to the investigational product(s) 
and trial patients. The investigator, pharmacist, or investigational drug storage manager will 
maintain records that document adequately that the patients were provided the doses specified 
by the CTP and reconcile all investigational product(s) received from the sponsor. At the time 
of return to the sponsor and/or appointed CRO the investigator /pharmacist/investigational 
drug storage manager must verify that all unused or partially used drug supplies have been 
returned by the clinical trial patient and that no remaining supplies are in the investigator’s
possession.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment
Rescue medication
Rescue medications to reverse the action of afatinib are not available. There is no specific 
antidote for overdosage with afatinib. In cases of suspected overdose, afatinib should be 
withheld and supportive care initiated. If indicated, elimination of unabsorbed afatinib may 
be achieved by emesis or gastric lavage. Potential adverse events should be treated 
symptomatically. The current version of the Investigator Brochure (IB) lists the AEs expected 


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with afatinib ( c01617169-04 ). Common adverse events of treatment with afatinib with 
specified management recommendations and/or requirements include diarrhoea, 
stomatitis/mucositis, and rash/acne. To improve tolerability and the probability of clinical 
benefit, patients should receive prompt and appropriate supportive care at the first signs of 
symptoms. Suggested treatments for AEs are described in Appendix 10.1. Symptomatic 
treatments of side effects or tumour -associated symptoms are allowed.
Emergency procedures
Careful assessment of all patients with an acute onset and/or unexplained worsening of
pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude Interstitial 
Lung Disease (ILD). Trial drug should be paused pending investigation of these symptoms. If 
interstitial lung disease is diagnosed, trial drug must be permanently discontinued and 
appropriate treatment instituted as necessary.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In this trial supportive treatments will be defined as the best care available judged by the 
investigator, according to the institutional standards for each center. Concomitant 
medications (or therapy) to provide adequate care may be given as clinically necessary.
For symptom control, palliative radiation therapy or total VATS is allowed. After trial 
enrolment, palliative radiotherapy may be given for bone pain or for other reasons (e.g. 
bronchial obstruction, skin lesions), provided that the total dose delivered is in a palliative 
range according to institutional standards. During palliative radiotherapy, trial treatment 
should be delayed and may be resumed once the patient has recovered from any radiation 
associated toxicity. If medication is continuously interrupted for more than 14 days, the 
decision to continue will be made by the investigator following discussion with the sponsor. 
All concomitant therapy must be recorded in the patient’s chart during the screening and 
treatment period, starting from the date of signature of informed consent, and ending at the 
Follow-Up Visit (FU). 
In case of major surgery (as judged by the investigator), it is recommended to stop treatment 
with afatinib around one week prior to the surgery, and to restart treatment after complete 
wound healing, provided that complete wound healing occurs ≤ 6 weeks.
Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy, 
hormone treatment (with the exception of megestrol acetate and use of anti-androgens and/or 
gonadorelin analogues for treatment of prostate cancer), or radiotherapy (other than palliative 
radiotherapy for symptom control) is not allowed concomitantly with the administration of 
trial treatment.
Afatinib is a substrate of the P-gp transporter. Strong inhibitors of P-gp (including: 
Amiodarone, Azithromycin, Captopril, Carvedilol, Clarithromycin, Conivaptan, 


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Cyclosporine, Diltiazem, Dronedarone, Erythromycin, Felodipine, Itraconazole, 
Ketoconazole, Lopinavir, Nelfinavir, Ritonavir, Quinidine, Ranolazine, Saquinavir, 
Tacrolimus, Ticagrelor, Verapamil) if administered prior to afatinib may lead to increased 
exposure to afatinib and therefore should be used with caution. If P-gp inducers (including:
Carbamazepine, Phenytoin, Rifampicin, St John’s Wort, Phenobarbital Salt, Tipranavir, 
Ritonavir) need to be taken, they should be administered simultaneously with or after 
afatinib. Concomitant treatment with strong inducers of P-gp may decrease exposure to 
afatinib (U12-1482-01).As the information on potent inhibitors and inducers of P-
glycoprotein may evolve, it is important for the investigator to assess such status on 
concomitant therapies.
4.2.2.2
Restrictions on diet and life style
Patients should be advised to avoid any foods known to aggravate diarrhoea (see Appendix
10.1.1).
To prevent skin related adverse events it is recommended to avoid long exposure to sunlight 
and intense exposure to UV light and/or harsh detergents (pH5 neutral), see also Appendix
10.1.2.
4.2.3
Contraception and pregnancy
Female patients must have a negative pregnancy test (β-HCG test in urine or serum) prior to 
commencing trial treatment.
Females will be considered to be of childbearing potential unless surgically sterilized by 
hysterectomy or bilateral tubal ligation/salpingectomy, or post-menopausal for at least two 
years. Women of childbearing potential who are sexually active and unwilling to be abstinent 
or to use an acceptable method of birth control during the trial and for at least 28 days after 
the end of active therapy are not allowed to participate in the trial.
Acceptable methods of contraception for females include abstinence, hormonal contraception 
and double barrier method. Double barrier method of contraception is defined as two barrier 
methods used simultaneously each time the patient has intercourse. Accepted barrier methods 
include diaphragm, female condom, cervical cap, male condom and Intrauterine Device 
(IUD) (the diaphragm and cervical cap must be used in conjunction with spermicidal 
jelly/cream). If hormonal contraceptives are used, at least one barrier method should also be 
used. Partner vasectomy, natural 'rhythm' and spermicidal jelly/cream are not acceptable as 
methods of contraception. Female patients who are not of childbearing potential due to being 
postmenopausal (2 years without menses) or surgical sterilization (oophorectomy, 
hysterectomy and/or tubal ligation) do not need to use contraception.
Male patients should use adequate contraception (e.g., condom and spermicidal jelly) during 
the trial and for at least 28 days after the end of active therapy.
If a woman becomes pregnant during the treatment period this must be reported as a drug 
exposure during pregnancy case, even if no event occurred. For cases of paternal exposure to 


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the BI product during the trial, the pregnancy (mother is not a participant in the trial) has also 
to be reported to BI, if the father (participant in the trial) voluntarily reports it to the 
investigator.
In both cases the pregnant woman has to be followed up until birth of the baby; then it has to 
be reported whether the woman had a normal delivery or not and whether the newborn 
showed any pathological findings. 
If pregnancy is associated with a SAE, both, SAE form and pregnancy monitoring form must 
be completed.
Table 4.2.3: 1
Pregnancy reporting
Timing of pregnancy
Action
Prior to commencing 
trial medication
Patient should be withdrawn from the trial immediately, as per 
exclusion criteria #7. No reporting necessary.
During trial treatment
Treatment must be stopped immediately and the pregnancy 
should be reported to the sponsor immediately using the 
pregnancy monitoring form (Part A). If the investigator wishes 
to give any further treatment with trial medication, this must 
be discussed and agreed upon with the BI clinical monitor. If 
trial medication is continued despite pregnancy, a risk/benefit 
analysis should be documented. 
The pregnancy should be followed up to final outcome and the 
outcome, including the health status of the newborn and/or any 
premature termination should be reported to the sponsor on the 
pregnancy monitoring form (Part B) (refer to Section 5.2.2.2).
If a pregnancy is accompanied by an SAE, an SAE form must 
also be completed. In addition, any event leading to the 
termination of pregnancy (i.e. spontaneous, accidental, or 
induced abortion; as well as miscarriage, intrauterine foetal 
demise/death) must be reported as an SAE.
End of Treatment 
(EOT) though Follow-
up visit
The pregnancy should be reported to the sponsor immediately 
using the pregnancy monitoring form (Part A).
The pregnancy should be followed up to final outcome and the 
outcome, including the health status of the newborn and/or any 
premature termination should be reported to the sponsor on the 
pregnancy monitoring form (Part B).
If a pregnancy is accompanied by an SAE, an SAE form must 
also be completed. In addition, any event leading to the 
termination of pregnancy (i.e. spontaneous, accidental, or 
induced abortion; as well as miscarriage, intrauterine foetal 


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demise/death) must be reported as an SAE.
4.3
TREATMENT COMPLIANCE
The trial medication will be given to the patient in accordance with the protocol and the 
instructions of the investigator. The appropriate number of afatinib tablets will be provided to 
the patient to be self-administered at home.  Patients will be asked to return all unused trial
medication at each visit. It is the investigator’s or his delegate’s responsibility to conduct 
compliance check at each of these returns.   At the end of each visit, remaining medication 
will be collected.  Discrepancies between the number of tablets remaining and the calculated 
number of tablets that patients should have taken will be documented and explained.  If the 
patient is eligible for a further course of treatment, of a new bottle will be dispensed.
Patients experiencing emesis should not take a replacement dose.  Afatinib must not be taken 
more than once a day under any circumstances.
A maximum of 20% of the dispensed afatinib doses may be missed for other reasons aside 
from drug-related AEs or instructions from investigator. Patients who miss afatinib treatment 
more frequently are considered non-compliant. All overdoses are considered as non-
compliance. 


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5.
VARIABLES AND THEIR ASSESSMENT
The primary endpoint of this study is the safety assessment; refer to Section 5.2.1 for a 
description of safety endpoints. 
5.1
EFFICACY 
Efficacy assessments are secondary endpoints.
5.1.1
Endpoints of efficacy
Time to symptomatic progression (TTSP) is defined as the time from first administration of 
afatinib to the date of first documented clinically significant symptomatic progression that 
requires change in or stopping anti-cancer treatment according to investigator’s assessment.
5.1.2
Assessment of efficacy
Progression will be assessed by investigator. Lung cancer-related symptoms will be assessed 
by investigator at each visit. The date in which patient experiences progression requiring 
change in anti-cancer medication or stopping trial treatment will be defined as date of
clinically significant symptomatic progression. 
Although radiological assessments are not part of this study, the investigators will be allowed 
to perform imaging assessments at their discretion. Radiological progression may not occur at 
same time point as symptomatic progression. . 
 
 
 
 
 
 
 


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5.2
SAFETY
5.2.1
Endpoints of safety
The primary endpoint for safety assessment is number of patients with serious adverse events 
(SAEs). 
Number of patients with adverse events assessed by the treating physician as related to 
afatinib will be evaluated as a secondary endpoint.
Safety will also be assessed by adverse events according to Common Terminology Criteria 
(CTCAE Version 3) in a descriptive fashion.
No confirmatory safety analysis is planned.
Please refer to Section 5.2.2.2 for details on the collection and reporting of adverse events 
and SAEs.
5.2.2
Assessment of adverse events
Safety assessments will consist of monitoring and recording all adverse events (AEs) and 
serious adverse events (SAEs) and includes daily record of diarrhea status as reported by the 
patient.  In addition, any SAE that the investigator becomes aware of after the FU visit (End 
of Residual effect Phase) which is considered related to trial medication or trial design must 
also be reported.  Residual Effect Phase is defined as >28 days after last trial drug 
administration.
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions.


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The following hospitalizations are not considered to be serious adverse events (SAEs) 
because there is no “adverse event” (i.e., there is no untoward medical occurrence) associated 
with the hospitalization:

Hospitalizations for respite care 

Hospitalization planned prior to informed consent (where the condition requiring the 
hospitalization has not changed post trial drug administration)
Intensity of adverse event
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0 in the eCRF.
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms.
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE.
Worsening of underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the eCRF.
If progressive disease occurs and is associated with symptoms , the term “Progressive 
Disease” should not be reported as AE, however, signs and symptoms of progressive disease 
will be reported as an (S)AE (if applicable). Exception to this: Death due to progressive 
disease and where no signs or symptoms are available should be reported as “malignant 
neoplasm progression (grade 5, outcome fatal).” 
Changes in vital signs, physical examination, and laboratory test results 
Changes in vital signs, physical examination and laboratory test results will be recorded as an 
(S)AE in the (e)CRF , if they are judged clinically relevant by the investigator.
If the investigator determines any protocol-specific significant event is related to trial drug, 
the administration of the trial drug must be managed according to Section 4.1.4.1 of the 
protocol.
Expected Adverse Events


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For expected (listed) AEs of afatinib, see the current version of the IB ( c01617169-04). 
5.2.2.2
Adverse event and serious adverse event reporting
Table 5.2.2.2: 1
AE/SAE reporting requirements
Time period
Reporting requirements
From signing of informed consent to ≤28 
days after last trial drug administration
Report all AEs and SAEs regardless of 
relatedness or whether the trial drug was 
administered. This includes all deaths.
Post-treatment. (Residual Effect Phase) (>28 
days after last trial drug administration)
Report any SAE that the treating physician 
becomes aware of after the FU visit (End of 
Residual Phase) which is considered related 
to trial medication or trial design. This 
includes all deaths. 
A diagram of the Adverse Event/Serious Adverse Event reporting requirements is provided in 
Appendix 10.3. 
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non-serious
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the event.  If the event description is correct, the 
item “serious” needs to be ticked and an SAE has to be reported in expedited fashion 
following the same procedure as above. The list of these adverse events can be found via the 
RDC-system.
The investigator must report the following events using the SAE form immediately (within 
24 hours) to the sponsor: SAEs, non-serious AEs relevant to a reported SAE, adverse events 
of special interest. Further details regarding AE reporting procedure are provided in the ISF.
Pregnancy
Pregnancy is an exclusion criterion in this trial.
In rare cases, pregnancy might occur in clinical trials and observational trials. In such cases 
the actions delineated in Table 4.2.3: 1 should be followed. 
Once a female subject has been entered into the clinical trial, after having taken trial
medication, the investigator must report immediately any drug exposure during pregnancy to 
the sponsor. Drug exposure during pregnancy has to be reported immediately (within 24 
hours) to the defined unique entry point for SAE forms of the respective BI OPU (country-
specific contact details will be provided in the Investigator Site File). The outcome of the 
pregnancy associated with the drug exposure during pregnancy must be followed up. In the 


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absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical Trials, not the SAE 
form, is to be completed. The ISF will contain the Pregnancy Monitoring Form for Clinical 
Trials (Part A and Part B). In the presence of an (S)AE, both the Pregnancy Monitoring Form 
for Clinical Trials and the SAE form must be completed (see Table 4.2.3: 1).
5.2.3
Assessment of safety laboratory parameters
Safety laboratory samples will be analyzed at the investigator’s local laboratory. Safety 
laboratory examinations will include haematology and biochemistry examinations. All 
laboratory tests mentioned in Table 5.2.3: 1 should be performed at screening (Visit 1) and 
every 12 weeks thereafter. All other laboratory testing is optional and should be performed at 
the discretion of the investigator and in accordance to the current standard of care. The 
recommended safety laboratory examinations laboratory tests can also be found in Table 
5.2.3: 1.
Table 5.2.3: 1
Clinical laboratory tests
Category
Parameters
Haematology
Haemoglobin, platelet count, and White Blood Cell (WBC), ANC
Chemistry
Electrolytes:
Sodium, and potassium
Liver function tests:
Alkaline phosphatase, aspartate amino transferase (AST/SGOT), alanine amino 
transferase (ALT/SGPT), γ-glutamyltransferase (GGT), total bilirubin
Renal function parameters:
Blood urea/Blood Urea Nitrogen (BUN), creatinine 
Other:
Glucose, albumin, phosphorus, lactate dehydrogenase (LDH), total protein, 
Urinalysis
pH, protein, glucose, blood/erythrocytes, leucocytes, nitrite; in case of clinically 
significant finding  further evaluation should be performed and results documented. 
Dipstick testing is sufficient. 
Pregnancy 
test
β-HCG testing in urine or serum in Women Of Child-Bearing Potential (WOCBP) 
(see Section 4.2.3)
5.2.4
Electrocardiogram
Twelve-lead ECGs will be only performed at the discretion of the investigator in accordance 
to local current standard of care for patients.


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5.2.5
Assessment of other safety parameters
5.2.5.1
Physical examination 
A general physical examination (which includes measurement of height (in cm) and body 
weight (in kg)) will be performed at screening and at the time points specified in the Flow
chart. 
5.2.5.2
Vital signs
Vital signs (blood pressure and pulse rate after two minutes rest) and temperature (preferably 
oral and/or tympanic: if other locations are used the same location should be used at each 
time point when body temperature is measured) will be recorded at the time points specified 
in the Flow chart.
5.2.5.3
Left ventricular function
Left Ventricular Ejection Fraction (LVEF) as measured by Echocardiography (ECHO) or 
Multiple Gated Acquisition scan (MUGA) will be considered in patients that develop relevant 
cardiac sign/symptoms during treatment.  In patients with an ejection fraction below the 
institution’s lower limits of normal, cardiac consultation as well as afatinib treatment 
interruption or discontinuation should be considered.  Patients with cardiac risk factors and 
those with conditions that can affect patients that develop cardiac signs/symptoms during 
treatment, cardiac monitoring including LVEF assessment should be considered.
5.3
OTHER
5.3.1
Documentation of diarrhoea
Patients will receive a diarrhoea diary for the first 2 cycles of Afatinib treatment. Patients will 
receive instructions on how to record daily diarrhoea events.  A copy of the instructions and 
the diary will be provided in the ISF.
All data on the diaries will be reviewed at visit 2 and 3 and will be checked against the 
reported AEs and adherence to the instructions in Section 10.1.1(management of diarrhoea
and hydration status following treatment with afatinib). 
Use of a daily recording diary will capture quantitative daily diarrhea data (number of bowel 
movements and consistency of diarrhoea.  The diary will be used as a tool for investigators in 
order to get more granular information on the severity and duration of diarrhoea and whether 
patients followed recommendations in terms of anti-diarrheal concomitant medication and 
sufficient hydration.  The diary is also a tool for the patient which reminds to contact the 
investigator in case high number of bowel movements are present over some days or in case 
of any concerns.
Accurate and constant assessment of diarrhoea symptoms, timely initiation of anti-diarrhoeal 
medication at first signs of diarrhea, appropriate anti-diarrhoeal medication dose 
modifications based on the daily diarrhoea symptoms and non-pharmacologic interventions 


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will facilitate early and appropriate interventions to minimize the duration and severity of 
dose limiting afatinib-induced diarrhoea. A sample of the diary can be found in Appendix 
10.4.
5.4
APPROPRIATENESS OF MEASUREMENTS
Safety assessment is the primary objective of the trial.  CTCAE criteria are used in the 
assessment of adverse events in cancer patients. Although an updated version is published, in 
the present trial CTCAE version 3.0 will be used. As several pivotal oncology trials are 
currently ongoing with the investigational product that utilize CTCAE version 3.0, it is 
considered more appropriate to continue to collect safety data using the same criteria
applicable.
For patients with EGFR mutation and responding to treatment with an EGFR TKI, 
continuation of same treatment has shown to improve survival compared to switching 
patients to chemotherapy (R12-5456). In this protocol, patients can continue to receive 
afatinib until investigator considers patient to have developed clinically significant increase 
in lung-cancer symptoms that requires change in treatment. This date will be defined as date 
of symptomatic progression. Time to symptomatic progression is a well-accepted endpoint to 
measure clinical benefit. 
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Not applicable since no pharmacokinetic data will be collected or analyzed in this trial.
5.6
BIOMARKER 
5.6.1
Endpoint based on biomarker
Not applicable
5.6.2
Methods of sample collection
Not applicable
5.6.3
Analytical determinations 
Not applicable
5.7
PHARMACODYNAMICS
Not applicable since no pharmacodynamic data will be collected or analyzed in this trial.
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
Not applicable since no pharmacokinetic or pharmacodynamic data will be collected or 
analyzed in this trial.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
6.1.1
Screening visit (Visit 1)
Patients considered for this trial will sign an informed consent before screening for eligibility 
(see Flow chart).
6.1.2
Baseline visit (Visit 1)
If patients meet all eligibility requirements they will be dispensed drug for the first 28 day 
treatment cycle.
6.1.3
Treatment and safety evaluation visits
Safety evaluation visits are to be conducted after afatinib administration, at Day 28 
(-7/+2)/Visit 2, and every 28 (-7/+2) days onwards. Please refer to the required and optional 
procedures to be performed at these visits in the Flow Chart and in Section 6.2.1. A phone 
call is recommended 15 days (+/- 3 days) after first dose to assess any AEs.
The investigator is responsible for determining the necessity and frequency of any 
additional/unscheduled visits as well as the extent of the evaluation (e.g., physical 
examination, laboratory testing, adverse events, etc.) performed at these visits. At a minimum 
the investigator should note in the patient’s chart when an additional/unscheduled visit occurs 
and make relevant entries on the AE and medication dispensing eCRFs. 
A treatment cycle is defined as 28 days.
6.1.4
End of Treatment (EOT) visit
All patients should be evaluated at the end of their trial treatment. This visit should be 
completed on the day of the patient’s last dose on trial medication or up to 14 days later.
6.1.5
Follow-Up (FU) visit
Patients should be contacted 28 (+7) days after the EOT visit to follow-up on their general 
condition and any adverse events which were not yet recovered at the EOT visit or any AEs 
that started since then. In addition, information regarding patients’ status will be collected at 
this visit. This information can be obtained by a phone call. A window period of 7 days is 
allowed. 
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The trial procedures are summarized in the Flow chart. 


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6.2.1
Screening and baseline periods
Visit 1/Day -1 – Screening/baseline visit
Informed consent and authorization to release protected health information must be obtained 
prior to any trial related procedures taking place.
Tests for which results are not already available as part of the patient’s standard of care, may 
be ordered after the patient signs informed consent.
Prior to starting study medication the investigator should: 1) review all information obtained 
at this visit, 2) review the inclusion/exclusion criteria and 3) confirm that the patient has 
discontinued all prohibited therapy or medications (see Sections 4.2.2 and 4.2.2.1) and an 
adequate washout period has passed.
Table 6.2.1: 1
Visit 1 / – Screening visit and baseline visit
The following must be performed and 
information recorded in the patient’s chart
What to include in eCRF
Informed Consent
Written informed consent and authorization 
to release protected health information must 
be obtained prior to any trial related 
procedures taking place.
Date of informed consent
Demographics
Obtain the following demographic data: 
sex, birth date, race, smoking and alcohol 
history
Sex, birth date, race, ethnicity, and 
smoking history
Medical history
Oncological and relevant non-oncological 
history including details of previous 
treatment for NSCLC (including pathology)
History of NSCLC:
Oncological and relevant non-oncological 
history including details of any previous 
treatment for NSCLC
The date of first histological diagnosis, 
the primary tumour site, the number and
location of metastatic sites (bone, brain, 
liver, pleural effusion, other)
Tumour assessment/stage at the time of 
diagnosis according to the 
TNM-classification
Previous surgeries for NSCLC
Previously administered chemo-, 
immuno-, hormone therapy will be 
reported including start and end dates, the 
treatment regimen with the number of 
courses (chemo-, immunotherapy), the 
best response obtained (complete 
response, partial response, stable disease, 
progressive disease, unknown), and 
progression date.
Previous radiotherapy - the total radiation 
dose and radiation field will be recorded


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The following must be performed and 
information recorded in the patient’s chart
What to include in eCRF
Inclusion and 
Exclusion criteria 
Assessment of eligibility according to 
inclusion and exclusion criteria should be 
performed. 
Verify that the patient has met all the 
inclusion and exclusion criteria.
Physical 
examination
Physical examination results (see Flow 
chart). The evaluation of the ECOG 
performance score will be performed.
Verify that this physical examination was 
performed and record results (see Flow
chart). 
Safety Laboratory 
Testing
Hematology, and Biochemistry 
examination. See Section 5.2.3 for 
recommended safety laboratory evaluations.
Blood samples may be collected to perform 
the following:
- Retest for missing laboratory test results 
required to establish eligibility
- Safety laboratory testing as deemed 
necessary by the investigator
Verify that all recommended safety 
laboratory testing were performed and that 
values met eligibility criteria according to 
the protocol.
No lab values are to be recorded on the 
CRF.
Urine 
Examination 
Urine examination. (see Section 5.2.3)
Verify if all recommended urine testing 
was performed.
No lab values are to be recorded on the 
CRF.
Pregnancy test
β-HCG testing in urine or serum will be 
performed in females of childbearing 
potential (see Section 5.2.3). A negative 
result is required for enrolment in the trial.
Verify that β-HCG testing in urine or serum 
was performed and that patient is not 
pregnant.
 
 
 


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The following must be performed and 
information recorded in the patient’s chart
What to include in eCRF
Adverse events
Patients should be asked to report any 
hospitalizations, emergency treatments, or 
new medications as well as any general 
health issues that may have surfaced since 
signing the informed consent form. All the 
information collected should be recorded in 
the patient’s chart. Refer to Sections: 5.2.2
and 5.2.2.2 for protocol specific 
requirements regarding the collection and 
reporting of adverse event information.
All relevant AEs.
Concomitant 
Medications
Patients should be asked to report any 
concomitant drug use (including, but not 
limited to: non-prescription medications, 
anaesthetic agents, homeopathic/herbal 
remedies and dietary supplement 
preparations).
No concomitant medications will be 
recorded on eCRFs except for those for 
rash and diarrhoea.
Dispense Trial 
Medication
Dispense 1 bottle of afatinib for the 28 day 
treatment cycle (see Section 4.1.4.)
Record: dose dispensed, all medication 
numbers and date of first dose 
administration
Tumour 
Assessment
Tumour assessment will be based on the 
assessment prior to study entry
Radiological assessment to be included on 
CRF
6.2.2
Treatment periods
Safety evaluation visits are to be conducted after the initiation of afatinib, at Day 28 
(-7/+2)/Visit 2 and every 28 (-7/+2) days onwards. Additional safety evaluation visits may be 
conducted as necessary, at the investigator’s discretion. The investigator is responsible for 
determining the necessity and frequency of the additional safety visits as well as the extent of 
the evaluation (physical examination, laboratory testing, etc.) at each visit. 
Investigator must make a phone call to patient on day 15 to enquire about tolerability. If lack 
of tolerance is suspected, patient must visit site for dose reduction. 


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Table 6.2.2:1
Visit 2/Day 28 (-7/+2) and every 28 (-7/+2) days onwards - treatment 
and safety evaluation 
The following must be performed and information 
recorded in the patient’s chart
What to include in eCRF
Physical 
examination
Physical examination results (see Flow Chart).
Verify that this physical examination 
was performed and record results
(see Flow Chart).
 
 
 
 
 
 
Tumour 
assessment 
Tumour Assessment will be based on the 
assessment of cancer related symptoms and, if 
available, radiologic assessments as per standard 
of care at the site. There is no specific schedule for 
tumour assessment and can be according to 
standard of care or every 3 cycles. 
Tumour assessment where available 
will be captured in the CRF
Safety Laboratory 
Testing 
Hematology, and Biochemistry examination. See 
Section 5.2.3 for recommended safety laboratory 
evaluations and Flow Chart for schedule.
Verify if all recommended safety 
laboratory testing was performed 
and that values were acceptable 
according to the protocol. If not, see 
Sections: 4.1.4.1 and 5.2.2.1
No lab values are to be recorded on 
the eCRF.
Urine 
Examination –
Optional
Urine examination. See Section 5.2.3 for 
recommended urine examinations.
Urine Examination is optional at this visit and may 
be performed at the discretion of the investigator 
and in accordance to the current standard of care.
Verify if all recommended urine 
testing was performed. 
No values from the urine 
examination are to be recorded on 
the eCRF.
Adverse events
Patients should be asked to report any 
hospitalizations, emergency treatments, or new 
medications as well as any general health issues 
that may have surfaced since their last visit. All the 
information collected should be recorded in the 
patient’s chart. Refer to Sections: 5.2.2 and 5.2.2.2
for protocol specific requirements regarding the 
collection and reporting of adverse event 
information.
All relevant AEs.
Compliance
Check number of tablets remaining and that trial 
medication was taken correctly, collect any used 
bottles of afatinib.
Record if the patient is taking the 
medication according to the 
protocol.


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The following must be performed and information 
recorded in the patient’s chart
What to include in eCRF
Concomitant 
Medications
Patients should be asked to report any concomitant 
drug use (including, but not limited to,: non-
prescription medications, anaesthetic agents, 
homeopathic/herbal remedies and dietary 
supplement preparations)
No concomitant medications will be 
recorded on eCRFs except for those 
for rash and diarrhoea.
Dispense Trial 
Medication
Dispense sufficient medication for the next cycle 
of treatment (see Section 4.1.4).
Record: dose dispensed, medication 
bottle numbers, and only the start 
date of any dose changes (if 
applicable).
Phone Call
A phone call is required 15 (±3) days after the 
patient’s first dose to assess AEs and dose 
reductions.
Record when this phone call took 
place.
6.2.3
End of Treatment and follow-up period
The End of Treatment (EOT) visit marks the end of the patient’s treatment, and should be 
conducted as soon as the patient discontinues trial medication (afatinib), and may occur at 
any time during the trial. The investigator may discontinue patients due to any of the reasons 
presented in Section 3.3.4.1.
Table 6.2.3: 1 End of Treatment (EOT) Visit
The following must be performed and information 
recorded in the patient’s chart
What to include in eCRF
Physical 
examination
Physical examination results (see Flow Chart).
Verify that this physical examination 
was performed and record results 
(see Flow Chart).
ECOG Score
The evaluation of the ECOG performance score 
will be performed
Verify ECOG performance Status
 
Tumour 
assessment 
Tumour Assessment will be based on the 
assessment of cancer related symptoms and, if 
available, radiologic assessments as per standard 
of care at the site.
Tumour assessment where available 
will be captured in the CRF
Safety Laboratory 
Testing
Hematology, and Biochemistry examination. See 
Section 5.2.3 for recommended safety laboratory 
evaluations.
Verify if all recommended safety 
laboratory testing was performed 
and that values were acceptable 
according to the protocol. If not, see 
Section 5.2.2.1
No lab values are to be recorded on 
the CRF.


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The following must be performed and information 
recorded in the patient’s chart
What to include in eCRF
Urine 
Examination 
Urine testing. See Section 5.2.3 for recommended 
safety laboratory evaluations.
No values from the urine 
examination are to be recorded on 
the CRF.
Pregnancy test
β-HCG testing in urine or serum will be performed 
in females of childbearing potential.
Verify that β-HCG testing in urine 
or serum was performed and that 
patient is not pregnant.
Adverse events
Patients should be asked to report any 
hospitalizations, emergency treatments, or new 
medications as well as any general health issues 
that may have surfaced since their last visit. All the 
information collected should be recorded in the 
patient’s chart. Refer to Sections: 5.2.2 and 5.2.2.2
for protocol specific requirements regarding the 
collection and reporting of adverse event 
information.
All relevant AEs.
Compliance
Collect all unused or partially used and empty 
bottles of afatinib from the patient.
Check number of tablets remaining and check that 
trial medication taken correctly.
Record if the patient took the 
medication according to the 
protocol. This information should be 
captured on the Termination of Trial 
Medication eCRF.
Concomitant 
Medications
Patients should be asked to report any concomitant 
drug use (including, but not limited to,: non-
prescription medications, anaesthetic agents, 
homeopathic/herbal remedies and dietary 
supplement preparations).
No concomitant medications will be 
recorded on eCRFs except for those 
for rash and diarrhoea.
Termination of 
Trial Medication
Document any information regarding the patient’s 
last dose of trial drug and why it was stopped. 
(e.g., date of withdrawal of consent, lost to follow-
up, disease progression)
When applicable, every effort should be taken to 
collect and document information on date of death.
Date when the last dose of trial 
medication was ingested.
Reason for discontinuation.
* The term “Death” should not be reported as the SAE, it is the outcome of an AE.
6.2.4
Follow-Up
The Follow-up (FU) visit should occur 28 (+7) days after the EOT visit.
This visit marks the end of the patient’s participation in the trial. Patients will not be required 
to attend the clinic for this visit. The clinic staff will contact the patients or their caregivers by 
telephone and inquire about any adverse events that might have occurred since the last visit 
and if applicable follow up on any unforeseen pregnancy during the trial. All concomitant 
medication should be added to the patient’s chart. The Patient Status eCRF will be completed 
at this time.


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Any additional (unscheduled) follow-up visits should be scheduled for patients with 
unresolved SAEs, AEs, or laboratory abnormalities who have discontinued trial participation. 
These events must be followed until resolution or until agreement is reached between the 
local medical monitor and the investigator that further follow-up is no longer required. 
Patients without clinical progression at EOT will be followed as per site standard practice 
until appearance of clinical progression or start of other anti-cancer treatment whichever 
occurs earlier. 
Table 6.2.4: 1 
Follow-up (FU) Visit/EOT + 28 Days (+7)
What to Include in the Patient’s Chart
What to include in eCRF
Adverse events
Patients should be asked to report any 
hospitalizations, emergency treatments, or new 
medications as well as any general health issues 
that may have surfaced since their last visit. All the 
information collected should be recorded in the 
patient’s chart. Refer to Sections: 5.2.2 and 5.2.2.2
for protocol specific requirements regarding the 
collection and reporting of adverse event 
information.
All relevant AEs.
Patient Status
Document any information regarding the patient’s 
status during the planned observation time (i.e., 28 
days after the patient’s last dose of medication).
When applicable, every effort should be taken to 
collect and document information on date of death.
Note: any AE which results in death is considered 
an SAE.
Any new anti-cancer medication 
(including date when the new anti-
cancer medication is taken) that the 
patient has taken since EOT visit.  
Date when the patient completed the 
planned observation time.
Date of death
Patient’s status


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
Exploratory descriptive statistics of demographic, efficacy and safety data will be presented.
7.1
STATISTICAL DESIGN - MODEL
This is an open-label, multi-centre, non-randomised, uncontrolled, single arm trial designed 
to evaluate the safety and efficacy of the investigational drug afatinib in a particular patient 
population. After the initial screening visit, patients will enter the open-label treatment period 
with scheduled visits at approximately every 28 days until the end of the trial.
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses with regard to the endpoints described in 
Section 7.3.2 confirmatory sense since the objective of this trial is to describe the safety of 
long term use of afatinib in this patient population in an uncontrolled manner.
7.3
PLANNED ANALYSES
All analyses will be based on the Treated Set (TS) which includes all patients who were 
dispensed trial medication and documented to take at least one dose of investigational 
treatment (afatinib).
7.3.1
Primary analyses
Refer to Section 7.3.3 for a description of the analysis of safety and tolerability, the primary 
objectives of this trial.
7.3.2
Secondary analyses
TTSP
TTSP is the time from the date of the first administration of afatinib to the date of first 
documented clinically significant symptomatic progression that requires stopping afatinib
according to investigator’s assessment.
TTSP [days] = date of last administration of trial drug– (date of start of treatment) + 1  
Kaplan-Meier estimates and 95% confidence intervals for the 25th, median, and 75th
percentiles of the survival distribution will be calculated for TTSP, using Greenwood’s 
standard error estimate.  Kaplan-Meier curves will be produced without confidence intervals. 
 


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7.3.3
Safety analyses
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between first drug intakes until 
28 days (inclusive) after last treatment administration will be considered 
‘treatment-emergent’. Adverse events that start before first drug intake and deteriorate under 
treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA).
Adverse events will be graded according to CTCAE, Version 3.0 (R04-0474).
CTC grades will be applied to laboratory parameters using the current BI oncology standard 
as detailed in the document ‘Conversion of laboratory parameters to CTCAE grades within 
BI.’
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.


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7.3.4
Interim analyses
This is a single-arm open-label study. The interim analyses may be done after over 80% 
percent of patients have entered the study. The analyses will include the assessment of safety 
and efficacy if conducted.  The result from the interim analyses may be presented at 
professional conferences and published in articles after stop of recruitment.
7.4
HANDLING OF MISSING DATA
Missing or incomplete AE dates are imputed according to BI standards.

For Time to Symptomatic Progression, if a patient is known to have progressed, but 
the date of progression is not attainable, the last date when the patient was assessed
will be used as date of progression.

If a patient is known to have died, but date of death is not attainable, the last contact 
date will be used as date of death.
7.5
RANDOMISATION
No randomisation is required since all patients will be treated with afatinib. 
7.6
DETERMINATION OF SAMPLE SIZE
The number of patients included into this trial is not based on formal sample size 
calculations. The sample size consideration in this trial is to expand the access of afatinib
treatment to additional patients in the region.  The number of patient is determined by the 
pre-trial feasibility including budget and recruitment.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the
Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the investigator of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol/GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a general rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File).
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and Competent Authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be informed that his/her personal trial-related data will be used by BI in 
accordance with the local data protection law. The level of disclosure must also be explained 
to the patient.
The patient must be informed that his/her medical records may be examined by authorized 
monitors Clinical Monitor Local (CML), Clinical Research Associate (CRA) or Clinical 
Quality Assurance auditors appointed by BI, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.


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8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor via remote 
data capture. Since this is an open label trial emergency code breaks will not be necessary. 
For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported on Electronic Case Report Forms (eCRFs) that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer records, 
depending on the trial; also current medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g., Food and Drug Administration 
(FDA). The Clinical Research Associate (CRA)/on site monitor and auditor may review all 
CRFs/eCRFs, and written informed consents. The accuracy of the data will be verified by 
reviewing the documents described in Section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfill the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e., is a known side effect of the drug or not. 
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For the BI investigational product (afatinib) this is the current version of the Investigator’s 
Brochure (c01617169-04). The current version of this reference document is provided in the 
ISF.


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8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g., Suspected Unexpected Serious Adverse 
Reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P07-11507
Moy B, Goss PE Lapatinib-associated toxicity and practical management 
recommendations.Oncologist 2007; 12 (7), 756 - 765.
P08-06904
Li D, Ambrogio L, Shimamura T, Kubo S, Takahashi M, Chirieac LR, et al. 
BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in 
preclinical lung cancer models. Oncogene. 2008; 27(34), 4702 - 4711.
P11-09424
Porta C, Osanto S, Ravaud A, Climent MA, Vaishampayan U, White DA, et 
al. Management of adverse events associated with the use of everolimus in 
patients with advanced renal cell carcinoma. Eur J Cancer 2011; 47, 1287 -
1298 .
P12-03681
Yang JCH, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SHI, et al. Afatinib for 
patients with lung adenocarcinoma and epidermal growth factor receptor 
mutations (LUX-Lung 2): a phase 2 trial. Lancet Oncology, Published Online 
March 26, 2012, doi:10.1016/S1470-2045(12)70086-4 Lancet Oncol 2012.
P13-06250      Wu YL, Zhou C, Hu CP, Feng JF, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee 
KY, Massey D, Shi Y, Chen J, Zazulina V, Geater SL.   LUX-Lung 6: a 
randomized, open-label, phase III study of afatinib (A) vs emcitabine/cisplatin 
(GC) as first-line treatment for Asian patients (pts) with EGFR mutation-
positive (EGFR M+) advanced adenocarcinoma of the lung.   49th Ann Mtg of 
the American Society of Clinical Oncology (ASCO), Chicago, 31 May - 4 Jun 
2013 J Clin Oncol 31 (Suppl), (2013)
R04-0474
Common terminology criteria for adverse events v3.0 (CTCAE) (publish date: 
December 12, 2003). http://ctep.cancer.gov/forms/CTCAEv3.pdf ; Cancer 
Therapy Evaluation Program, Common Terminology Criteria for Adverse 
Events, Version 3.0, DCTD, NCI, NIH, DHHS, 31 March 2003, Publish Date: 
12 December 2003 (2003).
R05-0867
Shepherd FA, Rodrigues Pereira J, Ciuleanu T, Tan EH, Hirsh V, 
Thongprasert S, et al,National Cancer Institute of Canada Clinical Trials 
Group. Erlotinib in previously treated non-small-cell lung cancer.
N Engl J Med 2005; 353 (2), 123 - 132 .
R05-0876
Schrump DS, Altorki NK, Henschke CL, Carter D, Turrisi AT, Gutierrez ME. 
Non-small cell lung cancer. Cancer: principles and practice of oncology, 7th 
Edition, DeVita VT, Hellman S, Rosenberg SA (eds.), Lippincott Williams 
and Wilkins. 2005; 753-809.


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R06-1262
Pao W, Miller VA. Epidermal growth factor receptor mutations, small 
molecule kinase inhibitors, and non-small-cell lung cancer: current knowledge 
and future directions. J Clin Oncol. 2005; 23: 2556-2568.
R06-1301
Lynch TJ, Adjei AA, Bunn PA, Eisen TG, Engelman J, Goss G, et al      
Summary statement: Novel agents in the treatment of lung cancer: Advances 
in epidermal growth factor receptor-targeted agents. Clin Cancer Res. 2006; 
12(14 Suppl.): 4365-4371.
R06-1302
Engelman JA, Cantley LC. The role of erbB family members in non-small cell 
lung cancers sensitive to epidermal growth factor receptor kinase inhibitors. 
3rd Cambridge Con on Novel Agents in the Treatment of Lung Cancer: 
Advances in EGFR-Targeted Agents, Cambridge, 23-24 Sep 2005. Clin 
Cancer Res. 2006; 12(14 Suppl.): 4372-4376.
R06-1306
Jaene PA, Johnson BE. Effect of epidermal growth factor receptor tyrosine 
kinase domain mutation on the outcome of patients with non-small cell lung 
cancer treated with epidermal growth factor receptor tyrosine kinase 
inhibitors. 3rd Cambridge Con on Novel Agents in the Treatment of Lung 
Cancer: Advances in EGFR-Targeted Agents, Cambridge, 23-24 Sep 2005. 
Clin Cancer Res. 2006; 12(Suppl.14): 4416-4420.
R06-1307
Heymach JV, Nilsson M, Blumenschein G, Papadimitrakopoulou V, Herbst R. 
Epidermal growth factor receptor inhibitors in development for the treatment 
of non-small cell lung cancer. 3rd Cambridge Con on Novel Agents in the 
Treatment of Lung Cancer: Advances in EGFR-Targeted Agents, Cambridge, 
23-24 Sep 2005. Clin Cancer Res. 2006; 12(14 Suppl.): 4441-4445.
R06-1393
Johnson BE, Jaenne PA. Epidermal growth factor receptor mutations in 
patients with non-small cell lung cancer. Cancer Res. 2005; 65(17): 
7525-7529.
R06-1394
Doroshow JH. Targeting EGFR in non-small-cell lung cancer. N Engl J Med. 
2005; 353(2): 200-202.
R07-1162
Sequist LV. Second generation epidermal growth factor receptor tyrosine 
kinase inhibitors in non-small cell lung cancer. Oncologist. 2007; 12: 325-330.
R07-4077
Giaccone G, Melosky B, Reck M. Epidermal growth factor receptor inhibitor 
(EGFRI)-associated rash: a suggested novel management paradigm. A 
consensus position from the EGFRI dermatologic toxicity forum.ECCO 14, 
14th Eur Cancer Conf, Barcelona, 23 - 27 Sep 2007 (Poster).
R07-4078
Lynch TJ, Kim ES, Eaby B, Garey J, West DP, Lacouture ME. Epidermal 
growth factor receptor inhibitor-associated cutaneous toxicities: an evolving 
paradigm in clinical management. Oncologist 2007; 12 (5), 610 - 621 .


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R11-0826
Potthoff K, Hofheinz R, Hassel JC, Volkenandt M, Lordick F, Hartmann JT, et 
al. Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a 
German expert opinion. Ann Oncol 2011; 22 (3), 524 - 535 .
R12-5456
Tu L, Sun L. Rechallenge treatment of small molecule inhibitors in NSCLC 
patients beyond progression. J Thoracic Dis 2012; 4 (6): 647 – 64
9.2
UNPUBLISHED REFERENCES
c01617169-04 Investigator’s brochure. Afatinib (BIBW 2992). Version17, 1200.P1 -
1200.P13.  05 Jul 2016
U02-1083
 Study of BIBW 2992BS, BIBW 3022BS, and BIBW 3049BS in 
various receptor binding assays. 03-02 8810241. 30January 2002.
U02-1391
 Effects of BIBW 2992 on endogenous EGFR and HER2 
phosphorylation states and on proliferation in various cell lines. 22-02 23. 
June 2002.
U02-1614
 Anti-tumour activity of the combined EGFR and HER2 inhibitor 
BIBW 2992 BS in nude mouse xenografts derived from the human gastric
carcinoma cell NCI-N87. 25-02. 16 October 2002.
U02-1660
 Anti-tumour activity of the combined EGFR and HER2 inhibitor
BIBW 2992 BS in nude mouse xenografts derived from the human ovarian 
carcinoma cell line SKOV-3. 26-02 4 November 2002 
U02-1702
 Minimum effective dose of the epidermal growth factor receptor
(EGFR) inhibitor BIBW 2992 BS in nude mouse xenografts derived from the 
EGFR-overexpressing human epidermoid carcinoma cell line A431. 32-02. 
25 November 2002.
U02-1703
 Anti-tumour activity of the combined EGFR and HER2 inhibitor 
BIBW 2992 BS in nude mouse xenografts derived from human breast 
carcinoma cell line MDA-MB-453. 31-02 25 November 2002.
U03-1086
 Inactivation of the EGF signaling pathway by BIBW 2992: 
A time course analysis.28-02 30November 2002.
U07-1338
 BIBW 2992, an irreversible dual EGFR/HER2 kinase 
inhibitor, shows activity on L858R- and L858R/T790M-EGFR mutants, 
07-06. 11 June 2007.
U07-3128-02
 A phase I open- label dose escalation study of 
continuous once-daily oral treatment with BIBW 2992 in patients with 
advanced solid tumours. 30-March-2007. Revised 23-April-2010.


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U08-1023-03
   A phase I open- label dose escalation study of
continuous once-daily oral treatment with BIBW 2992 in patients with 
advanced solid tumours. 30-January-2008. Revised 25-October-2011.
U10-3048-01
 Phase IIb/III randomized,  
double-blind trial of BIBW 2992 plus best supportive care (BSC) versus 
placebo plus BSC in non-small cell lung cancer patients failing erlotinib or 
gefitinib (LUX-Lung 1) 15 December 2011
U11-2645-01
 Potency of BIBW 2992 in HER4 kinase assays in vitro. 
23 November 2011.
U11-3644-01
 LUX Lung 2: A phase II single-
arm trial of BIBW 2992 in non-small cell lung cancer patients with EGFR 
activating mutations. 06 December 2011.
U12-1167-01 
 Phase III randomized trial of BIBW 2992 plus 
weekly paclitaxel versus investigators choice of chemotherapy following 
BIBW 2992 monotherapy in non-small cell lung cancer patients failing 
previous erlotinib or gefitinib treatment. 17 April 2012
U12-1170-01
 Relative bioavailability of a 
single oral dose of 40 mg afatinib given alone compared to concomitant and 
timed administration of multiple oral doses of ritonavir - an open-label, 
randomised, three-way crossover trial in healthy male volunteers.16-May-
2012.
U12-1199-01
  LUX-Lung 3; A randomised, 
open-label, phase III study ofBIBW 2992 versus chemotherapy as first-line 
treatment for patientswith stage IIIB or IV adenocarcinoma of the lung 
harbouring anEGFR-activating mutation. 04-July-2012.
U12-1482-01
 Clinical Summary: Afatinib film-coated tablets, 
20mg, 30 mg, 40 mg, 50 mg. 25-Jul-2012.


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10.
APPENDICES
10.1 
MANAGEMENT OF EXPECTED ADVERSE EVENTS
Dermatologic adverse events and diarrhoea are the most common side-effects associated with 
treatment with afatinib. Treatment of these side-effects should be proactive and should be 
started as early as possible after onset of symptoms.
10.1.1
Management of diarrhoea and hydration status following treatment with 
afatinib
Patients should be advised to avoid foods known to aggravate diarrhoea, such as: spicy, 
greasy, or fried foods, raw vegetables, fresh fruit or whole grain bread.
Diarrhoea occurs at a high frequency and generally begins within 2 weeks of exposure to 
afatinib. Although usually mild to moderate, diarrhoea may lead to dehydration and compel 
treatment modification or discontinuation, so early management is essential (Table 10.1.1: 1). 
At the time of initiation of treatment with afatinib patients should be given a supply of 
loperamide to keep with them at all times and should be counselled on the appropriate use.
Patients should be advised to start taking loperamide with the onset of diarrhoea.
Patients must be advised to drink an adequate amount of fluids to make up for the fluid lost 
through diarrhoea. A daily fluid intake of approximately ≥2 liters is recommended to avoid 
dehydration; some fluids should contain sugar or salt to avoid hyponatremia and hypokalemia 
caused by electrolyte loss.


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Table 10.1.1: 1
Grade specific treatment recommendations for afatinib related 
diarrhea
Severity               
(CTCAE Grading)
Description
Intervention 
concerning afatinib
treatment 
Specific intervention 
Mild (Grade 1)
Increase of < 4 stools per 
day over baseline; mild 
increase in ostomy output 
compared with baseline
Continue same dose
Stop laxatives and advise 
patient to drink at least 8-
10 glasses of water or 
clear fluids per day; 4 mg 
(2 tablets) of loperamide to 
be taken immediately, 
followed by 2 mg (1 tablet) 
after each loose stool (up 
to 16 mg/day) until bowel 
movements cease for 12 
hours
Moderate (Grade 
2)
Increase of 4-6 stools per 
day over baseline; i.v. 
fluids indicated < 24 
hours; moderate increase 
in ostomy output 
compared with baseline; 
not interfering with 
Activities of Daily Living 
(ADL)
Continue same dose 
unless Grade 2 
diarrhoea continues 
for ≥ 2 days (48 
hours) in which case 
treatment must be 
paused until 
recovered to ≤ 
Grade 1 followed by 
dose reduction
See Grade 1; continue 
loperamide; assess for 
dehydration and electrolyte 
imbalance; consider 
intravenous fluids and 
electrolyte replacement.
Severe (Grade 3)
Increase of ≥ 7 stools per 
day over baseline; 
incontinence; IV fluids > 
24 hours; hospitalization; 
severe increase in ostomy 
output compared with 
baseline; interfering with 
ADL
Pause dose until 
recovered to ≤Grade 
1 followed by dose 
reduction*
See Grade 2; plus: an 
infectious process should 
be ruled out with stool 
cultures; aggressive iv 
fluid replacement ≥ 24 
hours; hospitalization to 
monitor progress; consider 
prophylactic antibiotics if 
patient is also neutropenic;
Life threatening 
(Grade 4)
Life-threatening 
consequences (e.g. 
haemodynamic collapse)
Pause dose until 
recovered to ≤Grade 
1 followed by dose 
reduction*
See Grade 3
* If despite optimal supportive care and a treatment pause, diarrhoea does not resolve to CTCAE Grade ≤1 or 
baseline (CTCAE Grade at the start of treatment) within 6 weeks, treatment with afatinib must be permanently 
discontinued. In the event that the patient is deriving obvious clinical benefit according to the investigator’s 
judgment, further treatment with afatinib will be decided by the investigator.
10.1.2
Management recommendations for dermatological AEs following treatment 
with afatinib
Dermatologic AEs of afatinib include rash, acne, dermatitis acneiform, and dry skin. General 
recommendations for prophylaxis are summarized in Table 10.1.2: 1 and grade-specific 


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treatment recommendations are summarized in Table 10.1.2: 2. For dose adjustment of 
afatinib refer to Table 4.1.4.1: 1.
Specific interventions should be reassessed at least after 2 weeks or at any worsening of 
symptoms, in which case the specific intervention should be adjusted and, depending on own 
clinical experience, early involvement of a dermatologist should be considered. (Adapted 
from R11-0826)
Patients with an intolerable NCI-CTCAE grade 2 or who develop a grade 3 or higher 
dermatological event should be referred to a dermatologist, with prior experience of treating 
patients who have received EGFR therapy, for a more appropriate dermatologic treatment 
option.
Table 10.1.2: 1
General recommendations for prophylaxis while receiving afatinib
Personal hygiene
Use of gentle soaps and shampoos for the body, e.g. pH5 neutral bath and 
shower formulations and tepid water.
Use of very mild shampoos for hair wash.
Only clean and smooth towels are recommended because of potential risk of 
infection. The skin should be patted dry after a shower, whereas rubbing the skin
dry should be avoided.
Fine cotton clothes should be worn instead of synthetic material.
Shaving has to be done very carefully.
Manicure, i.e. cutting of nails, should be done straight across until the nails no 
longer extend over the fingers or toes. Cuticles are not allowed to be trimmed 
because this procedure increases the risk of nail bed infections.
Sun protection
Sunscreen should be applied daily to exposed skin areas regardless of season. 
Hypoallergenic sunscreen with a high SPF (at least SPF30, PABA free, 
UVA/UVB protection), preferably broad spectrum containing zinc oxide or 
titanium dioxide are recommended.
Patients should be encouraged to consequently stay out of the sun.
Protective clothing for sun protection and wearing a hat should be recommended.
Moisturizer treatment
It is important to moisturize the skin as soon as anti-EGFR therapy is started.
Hypoallergenic moisturizing creams, ointments and emollients should be used 
once daily to smooth the skin and to prevent and alleviate skin dryness.
Note: avoid greasy creams (e.g. petrolatum, soft paraffin, mineral oil based) and 
topical acne medications.
Prevention of paronychia 
Patients should keep their hands dry and out of water if ever possible.
They should avoid friction and pressure on the nail fold as well as picking or 
manipulating the nail.
Topical application of petrolatum is recommended around the nails due to its 
lubricant and smoothing effect on the skin.


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Table 10.1.2: 2
Grade specific treatment recommendations of skin reactions to 
afatinib
Severity 
(CTCAE Grading)
Description
Specific intervention
ACNEIFORM RASH
Mild (Grade 1)
Macular or papular eruptions or 
erythema without associated 
symptoms
Consider topical antibiotics (b.i.d) e.g.: 
clindamycin 1-2%, or topical erythromycin 
1-2% cream of metronidazole 1% or topical 
nadifloxacin 1%;                                
Isolated scattered lesion: cream preferred 
Multiple scattered areas: lotion preferred
Moderate (Grade 2)
Macular or papular eruptions with 
pruritus or other associated 
symptoms; localized desquamation 
or other lesions covering <50% of 
BSA 
Topical steroid treatment as for Grade 1 
plus short term topical steroids, e.g. 
prednicarbate cream 0.02% plus oral 
antibiotic (for at least 2weeks) e.g.,
Doxycycline 100 mg b.i.d, Minocycline 
hydrochloride 100mg b.i.d. 
Severe (Grade 3)
Severe, generalized erythroderma or 
macular, popular or vesicular 
eruption; desquamation covering ≥ 
50% of BSA; associated with pain, 
disfigurement, ulceration or 
desquamation 
Topical and systemic treatment as for 
Grade 2. 
Consider referral to dermatologist
Consider systemic steroids
Life threatening 
(Grade 4)
Generalized exfoliative, ulcerative, 
or bullous dermatitis 
See Grade 3 
Systemic steroids are recommended


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Severity 
(CTCAE Grading)
Description
Specific intervention
EARLY AND LATE XEROTIC SKIN REACTIONS - PRURITUS
Mild (Grade 1)
Mild or localized 
Topical polidocanol cream.
Consider oral antihistamines, e.g. 
diphenhydramine, dimethindene, cetirizine, 
levocetirizine, desloratidine, fexofenadine 
or clemastine)
Moderate (Grade 2)
Intense or widespread 
See Grade 1 plus oral antihistamines (e.g:
levocetirizine 5 mg qd, desloratadine 5 mg 
qd, diphenhydramine 25–50 mg t.i.d, 
hydroxyzine 25 mg t.i.d, fexofenadine 60 
mg t.i.d). Consider topical steroids, e.g. 
topical hydrocortisone
Severe (Grade 3)
Intense or widespread and interfering 
with ADL 
See Grade 2
XEROSIS (DRY SKIN)
Mild (Grade 1)
Asymptomatic 
Soap-free shower gel and/or bath oil.
Avoid alcoholic solutions and soaps.
Urea- or glycerin-based moisturizer.
In inflammatory lesions consider topical 
steroids (e.g. hydrocortisone cream)
Moderate (Grade 2)
Symptomatic, not interfering with 
ADL 
See Grade 1.
In inflammatory lesions consider topical 
steroids (e.g. hydrocortisone cream)
Severe (Grade 3)
Symptomatic, 
interfering with ADL 
See Grade 2. 
Topical steroids of higher potency (e.g. 
prednicarbate, mometasone furoate) 
Consider oral antibiotics 
FISSURES
Mild (Grade 1)
Asymptomatic 
Petroleum jelly, Vaseline® or Aquaphor for 
30 minutes under plastic occlusion every 
night followed by application of 
hydrocolloid dressing; antiseptic baths (e.g. 
potassium permanganate therapeutic baths, 
final concentration of 1:10,000, or 
povidone-iodine baths)
Topical applications of  aqueous silver 
nitrate solutions to fissures
Moderate (Grade 2)
Symptomatic, not interfering with 
ADL 
See Grade 1. 
Consider oral antibiotics. 
Severe (Grade 3)
Symptomatic, 
Interfering with ADL 
See Grade 2. 
If Grade 2 rash persists for ≥7 days despite treatment and is poorly tolerated by the patient, the investigator
may choose to pause treatment up to 14 days followed by a reduction in the dose of afatinib according to the 
dose reduction scheme in Table 4.1.4.1: 1


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10.1.3
Management of mucositis/stomatitis
General and grade specific recommendations are described in Table 10.1.3: 1. For dose 
adjustment refer to Section 4.1.4.1 and for restrictions on concomitant therapies refer to 
Sections 4.2.2.
Treatment is supportive and aimed at symptom control. These may include atraumatic
cleansing and rinsing with non-alcoholic solutions such as normal saline, diluted salt and 
baking soda solution (e.g. one-half teaspoonful of salt and one teaspoon of baking soda in one 
quart of water every four hours); avoidance of agents containing iodine, thyme derivatives 
and prolonged use of hydrogen peroxide; dietary maneuvers such as promotion of soft, non 
irritating foods like ice-creams, mashed/cooked vegetables, potatoes and avoidance of spicy, 
acidic or irritating foods such as peppers, curries, chilies, nuts and alcohol. If the patient is 
unable to swallow foods or liquids, parenteral fluid and/or nutritional support may be needed. 
Examples of some of the agents suggested in Table 10.1.3: 1 include: topical analgesics –
viscous lidocaine 2%; mucosal coating agents - topical kaolin/pectin; oral antacids, 
maltodextrin, sucralfate; topical antifungals – nystatin suspension. (Adapted from 
P11-09424)


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Table 10.1.3: 1
Grade specific treatment recommendations for afatinib related 
mucositis/stomatitis
Severity               
(CTCAE Grading)
Description
Treatment 
recommendations 
Intervention concerning 
afatinib treatment/dose 
modification 
Mild (Grade 1)
Minimal symptoms; 
normal diet 
Oral rinses with agents 
such as non-alcoholic 
mouth wash, normal 
saline, diluted salt and 
baking soda solution. 
No change. 
Moderate (Grade 2)
Symptomatic, but 
can eat and swallow 
modified diet 
Addition of topical 
analgesic mouth 
treatments, topical 
corticosteroids, antiviral 
therapy if herpetic 
infection confirmed, 
antifungal therapy 
preferably topical on a 
case by case basis. 
Maintain dose if tolerable; 
Hold dose if intolerable 
until recovery to grade ≤1, 
then restart at the same 
dose. 
Severe (Grade 3)
Symptomatic and 
unable to adequately 
aliment or hydrate 
orally 
Same as for Grade 2; 
institute additional 
symptomatic therapy 
(topical or systemic) as 
clinically indicated. 
Hold dose until recovery to 
grade ≤1 or baseline, then 
restart at the reduced dose 
according to Section
4.1.4.1. 
Life threatening 
(Grade 4)
Symptoms 
associated with life-
threatening 
consequences 
Same as for Grade 2; 
institute additional 
symptomatic therapy 
(topical or systemic) as 
clinically indicated. 
Hold dose until recovery to 
grade ≤1 or baseline, then 
restart at the reduced dose 
according to Section
4.1.4.1.
10.1.4
Management of interstitial lung disease (ILD) and keratitis
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude interstitial 
lung disease (ILD). Study drugs should be interrupted pending investigation of these 
symptoms. If interstitial lung disease is diagnosed, study drug must be permanently 
discontinued and appropriate treatment instituted as necessary. 
Patients who present with symptoms of keratitis, such as acute or worsening eye 
inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be 
referred promptly to an ophthalmic specialist. If a diagnosis of ulcerative keratitis is 
confirmed, treatment with afatinib should be interrupted or discontinued. If keratitis is 
diagnosed, the benefits and risks of continuing treatment with afatinib should be carefully 
considered. Afatinib should be used with caution in patients with a history of keratitis, 
ulcerative keratitis or severe dry eye. Contact lens use is a risk factor for keratitis and 
ulceration.


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10.2
NEW YORK HEART ASSOCIATION CLASSIFICATION OF HEART 
FAILURE
Class
Patient Symptoms
Class I (Mild)
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, or dyspnoea (shortness of 
breath)
Class II (Mild)
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or dyspnoea.
Class III 
(Moderate)
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnoea.
Class IV (Severe)
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased.


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10.3
ADVERSE EVENT/SERIOUS ADVERSE EVENT REPORTING
Yes
No
Complete 
SAE Form 
and eCRF
Complete
SAE Form
Other
SAE 
(including 
those with 
fatal 
outcomes)
Disease
Progression
(PD)
If Serious
Did event occur from date ICF 
was signed through the FU visit?
If Nonserious
Is Event Serious?*
Any SAE that the 
investigator 
becomes aware of 
after the FU visit 
 *Results in Death
    Life-threatening
    Hospitalization/prolongation of hospitalization
    Persistent/significant disability
    Congenital anomaly/birth defect
    Important medical event
If progressive disease occurs 
and is associated with 
symptoms, the term 
“Progressive Disease” should 
not be reported as an AE, 
however, signs and symptoms 
of progressive disease will be 
reported as an (S)AE (if 
applicable). Exception to this: 
Death due to progressive 
disease and where no signs or 
symptoms are available 
should be reported as 
“malignant neoplasm 
progression (grade 5, outcome 
fatal).
If during this period, 
patient experienced:
Adverse Event that is not a Pre-existing condition 
documented during screening
Yes
No
Complete
eCRF
Did event occur from date ICF 
was signed through to the FU visit 
(28 days post EOT)?
Do not 
report


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10.4
SAMPLE DIARRHOEA DIARY


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1
Date of CTP revision
25 Jun 2013
EudraCT number
NA
BI Trial number
1200.66
BI Investigational Product(s)
afatinib (BIBW 2992)
Title of protocol
An open label, multicentre, single-arm trial to assess 
the safety  of afatinib for patients with locally 
advanced or metastatic non-small cell lung cancer 
(NSCLC)  harboring EGFR mutation(s)
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB/IEC/Competent Authority 
to be notified of change with 
request for approval
Can be implemented without 
IRB/IEC/Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Sections to be changed
Flow Chart
Description to be changed
Deletion of ECG assessment. Addition of following 
notation under legend No 3.  “assessment should be 
considered only in patients with cardiac risk factors 
and those with condition that can affect LVEF”
Rationale
Global Drug Safety and Therapeutical Area Head 
agreement that monitoring of cardiac function on 
regular basis is not required. The protocol should 
follow CCDs (label) recommendation.
Sections to be changed
Flow Chart
Description of change
Delete LVEF assessment for all assessments visits.
Addition of following notation under legend No 3
Assessment should be consider only in patients with 
cardiac risk factors, those with condition that can 
affect LVEF and in accordance to the current standard 
of care.  Patients with ejection fraction below the 
institution’s lower limits of normal, cardiac 
consultation as well as afatinib treatment interruption 


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or discontinuation should be considered.
Rationale for change
Global Drug Safety and Therapeutical Area Head 
agreement that monitoring of and cardiac function on 
regular basis is not required. The protocol should 
follow CCDs (label) recommendation.
Sections to be changed
Flow Chart
Description of change
Deletion of D to Dispense Trial Medication
Rationale for change
Typographical Error
Sections to be changed
Section 2.3 and Table 2.3.1
Description of change
Addition of supporting data on afabinib
Rationale for change
Update of information
Sections to be changed
Section 3.3.2
Description of change
Deletion of exclusion criterion of LVEF>50% 
Rationale for change
Consistent with protocol requirement
Sections to be changed
Section 3.3.3
Description of change
Amend NYHA classification of >3 to >3
Rationale for change
Typographical error
Sections to be changed
Section 4.1.6
Description of change
Addition of Polypropylene (PP bottles) in additional to 
the HDPE as it is currently written
Rationale for change
Update of information
Sections to be changed
Section 5.1.2
Description of change
Amend from :
However, radiological progression may not occur at 
same time point as symptomatic progression and study 
treatment can be continued at the discretion of the 
investigator until protocol-defined progression is met. 
Amend to:
However, radiological progression may not occur at 
same time point as symptomatic progression and study 
treatment can be either discontinued based on 
radiological progression or continued at the discretion 
of the investigator until protocol-defined progression 
is met
Rationale for change
Provide clarity to the situation for continuation / 
discontinuation of treatment
Sections to be changed
Section 5.2.2 and Table 5.2.2.2:1
Description of change
Amend the sentence from:
Report any SAE that the investigator becomes aware 
of after the FU visit (End of Residual Phase). This 
includes all deaths.


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Amended to:
Report any SAE that the investigator becomes aware 
of after the FU visit (End of Residual Phase) 
considered related to trial medication or trial design 
must be reported. This includes all deaths.
Rational for Change
In accordance to recent SOP variation for Oncology 
Trials where SAEs reporting after FU period means 
that reporting is limited the Drug related or trial 
related SAEs events only.
Sections to be changed
Section 5.2.2.1 
Description of Change
Deletion of mandatory ECG assessment
Rational for Change
Compliant with protocol requirement
Sections to be changed
Section 5.2.4, Tables 6.2.1:1; 6.2.2:1 and 6.2.3:1
Description of Change
ECG assessment is recommended/optional test or 
procedure according to patient’s course as required by 
clinical condition
Rationale for Change
Consistent with protocol requirement.
Sections to be changed
Section 5.2.5.3; Table 6.2.2.1; Table 6.2.3.1
Description of change
Deletion of LVEF assessment for all assessment 
except for patients with cardiac risk factors, those with 
condition that can affect LVEF and in accordance to 
the current standard of care.  Patients with ejection 
fraction below the institution’s lower limits of normal, 
cardiac consultation as well as afatinib treatment 
interruption or discontinuation should be considered.
Rationale for change
Global Drug Safety and Therapeutical Area Head 
agreement that monitoring of LVEF and cardiac 
function on regular basis is not required. The protocol 
should follow CCDs (label) recommendation.
Sections to be changed
Table 6.2.1; 6.2.2.1; 6.2.3.1
Description of change
Corrected information of data that is to be collected 
for the eCRF
Rationale for change
Administrative change in order to provide clarity on 
what data is collected by the eCRF
Sections to be changed
Section 9.1
Description of change
Addition of literature reference to support afatinib
Rationale for change
Additional reference
Sections to be changed
Section 10.4
Description of change
Correction of name of Diary
Rationale for change
Typographical error


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Number of global amendment
2
Date of CTP revision
27 May 2014
EudraCT number
NA
BI Trial number
1200.66
BI Investigational Product(s)
Giotrif®/ Gilotrif™ (afatinib)
Title of protocol
An open label, multicentre, single-arm trial to assess 
the safety  of afatinib for patients with locally 
advanced or metastatic non-small cell lung cancer 
(NSCLC)  harboring EGFR mutation(s)
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB/IEC/Competent Authority 
to be notified of change with 
request for approval
Can be implemented without 
IRB/IEC/Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Sections to be changed
Title page.
Description of change
Addition of brand name of Afatinib and change in 
TCM.
Rationale for change
Update.
Sections to be changed
Clinical Trial Protocol Synopsis.
Description of change
Addition of brand name to name of finished product.
Rationale for change
Update.
Sections to be changed
Flow Chart.
Description of change
Addition of columns to indicate visits V4, V7, V10, 
V13 and V16 onwards.
Rationale for change
For clarity on schedule for tumour clinical assessment, 
and safety laboratory testing. 
Sections to be changed
Flow Chart.
Description of change
Deletion of ECG and LVEF.
Rationale for change
Update that these are not required per study (can be 
done as per site standard of care).


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Sections to be changed
Flow chart Footnote 1.
Description of change
Indicate that procedures done as standard of care for 
patient prior to consent can be used for screening for 
study. 
Rationale for change
Clarification to avoid unnecessary repeat of tests for 
patients. 
Sections to be changed
Flow chart Footnote 3 (from 11).
Description of change
Amend of footnote A from: 
Patient progress assessed by investigator according to 
local standard and will be recorded at screening and 
after treatment at each visit until EOT (whenever 
available). See definition of PD in Section 5.2.
Amend to: 
Footnote 3: Tumour assessment should be performed 
by investigator according to local standard at the time 
of screening. During treatment period, tumour 
assessment should be conducted according to local 
standard of care or recorded every 3 cycles.  Diagnosis 
of progression is at the discretion of the investigator. 
See definition of PD in Section 5.1.
Rationale for change
For clarity on schedule for tumour clinical assessment.
Sections to be changed
Flow chart Footnote 4 (from 11).
Description of change
Indicate the visits at which 
will be done. 
Rationale for change
Clarification for sites. 
Sections to be changed
Flow chart Footnote 5 (from 4).
Description of change
Indicate that safety laboratory testing consists of 
haematology and biochemistry (not urine) to be done 
every 12 weeks. 
Rationale for change
Update to allow more flexibility for sites where 
standard of care does not require as frequent safety lab 
assessments. 
Sections to be changed
Flow chart Footnote 6 (from 7).
Description of change
Indicate that urine examination to be done at EOT.
Rationale for change
Update for safety assessment required. 
Sections to be changed
Flow chart Footnote 7 (from 6); 8 (from P); 9 (from 
14) and 10 (from 7).
Description of change
Numbering update.
Rationale for change
Admin update. 
Sections to be changed
Flow chart Footnote 11 (from 10)
Description of change
Deletion of word “card” from diarrhoea diary card. 


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Rationale for change
Update for clarity, to consistently use diarrhoea diary 
term. 
Sections to be changed
Flow chart Footnote **
Description of change
Clarification that follow-up after EOT and prior to 
clinical progression will be at frequency per site 
standard practice.
Rationale for change
Update to allow more flexibility for sites where 
standard of care does not require as frequent follow-
up. 
Sections to be changed
Flow chart Footnote O and 8.
Description of change
Deletion of recommended test and LVEF.
Rationale for change
Update as these are not needed for study, to be done 
per site standard of care. 
Sections to be changed
Table of contents section 6.1.2.
Description of change
Change to indicate that Baseline visit is visit 1.
Rationale for change
Correction of typographical error.
Sections to be changed
Abbreviations.
Description of change
Deletion of abbreviations not used in protocol.
Rationale for change
Correction of typographical errors.
Sections to be changed
Section 1.1
Description of change
Deletion that trial will only enrol first line EGFR TKI 
naïve patients with EGFR mutation positive tumours.
Rationale for change
Corrections of admin / typographic error for clarity.
Sections to be changed
Section 3.3.
Description of change
Correction that trial will recruit 350 patients.
Rationale for change
Correction of typographic error.
Sections to be changed
Section 3.3.2 Inclusion criteria 4e
Description of change
Amend from: 
Aspartate Amino Transferase (AST) or Alanine 
Amino Transferase (ALT) < three times the upper 
limit of (institutional) normal (ULN) (if related to liver 
metastases < five times ULN). 
Amend to: 
Aspartate Amino Transferase (AST) and Alanine 
Amino Transferase (ALT) < three times the upper 
limit of (institutional) normal (ULN) (if related to liver 
metastases < five times ULN). 
Rationale for change
Clarification of the adequate liver function required.


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Sections to be changed
Section 3.3.3 Exclusion criteria 2
Description of change
Amend from:                                                     
hormonal anti-cancer treatment within 2 weeks prior 
to start of trial treatment (continued use of anti-
androgens and/or gonadorelin analogues for treatment 
of prostate cancer permitted) 
Amend to:                                                                     
use of anti-cancer treatment within 2 weeks prior to 
start of trial treatment (continued use of anti-
androgens and/or gonadorelin analogues for treatment 
of prostate cancer permitted) 
Rationale for change
Clarification on wash-out period needed for previous 
anti-cancer therapy. 
Sections to be changed
Section 3.3.3 Exclusion criteria 3
Description of change
Amend from:                                                                
radiotherapy within 14 days prior to drug 
administration 
Amend to:                                                                     
radiotherapy within 4 weeks prior to drug 
administration
Rationale for change
Correction of typographic error.
Sections to be changed
Section 3.3.3 Exclusion criteria 7
Description of change
Change that contraception needs to be used for at least 
4 weeks after treatment with Afatinib ended. 
Rationale for change
Clarification in line with residual effect period of 
afatinib and label for afatinib.
Sections to be changed
Section 3.3.3 Exclusion criteria 16
Description of change
Amend from:                                                           
symptomatic brain metastases (patients with 
asymptomatic brain metastases, who were previously 
treated, are eligible provided they have asymptomatic 
brain metastasis had Stable Disease (SD) for at least 4 
weeks on stable doses of medication) 
Amend to:                                                             
symptomatic brain metastases (patients with brain 
metastases, who were previously treated, are eligible 
provided they have asymptomatic brain metastasis for 
at least 4 weeks on stable doses of medication) 
Rationale for change
Clarification on type of brain metastasis excluded. 
Sections to be changed
Section 4.1.1


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Description of change
Revised the statement that FD&C Blue No. 2 11-14% 
is not included in the 20 mg tablet to “may not be 
included in 20mg tablet”. 
Rationale for change
Clarification of excipient for afatinib 20mg tablet
Section to be changed
Section 4.1.4.1
Description of change
Amend from:
After treatment pause due to adverse events, treatment 
at a reduced dose (i.e., with a new bottle of 
medication) will restart at the predefined 
schedule/cycle (i.e., 28 days (-7/+2 days) on the new 
dose).
Amend to:
After treatment pause due to drug related adverse 
events, treatment with afatinib can be resumed after 
patient recovers to < Grade 1. Dose reduction should 
always follow a treatment pause for drug related AE 
more than grade 1. In the event of any unrelated 
adverse events, the investigator may choose to pause 
the medication to allow the patient to recover, but no 
dose reduction is required.
Rationale for Change
Clarification on re-starting afatinib after pause due to 
drug related AE or non-drug related AE. 
Sections to be changed
Section 4.2.3
Description of change
Change that contraception needs to be used for at least 
28 days (instead of 14 days) after treatment with 
Afatinib ended. 
Rationale for change
Clarification in line with residual effect period of 
afatinib and label for afatinib.
Sections to be changed
Section 4.3
Description of change
Added treatment compliance expected, outside which 
will be considered as non-compliance. 
Rationale for Change
Clarification on expectations
Sections to be changed
Section 5 & 5.1.
Description of change
Added that primary endpoint for study is safety 
assessment and efficacy assessments are secondary 
endpoints. 
Rationale for Change
Stating this at start of section for clarity.
Sections to be changed
Section 5.1.3
Description of change
Update that 
 to be completed health care 
professional is not optional but mandatory. 
Rationale for Change
Correction of typographical error


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Sections to be changed
Section 5.2.1
Description of change
Added specific definition of the primary endpoint and 
secondary endpoint for safety assessments.
Rationale for Change
Clarification of primary and secondary endpoints for 
safety to fulfil the requirements in the recent updated 
SOP for CTP on endpoint specification.
Sections to be Changed
Section 5.2.3
Description of Change
Indicate that safety laboratory testing consists of 
haematology and biochemistry (not urine) to be done 
every 12 weeks. 
Rationale for Change
Update. 
Sections to be changed
Section 5.2.4
Description of change
Indicate that ECG is not required for the study, to be 
done according to local standard of care. 
Rationale for change
Update.
Sections to be Changed
Section 5.3.2.1
Description of Change
Correction of typographical error of dehydration when 
it should have been hydration
Rationale for Change
Correction of typographical error
Sections to be Changed
Section 6.1.2
Description of Change
Change to indicate that Baseline visit is visit 1
Rationale for Change
Correction of typographical error
Sections to be Changed
Section 6.2.1
Description of Change
Change to indicate that visit 1 is screening and 
baseline visit. 
Rationale for Change
Correction of typographical error
Sections to be Changed
Table 6.2.1:1, Table 6.2.2:1 and Table 6.2.3:1
Description of Change
Update on the study procedures and schedule. 
Rationale for Change
Updates 
Sections to be Changed
Section 10.5
Description of Change
Update that 
 to be completed health care 
professional is not optional but mandatory. 
Rationale for Change
Correction of typographical error


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Number of global amendment
3
Date of CTP revision
18 Dec 2015
EudraCT number
NA
BI Trial number
1200.66
BI Investigational Product(s)
Giotrif®/ Gilotrif™ (afatinib)
Title of protocol
An open label, multicentre, single-arm trial to assess 
the safety  of afatinib for patients with locally 
advanced or metastatic non-small cell lung cancer 
(NSCLC)  harboring EGFR mutation(s)
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB/IEC/Competent Authority 
to be notified of change with 
request for approval
Can be implemented without 
IRB/IEC/Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Sections to be changed
Clinical Trial Protocol Synopsis.
Description of change
Change in total patients entered from 350 to 500.
Rationale for change
Update for extension of recruitment numbers for 
China.
Sections to be changed
Flow Chart.
Description of change
Format of column of Day 15.
Rationale for change
For clarity that phone call is only needed on day 15 
post first dose.  
Sections to be changed
Flow Chart.
Description of change
Visit window for FU visit is changed to +7 instead of -
7 days.
Rationale for change
REP for Afatinib is 28 days so FU visit should not be 
less than 28 days post last dose. 
Sections to be changed
Flow Chart Footnote 3.
Description of change
Added that cancer related symptoms and clinical 
benefit for continuing Afatinib need to be assessed at 
each visit.


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Rationale for change
For clarity the assessments needed before patient 
continues on with next treatment cycle.
Sections to be changed
Table of contents.
Description of change
Added section 10.1.4
Rationale for change
To indicate added section 10.1.4
Sections to be changed
Section 1.2
Description of change
Added information about Afatinib profile and update 
of IB version.
Rationale for change
Update per information in current IB.
Sections to be changed
Section 3.3
Description of change
Change in total patients entered from 350 to 500; 
number of sites from 35 to 40.
Rationale for change
Update for extension of recruitment numbers for 
China.
Sections to be changed
Section 3.3.4.1
Description of change
Deleted deterioration in LVEF as one of the reasons 
for discontinuing patients. 
Rationale for change
Patients with clinically relevant cardiovascular 
abnormalities are excluded from the study and 
elevated LVEF is not an AE of special interest related 
to afatinib, therefore, it is not necessary to stress 
LVEF Grade ≥ 3 here.
Sections to be changed
Section 3.3.4.1
Description of change
Update wording for discontinuation due to cancer 
related symptoms deterioration and unequivocal 
disease progression.
Rationale for change
To clarify discontinuation due to unequivocal disease 
progression. Patients with stable symptoms do not 
need to be discontinued. 
Sections to be changed
Section 3.3.4.1
Description of change
Added that sponsor may move patients from study 
post primary analysis if patients have access to 
Afatinib via other alternatives such as marketed 
source, expanded access program, named patient use 
program. 
Rationale for change
Update possible supply of Afatinib for patients post 
completion of primary analysis and procedures 
needed. 
Sections to be changed
Section 4.1.2
Description of change
Change in total patients entered from 350 to 500. 
Added that all eligible patients will receive Afatinib.


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Rationale for change
Update for extension of recruitment numbers for 
China.
Sections to be changed
Section 4.2.1
Description of change
Added procedures in case of overdose of Afatinib.
Rationale for change
Update.
Sections to be changed
Section 5.2.2.1
Description of change
Updated version number of IB.
Rationale for change
Update.
Sections to be changed
Section 6.1.5
Description of change
Add that FU visit should be done 28 (+7) days post 
EOT visit. 
Rationale for change
Correct visit window to +7 and not -7 days. REP for 
Afatinib is 28 days so FU visit should not be less than 
28 days post last dose. 
Sections to be changed
Section 6.2.4
Description of change
Visit window for FU visit is changed to +7 instead of -
7 days. 
Rationale for change
REP for Afatinib is 28 days so FU visit should not be 
less than 28 days post last dose. 
Sections to be changed
Section 6.2.4
Description of change
Added that patients without clinical progression at 
EOT will be followed per site standard practice. 
Rationale for change
Add to be consistent with flow chart.
Sections to be changed
Table 6.2.4:1
Description of change
Visit window for FU visit is changed to +7 instead of -
7 days. 
Rationale for change
REP for Afatinib is 28 days so FU visit should not be 
less than 28 days post last dose. 
Sections to be changed
Table 6.2.4:1
Description of change
Add that date when new anti-cancer medication is 
taken is collected. 
Rationale for change
To be consistent with information being collected in 
RDC. 
Sections to be changed
Section 8.4.1
Description of change
Updated version number of IB.
Rationale for change
Update.
Sections to be changed
Section 9.2
Description of change
Updated version number of IB.


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Rationale for change
Update.
Sections to be changed
Table 10.1.2:1
Description of change
Correct for typing error of PABA-free.
Rationale for change
Correction of typing error.
Sections to be changed
Table 10.1.2:2
Description of change
Update on treatment recommendation of skin 
reactions.
Rationale for change
Update per latest core protocol for all Afatinib trials.
Sections to be changed
Section 10.1.4
Description of change
Added wording for management of ILD and keratitis.
Rationale for change
Update per information in current IB.
Number of global amendment
4
Date of CTP revision
1 Feb 2017
EudraCT number
c14890504-01
BI Trial number
1200.66
BI Investigational Product(s)
Giotrif®/ Gilotrif™ (afatinib)
Title of protocol
An open label, multicentre, single-arm trial to assess 
the safety of afatinib for patients with locally 
advanced or metastatic non-small cell lung cancer 
(NSCLC)  harboring EGFR mutation(s)
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB/IEC/Competent Authority 
to be notified of change with 
request for approval
Can be implemented without 
IRB/IEC/Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only
Sections to be changed
1.2 drug profile
Description of change
Update the maximum plasma concentrations of 
Afatinib and Afatinib approval information.
Rationale for change
Update it according to the current version of IB.


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Sections to be changed
3.1 overall trial design and plan
Description of change
Clarify that In this trial disease progression is 
determined by the investigator. Afatinib must be 
permanently discontinued when investigator judges 
that patient is no longer benefiting from treatment with 
afatinib. 
Rationale for change
Clarify the trial design.
Sections to be changed
3.3.2 inclusion criteria
Description of change
Add the age range of India patient.
Rationale for change
Add India local protocol amendment information to 
main protocol.
Sections to be changed
3.3.4.1 Removal of individual patients
Description of change
Clarify that patient may be discontinued if patient 
receives any other anti-cancer treatment.
Delete “cancer related symptomatic disease 
progression, or documented unequivocal disease 
progression except patients with stable symptoms.”
Rationale for change
Clarify the rules of removal of individual patients.
Sections to be changed
3.3.4.2 Discontinuation of the trial by the sponsor
Description of change
Delete “The investigator / the trial site will be 
reimbursed for reasonable expenses incurred in case of
trial termination (except in case of the third reason).”
Rationale for change
This information is in the contract between site and 
Sponsor.
Section to be changed
4.1.4 drug assignment and administration of doses of 
each patient
Description of change
Clarify that treatment will stop when patient meets 
withdrawal criteria listed in section 3.3.4.1.
Rationale for change
Clarify the criteria of stop treatment.
Sections to be changed
4.1.7 storage conditions
Description of change
Clarify “in the event that the temperature would be out 
of range, this has to be documented in the ISF and 
reported to the sponsor according to Storage 
conditions for Trial Medications (STORM) in the ISF.
Rationale for change
Update according to the current process of reporting 
temperature excursion. 
Sections to be changed
5.1.1 Endpoint of efficacy
Description of change
Move the definition of 
  to section 5.1.3 other 


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efficacy  assessment.
Rationale for change
 is the other efficacy assessment.
Sections to be changed
5.1.2 Assessment of efficacy
Description of change
Re-wording the assessment of efficacy.
Rationale for change
Clarify the assessment of efficacy.
Sections to be changed
5.1.3 Other efficacy assessment
Description of change
Move the definition of 
from section 5.1.1 to 5.1.3. 
Move the wording regarding 
 from section  
5.3.1.1 to 5.1.3
Rationale for change
is the other efficacy assessment.
Sections to be changed
Section 5.3 Other
Description of change
Move the wording regarding 
from section 
5.3.1.1 to 5.1.3. Renumber 5.3.2.1 Documentation of 
diarrhoea as 5.3.1. 
Rationale for change
Correct error.
Sections to be changed
Section 6.2.3 End of treatment and Follow up
Description of change
Change “End of trial” to “End of treatment”.
Rationale for change
Correct typo.
Sections to be changed
Section 7.3.2
Description of change
Add TTSP in the secondary analysis and clarify the 
definition of 
and delete 
 analysis.
Rationale for change
Clarify secondary analysis to be consistent with 
section 5 efficacy endpoint.
Sections to be changed
Section 7.3.4 interim analyses 
Description of change
Add information regarding interim analyses.
Rationale for change
Include interim analysis in protocol.
Sections to be changed
Section 7.4 handling of missing data
Description of change
Delete the word 
Rationale for change
Correct typo.
Sections to be changed
Section 9.2 unpublished  references
Description of change
Update the document number, version and date of 
current IB.
Rationale for change
New IB is issued on 03 Jul 2016.

SAP_000.pdf: 
Reference Document “Template Trial Statistical Analysis Plan – template”
001-MCG-160_RD-06 (7.0) / Saved on: 08 Jun 2015
TITLE PAGE
Trial Statistical Analysis Plan
c02331303-02
BI Trial No.:
1200.66
Title:
An open label, multicenter, single-arm trial to assess the safety of 
afatinib for patients with locally advanced or metastatic non-small 
cell lung cancer (NSCLC) harboring EGFR mutation(s)
Including Protocol Amendment 1 [U13-3195-02] 
Including Protocol Amendment 2 [c02368116-01])
Including Protocol Amendment 3 [c09028632-0.4])
Including Protocol Amendment 4 [c14890504-01])
Investigational
Product(s):
Giotrif®/ Gilotrif™(afatinib)
Responsible trial 
statistician(s):
Phone:
Fax: 
Date of statistical 
analysis plan:
28 MAR 2017SIGNED
Version:
Revised
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................3
2.
LIST OF ABBREVIATIONS ..............................................................................4
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINT(S).......................................................................................................8
5.1
PRIMARY ENDPOINT .......................................................................................8
5.2
SECONDARY ENDPOINTS...............................................................................8
5.2.1
Key secondary endpoint .......................................................................................8
5.2.2
Secondary endpoints.............................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS ............................................................9
6.1
TREATMENT.......................................................................................................9
6.2
IMPORTANT PROTOCOL VIOLATIONS .....................................................9
6.3
PATIENT SETS ANALYSED...........................................................................12
6.5
POOLING OF CENTRES .................................................................................13
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................13
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................14
7.
PLANNED ANALYSIS......................................................................................15
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........15
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................15
7.3
TREATMENT COMPLIANCE........................................................................16
7.4
PRIMARY ENDPOINT .....................................................................................16
7.5
SECONDARY ENDPOINTS.............................................................................16
7.5.1
Key secondary endpoint .....................................................................................16
7.5.2
Secondary endpoints...........................................................................................16
7.7
EXTENT OF EXPOSURE.................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................21
7.8.1
Adverse events.....................................................................................................21
7.8.2
Laboratory data ..................................................................................................22
7.8.3
Vital signs.............................................................................................................22
7.8.4
ECG......................................................................................................................23
7.8.5
Others...................................................................................................................23
8.
REFERENCES....................................................................................................24
9.
ADDITIONAL SECTIONS ...............................................................................25
10.
HISTORY TABLE..............................................................................................26


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LIST OF TABLES
Table 6.2: 1
Important protocol violations ...........................................................................10
Table 10: 1
History table .....................................................................................................26


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
BRPM
Blinded report planning meeting
CR
Complete response
CTCAE
Common Terminology Criteria  for Adverse Events
CTP
Clinical Trial Protocol
eCRF
Electronic case report form
ECG
Electrocardiography
ECOG
Eastern Cooperative Oncology Group
EGFR
Epidermal growth factor receptor
EMA
European Medicines Agency
EoT
End of treatment
HEP C
Hepatitis C
HIV
Human Immunodeficiency Virus
ICH
International Conference on Harmonisation
IPV
Important protocol violation
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
Min
Minimum
N
Denotes number of patients
NSCLC
Non-small cell lung cancer
PD
Progressive disease
PP
Per-protocol 
PT
Preferred term
SAE
Serious adverse event
SD
Standard deviation
SOC
System organ class


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Term
Definition / description
TKI
Tyrosine kinase inhibitor
TS
Treated set
TSAP
Trial statistical analysis plan
TTSP
Time to symptomatic progression


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as written 
in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP 
readers may consult the CTP for more background information on the study, e.g., on study 
objectives, study design and population, treatments, definition of measurements and variables, 
planning of sample size, randomization.
SAS® Version 9.4 will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
 
 
 
 
 
The definition of time to symptomatic progression (TTSP) has been clarified in Section 7.5.2.
 


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5.
ENDPOINT(S)
This is an open-label, multi-centre, non-randomised, uncontrolled, single arm trial designed to 
evaluate the safety, tolerability and efficacy of afatinib (Giotrif®) in patients with locally 
advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutation(s) and 
have never been treated with an EGFR-TKI. After the initial screening visit, patients will 
enter the open-label treatment period with safety visits at approximately every 28 days until 
the end of the trial. The trial objective is to evaluate the safety and tolerability of afatinib 
(Giotrif®) in this cohort of patients. Of main interest are adverse events, collected throughout 
the study.
No specific tumour measurements are required in this program.  Data regarding tumour 
assessments are performed at clinic visits as per local standard of care for NSCLC.  
 
5.1
PRIMARY ENDPOINT

Number of patients with serious adverse events (SAEs).
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
There are no key secondary endpoints.
5.2.2
Secondary endpoints

Number of patients with drug related adverse events.

Time to symptomatic progression (TTSP)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT
There is only one treatment in this study, which is afatinib.  The starting dose for all patients 
is 40 mg with an option to reduce the dose to 30 mg or 20 mg based on individual tolerability.  
Unless otherwise stated, for all analyses, treated patients will be presented under the starting 
dose.
The following study periods based on key visit dates and actual start and stop dates of study 
treatment administration are defined:

Screening: From day of informed consent to day prior to starting study treatment.
Special handling rule: 
If informed consent date = date of first administration of active treatment in the trial, 
derive start of screening phase on the day of informed consent – 1 day.

On-treatment: From day of first administration of study treatment to the day of last 
administration of study treatment.

Residual effect period (REP): From day after last administration of study treatment to the 
28th day after last administration of study treatment.

Follow-up: After the residual effect period and up to the last per protocol contact.

Post-study: After the last per protocol contact but entered in the database before database 
lock.
For safety summaries data recorded up to 28 days after last administration of study treatment 
will be considered as on-treatment (i.e. the actual on-treatment and REP periods defined 
above will be combined into one ‘on-treatment’ analysis period).
Safety data recorded after follow-up period will be listed as post-study events but not 
tabulated.
6.2
IMPORTANT PROTOCOL VIOLATIONS
No per protocol analysis will be performed for this study; however patients with potentially 
important protocol violations (IPVs) will be documented.  The following list of potentially 
IPVs will be used; note that this is a working list and may not be finalised until the final 
Blinded Report Planning Meeting (BRPM) prior to database lock.


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Table 6.2: 1
Important protocol violations
Category / 
Code
Description
Comment/Example
Efficacy / 
Safety
A
Entrance Criteria Not Met
A1
Inclusion Criteria Not Met
A1.1
Not locally advanced or metastatic Non-Small 
Cell Lung Cancer (NSCLC)
Inclusion criteria IN1 not 
met
E
A1.2
No presence of Epidermal Growth Factor 
Receptor (EGFR) mutation in tumour biopsy.
Inclusion criteria IN2 not 
met
or
EGFR mutation negative
E
A1.3
Male or female patients age <18 years
Inclusion criteria IN3 not 
met
or
patient’s age <18 years
E/S
A1.4.1
Inadequate organ function as defined in 
protocol version 2.
Inclusion criteria IN4 not 
met
E/S
A1.4.2
Inadequate organ function as defined in 
protocol version 3.
Inclusion criteria IN4 not 
met
E/S
A1.5
ECOG score not between 0 – 2
Inclusion criteria IN5 not 
met,
or
baseline ECOG score not 
between 0-2.
E/S
A2
Exclusion Criteria Met
A2.1
Prior treatment with an EGFR tyrosine kinase 
inhibitor (TKI)
Exclusion criteria EX1 met
E
A2.2.1
hormonal anti-cancer treatment within 2 
weeks prior to start of trial treatment as 
defined in protocol version 2.
Exclusion criteria EX2 met
E
A2.2.2
Use of anti-cancer treatment within 2 weeks 
prior to start of trial treatment as defined in 
protocol version 3.
Exclusion criteria EX2 met
E
A2.3.1
Radiotherapy within 14 days prior to drug 
administration as defined in protocol version 
2.
Exclusion criteria EX3 met
E
A2.3.2
Radiotherapy within 4 weeks prior to drug 
administration as defined in protocol version 
3.
Exclusion criteria EX3 met
E
A2.4
Major surgery within 4 weeks from day 1 of 
first dose of afatinib, or minor surgical 
procedures including placement of an access 
device or fine needle aspiration within 7 days, 
or diagnostic or palliative video-assisted 
thoracoscopic surgery (VATS) within 14 days.
Exclusion criteria EX4 met
E/S
A2.5
Known hypersensitivity to afatinib or any of 
its excipients
Exclusion criteria EX5 met
S
A2.6
History or presence of clinically relevant 
cardiovascular abnormalities or myocardial 
infarction within 6 months prior to starting 
trial treatment
Exclusion criteria EX6 met
S


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Category / 
Code
Description
Comment/Example
Efficacy / 
Safety
A2.7.1
Women of Child-Bearing Potential or man 
who is able to father a child, unwilling to be 
abstinent or use adequate contraception prior 
to trial entry, for the duration of trial 
participation and for at least 2 weeks after 
treatment has ended as defined in protocol 
version 2.  
Exclusion criteria EX7 met
S
A2.7.2
Women of Child-Bearing Potential or man 
who is able to father a child, unwilling to be 
abstinent or use adequate contraception prior 
to trial entry, for the duration of trial 
participation and for at least 4 weeks after 
treatment has ended as defined in protocol 
version 3.
Exclusion criteria EX7 met
S
A2.8
Childbearing potential who:
a. are nursing or
b. are pregnant or
c. are not using an acceptable method of birth 
control, or do not plan to continue using this 
method throughout the trial and/or do not 
agree to submit to pregnancy testing required 
by this protocol
Exclusion criteria EX8 met
S
A2.9
Any history of or co-existing condition that, in 
the opinion of the investigator, would 
compromise the patient’s ability to comply 
with the trial or interfere with the evaluation 
of safety for the trial drug
Exclusion criteria EX9 met
E/S
A2.10
Previous or concomitant malignancies at other 
sites, except effectively treated nonmelanoma
skin cancers, carcinoma in situ of the cervix, 
ductal carcinoma in situ or effectively treated 
malignancy that has been in remission for 
more than 3 years and is considered to be 
cured.
Exclusion criteria EX10 met
E/S
A2.11
Requiring treatment with any of the prohibited 
concomitant medications that cannot be 
stopped for the duration of trial participation
Exclusion criteria EX11 met
E
A2.12
Known pre-existing interstitial lung disease 
Exclusion criteria EX12 met
S
A2.13
Presence of poorly controlled gastrointestinal 
disorders that could affect the absorption of 
the trial drug based on investigator assessment
Exclusion criteria EX13 met
E
A2.14
Known active hepatitis B infection, active 
Hepatitis C (HEP C) and/or known Human 
Immunodeficiency Virus (HIV) carrier.
Exclusion criteria EX14 met
S
A2.15
Meningeal carcinomatosis
Exclusion criteria EX15 met
E/S
A2.16
Symptomatic brain metastases
Exclusion criteria EX16 met
E/S
B
Informed Consent
B1
Informed consent not given
Inclusion criteria IN6 not 
met
or
consent date is missing
S
B2
Informed consent given too late
Inclusion criteria IN6 not 
met
S
B3
Re-consent for updated informed consent
form not given or given too late
IPV if the change affects the 
safety and right of the 
patient
S


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Category / 
Code
Description
Comment/Example
Efficacy / 
Safety
C
On Study
C1
Incorrect trial medication dose
affecting the safety of the patient
S
C2
Local lab test not done affecting the 
safety of the patient
S
C3
Expired IP taken by patient and 
confirmed by CTSU as not suitable for 
administration
E/S
C4
Other PV affecting efficacy 
E
C5
Other PV affecting safety
S
Note: Missing visits, evaluations, and tests will be considered missing data, not protocol deviations. All the potential IPVs 
listed in the table will be identified programmatically.
6.3
PATIENT SETS ANALYSED
Enrolled set (ES)
The enrolled set consists of all patients who signed informed consent.
Treated set (TS)
All planned analyses will be based on the Treated Set (TS) which includes all patients who 
were dispensed trial medication and are documented to have taken at least one dose of 
investigational treatment (afatinib).


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6.5
POOLING OF CENTRES
This section is not applicable because there will be no pooling of centres or countries and no 
modelling thereof.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”).(1)
For efficacy data, the following rules will apply:
 
 
 
 
 
 
 
 
 
 
In addition, time since first diagnosis of NSCLC will be calculated from the date of diagnosis 
and the date of the start of the study treatment.  As the date of diagnosis is likely to be partial 
in many cases, the following rules will be used


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
If day is missing but month and year are present, impute to first day of the month.

If only year is present, set to January 1st.
For partial treatment discontinuation date, the following logic is applied:
If month and year are known but day is missing, then use date of death if within the same 
month for a patient who died. Otherwise use last day of the month. 
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Where a baseline value is required, this will be defined as the last non-missing value prior to 
first administration of afatinib.
The time windows for subsequent clinic visits is 28 -7/+2 days.  The end of treatment (EoT) 
visit can be anything up to a maximum of 14 days after the last trial drug intake and the 
follow-up visit should be between 28 and 35 days after the EoT visit.
Nominal visit numbers as recorded in the eCRF will be used where required and there will be 
no windowing.  
Study day will be calculated relative to the date of the first administration of study drug.  The 
day prior to first administration of study drug will be ‘Day -1’ and the day of first 
administration of study drug will be ‘Day 1’; therefore ‘Day 0’ will not exist.
 
 


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7.
PLANNED ANALYSIS
Unless otherwise stated, for end-of-text tables, the set of summary statistics is: N / Mean / SD 
/ Min / Median / Max.
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group, unless otherwise stated. Percentages will be rounded to one 
decimal place. The category missing will be displayed only if there are actually missing 
values. 
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. Demographic and baseline 
characteristic parameters collected and to be presented include

Age [years]

Age class  (<65, ≥65 years and <75,≥75 years)

Gender  (Male, Female)

Race and ethnicity(as defined in the eCRF)

Country

Height [cm]

Weight [kg]

Body mass index [kg/m2] (defined as weight [kg]/(height [cm]/100)2)

Body surface area [m2] (defined as: 0.007184*(height0.725)*(weight0.425))

Smoking status  (Never-smoked, Ex-smoker, Current smoker)

Smoking history [pack-years]

Baseline ECOG score

EGFR mutation type (common, uncommon only)

Oncology history

Previous therapies:
-
Systemic chemotherapies 
-
Other anti-cancer therapies
-
Radiotherapies

Previous surgeries for trial disease
This section will include a summary of all the subgroup variables detailed in Section 6.4.  
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. Only concomitant 
therapies for rash and diarrhoea were collected on the CRF and will be summarised.
For baseline conditions and signs and symptoms of the trial disease also only descriptive 
statistics will be presented.


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7.3
TREATMENT COMPLIANCE
There is no analysis planned for treatment compliance.
7.4
PRIMARY ENDPOINT
Refer to Section 7.8.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoints have been specified in the 
protocol.
7.5.2
Secondary endpoints
The secondary endpoints will be analysed as described below:
Number of patients with drug related adverse events
Refer to Section 7.8.
Time to symptomatic progression (TTSP) 
Defined as the time (number of days) from first administration of afatinib to the date of first 
documented clinically significant symptomatic progression that required stopping afatinib 
according to investigator’s assessment.
Patients will be considered to have clinically significant symptomatic progression if the 
reason for termination of trial medication is recorded as ‘progressive disease’ or ‘worsening 
or AE of underlying cancer disease’, on the termination of trial medication eCRF page. 
Therefore TTSP will be derived as:
TTSP [days] = date of last administration of trial drug (where ‘progressive disease’ or 
‘worsening or AE of underlying cancer disease’ selected on the termination of trial drug 
eCRF page) – (date of start of treatment) + 1  
Kaplan-Meier estimates and 95% confidence intervals for the 25th, median, and 75th 
percentiles of the survival distribution will be calculated for TTSP. Greenwood’s standard 
error estimate will be used. Kaplan-Meier curves will also be produced.
Censoring rules for TTSP:

For patients who have ‘other AE’, ‘non-compliance with protocol’, ‘lost to follow-up’, 
‘patient refusal to continue taking trial medication’ or ‘other’ recorded on the termination 
of trial medication eCRF page, these patients will be censored at the date of last 
administration of the trial drug recorded on the termination of trial drug page;

For patients who are still on treatment, these patients will be censored at cut-off date for 
interim analysis and at the date of EOT visit for final analysis.


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7.7
EXTENT OF EXPOSURE
Total treatment time (days) will be calculated for each patient; total treatment time will 
include any dose interruptions or off-drug periods. 
The definition of exposure is:
Treatment stop date – treatment start date + 1
In case of death due to any cause, the treatment stop date will be imputed as the earlier of 
(date of last administration of afatinib treatment, date of death) + 1 day
Standard descriptive summaries of these data will be provided for the treated set of patients.
Total treatment time (days) will be summarized by afatinib dose level (40 mg, 30 mg, 20 mg 
and total), and by number of therapy lines. The number of therapy lines for afatinib will be 


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derived as: the number of all previous therapy lines + 1. The number of all previous therapy 
lines that the patient received prior to the start of the treatment includes number of lines of all 
of the following:

Systemic chemotherapies: count the number of previous chemotherapies obtained from 
the field “Line of therapy” on the previous chemotherapies eCRF page . 

Other anti-cancer therapies: count the number of anti-cancer therapies obtained from the 
field “Line of therapy” on the other anti-cancer therapies eCRF page. If there is a therapy 
with the same name and same start and end dates as a therapy present in Systemic 
chemotherapies eCRF page, then ignore this as it has already been counted earlier.  
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. 
7.8.1
Adverse events
The intensity of adverse events were classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0 in the eCRF.
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of patients with AEs and NOT on the number of 
AEs.
Furthermore, for analysis of AE attributes such as duration, severity, etc. multiple AE 
occurrence data on the CRF, will be collapsed into AE episodes provided that all of the 
following apply:

The same MedDRA lowest level term was reported for the occurrences

The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)

Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence
For further details on summarization of AE data, please refer to the guideline 'Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries' (2)
[001-MCG-156]
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first study drug intake until 28 
days after last study drug intake will be assigned to be treatment-emergent. All AEs occurring 
outside of this period will be handled according to the treatment definition period definitions 
detailed in Section 6.1 and will only be listed unless stated otherwise.
An overall summary of adverse events will be presented.  This summary will exclude the 
rows ‘Severe AEs’, ‘Significant AEs’ and ‘Other significant AEs’ but will include additional 


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rows for ‘AEs leading to dose reduction’ and ‘AEs by highest Common Terminology Criteria 
(CTC)’ grade.  
The frequency of patients with adverse events will be summarised by highest CTC grade 
(grades 3, 4, 5 and all grades including also grade 1 and 2), treatment, primary system organ 
class (SOC) and preferred term (PT) for each of the following AE tables: 

All AEs collected

Drug related AEs.

AEs leading to dose reduction.

AEs leading to treatment discontinuation.

Drug related AEs leading to treatment discontinuation

Serious AEs.

Drug related serious AEs.

AEs leading to death.
All tables will be sorted by SOC according to the standard sort order specified by the 
European Medicines Agency (EMA); PTs will be sorted by frequency (within SOC).
The above tables except for AEs leading to death will be repeated with the project defined 
grouping of AE terms (rash, stomatitis, ocular effects, lip effects, nail effects and fatigue).  
Details of the project defined groupings are defined in the technical TSAP.  In these tables the 
grouped AEs will replace the original PTs for all AEs that are included within the grouped 
term.  The grouped AE categories will then be tabulated along with all remaining MedDRA 
PTs, sorted by descending frequency.  A reference table presenting all of the project defined 
groupings and MedDRA PTs within each grouping will also be produced.
Additional AE tables will be produced for AEs of special interest (diarrhoea, and the project 
defined groupings of rash and renal insufficiency), providing further details on highest CTC 
grade, action taken with study drug and time to first onset of AE.
Number of patients with adverse events with incidence greater than 5% will be summarised 
by treatment, primary system organ class (SOC) and preferred term (PT).
7.8.2
Laboratory data
Only the date of samples are collected; laboratory data are not collected. Laboratory values 
that are considered clinically relevant will be recorded with Baseline Conditions or Adverse 
Events as appropriate.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report. A summary of the actual 
value and the change from baseline will be presented in 4-week periods for the following 
parameters: Systolic blood pressure, Diastolic blood pressure, Pulse rate, Temperature, 
Weight. 
Other than at baseline, repeat, ad-hoc or unscheduled data will not be included in the 
summary tables.


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A listing for pregnancy test results of patients with child bearing potential will be provided.
7.8.4
ECG
Only the date of the tracing is collected if this is done per site standard of care. Abnormalities 
will be recorded with Baseline Conditions or Adverse Events as appropriate.
7.8.5
Others
Not applicable.


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8.
REFERENCES
1
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
2
001-MCG-156: "Handling and summarisation of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.


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9.
ADDITIONAL SECTIONS
 
 
9.2
PROGRAMMING CODE FOR TIME TO EVENT ENDPOINTS
For Kaplan-Meier estimates the following SAS code will be used:
proc lifetest data=<DATA> method=KM;
time <ENDPOINT>*<CENSORED FLAG>(1);
run;
Where:
DATA – name of the input dataset.
ENDPOINT – is the time variable (i.e. TTSP, 
 
CENSORED FLAG – is the binary variable with value 1 denoting a censored observation and 
value 0 (zero) indicating the observation that was not censored (so the event had occurred)


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
26-NOV-15
None
This is the final TSAP without any 
modification.
Revised
28-MAR-17
5.3, 6.1, 
6.7, 
7.5.2, 
7.6, 9.1
and 
Revised the definition of study period in 
section 6.1;
Changed the follow-up visit window 
(section 6.7) to be consistent with the
flow chart in CTP;
Revised the censoring rules for TTSP in 
section 7.5.2; 
 
and