Clinical trial NCT02597946
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim
Start date: 2016-03-18; Completion date: 2018-07-22
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
to investigate effectiveness and safety of afatinib in the advanced NSCLC patients with HER2 mutations, previously treated with 1 or 2 chemotherapy regimens

Detailed description:

Arms: arm 1: Part A: all enrolled patients will receive afatinib monotherapy. Part B: all eligible patients will receive afatinib combined with weekly paclitaxel.
Interventions: intervention 1: afatinib intervention 2: paclitaxel
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_001.pdf: 
abcd
Clinical Trial Protocol
TITLE PAGE
Document Number:
c08988429-02
BI Trial No.:
1200.222
BI Investigational 
Product(s):
BIBW2992 (afatinib)/ Giotrif®/ GiotrifTM
Title:
A phase II study of afatinib in patients with advanced NSCLC 
harboring HER2 mutations, previously treated with chemotherapy
Brief Title:
Afatinib in NSCLC with HER2 mutation
Clinical Phase:
II
Trial Clinical 
Monitor:
Phone: 
Fax: 
Principal 
Investigator:
Phone:
Fax: 
Status:
Final Protocol 
(Revised protocol (based on global amendment 02)
Version and Date:
Version:
Date:
3.0
16 Aug 2017
Page 1 of 89
Proprietary confidential information.
2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Giotrif®/ GiotrifTM
Name of active ingredient:
BIBW2992 (afatinib)
Protocol date:
17 Jun 2015
Trial number:
1200.222
Revision date:
16 Aug 2017
Title of trial:
A phase II study of afatinib in patients with advanced NSCLC harboring HER2 
mutations, previously treated with chemotherapy
Principal Investigator:
Trial site(s):
Multi-centre trial
Clinical phase:
II
Objective(s):
To investigate efficacy and safety of afatinib in the advanced NSCLC patients with 
HER2 mutations, previously treated with chemotherapy
Methodology:
Open label, single arm study
No. of patients: 
Approximately 1400 screened patients, 40 entered patients
Diagnosis :
HER2 mutant metastatic NSCLC
Main criteria
for inclusion:
Inclusion criteria for part A:
1.
Patients with Histologically or cytologically confirmed diagnosis of stage 
IIIb/ IV NSCLC (AJCC 7.0), who had failed one or two systemic 
chemotherapy regimens, one of which must be platinum-based.
2.
Presence of HER2 mutation in tumor tissue as confirmed by AmoyDx® 
HER2 Mutation Detection Kit
3.
Patients with at least one measurable tumor lesion that can accurately be 
measured by CT scan or MRI according to RECIST 1.1 (R09-0262)
4.
Age >18 years
5.
ECOG performance score 0 or 1
6.
Adequate organ function
7.
Recovered from any previous therapy related toxicity to ≤Grade 1 at study 
entry (except for stable sensory neuropathy ≤Grade 2 and alopecia)
8.
Written informed consent that is consistent with ICH-GCP and local GCP 
guidelines
Inclusion criteria for part B: 
1.
Adequate organ function, as per inclusion criteria No.6 in part A


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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
Giotrif®/ GiotrifTM
Name of active ingredient:
BIBW2992 (afatinib)
Protocol date:
17 Jun 2015
Trial number:
1200.222
Revision date:
16 Aug 2017
2.
ECOG performance score ≤2
3.
More than 12 weeks clinical benefit in part A
Test product(s):
Dose and mode of 
administration:
Part A of study:
Afatinib, starting 40  mg per day
Oral, once daily continuous
Part B of study:
Afatinib plus Paclitaxel 80 mg/m2 intravenously, weekly. Patients will be allowed
to rest from treatment every 8th week (7 weeks on/1 week off) at the discretion of 
investigator.
Dose of afatinib in part B will be last dose received in part A of study
Duration of treatment:
Part A: continuous treatment with afatinib until disease progression or intolerable
toxicity or consent withdrawal for any reason. 
Part B: patient with more than 12 weeks clinical benefit in part A before disease 
progression would enter into Part B, and be treated with afatinib combined with 
weekly paclitaxel, continuous treatment until disease progression or intolerable
toxicity or consent withdrawal for any reason.
Endpoints
Primary endpoint: 
Objective response in part A according to RECIST 1.1, 
Secondary endpoints:
Disease control in part A
Progression free survival (PFS) in part A,,
Overall survival (OS),
Time to progression(TTP) in part A,
Duration of response(DOR) in part A,
Safety criteria:
Safety assessed by intensity and incidence of adverse events according to Common 
Terminology Criteria for Adverse Events (CTCAE Version 4.0)
Statistical methods:
Efficacy analysis:
The objective response rate and its exact 95% Clopper-Pearson confidence interval 
will be calculated. The disease control rate will also be calculated similarly. All of 
the time-to-event data (PFS, TTP, DOR and OS) will be estimated using Kaplan-
Meier method, and the median along with two-sided 95% CI will be displayed(use 
the Greenwood’s formula for estimation of standard errors).
Safety analysis:
Incidence and severity of adverse events according to the NCI-CTCAE (V 4.0) will 


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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim 
Name of finished product:
Giotrif®/ GiotrifTM
Name of active ingredient:
BIBW2992 (afatinib)
Protocol date:
17 Jun 2015
Trial number:
1200.222
Revision date:
16 Aug 2017
be summarized and displayed in number/percentage. The exposure extent to the 
study drug will be displayed


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FLOW CHART: PART A (AFATINIB MONOTHERAPY)
Screening
Afatinib Treatment Cycles
End of 
Treatment in 
Part A
Follow-up for patient not 
entering Part B 9
Cycle-1
Cycle-2 
onwards7
Visit (V) 
SV1
SV2
A-C1V1
A-C1V2
A-CxV1
A-EOT8
A-FU1
A-FU-x
Days 
SV1 is prior to 
or at the same 
day as SV2, 
total duration 
of SV2 is up to 
28
Day 1
Day 8+3
Day 28+2
0-14 days
after last
administration
EOT + 30
(+3) days
Every 60(+7) 
days
(telephone call)
Informed Consent 1
X
Medical History and Demography
X
Documentation of HER2 
Mutation Status2
X
12 Lead Digital ECG**
X
X
Review of in-/exclusion Criteria
X
Physical examination3*
X
X
X
X
Vital Signs *
X
X
X
X
X
X
ECOG Performance Status *
X
X
X
X
X
X
Safety Lab4**
X
X
X
X
Pregnancy Test5
X
Tumour Assessment6
X
At weeks 8, 12, then every 8 weeks till week 
52, then 12 weeks interval after week 52
X
Concomitant Medications ***
X
X
X
X
X
X
X
Study Medication Compliance 
Check 
X
X
X
Adverse Events ***
X
X
X
X
X
X
X
X
Dispense Trial drug (afatinib)
X
X
Afatinib treatment 
X
X
X
Termination of Trial Medication 
X
Screening visit part B of study
X
Collection of Vital Status and 
further anti-cancer treatment 
Information
X


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1.
Written informed consent must be obtained from patient before any protocol specific screening assessments are performed, procedure performed as part of routine 
clinical care do not need to be repeated at screening visit if they are within the allowed time window. 
2.
For patient who has already tested positive for HER2 mutation as confirmed by AmoyDx® HER2 Mutation Detection Kit before enrollment to this trial, the repeated 
HER2 mutation testing is not required again.
For patients who have HER2 mutation tested negative in screening visit 1, no need proceed to screening visit 2.
3.
Physical examination must include recording of height only at screening visit, 
4.
Safety lab would be performed at local lab. The normal reference ranges must be available. Results of previous testing are acceptable and need not be repeated if 
performed within one week of scheduled test.
5.
Pregnancy test can be performed either by urine or blood, should be done within 28 days prior to the start of treatment in Part A.
6.
Tumour assessments should include CT scans of the chest and abdomen and, if clinically indicated, imaging of any other known or suspected sites of disease (e.g., pelvis 
brain) using an appropriate method.  The same radiographic procedure must be used throughout the study. In case of suspected (but not confirmed) bone metastasis at 
screening, tumour assessment at screening should include a bone scan. If bone lesions are already known or confirmed at screening, correlative imaging (X-ray or CT 
scan) should be performed. Correlative imaging should then be repeated at each tumour assessment. Assessment will be performed at Screening Visit, weeks 8 and 12
(for week 12 tumor assessment, time window is +1week), then every 8 weeks thereafter, after week 52, assessments will be performed every 12 weeks until progression
or start of further treatment. Tumour assessment does not need to be performed at the Screening Visit if there are valid results available from assessments which were 
performed as part of a routine clinical practice within 28 days prior to start of treatment. In the event of early discontinuation or an interruption/delay to treatment,
tumour assessment schedule should not be changed, that means, if patient discontinue trial treatment prematurely without objective progression, then tumor assessment 
would be continued in follow up visit until progression or death or start of new anti-cancer treatment
7.
A window period of 2 days is acceptable for each cycle.
8.
If the decision to permanently discontinue afatinib is taken during a scheduled visit, the End of Treatment (EOT) Visit should be performed instead of the scheduled visit. 
Otherwise, 0-14 days after the last administration. For patients who continue to part B, EOT visit can be merged with screening visit of part B. 
9.
Patients not willing or not eligible to continue in part B of the study can withdraw from main study. These patients will only be followed through telephone for gathering 
information on vital status. In the event tumor assessment continue in follow up visit, the visit interval would be modified to every 8 or 12 weeks to match the tumor 
assessment interval.    
*: If Physical examination, Vital Signs and ECOG Performance Status  in screening period is done within 3 days prior to start of treatment , no need to be repeated on day 1 in cycle 1.
**: the 12 Lead Digital ECG in SV2 should be done within one week prior to the start of treatment.
***: In SV1, only those SAE related with study procedure need to be reported ；the AE and Concomitant  Medication do not need to be collected in EDC.


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FLOW CHART: PART B (AFATINIB PLUS PACLITAXEL THERAPY)
Screening5
(EOT of 
part A)
Treatment Cycles6
End of Treatment
Follow-up
Observation 
period
Visit (V)
SV
B-CxV1
B-CxV2
B-CxV3
B-CxV4
B-EOT8
B-FUx10
B-OPx 12
Days 
n.a
Day 1
Day 
8+3
Day 
15+3
Day 
22+3
0-14 days
after last
administration
EOT + 30 (+3) 
days11
FU + 60 (+7) 
days
Review in-/exclusion Criteria of part B1
X
Physical examination
X
X
X
Vital Signs 
X
X
X
X
X
X
X
ECOG performance status 
X
X
X
X
X
X
X
Safety Lab 2
X
X7
X7
X7
X7
X
12 Lead Digital ECG
X
X
X
Tumour Assessment 3
X
At weeks 8, 12, then every 8 weeks till week 
52, then 12 weeks interval after week 52
X
X11
Concomitant Medications 
X
X
X
X
X
X
X
Adverse Events 
X
X
X
X
X
X
X
X
Dispense Afatinib 
X
Afatinib treatment
X
X
X
X
Premedication and Paclitaxel Administration4
X
X
X
X
Study Medication Compliance Check
X
X
Termination of Trial Medication 
X9
Collection of Vital Status and further anti-
cancer treatment Information 
X


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1.
Inclusion/exclusion criteria, particularly Part B-specific criteria, will be reviewed. Patients who fail screening and are not eligible to enter Part B will have their FU Visit 
as described in Part A.
2.
Safety lab would be performed at local lab. The normal reference ranges must be available. Results of previous testing are acceptable and need not be repeated if 
performed within one week of scheduled test. 
3.
Tumour assessments should include CT scans of the chest and abdomen and, if clinically indicated, imaging of any other known or suspected sites of disease (e.g., pelvis 
brain) using an appropriate method.  The same radiographic procedure must be used throughout the study. In case of suspected (but not confirmed) bone metastasis at 
screening, tumour assessment at screening should include a bone scan. If bone lesions are already known or confirmed at screening, correlative imaging (X-ray or CT 
scan) should be performed. Correlative imaging should then be repeated at each tumour assessment. Assessment will be performed at Screening Visit and every 8 weeks 
thereafter until progression or start of further treatment, after week 52, assessments will be performed every 12 weeks. Tumour assessment does not need to be performed 
at the Screening Visit if there are valid results available within 28 days prior to start of part B treatment.  In the event of early discontinuation or an interruption/delay to 
treatment tumour assessment schedule should not be changed, that means, if patient discontinue trial treatment prematurely without objective progression, then tumor 
assessment would be continued in follow up visit until progression or death or start of new anti-cancer treatment.
4.
For pretreatment medication, package label/summary of product characteristics should be followed. Standard pretreatment medications include dexamethasone 20 mg   
intravenous (IV), diphenhydramine 50 mg, and ranitidine 50 mg IV or cimetidine 300 mg IV 30 minutes prior to weekly paclitaxel; however, a reduction in the dose of 
dexamethasone is allowed if patients exhibit no signs of hypersensitivity. Patients will be allowed to rest from treatment every 8th week (7 weeks on/1 week off) at the 
discretion of investigator.
5.
Screening Visit should occur during the scheduled visit at which progression is determined (Part A) or as soon as possible (within 14 days of last afatinib dosage).  
Patient should continue with treatment at the same dose last taken in Part A. Screening visit for part B can be combined with EOT visit of part A and seamlessly with 
Day 1 of Cycle 1 in part B. 
6.
Cycles are 28 days (+2 days).  Each new cycle should occur within 28 + 2 days from Day 1 of the preceding cycle.  X: cycle number, V: Visit, B: Part B.  
7.
Hematology only before each administration of chemotherapy. This can be done up to one day before the visit.
8.
0-14 days after last administration.
9.
In case patient can’t tolerate the combination therapy, if there is clinical benefit to continue the monotherapy of Afatinib as the discretion of investigator, investigator 
could report this case to sponsor and obtain the permission from TCM.
10. All patients should have a first Follow-Up Visit 30 (+3) days after the EOT visit. Patients who have not progressed and have not started further treatment should have 
tumour assessments until progression or start of further treatment.
11. In the event of tumor assessment continue in follow up visit, the visit interval would be modified to every 8 or 12 weeks to match the tumor assessment interval after
FU1.
12. X is the number of Observation Period Visits.  Every 60 days (+7 days) after last FU Visit until death or lost to follow-up. These visits may also be performed by e.g. 
telephone interview or via written correspondence in case the patient is unable to visit the investigator. 


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART: PART A (AFATINIB MONOTHERAPY)..............................................5
FLOW CHART: PART B (AFATINIB PLUS PACLITAXEL THERAPY).....................7
TABLE OF CONTENTS ........................................................................................................9
ABBREVIATIONS................................................................................................................13
1.
INTRODUCTION...............................................................................................16
MEDICAL BACKGROUND.............................................................................16
1.1
DRUG PROFILE................................................................................................16
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....19
RATIONALE FOR PERFORMING THE TRIAL.........................................19
2.1
TRIAL OBJECTIVES........................................................................................20
2.2
BENEFIT - RISK ASSESSMENT.....................................................................20
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................22
OVERALL TRIAL DESIGN AND PLAN .......................................................22
3.1
3.1.1
Administrative structure of the trial .................................................................23
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP...........................................................................................23
SELECTION OF TRIAL POPULATION .......................................................24
3.3
3.3.1
Main diagnosis for trial entry ............................................................................24
3.3.2
Inclusion criteria in part A.................................................................................24
Inclusion criterion for Part B ................................................................................25
3.3.2.1
3.3.3
Exclusion criteria in part A................................................................................25
Exclusion criterion for Part B ...............................................................................26
3.3.3.1
3.3.4
Removal of patients from therapy or assessments...........................................27
Removal of individual patients .............................................................................27
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................27
3.3.4.2
4.
TREATMENTS...................................................................................................28
TREATMENTS TO BE ADMINISTERED.....................................................28
4.1
4.1.1
Identity of BI investigational product(s)...........................................................28
4.1.2
Method of assigning patients to treatment groups...........................................29
4.1.3
Selection of doses in the trial..............................................................................29
4.1.4
Drug assignment and administration of doses for each patient......................29
Administration of afatinib.....................................................................................29
4.1.4.1
4.1.4.1.1
Dose escalation for afatinib...................................................................................30
4.1.4.1.2
Dose reduction for afatinib ...................................................................................30
4.1.5
Blinding and procedures for unblinding...........................................................32
4.1.6
Packaging, labelling, and re-supply...................................................................32


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4.1.7
Storage conditions...............................................................................................33
4.1.8
Drug accountability.............................................................................................33
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................33
4.2.1
Rescue medication, emergency procedures, and additional treatments........33
4.2.2
Restrictions ..........................................................................................................34
Restrictions regarding concomitant treatment ......................................................34
4.2.2.1
Restrictions on diet and life style..........................................................................35
4.2.2.2
Restrictions regarding women of childbearing potential ......................................35
4.2.2.3
4.2.3
Management of expected adverse events ..........................................................35
Management of diarrhoea and hydration status following treatment with afatinib
4.2.3.1
...............................................................................................................................35
Management recommendations for dermatological AEs following treatment with 
4.2.3.2
afatinib ..................................................................................................................38
Management of mucositis/stomatitis ....................................................................42
4.2.3.3
Management of interstitial lung disease (ILD) and keratitis.................................43
4.2.3.4
TREATMENT COMPLIANCE........................................................................44
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................45
TRIAL ENDPOINTS..........................................................................................45
5.1
5.1.1
Primary Endpoint ...............................................................................................45
5.1.2
Secondary Endpoints..........................................................................................45
ASSESSMENT OF EFFICACY........................................................................45
5.2
5.2.1
Tumor assessment...............................................................................................45
ASSESSMENT OF SAFETY.............................................................................46
5.3
5.3.1
Physical examination ..........................................................................................46
5.3.2
Vital Signs............................................................................................................46
5.3.3
Safety laboratory parameters ............................................................................46
5.3.4
Electrocardiogram ..............................................................................................48
5.3.5
Assessment of adverse events.............................................................................48
Definitions of AEs ................................................................................................48
5.3.5.1
5.3.6
Adverse event collection and reporting.............................................................50
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................52
ASSESSMENT OF EXPLORATORY BIOMARKER...................................52
5.5
OTHER ASSESSMENTS...................................................................................52
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................53
5.7
6.
INVESTIGATIONAL PLAN.............................................................................54
VISIT SCHEDULE.............................................................................................54
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................55
6.2
6.2.1
Screening for Part A ...........................................................................................55
6.2.2
Treatment periods in Part A..............................................................................55
6.2.3
End of study treatment and follow-up period in Part A .................................55
6.2.4
Screening for Part B ...........................................................................................56
6.2.5
Treatment periods in Part B ..............................................................................56


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6.2.6
Follow-up period and Trial Completion in Part B...........................................56
End of treatment visit (EOT) ................................................................................56
6.2.6.1
Residual effect period (REP) ................................................................................56
6.2.6.2
Extended follow-up period....................................................................................56
6.2.6.3
6.2.6.3.1
Follow-up for progression.....................................................................................56
6.2.6.3.2
Observation period for Overall Survival...............................................................57
Trial completion for an individual patient ............................................................57
6.2.6.4
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................58
STATISTICAL DESIGN - MODEL.................................................................58
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................58
7.2
PLANNED ANALYSES.....................................................................................58
7.3
7.3.1
Primary endpoint analyses.................................................................................58
7.3.2
Secondary endpoint analyses .............................................................................59
7.3.4
Safety analyses.....................................................................................................60
7.3.5
Pharmacokinetic analyses ..................................................................................61
INTERIM ANALYSES ......................................................................................61
7.4
HANDLING OF MISSING DATA ...................................................................62
7.5
7.5.1
Table 7.5:1 Endpoint determination for PFS in part A ..................................63
7.5.2
Table 7.5:2 Endpoint determination for overall survival................................64
RANDOMISATION ...........................................................................................64
7.6
DETERMINATION OF SAMPLE SIZE .........................................................65
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........66
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................66
DATA QUALITY ASSURANCE ......................................................................67
8.2
RECORDS...........................................................................................................67
8.3
8.3.1
Source documents ...............................................................................................67
8.3.2
Direct access to source data and documents.....................................................68
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS68
8.4
8.4.1
Listedness.............................................................................................................68
8.4.2
Expedited reporting to health authorities and IEC / IRB...............................68
STATEMENT OF CONFIDENTIALITY........................................................68
8.5
END OF TRIAL..................................................................................................68
8.6
9.
REFERENCES....................................................................................................70
PUBLISHED REFERENCES............................................................................70
9.1
UNPUBLISHED REFERENCES......................................................................72
9.2
10.
APPENDICES.....................................................................................................73
RECIST 1.1 CRITERIA.....................................................................................73
10.1
10.1.1
Table 10.1:1 Evaluation of target lesions..........................................................75
10.1.2
Table 10.1:2 Evaluation of non-target lesions and new lesions.......................76
10.1.3
Table 10.1:3 Algorithm for evaluation of overall best response.....................77


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CLINICAL EVALUATION OF LIVER INJURY ..........................................77
10.2
10.2.1
Introduction.........................................................................................................77
10.2.2
Procedures ...........................................................................................................77
COCKCROFT-GAULT FORMULA ...............................................................79
10.3
NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
10.4
CLASSIFICATION ............................................................................................80
LIST OF POTENT INHIBITORS AND INDUCERS OF PGP .....................81
10.5
ECOG PERFORMANCE STATUS..................................................................82
10.6
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................83


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ABBREVIATIONS
ADL
Activity of daily living
AE
Adverse Event
ALT
Alanine Amino Transferase
ANC
Absolute Neutrophil Count
AESI
Adverse Event of Special Interest
ASE
American Society of Echocardiography
AST
Aspartate Amino Transferase
ATP
Adenosine Triphosphate
AUC
Area under the Curve
β-HCG
Beta-Human Chorionic Gonadotropin
BSA
Body surface area
b.i.d.
bis in die (twice daily dosing)
BIRDS
Boehringer Ingelheim Regulatory Documents for Submission
CA
Competent (Regulatory) Authority
CCDS
Company Core Data Sheet
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
CML
Local Clinical Monitor 
CPK
Creatine Phosphokinase
CR
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form
CT
Computed Tomography
CTC
Common Terminology Criteria
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP3A4
Cytochrome P450 3A4
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic Acid
eCRF
Electronic Case Report Form
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EDC
Electronic Data Capture
EGF
Epidermal Growth Factor
EGFR
Epidermal Growth Factor Receptor
EORTC
European Organisation for Research and Treatment of Cancer
EOT
End of Treatment
erbB
Epidermal Growth Factor family of receptors (erB1/EGFR/HER1, 
erB2/HER2, erB3/HER3, erB4/HER4)
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FC
Flow Chart


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FU
Follow-up Visit
GI
Gastrointestinal
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
gMean
Geometric Mean
HER
Human Epidermal Growth Factor Receptor
HERG
Human à ether go-go Gene
HIV
Human Immunodeficiency Virus
HR
Hazard Ratio
HPC
Human Pharmacology Center
IB
Investigator’s Brochure
ICC
Investigator’s choice chemotherapy 
ICH
International Conference on Harmonisation
IND
Investigational New Drug
IEC
Independent Ethics Committee
INR
International Normalised Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
i.v.
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web-based Response System
K-RAS
v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog
LD
Longest Diameter
LVEF
Left Ventricular Ejection Fraction
MASCC
Multinational Association of Supportive Care in cancer
MDR1
MultiDrug-Resistance protein 1
mg
Milligram
min
Minute
ml
Millilitre
MRI
Magnetic Resonance Imaging
MedDRA
Medical Dictionary for Drug Regulatory Activities
MST
Medical Sub team
NSCLC
Non-small cell lung cancer
NYHA
New York Heart Association
OPU
Operative Unit
OP
Observation Period
ORR
Objective response rate
OS
Overall Survival
PCR
Polymerase Chain Reaction
PD
Progressive Disease
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per Protocol Set
p.o.
per os (oral)
PT
Prothrombin Time


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PTT
Partial Thromboplastin Time
PCC
Protocol Challenge Committee
q.d.
quaque die (once a day)
RBC
Red Blood Cell
RECIST
Response Evaluation Criteria in Solid Tumours
SAE
Serious Adverse Event
s.c.
Subcutaneous
SD
Stable Disease
SOC
System Organ Class
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
TKI
Tyrosine Kinase Inhibitor
t.i.d.
ter in die (3 times a day)
TMF
Trial Master File
TMW
Trial Medical Writer
TNM
Tumour, (lymph) Node, Metastasis
TSAP
Trial Statistical Analysis Plan
WBC
White Blood Cell


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1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally with an
estimated one million new cases diagnosed and 880,000 deaths each year. The therapeutic 
landscape of NSCLC has dramatically changed in the last few years with the introduction of 
molecularly targeted agents, leading to unprecedented results in lung tumors with a 
paradigmatic shift from a “one size fits all” approach to a histologic and molecular-based 
approach. Among them, epidermal growth factor receptor (EGFR) –activating mutations or 
rearrangement of the anaplastic lymphomakinase (ALK) gene are associated with better 
outcomes when targeted by selective tyrosine kinase inhibitors. Based on these results, the 
identification of other activating mutations has been pursued in hopes of improving survival 
in NSCLC by specifically treating the genomic alterations.
Human epidermal growth factor 2 (HER2 erbB-2/neu) is a member of the erbB receptor 
tyrosine kinase family. The ERBB2 gene, which encodes for HER2, is a major proliferative 
driver that activates downstream signaling through PI3K-AKT and MEK-ERK pathways
(R13-1023). No ligand has been described for this receptor, which is activated by 
homodimerization or heterodimerization with other members of the erbB family.
Recently, a renewed interest has been emerging on the human epidermal growth factor-2 
(HER2) pathway. Genetic aberrations of this signaling pathway have been reported over time 
to be associated in NSCLC with different sensitivity to the EGFR TKIs, to have a possible 
prognostic role and more recently have been emerged as a possible mechanism in EGFR-
mutated tumors of acquired resistance to the EGFR TKIs. In addition, dysregulation of the 
HER2 pathway, in particular HER2 mutations, may represent a possible novel therapeutic
target in NSCLC, paving the way for a new generation of targeted agents in NSCLC. Since 
anecdotal case reports of clinical activity of anti-HER2 agents in NSCLC patients with HER2 
mutations, several targeted agents have been evaluated in HER2-mutated patients, generating 
a growing interest in this oncogenic driver, leading to the design of molecularly selected trials 
with anti-HER2 compounds, such as Afatinib (P09-10062, P13-05288).
In this trial, patients with adenocarcinoma of the lung with mutant HER2 will receive the 
irreversible ErbB family blocker afatinib to explore the efficacy and safety of afatinib in 
those patients population.
DRUG PROFILE
1.2
For the latest information on the drug profile of afatinib, please refer to the current 
Investigator’s Brochure (IB) (c01802941-09) and/or local product label information.  All 
references in this protocol concerning afatinib refer to the free base compound which is used 
as the oral formulation.
Afatinib (BIBW2992) is a small molecule, selective and irreversible erbB family blocker. In 
preclinical models, it effectively inhibits EGFR, HER2 and HER4 phosphorylation resulting 


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in tumour growth inhibition and regression of established subcutaneous tumours derived from 
four human cell-lines known to co-express erbB receptors. 
Afatinib is moderately fast absorbed after oral administration. Maximum plasma 
concentrations of afatinib were achieved mainly at 2 to 5 hours after oral drug administration. 
Afatinib maximum plasma concentrations and area under the curve increased slightly over-
proportional with increasing doses in the therapeutic range of 20-50mg. Moderate to high 
inter- and intra-individual differences in plasma concentration were observed. 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 faeces. After food intake, a decreased systemic exposure was observed compared to 
administration under fasted conditions. The 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-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 	 and Cmax when given 1 hour before afatinib,
respectively. Pretreatment with the potent P-gp inducer rifampicin decreased the plasma
exposure of 40 mg afatinib by 34 % afatinib (	) and 22 % (Cmax), respectively.
Caution should be exercised when combining afatinib with potent P-gp modulators.
In pre-clinical studies 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 phases I open label dose-escalation studies determined the MTD with continuous dosing 
of afatinib in patients with advanced solid tumours at 40mg and 50mg daily, respectively 
[U08-1023-02]. Both daily doses (40mg and 50mg) have been used in Phase II and Phase III 
trials depending on the patient population evaluated. Adverse events (AE) observed with 
afatinib are consistent with those reported for EGFR and dual EGFR/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, mucositis/stomatitis and skin rash 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, P13-03658 and P13-03659].


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Afatinib was approved as monotherapy to treat patients with advanced or metastatic non-
small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor 
(EGFR) mutations worldwide, including US, Europe, Japan and many other countries.  


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
HER2 overexpression and gene amplification has been observed in breast, gastric and ovarian 
malignancies, inducing sensitivity to HER2 targeting drugs. Both amplification and high 
copy number gains have also been identified in NSCLC. Considering that HER2-mutant or 
HER2–amplified NSCLC may benefit from HER2 inhibition or duel EGFR/HER2 inhibition, 
but not from single blockage of EGFR, novel TKIs simultaneously targeting EGFR/HER2 is 
investigated.
ErbB family blocker including afatinib have been shown to be effective in lung cancer with 
HER2 mutations in pre-clinical setting and with HER2 mutations or amplification in limited 
clinical studies (P09-10062, P13-05288). Afatinib as monotherapy or in combination with 
sirolimus displays antitumor activity in transgenic animals expressing HER2 mutations (P09-
00886). Furthermore, afatinib combination with taxanes have also shown additive anti-
tumour effects (P07-03251). Therefore, a clinical study assessing the effect of afatinib in lung 
adenocarcinoma with genetic aberrations (mutations) of HER2 should be warranted.
The efficacy and safety of afatinib monotherapy in the subset of EGFR mutation positive
NSCLC have been demonstrated through robust clinical data (P14-00758). Moreover, in later 
lines of treatment afatinib may be more effective in combination with cytotoxic drugs (U12-
1167). Phase I clinical data have shown clinical activity with combination therapy at doses 
that were well tolerated (P09-10062, P09-10056). 1200.42 trial is a randomized, phase III 
study to compare the efficacy and safety of Afatinib combine weekly paclitaxel with 
investigator’s choice chemotherapy (ICC) in the treatment of NSCLC patients with previous 
EGFR TKIs and at least one chemotherapy treatment failure. The results demonstrated 
Afatinib combining weekly paclitaxel treatment with afatinib plus paclitaxel led to a 
statistically significant and clinically meaningful prolongation of PFS compared with 
treatment with ICC (hazard ratio 0.60; 95% CI 0.43, 0.85; p=0.0031). Median PFS was 5.59 
months in the afatinib plus paclitaxel arm and 2.79 months in the ICC arm.and safety is 
manageable (U12-1167). Clinical benefit of continuing EGFR TKI beyond radiological 
progression has the potential to improve survival in patients with NSCLC with mutation in 
EGFR gene. Furthermore, both Afatinib monotherapy and Afatinib combining with weekly 
paclitaxel showed benefit to patients with HER2 mutation even after failure of other EGFR 
and/or HER2 targeting treatment (P12-01885).
This study will include only NSCLC patients with documented evidence of HER2 mutation. 
The study is divided into two parts. In part A, metastatic NSCLC patients with Her 2 
mutation who has progressed after 1 or 2 chemotherapy treatment including one platinum-
based chemotherapy will receive afatinib 40mg/day monotherapy until disease progression, 
intolerable toxicity or withdrawal consent for any reason.


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Patients who experience more than 12 weeks clinical benefit before disease progression in 
part A of the study will continue treatment in part B of the trial and will receive afatinib in 
combination with weekly paclitaxel. Continuation of treatment with EGFR TKI beyond 
radiological progression is emerging as an acceptable option (P07-03251).
TRIAL OBJECTIVES
2.2
To investigate efficacy and safety of afatinib in NSCLC patients with HER2 mutation, 
previously treated with 1 or 2 of chemotherapy regimen which include one platinum-based 
regimen.
The primary objective of this study is to assess afatinib monotherapy’s efficacy in the 
treatment of advanced NSCLC patients with HER2 mutation, who previously received and 
failed 1 or 2 chemotherapy including one platinum-based regimen.
The secondary objectives of this study are to assess whether afatinib when given as 
monotherapy or in combination with paclitaxel is able to demonstrate favorable progression-
free survival, disease control rate (DCR), overall survival, time to progression and duration of 
response in NSCLC patients with HER2 mutation, and also drug safety.
BENEFIT - RISK ASSESSMENT
2.3
NCCN guidelines of NSCLC version 3 recommend trastuzumab and Afatinib for NSCLC 
patients with HER 2 mutation. In a retrospective study of patients with NSCLC with HER2 
mutation and previously treated with chemotherapy, a DCR of 100% was observed with
afatinib (n=3) treatment (P09-10062). This encouraging signal showing potential benefit of 
afatinib warrants further exploration in a prospectively designed phase II trial. 
The most frequent AE reported with afatinib treatment are GI-related side effects and skin 
rashes. Both are manageable and can be reversed with proactive management. 
Although rare, a potential for drug-induced liver injury is under constant surveillance by 
sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure patients´ 
safety, see also Section 5.3.3.
The recommended dose for combination therapy with paclitaxel is 40 mg afatinib daily and 
80 mg/m2 paclitaxel weekly. Toxicities with this dose were generally mild to moderate and
manageable (P09-05119). This dose, together with proactive management of common side
effects and the proposed dose reduction scheme, should be well tolerated. The most common
side effects are expected to be primarily gastrointestinal (including diarrhoea, 
nausea,vomiting and anorexia), as well as fatigue and rash. Although skin and gastrointestinal
adverse events are common with afatinib, they are rarely serious and almost always
reversible; chemotherapy, however, is associated with potentially life threatening side effects
as a result of bone marrow suppression, in some instances, as well as potentially irreversible
side effects.


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As this is a known class effect of other EGFR/HER2 inhibitors, patients with known 
interstitial lung disease (ILD) will be excluded from clinical trials with afatinib and careful 
monitoring of pulmonary symptoms with sudden onset is warranted in all clinical trial 
protocols. The risk benefit ratio remains unchanged. The clinical benefit of therapy with 
afatinib with paclitaxel is anticipated to outweigh the risks through 1200.42 study results
(U12-1167).


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This prospective, open-label, single-arm, multicentre, phase II study will be performed in 
patients with advanced NSCLC who have previously received and failed 1 or 2 cytotoxic 
chemotherapy regimens for metastatic disease and harbor HER2 mutation. It is planned that 
approximately 40 HER2 mutation patients will enter into the trial.
This trial will be performed by investigators with experience in treating patients with 
NSCLC.  The study is divided into two parts.
Part A: All eligible patients will first enter part A of the trial. Patients will initially receive a 
starting dose of 40 mg afatinib and thereafter investigator will be allowed to adjust dose of 
afatinib based on tolerability. Patients must receive afatinib as continuous daily dosing but for 
administrative reason, each 28 day treatment will be defined as one treatment cycle. Patients 
who tolerate afatinib well can be allowed to escalate dose of afatinib to 50 mg once daily 
from second cycle onwards. In the event of a drug-related adverse event, dose reduction will 
be allowed. Each dose reduction will decrease dose of afatinib by 10 mg with minimum 
acceptable dose of 20 mg afatinib. If the patient is not able to tolerate afatinib even after 
temporary interruptions and reducing dose to 20 mg then the patient must be permanently 
withdrawn from the trial due to reason of intolerable toxicity. Patients will continue to 
receive treatment with afatinib monotherapy until progression by RECIST 1.1 or intolerable 
toxicity or withdrawal of consent.
Part B: All patients who experience more than 12 weeks clinical benefit before disease 
progression in part A and are able to tolerate afatinib at least 20 mg will be allowed to enter 
part B of the study and continue treatment with afatinib combined with weekly paclitaxel (80 
mg/m2) until disease progression by RECIST 1.1 again or intolerable toxicity. 
All patients will visit the investigator at intervals described in the Flow Charts for 
determination of safety laboratory parameters, assessment of adverse events and additional 
investigations. An assessment of tumour response will be performed at Screening Visit, at 
weeks 8 and 12, then at 8 weeks intervals, till week 52 and then at 12 weeks interval 
thereafter in parts A of the study until documentation of disease progression by RECIST 1.1 
(R09-0262). For tumor assessment in Part B, 8 weeks interval would be followed (12 week 
intervals after 52 weeks) until documentation of disease progression by RECIST 1.1.
The trial drug afatinib will be provided by Boehringer Ingelheim or an authorized Contract 
Research Organization (CRO) to the study sites, where it will be stored according to the 
specified storage conditions.  Paclitaxel can be purchased from local hospital pharmacy by 
patient themselves and administered according to the manufacturer’s recommendations as 
described in the package insert, the costs of paclitaxel would be reimbursed by sponsor.
This trial will be entered into a publicly accessible trial registry.
Total patients =40 with HER2 mutation


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3.1.1
Administrative structure of the trial
This study is sponsored by Boehringer Ingelheim. The Coordinating Investigator as specified 
on the cover page of this protocol, coordinates the investigators at different sites participating 
in this multicenter, international trial. Tasks and responsibilities will be defined in a contract. 
Relevant documentation on the participating (Principal) Investigators and other important 
participants, including their curricula vitae, will be filed in BIRDS. The Principal Investigator 
(PI) at each site will be responsible for assuring the proper conduct of the trial, patient care, 
and safety at the site. The investigator or in some cases one or more sub-investigators will be 
responsible for the daily conduct of the trial, patient visits, eCRF completion, and for 
assisting the CRAs in site monitoring.
A complete list of investigators and other persons whose participation materially will affect 
the conduct of the trial will be filed in the Clinical Trial Master File (TMF) and provided in 
the Clinical Trial Report (CTR).
The safety laboratory investigations (haematological, biochemical, coagulation, and urine)
will be performed at the investigator site and no central laboratory will be used for this. The 
certification and/or accreditation for each laboratory or evidence that it participates in an 
established “quality” program must be provided by the investigator and filed at the Sponsor 
and the local ISF of the site, as well as the normal ranges of each test performed.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
All trial relevant documentation will be stored in BI’s clinical trial master file (TMF). Trial 
relevant documentation which has to be at the trial site will be filed in the investigator site 
file (ISF) at the investigator site. The Investigator Site File (ISF) document will be kept in 
print-out version at the sites as far as required by local regulation and BI-SOP.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP
The primary objective of this Phase II trial is to assess the efficacy of afatinib in patients with 
NSCLC harboring HER2 mutation who have progressed after previous chemotherapy 
treatment. The study is divided into two parts. 
Screening:
For 40 
Advanced 
NSCLC
patients 
with HER2
mutation
Part A:
Afatinib 
monotherapy 
until PD or 
intolerable 
AEs or ICF 
withdrawal
Part B:
Afatinib combined 
with weekly 
paclitaxel until PD 
or intolerable AEs
or ICF withdrawal
End of 
study
Survival 
data 
follow-
up


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Part A:   
Starting dose of 40 mg afatinib once daily oral dosing
Part B:
Afatinib (last received dose in part A) combined with paclitaxel weekly (for 
example, patients dose reduced to 30 mg afatinib in Part A due to a related 
adverse event will receive 30 mg afatinib once daily plus paclitaxel)
Patients will be treated until disease progression according to RECIST 1.1 (R09-0262), or
intolerable toxicity, or consent withdrawal for any reason, or study termination.
SELECTION OF TRIAL POPULATION
3.3
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not. It is estimated that there are approximately 1400 patients 
would be screened for 40 entered patients because of the low HER2 mutation rate in NSCLC
patients.
3.3.1
Main diagnosis for trial entry
The trial will be performed in metastatic NSCLC patients harbouring HER2 mutation who 
progressed from previous 1or 2 chemotherapy regimens, one of which is platinum-based 
chemotherapy. 
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria in part A
1. Patients with Histologically or cytologically confirmed diagnosis of stage IIIb/ IV 
NSCLC (AJCC 7.0), who had failed one or two systemic chemotherapy regimens, 
one of which is platinum-based.
2. Presence of HER2 mutation in tumor tissue as confirmed by AmoyDx® HER2 
Mutation Detection Kit
3. Patients with at least one measurable tumor lesion that can accurately be measured 
by CT scan or MRI according to RECIST 1.1 (R09-0262)
4. Age >18 years
5. ECOG performance score 0 or 1
6. 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)
Estimated creatinine clearance > 45ml / min. Refer to APPENDIX 10.3.


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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) or alanine amino transferase (ALT) ≤three times 
the upper limit of (institutional) normal (ULN) (if related to liver metastases ≤five 
times ULN).
7. Recovered from any previous therapy related toxicity to ≤Grade 1 at study entry 
(except for stable sensory neuropathy ≤Grade 2 and alopecia)
8. Written informed consents that is consistent with ICH-GCP and local GCP guidelines
Inclusion criterion for Part B
3.3.2.1
1. Adequate organ function, as inclusion criteria No.6 in Part A
2. ECOG performance score =< 2
3. More than 12 weeks clinical benefit  in part A (that is, tumor response at week 8 and 
week 12 is CR, PR or SD)
3.3.3
Exclusion criteria in part A
1. Prior treatment with EGFR or HER2 targeting small molecules or antibodies.
2. Any chemo-, or immune anticancer therapy within 4 weeks prior to start of study 
treatment, Hormonal treatment within 2 weeks prior to start of study treatment,   
Radiotherapy within 4 weeks prior to start of study treatment, except as follows:
i.) Palliative radiation to target organs other than chest may be allowed up to 2 
weeks prior to enter, and
ii.) Single dose palliative treatment for symptomatic metastasis outside above 
allowance to be discussed with sponsor prior to enrolling.
3. Major surgery within 4 weeks before starting study treatment or scheduled for 
surgery during the projected course of the study
4. Known hypersensitivity to afatinib or the excipients of any of the trial drugs
5. History or presence of clinically relevant cardiovascular abnormalities such as 
uncontrolled hypertension, congestive heart failure NYHA classification of ≥ 3 
(Refer to APPENDIX 10.4), unstable angina or poorly controlled arrhythmia as 
determined by the investigator. Myocardial infarction within 6 months prior to first 
Afatinib dose.
6. Any history of or concomitant condition that, in the opinion of the Investigator, 
would compromise the patient’s ability to comply with the study or interfere with 
the evaluation of the efficacy and safety of the test drug.
7. 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.
8. Requiring treatment with any of the prohibited concomitant medications listed in 
Section 4.2.2.1 that cannot be stopped for the duration of trial participation
9. Known pre-existing interstitial lung disease.
10. Any history or presence of poorly controlled gastrointestinal disorders that could 
affect the absorption of the study drug (e.g. Crohn’s disease, ulcerative colitis, 
chronic diarrhoea, malabsorption).
11. Active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B DNA), 
active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV 
carrier.
12. Known Leptomeningeal carcinomatosis.
13. Symptomatic brain metastases; To be eligible patients must be asymptomatic from 
brain metastases at least 4 weeks without requirement for steroids or anti-epileptic 
therapy
14. Women of child-bearing potential (WOCBP) and men who are able to father a child, 
unwilling to be abstinent or use highly effective methods of birth control that result 
in a low failure rate of less than 1% per year when used consistently and correctly 
prior to study entry, for the duration of study participation and for at least 2 weeks 
after treatment has ended.
15. Women who are pregnant, nursing, or who plan to become pregnant while in the 
trial
*Women of childbearing potential are defined as:
Any female who has experienced menarche and does not meet the criteria for "women not of 
childbearing potential" as described below.
Women not of childbearing potential are defined as:
Women who are postmenopausal (12 months with no menses without an alternative medical 
cause) or who are permanently sterilized (e.g., tubal occlusion, hysterectomy, bilateral 
oophorectomy or bilateral salpingectomy).
Exclusion criterion for Part B
3.3.3.1
1. Any known contraindication for paclitaxel treatment. 
2. Not able to tolerate lowest dose of 20 mg afatinib. 
3. Peripheral polyneuropathy >Grade 2.


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3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from trial treatment if:

The patient withdraws consent for study treatment or study participation, without the need 
to justify the decision.

The patient has radiologic documentation of progressive disease (APPENDIX 10.1). For 
patient eligible for part B treatment after end of part A, who would be treated with 
afatinib plus weekly paclitaxel until further progression or other treatment termination 
criteria is met.

The patient needs to take concomitant drugs that interfere with the investigational product 
or other trial medication.

The patient can no longer be treated with trial medication for other medical reasons (such 
as surgery, adverse events, other diseases, or pregnancy).

The patient is diagnosed with ILD.

Has the need for further dose reductions considered necessary but not allowed according 
to the protocol (Section 4.1.4)

The patient is allergy to afatinib or paclitaxel.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the flowchart and Section 6.2.3.
For all patients, the reason for withdrawal (e.g. adverse events) must be recorded in the 
eCRF. These data will be included in the trial database and reported.
The sponsor may remove patients from the study after completion of the primary efficacy 
analysis and the patient has access to afatinib through an expanded-access program, named 
patient use program, or compassionate use protocol, or other means based on local regulation.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial
4. At the discretion of the sponsor (BI) for other reason.
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
4.1.1
Identity of BI investigational product(s)
Table 4.1.1: 1
afatinib:
Substance:
Afatinib
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer-Ingelheim Pharma GmbH & Co. KG
Unit strength:
20, 30, 40 and 50 mg film-coated tablets (the dose of 
afatinib in the film-coated tablets is related to the free 
base equivalent to afatinib)
Posology
Once daily
Route of administration:
Oral
Duration of use
Continuous daily dosing until progression, 
unacceptable adverse events or other reason 
necessitating withdrawal. For administrative
purposes each treatment cycle is 4 weeks (28 days).
Table 4.1.1: 2
Paclitaxel:
Substance:
Paclitaxel
Pharmaceutical formulation:
Concentrate for intravenous infusion
Source:
Locally available commercial supply
Unit strength:
80 mg/m2 weekly infusion
Posology
weekly
Route of administration:
Intravenous infusion according to package insert or 
summary of product characteristics (SPC)
Duration of use
Continuous weekly dosing until progression, 
unacceptable adverse events or other reason
necessitating withdrawal. Patients will be allowed to 
rest from treatment every 8th week (7 weeks on/1 
week off) at the discretion of investigator.


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4.1.2
Method of assigning patients to treatment groups
Eligible patients will be screened and entered. Only one treatment regimen will be employed.
4.1.3
Selection of doses in the trial
Part A: The starting dose for afatinib continuous oral dosing is 40 mg.
In this trial development of afatinib will continue at a starting dose of 40 mg to optimize the 
tolerability and efficacy balance.  The daily dose will be modified following careful 
monitoring of patient’s drug-related adverse events and medication compliance; with option 
to dose-escalate to 50 mg for patients meeting the criteria specified in Section 4.1.4.1.1.
Part B: The starting dose of afatinib is last tolerated dose in part A, paclitaxel would be iv 
weekly at the dose of 80 mg/m2. Patients will be allowed to rest from treatment every 8th 
week (7 weeks on/1 week off) at the discretion of investigator.
For example, patients will start with 30 mg afatinib daily if dose was reduced to 30 mg in 
Part A. Paclitaxel will be administered every 7 days of each cycle and according to the 
package insert or SPC.
4.1.4
Drug assignment and administration of doses for each patient
Administration of afatinib
4.1.4.1
Eligible patients will take a single oral dose of afatinib each day starting at a dose of 40 mg, 
continuously, until the development of progressive disease or unacceptable adverse events. 
Dose escalation and reductions of afatinib can occur.  See Section 4.1.4.
The medication should be taken at approximately the same time each day without food (at 
least one hour before or at least three hours after a meal).  
Missed doses of afatinib can be made up during the same day as soon as the patient 
remembers.  However, if the next schedule dose is due within 8 hours then the missed dose  
must be skipped. Patients with emesis must not take a replacement dose.
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 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 naso-gastric tube.
Medication will be dispensed in bottles containing 30 tablets at the beginning of each 
treatment cycle.  For administrative purposes, a treatment cycle is defined as 28 days.  
Treatment will start when patient is eligible and entered C1V1 and stop when the patient is 
diagnosed with disease progression or for any reason detailed in Section 3.3.4.  Study drug 


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will be prescribed by the investigator and may be dispensed either by the investigator, site 
staff or affiliated pharmacy.
4.1.4.1.1
Dose escalation for afatinib
The dose of afatinib administered may be escalated to 50 mg at the start of Cycle 2 if all of 
the following criteria during Cycle 1 are met:

Absence of diarrhoea, skin rash, stomatitis, and other drug-related events of CTCAE > 1 
in the first 4 weeks

Afatinib dose was not previously reduced due to any of the AEs depicted in the Dose 
reduction scheme (Table 4.1.4.1.2: 1) 

Compliant dosing of afatinib, as described in Section 4.3
Dose escalation is prohibited in any situation other than that prescribed above.  The patient 
should remain on 50 mg unless dose reduction becomes necessary (see Table 4.1.4.1.2: 1)
4.1.4.1.2
Dose reduction for afatinib
Treatment related AEs will be managed by treatment interruptions and subsequent dose 
reductions of afatinib according to the schedule described in Table 4.1.4.1.2: 1. Dose 
reductions will apply to individual patients only. Once the dose has been reduced, it cannot 
be increased later.
To prevent the development of more severe adverse events, treatment related diarrhoea, 
nausea and vomiting or rash should be managed early and proactive as described in Section 
4.2. 
Table 4.1.4.1.2: 1 Dose reduction scheme for afatinib
AE type and CTCAE Grade
Action
Dose reduction scheme
Events related to study 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 
Pause treatment until 
patient has recovered to 
Grade ≤1 or baseline1.
Resume treatment at 
reduced dose according 
to schedule opposite.
If patient has not 
recovered to Grade ≤1 or 
baseline1 within 14 days 
study treatment must be 
If patient was receiving 50 
mg, resume treatment at a 
dose of 40 mg.
If patient was receiving 40 
mg, resume treatment at a 
dose of 30 mg.
If patient was receiving 30 
mg, resume treatment at a 
dose of 20 mg.
If patient was receiving 20 


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rate of more than 50% from 
baseline
Any drug related AE Grade ≥3
permanently 
discontinued2.
mg, discontinue afatinib.
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
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 judgement, further treatment with afatinib will be decided in agreement 
between the sponsor and the investigator.
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 should occur.  If the medication is 
interrupted for more than 14 days, the decision to continue with afatinib will be made by the 
BI clinical monitor in agreement with the investigator.
4.1.4.1.2.1 Dose reduction for Afatinib plus paclitaxel weekly 
All patients receiving IV paclitaxel should be premedicated with oral corticosteroids
(dexamethasone, 20 mg PO at 12 hours and 6 hours prior to treatment or dexamethasone 20 
mg IV as a single dose 30 minutes prior to the infusion). Additionally, patients should be
premedicated with diphenhydramine 25-50 mg IV or PO and a H2-receptor antagonist
(cimetidine 300 mg IV or PO, famotidine 20 mg IV or PO, or ranitidine 50 mg IV or PO) 30 
minutes prior to infusion. In case of good tolerability to paclitaxel the dosage of these
premedications may be reduced for future paclitaxel administration. Patients will be allowed 
to rest from treatment every 8th week (7 weeks on/1 week off) at the discretion of 
investigator. For antiemetic recommendations, please refer to the SmPC or package insert of 
paclitaxel.
In case of skin toxicity or diarrhoea, afatinib will be dose reduced according to Table 
4.1.4.1.2:1. If the patient has not recovered from skin toxicity or diarrhea after the two 
reductions with afatinib, the investigator will be allowed to reduce the dose of paclitaxel once
(refer to the SmPC or package insert of paclitaxel). If the patient still has not recovered after 
dose reduction with paclitaxel, the patient should be discontinued from the treatment.


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In case of hematoxicity requiring dose reduction, paclitaxel will be dose reduced. In cases of 
other side effects both compounds will be reduced in parallel. In case paclitaxel is dose 
reduced, the dose will be reduced to 70 mg/m2 in the event of the first drug-related adverse 
event. In the event of a second drug-related adverse event, the dose will be further reduced to 
60 mg/m2. No further reduction will be allowed.
Dose reduction should always follow a treatment pause (Table 4.1.4.1.2: 1). In the event of a
treatment pause, subsequent visits/cycles should not be delayed.
Any patient who experiences deterioration in left ventricular cardiac function (LVEF) with
resting ejection fraction to less than 50% or ILD will discontinue treatment (Section 3.3.2). In 
the event of a prolonged (≥7 consecutive days) >Grade 2 drug-related event not listed in
Table 4.1.4.1.2: 1, which is poorly tolerated by the patient, the Investigator may choose to 
pause the medication for up to 14 days to allow the patient to recover, followed by a dose 
reduction according to Section 4.1.4.1.2.
Any patient in Part B who does not recover to CTCAE <Grade 1 or baseline within 14 days
of treatment pause should be permanently discontinued.
In the event of any unrelated adverse event or unrelated serious adverse event, the
Investigator may choose to pause treatment for up to 14 days to allow the patient to recover,
but no dose reduction should occur. If the Investigator chooses to pause treatment for more
than 14 days and believes that the patient would derive clinical benefit from continuing
medication, the decision to continue medication will be made by the BI clinical monitor in
agreement with the Investigator.
4.1.5
Blinding and procedures for unblinding
Not applicable.
4.1.6
Packaging, labelling, and re-supply
Afatinib will be supplied as film-coated tablets. Available dosage strengths will be 20mg,
30mg, 40mg and 50mg. Tablets will be supplied in polypropylene (PP), child-resistant, 
tamper-evident bottles.
For details of packaging and the description of the label, refer to the ISF.
A new bottle of medication will be dispensed on day 1 of each cycle, regardless of the
number of tablets remaining in the bottle from the previous cycle. The patient will initially
receive one bottle of 40mg tablets and in the event that dose increase or reduction is
necessary the patient will return to the clinic and new medication will be dispensed.
Medication numbers will be unique to each bottle and will be used for tracking purposes
only.


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4.1.7
Storage conditions
Afatinib will be kept in their original packaging and a secure, limited access storage area 
according to the recommended storage conditions on the medication label. A temperature log 
must be maintained for documentation to be certain that the drug supplies are stored at proper
temperature.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The Investigator or pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee, 

Availability of a signed and dated clinical trial contract between the Sponsor and the head 
of the investigational site,

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
The Investigator or 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 disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / pharmacist / 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 products received from the Sponsor. At the time of return to the 
Sponsor 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.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
Rescue medication
Rescue medications to reverse the actions 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. 


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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 below.
Concomitant treatments
Concomitant medications or therapy to provide adequate supportive care may be given as 
clinically necessary. 
After study enrollment, 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. The irradiated area cannot be used for 
tumor response assessment. During palliative radiotherapy, study treatment should be delayed 
and may be resumed once the patient has recovered from any radiation associated toxicity.  If 
medication is interrupted for more than 14 days, the decision to continue will be made by the 
BI clinical monitor in agreement with the investigator.  Continuous interruption of >28 days 
due to palliative radiotherapy will not be allowed.
All concomitant therapy, including anaesthetic agents, vitamins, homeopathic/herbal
remedies, nutritional supplements, must be recorded in the eCRF during the screening and 
treatment period, starting from the date of signature of informed consent, and ending at the 
EOT visit. After the EOT visit, only concomitant therapy indicated for treatment of an AE 
has to be reported. 
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. If afatinib is interrupted for more than 14 days, the decision to continue will 
be made by the BI Clinical Monitor in agreement with the investigator.
There are no special emergency procedures to be followed.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Concomitant medications, or therapy to provide adequate supportive care, may be given as 
clinically necessary.
Palliative radiotherapy may be given as described in Section 4.2.1.
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 
study treatment. 


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Afatinib is a substrate of the P-gp transporter. Caution should be exercised when combining 
afatinib with P-gp modulators.  For a list of potent P-gp inhibitors and inducers see Appendix 
10.5.
Restrictions on diet and life style
4.2.2.2
Patients should be advised to avoid any foods known to aggravate diarrhoea.
To prevent skin related adverse events it is recommended to avoid intense irradiation with 
UV light and harsh detergents, see also Section 4.2.3.2.
Restrictions regarding women of childbearing potential 
4.2.2.3
Patients who are not of childbearing potential due to being postmenopausal (i.e. 12 months 
with no menses without alternative medical cause, predefined hormonal level according to 
local regulation or etc.) or being permanently sterilized  (bilateral oophorectomy, bilateral 
salphingectomy, hysterectomy and/or tubal ligation) do not need to use contraception to be 
eligible for the trial.
All other patients are considered to have childbearing potential and must use adequate 
contraception throughout the trial (from screening until end of trial participation or 2 weeks
after last dose of trial medication, whichever is later).
Highly effective methods of birth control should be applied to women of childbearing 
potential as those, alone or in combination, that result in a low failure rate (i.e., less than 1% 
per year – placement of intrauterine device or intrauterine system, “double barrier” methods 
of contraception, male sterilisation or etc.) when used consistently and correctly, and must be 
in accordance with local regulations where applicable. The list of contraception methods 
meeting these criteria is provided in the patient information. 
Women who become pregnant while participating in the study must discontinue study 
medication immediately. The pregnancy must be reported following procedures detailed in 
Section 5.3.6.
4.2.3
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.
Management of diarrhoea and hydration status following treatment with afatinib
4.2.3.1
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 4.2.3.1:
1). At the time of initiation of treatment with afatinib patients should be given a supply of 


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loperamide to keep with them at all times or access to loperamide should be confirmed; and 
patients should be counselled on the appropriate use. 
Patients must be advised to drink an adequate amount of fluids to make up for the fluid lost 
through diarrhoea. 


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Table 4.2.3.1: 1 Grade specific treatment recommendations for afatinib related diarrhoea 
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 of
clear fluids per day;
4 mg (2 tablets) of 
loperamide to be taken 
immediately, followed by 
2 mg (1 tablet) after each 
loose stool 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 ADL
Continue same dose 
unless Grade 2 
diarrhoea 
continues for ≥ 2 
days (48 hours) in 
which case 
treatment must be 
interrupted until 
recovered to ≤
Grade 1 followed 
by dose reduction
Continue loperamide; 
assess for dehydration and 
electrolyte imbalance;
consider IV 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
Dose interruption 
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) 
Dose interruption 
until recovered to 
≤Grade 1 followed 
by dose reduction*
See Grade 3
* If despite optimal supportive care and a treatment interruption, diarrhoea does not resolve to CTC AE Grade ≤ 
1 within 14 days, treatment with afatinib must be permanently discontinued. In the event that the patient is 


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deriving obvious clinical benefit according to the investigator’s judgement, further treatment with afatinib will 
be decided in agreement between the sponsor and the investigator.
Management recommendations for dermatological AEs following treatment 
4.2.3.2
with afatinib
Dermatologic AEs of afatinib include rash, acne, dermatitis acneiform, and dry skin. General 
recommendations for prophylaxis are summarized in Table 4.2.3.2: 1 and grade-specific 
treatment recommendations are summarized in Table 4.2.3.2: 2. For dose adjustment of 
afatinib refer to Table 4.1.4.1.2:1.  
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)


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Table 4.2.3.2: 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, PAPA 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 4.2.3.2: 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, e.g. 
clindamycin 2% or topical 
erythromycin 1% cream of 
metronidazole 0.75% 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 treatment as for Grade 1 
plus short term topical steroids, e.g. 
prednicarbate cream 0.02% plus
an oral antibiotic (for at least 2 
weeks) e.g. Doxycycline 100mg 
b.i.d. or 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
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)


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Table 4.2.3.2: 2 (continued) Grade specific treatment recommendations of skin reactions to 
afatinib
Severity 
(CTCAE Grading)
Description
Specific intervention
Moderate (Grade 
2)
Intense or widespread
See Grade 1 plus oral 
antihistamines;
Consider topical steroids, e.g. 
topical hydrocortisone
Severe (Grade 3)
Intense or widespread and 
interfering with activities of 
daily living (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 application of  aqueous 
silver nitrate solutions to fissures


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Table 4.2.3.2: 2 (continued) Grade specific treatment recommendations of skin reactions to 
afatinib
Severity 
(CTCAE Grading)
Description
Specific intervention
Moderate (Grade 
2)
Symptomatic, not interfering 
with ADL
See Grade 1. 
Consider oral antibiotics.
Severe (Grade 3)
Symptomatic,
Interfering with ADL
See Grade 2.
1 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 4.1.4.1.2: 1
Management of mucositis/stomatitis 
4.2.3.3
General and grade specific recommendations are described in Table 4.2.3.3:1. For dose 
adjustment refer to Section 4.1.4.1.2 and for restrictions on concomitant therapies refer to 
Sections 4.2.2, and 10.5.
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 manoeuvres 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, chillies, 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 4.2.3.3:1 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 4.2.3.3: 1
Grade specific treatment recommendations of study-drug 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
Management of interstitial lung disease (ILD) and keratitis 
4.2.3.4
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, 


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ulcerative keratitis or severe dry eye. Contact lens use is a risk factor for keratitis and 
ulceration.
Management of expected adverse events due to paclitaxel 
The major toxicities expected with paclitaxel are myelosuppression, nausea/vomiting and 
peripheral neuropathies. Appropriate measures should be instituted according to institutional 
procedures or the paclitaxel label before the first injection of paclitaxel and should be 
continued for as long as the product is being administered. In the case that paclitaxel is well 
tolerated the dosage of premedications may be reduced for subsequent paclitaxel 
administrations.
As a general rule, for warnings, precautions, contraindications and other information, see the
package insert or the SPC. Investigators should also follow institutional procedures for the
administration of chemotherapies.
TREATMENT COMPLIANCE
4.3
The study medication will be given in accordance with the protocol and the instructions of a 
site investigator. 
The appropriate number of afatinib tablets for 4-week of treatment will be provided to 
patients to be self-administered at home.
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on tablet counts, treatment compliance will be calculated as the number of capsules 
taken, divided by the number of capsules which should have been taken according to the 
scheduled period, multiplied by 100. Compliance will be verified by the on-site monitor 
authorised by the Sponsor.
Treatment compliance (%) =
Number of actually taken 100
Number of which should have been taken
If the number of doses taken is not between 80-120%, site staff will explain the patient the 
importance of treatment compliance.
The investigator and/or the sponsor can withdraw a patient from the study in the event of 
serious and persistent non-compliance which jeopardizes the patient’s safety or render study 
results for this patient unacceptable. Patients who do not attend a minimum of 75% of 
scheduled study visits, unless due to exceptional circumstances, should be discussed with the 
BI trial monitor and be evaluated for compliance. For afatinib, a maximum of 25% of the 
dispensed afatinib doses may be missed for other reasons than drug-related AEs. Patients who 
miss afatinib treatment more frequently are considered non-compliant.


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint
The primary endpoint is Objective Response in part A, defined as patients with tumor size 
reduction of a predefined amount using RECIST 1.1 in part A. Objective responses include
both confirmed partial responses (PR) plus complete responses (CR).
5.1.2
Secondary Endpoints
The secondary endpoints are:

Disease control in part A, defined as patients who have achieved confirmed complete 
response, partial response and stable disease per RECIST 1.1 in part A.

Progression free survival (PFS) in part A , defined as the time from the date of starting 
treatment of afatinib to the date of disease progression per RECIST 1.1, or to the date of 
death no matter which happens first in part A.

Overall survival (OS), defined as the time from start of treatment of afatinib until death 
from any cause.

Time to progression (TTP) in Part A, defined as the time from the date of starting 
treatment of afatinib to the date of disease progression per RECIST 1.1 in part A.

Duration of response (DoR) in part A, defined as the time from the first documented 
response PR or CR to the date of tumor progression evaluated according to RECIST 1.1
or death in part A.  
ASSESSMENT OF EFFICACY
5.2
5.2.1
Tumor assessment
Response and progression will be evaluated in this study using Response Evaluation Criteria 
in Solid Tumours (RECIST) guideline (version 1.1) (R09-0262).  Tumour response will be 
assessed by investigator assessment.


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For the purposes of this study, patients should be evaluated for response as specified in 
flowchart. The tumor assessments must occur seamlessly during Part A, Part B and until end 
of study at intervals of 8 weeks + 3 days (or 12 weeks + 3 days after week 52 ) regardless of 
treatment interruptions. In the event of a treatment delay, interruption or discontinuation of 
treatment, tumor assessment should continue to follow the original schedule of 8 weeks 
intervals (or 12 weeks interval after week 52) calculated from date of starting afatinib 
monotherapy in part A. Investigator will evaluate for each patient whether Complete 
Response (CR), Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD) 
occurred. 
See APPENDIX 10.1, RECIST 1.1 Criteria for details on lesion measurements, response 
assessment and response confirmation.
Every effort should be made to objectively evaluate tumor response and confirm tumor 
progression with radiological tumor imaging for all patients who enter into the trial, including 
those who discontinue prematurely.
ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
A physical examination will be performed at screening and at the time points specified in the 
Flow Chart.
A full physical exam serves as a clinical tumour assessment and should include a
cardiopulmonary examination, examination of the regional lymph nodes, examination of the
abdomen and an assessment of the mental and neurological status. Additional symptoms
which have not been reported during a previous examination should be clarified. Wherever
possible the same investigator should perform this examination.
Measurement of height (in cm), body weight (in kg) and body temperature and the evaluation 
of the ECOG performance score will be performed at the time points specified in the Flow 
Chart.
5.3.2
Vital Signs
Vital signs (blood pressure and pulse after 2 minutes supine rest or 5 minutes seating) and 
temperature will be recorded at the screening visit and at the time points specified in the Flow 
Chart
5.3.3
Safety laboratory parameters
Blood samples will be collected at the time points specified in the Flow Chart and analysed in 
a laboratory facility at the investigational site. Safety laboratory examinations include 
haematology and biochemistry. In case of neutropenia, blood will be examined as clinically 
indicated at the discretion of the investigator until recovery.


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In part A, approximately 6~10 blood samples will be drawn to test blood for safety. Each 
sample will require approximately 5ml blood from a vein. On average, approximately 
30~50ml blood will be drawn totally per patient. 
In part B, approximately 10~18 blood samples will be drawn to test blood for safety, each 
sample will require approximately 5ml or 2 ml (if only hematology testing is needed) of 
blood from a vein. On average, approximately 30~40ml blood will be drawn totally per 
patient.
Safety laboratory assessment may be performed according to local practice but must include 
at least the following parameters:
Category
Parameters 
Hematology
Red blood cell count (RBC), haemoglobin, 
haematocrit, platelet count, reticulocytes, white 
blood cell count ( WBC) and absolute differential
Coagulation
International Normalized Ratio (INR), activated 
Partial Thromboplastin Time (aPTT)
Chemistry
Electrolytes
sodium, potassium, calcium
Liver function tests
alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), γ-
glutamyltransferase (GGT), total  bilirubin
Renal function parameters
Blood urea/blood urea nitrogen (BUN), 
creatinine; Creatinine clearance will be calculated 
using the Cockroft-Gault Formula (see Appendix 
10.3).
Other
glucose, albumin, lactate dehydrogenase (LDH),
total protein, uric acid, creatine phosphokinase 
(CPK); in case of pathological CPK further 
evaluation (e.g by determination of isoenzymes, 
troponin assays, ECG exam) should be performed 
as clinically indicated
Urinalysis
pH, protein, glucose, ketones, blood, leucocytes,
nitrite, in case of pathological finding further 
evaluation should be performed and results 
documented 
Pregnancy test
β-HCG testing in urine or serum in women of 
childbearing potential ( WOCBP)


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At screening, creatinine clearance for study eligibility may be measured or may be calculated
using the Cockroft-Gault Formula (Appendix 10.3).
The investigator should complete additional evaluations of laboratory tests as clinically 
indicated.
Results from previous laboratory testing may be used at screening if testing was done within
one week prior to inclusion into the trial, i.e., no repeat investigation is requested for the
purpose of the trial. 
If haematology results [particularly red blood cell (RBC) count, haemoglobin (HB), 
haematocrit, white blood cell (WBC) count, absolute neutrophil count (ANC) or platelets] 
indicate Grade 3 or 4 toxicity the test should be repeated at least once per week and as 
clinically indicated to characterize the event. If haematologic toxicity resolves to Grade 2 
toxicity or upon discussion with the BI clinical monitor, the normal testing routine, as 
outlined in the Flow Charts and Section 6.2, may be followed.
5.3.4
Electrocardiogram
A 12-lead resting ECG will be performed at the time points specified in the Flow Charts.
ECGs will be performed using the routine facility at investigators’ sites. No central 
evaluation of ECG data will be performed.
5.3.5
Assessment of adverse events
Definitions of AEs 
5.3.5.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

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 judgment which may jeopardize the patient and may 


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require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
If cancer is the indication for treatment, only cancers of new histology and cases where there 
is clear evidence of exacerbation of an existing cancer qualify as a serious event.
Every new occurrence of cancer must be reported as a serious event regardless of the duration 
between discontinuation of the drug and the occurrence of the cancer.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the RDC. These events should 
always be reported as SAEs as described in Section 5.3.6
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.6.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

For patients with normal liver function at baseline (ALT, AST, and bilirubin within 
normal limits at baseline) : 
-
an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of total 
bilirubin ≥2 fold ULN measured in the same blood draw sample, and/or 
-
Marked peak aminotransferase (ALT, and/or AST) elevations ≥ 10 fold ULN

For patients with abnormal liver function at baseline (AST and/or ALT>ULN) 
-
an elevation of AST and/or ALT ≥ 5 fold ULN combined with an elevation of 
total bilirubin ≥2 fold ULN measured in the same blood draw sample, with the 
exclusion of the causes due to underlying diseases.
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” via the RDC-system.


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In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities”
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0 in the (e)CRF.
Causal relationship of AEs
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.
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.
The causal relationship must be provided by the Investigator for all potential trial drugs, i.e. 
the BI trial drug and for all other trial drugs (i.e. paclitaxel) and for trial procedure.
5.3.6
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate eCRF by the 
Investigator:
From signing the informed consent onwards through the Residual Effect period (REP), 
until the end of the REP all AEs (non-serious and serious), and AESIs, 
In SV1, only those SAE related with study procedure need to be reported; the E and
Concomitant Medication do not need to be collected in EDC. 
After the end of the REP until individual patient’s end of trial, all related SAEs and all related 
AESIs.
The REP is defined as 30 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment please see Section 7.3.4. Events which occurred after the REP will be considered as 
post treatment events.


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After the last per protocol contact the Investigator does not need to actively monitor patients 
for AEs. However, if the Investigator becomes aware of SAEs or AESIs that occurred after 
the last per protocol contact, the SAEs and AESIs should be reported by the Investigator to 
the Sponsor if considered relevant by the Investigator.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF).
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
(e)CRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug(s). The Investigator 
should determine the causal relationship to the trial medication, the trial procedures outlined 
under Section 6.2, and any possible interactions between the investigational drug(s) and a 
non-investigational medicinal product (NIMP).
The following should also be recorded as an (S)AE in the (e)CRF and SAE form:

Worsening of the underlying disease or of other pre-existing conditions

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Screening failures:
SAEs occurring in patients after having discontinued in the trial due to screening failures, i.e. 
after the screening period and who did not receive any trial medication, are to be reported if 
the Investigator considered the SAE related to the screening procedure. SAEs which occurred 
during the screening period are to be reported according to standard procedures.
Pregnancy
In the rare case that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
drug exposure during pregnancy (DEDP) to the Sponsor’s unique entry point (country-
specific contact details will be provided in the ISF). The Pregnancy Monitoring Form for 
Clinical Trials (Part A) should be used. 


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The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
Exemptions to SAE Reporting
Disease Progression in oncology trials is a study endpoint for analysis of efficacy. Disease 
progression is exempted from reporting as a (S)AE. Progression of the patient's underlying 
malignancy will be recorded in the appropriate pages of the (e)CRF as part of efficacy data 
collection.  Death due to disease progression is to be recorded on the appropriate (e)CRF 
page and not on a SAE form.
Examples of exempted events of PD are:

Progression of underlying malignancy (Progressive disease PD):  if PD is clearly 
consistent with the suspected progression of the underlying malignancy as defined by the 
respective response criteria. 

Hospitalization/Procedures due solely to the progression of underlying malignancy (PD)

Clinical symptoms and/or signs of progression (with or without confirmation by objective 
criteria e.g. imaging, clinical measurement): if the symptom can exclusively be 
determined to be due to the progression of the underlying malignancy and does meet the 
expected pattern of progression for the disease under study.
When there is evidence suggesting a causal relationship between the drug and the progression 
of the underlying disease, the event must be reported as (S)AE on the eCRF and SAE form.
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
Not applicable.
ASSESSMENT OF EXPLORATORY BIOMARKER
5.5
Not applicable.
OTHER ASSESSMENTS
5.6
Not applicable.


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APPROPRIATENESS OF MEASUREMENTS
5.7
All clinical assessments are standard measurements commonly used in studies of advanced 
solid tumours. Response evaluation criteria in solid tumours (RECIST) version 1.1 are used 
for assessment of the change in tumour burden. These criteria are well established and well 
received by the regulatory authorities and scientific community. 
The CTCAE criteria are used in the assessment of adverse events in cancer patients. In the 
present trial CTCAE version 4.0 will be used although an updated version is published. Since 
several pivotal oncology trials are currently ongoing with the investigational product it is 
considered more appropriate to continue to collect safety data using the same criteria.


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6.
INVESTIGATIONAL PLAN
This trial is an open-label trial for patients with NSCLC harbouring HER2 mutation Patients 
meeting all the inclusion and none of the exclusion criteria and who have given their written 
informed consent are eligible for participation.
VISIT SCHEDULE
6.1
The Screening Visit must be performed prior to the first administration of afatinib
monotherapy for Part A of the trial,  Each treatment cycle is defined as 28 days.  
Patients who progress after afatinib monotherapy in Part A but are ineligible to continue into 
Part B or patients who no longer wish to participate in the trial for other reasons (Section 
6.2.3) should have their EOT evaluation within 14 days after their last afatinib administration. 
The first Follow-Up Visit would be undergo 30 + 3 days after the EOT Visit. Further Follow-
Up Visits will only be performed to obtain vital status and can be done through telephone
every 60 + 7 days until death.
In case patient is eligible for participation in the Part B of the trial. EOT Visit of Part A will 
be same as Screening Visit of Part B. 
Before the treatment of Part B, tumor will be assessed to establish a new ‘baseline’ according 
to RECIST 1.1. In case there are valid assessments within 4 weeks before first medication 
administration of part B, tumor assessment does not need to be performed at the Screening 
Visit of Part B.
Treatment in part B must commence as soon as patient is found eligible. Treatment with 
afatinib must be continued at the dose taken in Part A and combined with weekly 80 mg/m2
paclitaxel. These patients will be treated until progression, withdrawal, study termination, 
death or are lost to follow-up. In the event that patients progress further (compare to the new 
baseline in part B and according to RECIST 1.1) or no longer wish to participate in the trial, 
they will undergo an EOT evaluation within 14 days of their last treatment administration, 
followed by a first Follow-Up Visit 30 + 3 days after the EOT Visit. If patients experience no 
PD before EOT visit (for those who withdraw or are removed from treatment), patients will 
have further tumor assessment in future FU Visits until disease progression, death, start of a 
new anti-cancer therapy, study termination, or are lost to follow-up.  After the final Follow-
Up Visit, the patients will be observed (Observation Period through Telephone) every 60 + 7
days until death, study termination or are lost to follow-up.
If a visit is missed and the patient reports to the Investigator between the missed visit and the 
next scheduled visit, the missed visit should be performed.  The current date and the reason 
for the delayed visit should be noted in the patient’s chart.  The next visit, however, should 
take place at the scheduled time after the first administration of the trial drug in the respective 
treatment cycle.


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DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
Please refer to flowchart for detailed trial procedures information at each visit.
6.2.1
Screening for Part A
Informed consent would be signed (including consent form for archival tumour biopsy 
sampling for HER2 mutation) before demographics (sex, birth date, race, smoking, alcohol
status and histological subtype) would be collected.
In screening visit 1,if HER2 mutation had been confirmed by AmoyDx® HER2 Mutation 
Detection Kit before enrollment to this trial (the specification of AmoyDx® HER2 Mutation 
Detection Kit could be found in the investigator study folder), and solid documentation of test 
results are available, the repeated HER2 Mutation testing is not required again, other trial 
screening activities in screening visit 2 could be initiated after HER2 mutation positive result 
is available
For patients who have HER2 mutation tested negative in screening visit 1, no need proceed to 
screening visit 2.
6.2.2
Treatment periods in Part A
The daily treatment with Afatinib monotherapy would continue until disease progression or 
other criteria for stopping medication (refer to Section 6.2.3).
Treatment is divided into 28-day cycles for administrative purposes.
6.2.3
End of study treatment and follow-up period in Part A
EOT Visit will only be performed in patients who will not continue into Part B of the trial.
For patients entering part B, EOT visit will be merged with screening visit of Part B.
In case the patient did not progress on treatment in part A, but discontinue the Afatinib
monotherapy treatment because of intolerant toxicity or other reason, the tumor assessment 
would be repeated as scheduled time slot (every 8 weeks firstly, then 12 weeks after 52
weeks) until:

Lost to follow-up

Disease progression

Start of a new anti–cancer therapy  

Death
All patients not entering Part B will have the FU Visit to obtain vital status information from 
patient or caregivers until death of patient or lost to follow-up after the first follow-up visit. 
The information can be obtained through telephone and recorded in eCRF every 60+/-7 days.


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6.2.4
Screening for Part B
Screening Visit should occur during the scheduled visit at which progression is determined in 
Part A or as soon as possible, but no more than 14 days after last dosage in part A. For
patients who are eligible to Part B, No separated informed consent would be signed for Part B 
since all the Part B related procedure and requirement had been mentioned in inform consent 
before enrolled into Part A.
6.2.5
Treatment periods in Part B
In part B, patient would be treated with Afatinib combined with weekly paclitaxel (80 mg/m2, 
iv) until further disease progression or other criteria for stopping medication (refer to Section 
6.2.3). Patients will be allowed to rest from treatment every 8th week (7 weeks on/1 week 
off) at the discretion of investigator
In case patient can’t tolerate the combination therapy, if there is clinical benefit to continue 
the monotherapy of Afatinib as the discretion of investigator, investigator could report this 
case to sponsor and obtain the permission from TCM.
The tumor assessments must occur seamlessly during Part A, Part B and until end of study at 
intervals of 8 weeks regardless of treatment interruptions (refer to Section 5.2.1).
6.2.6
Follow-up period and Trial Completion in Part B
End of treatment visit (EOT) 
6.2.6.1
The EOT visit will be performed after permanent discontinuation of trial medication for any 
reason as soon as possible but no later than 14 days after permanent discontinuation of the 
trial medication or when the investigator decided with the patient to permanently discontinue 
the trial medication or became aware that the trial medication had been terminated.
Residual effect period (REP)
6.2.6.2
The REP is defined in Section 5.3.6. The End of REP (EoR) visit should not be performed 
earlier than 30 days after permanent discontinuation of the trial medication. The information 
collected at this visit should include all new AEs that occurred after EOT and a follow-up of 
adverse events ongoing at EOT. In this trial, the REP visit would be the same visit of first 
follow-up visit after EOT as specified in flowchart.
Extended follow-up period
6.2.6.3
6.2.6.3.1
Follow-up for progression
Additional follow-up visits after the first follow-up visit will be performed for patients who 
did not progress on treatment.
The follow-up for progression period will end at the earliest if one of the following events is 
met:


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
Lost to follow-up

Disease progression

Start of a new anti–cancer therapy  

Death

End of whole trial as specified in Section 8.6
The following will be obtained and / or performed during the follow-up visits.

Record AESI or SAEs assessed as related by the investigator and a follow-up of adverse 
events ongoing since EoR to EoFU as entered in source data 

Concomitant medications for treatment of an adverse event reported in the (e)CRF 
including trade name, indication and dates of administration

Record performance score (e.g. ECOG) 

Perform tumour assessment and imaging every 8 weeks (+/- 3 days), and 12 weeks (+/- 3
days) interval after 52 weeks until progression or death.

Outcome (date of and reason for death, in case the patient had PD the actual date of PD 
shall be recorded)
6.2.6.3.2
Observation period for Overall Survival 
All patients will be followed-up for overall survival at 2 monthly intervals after the last 
follow-up for progression visit (as specified in Section 6.2.6.3.1) until death, lost to follow-up 
or completion of the whole trial (as specified in Section 8.6) whatever occurs earlier. For 
patients who progressed on treatment, the observation period for overall survival starts after 
patient complete the first FU visit.
These visits may also be performed by e.g. telephone interview or via written correspondence 
in case the patient is unable to visit the investigator. 
The following information will be collected during the survival observation period:

Date and type of contact

Further anti-cancer treatment: regimen and drug name, start and stop dates, reason for 
stopping this treatment

Outcome event (Record date of and reason for death)

Follow-up of adverse events in case they were not yet recovered at previous visit.
Trial completion for an individual patient
6.2.6.4
A patient is considered to have completed the trial in case any of the following applies:

Completion of planned follow-up and observation period 

Lost to follow-up

Withdrawal to be followed-up

Death
At the earliest of the above criteria, the Patient Completion (PC) information should be 
entered in the CRF.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is an open-label, single-arm, multi-center Phase II trial that is designed to explore the 
efficacy of afatinib in treating patients with NSCLC harbouring HER2 mutation. The primary 
endpoint of this trial is the objective response in part A, as determined according to RECIST 
1.1.
NULL AND ALTERNATIVE HYPOTHESES
7.2
In this exploratory trial, inferences about the effects of afatinib in the patients with advanced 
NSCLC harbouring HER2 mutations will be based upon the magnitude and consistency of 
the results over time, and across endpoints and prognostic factors, rather than on formal 
hypothesis tests.
PLANNED ANALYSES
7.3
All patients that receive at least one dose of afatinib will be included in the analyses of 
efficacy and safety.
Two separate analyses will be performed for objective response rates. One based on all 
patients treated with afatinib monotherapy (Part A) and the second for all patients treated 
with afatinib and paclitaxel (Part B). The first analysis will consider all assessment from start 
of monotherapy until progression under afatinib monotherapy. The second analysis will 
consider all assessments from start of treatment in part B until progression under treatment 
with afatinib + paclitaxel.
7.3.1
Primary endpoint analyses
The primary endpoint is Objective Response   in   part A by investigator assessment per 
RECIST 1.1 criteria. The Objective Response Rate (ORR) is defined as the proportion of 
patients with objective response of confirmed CR or PR  in  part A.
The primary analysis of response will be done when all treated patients are evaluable for 
response, which is expected to be approximately 20 weeks after the last patient starts 
treatment.
An exact 95% Clopper-Pearson confidence interval will be calculated for ORR. 
Each patient will be assigned to one of the following RECIST categories based on 
Investigator assessment, irrespective of protocol violations or missing data: 

CR (complete response)

PR (partial response)

SD (stable disease)


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
PD (progressive disease)

unknown (not assessable, insufficient data)
Patients’ objective responses during treatment, determined without requiring confirmation, 
will be tabulated separately.
7.3.2
Secondary endpoint analyses
• Disease Control Rate in Part A
One of the secondary endpoint is Disease control in part A by investigator assessment per 
RECIST 1.1 criteria. The Disease Control Rate (DCR) is defined as the proportion of patients 
with objective response of confirmed CR, PR and SD. It will be estimated and the exact 95% 
Clopper-Pearson confidence interval will be calculated.
• PFS in Part A
Disease progression will be evaluated according to the RECIST 1.1 criteria (R09-0262). 
PFS with regard to Part A is given as:

PFSday] = date of progression (under afatinib monotherapy) or death – date of first 
administration of afatinib in part A+1.
For patients known to be alive and without progression by the end of study or follow-up visit, 
they will be censored at the date of last imaging without progression. Patients with unknown 
disease progression status or date, or who are treated with new anticancer therapy will be 
handled as described in Section 7.6.
The distribution of PFS will be estimated using the Kaplan-Meier method. The median PFS 
along with 95% confidence interval, using Greenwood’s standard error estimate, will be 
presented.
• Overall Survival (OS)
OS is defined as time from the date of first administration of afatinib until death due to any 
cause.
OS time for patients who are alive at the end of the study or are lost to follow-up will be 
censored at the date of last contact. Rules for missing dates of death are described in Section 
7.6.
OS will be estimated using the Kaplan-Meier method. The median OS along with 95% CI 
will be presented.
• Time to Progression (TTP) in part A
TTP in part A is defined as the time from the date of starting treatment of afatinib to the date 
of disease progression in part A. It will be estimated using the Kaplan-Meier method, and the 
median TTP along with 95% CI will be presented.
• Duration of Response (DoR) in part A
Among all the patients with confirmed PR or CR in part A, DoR is defined as the time from 
the first documented response PR or CR to the date of tumor progression according to 


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RECIST 1.1 or death in part A. It will be estimated using the Kaplan-Meier method, and the 
median DoR along with 95% CI will be presented.
Duration of response (DoR) in part A, defined as the time from the first documented response 
PR or CR to the date of tumor progression evaluated according to RECIST 1.1 or death in 
part A.
7.3.4
Safety analyses
All patients who receive at least one dose of trial medication will be included in the safety 
analysis. All safety analysis described below will be performed for patients in part A and part 
B separately.
Adverse events will be graded according to CTCAE, Version 4.0. 
Adverse events will be coded using the Medical Dictionary for Regulators Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the residual effect period 
(REP), a period of 30 days after the last dose if trial medication, will be assigned to the 
treatment period for evaluation. 
Standard tabulations arranged by MedDRA SOC and PT will include: 

the overall incidence and intensity of adverse events, 

AE judged to have been related to afatinib

AE leading to dosage reduction 

AE leading to permanent treatment discontinuation

SAE

Fatal outcome


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These standard tables will be supplemented with tables in which MedDRA SMQ and HLT 
(with some modifications) will be used to group MedDRA PT for the following:

rash/acne

stomatitis 

paronychia

fatigue
Listings will be prepared of patients who are identified as having experienced any of the 
following AE.  For AE other than dehydration, identification will be based upon modified 
MedDRA SMQ and HLT groupings.

dehydration

renal insufficiency

hepatic impairment

ILD-like events

heart failure

Keratitis

Pancreatitis

Severe skin reaction

Gastrointestinal perforation

Hypersensitivity reaction

Developmental toxicity
Primary laboratory tests are defined as:

Low values (-): haemoglobin, total WBC, platelets, neutrophils, lymphocytes, potassium, 
magnesium, sodium, Creatinine clearance and GFR

High values (+): AST, ALT, Alkaline Phosphatase, aPTT, INR, and Total Bilirubin 
The following analyses will be presented for the primary laboratory tests:

descriptive statistics at each planned assessment, 

frequency of patients with transitions in CTCAE grade from baseline to worst and last 
values during treatment, and 

frequency of patients with possible clinically significant abnormalities.
Possible clinically significant abnormalities are defined as CTCAE grade of 2 or greater, with 
an increase of at least one grade from baseline.
7.3.5
Pharmacokinetic analyses
Not applicable
INTERIM ANALYSES
7.4
No interim analysis will be done, but the primary analysis  will take place after the last 
enrolled patient complete the 20- week treatment and tumor evaluation in part A .. All 
efficacy and safety analysis for patients treated in part A will be performed.


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Moreover , a secondly analysis will be done after the last enrolled patient complete the 
Afatinib treatment in Part A.
Additional exploratory efficacy and safety analyses for part B will be performed in the final 
analysis when study ends.
HANDLING OF MISSING DATA
7.5
Patients will continue to be followed for both progression and death after discontinuation of 
study treatment. All reasonable efforts will be undertaken to determine date and cause of 
death for each patient.
Table 7.5:1 describes how patients will be classified for the analysis of PFS. Sensitivity 
analyses will examine the effect of using alternative rules.


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7.5.1
Table 7.5:1
Endpoint determination for PFS in part A
Situation
Outcome 
(event or censored)
Date of PFS or censoring
No baseline tumour 
assessment for part A
censored
Date of first treatment (Part A)
Progressed according to 
imaging 
(no missed radiological 
assessments)
event
Date of PD in part A
Non-PD from imaging 
assessment1, death before next 
scheduled assessment
event
Date of death 
Non-PD from imaging 
assessment1, 
one missed assessment, death 
or progression after date of 
missed assessment, but before 
a second scheduled assessment
event
Date of PD in part A or death
Non-PD from imaging 
assessment1, 
more than one consecutive 
missed assessment, 
death or progression after date 
of  second missed assessment
censored
Date of last imaging in part A
before missed assessment
New anti-cancer medication 
before progression or death
censored
Date of last imaging in part A 
before new anti-cancer medication
Death  before the scheduled 
date of first imaging
event
Date of death
No imaging performed post-
baseline, patient dies between 
first and second scheduled 
assessments
event
Date of  death
No imaging performed post-
baseline, 
Patient dies after second 
scheduled assessment
censored
Date of first treatment (Part A)
No imaging performed post-
baseline, vital status is 
unknown or patient is known 
censored
Date of first treatment (Part A)


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Situation
Outcome 
(event or censored)
Date of PFS or censoring
to be alive
Table 7.5:1 (continued)
Endpoint determination for PFS in part A
Situation
Outcome 
(event or censored)
Date of PFS or censoring
Alive and not progressed 
according to imaging 
assessment (no missed 
radiological assessments)
censored
Date of last imaging in part A
1 This is from the last assessment at which non-PD (SD or better) was assessed.
 
 
 
Table 7.5:2 describes how patients will be classified for the analysis of death. Patients will be 
censored at the date of last contact if the Investigator is no longer able to contact a patient or 
caregiver, and vital status cannot otherwise be determined, provided that no other information 
indicates that the patient was near death at that point.
7.5.2
Table 7.5:2
Endpoint determination for overall survival
Situation
Outcome (event or 
censored)
Date of death or 
censoring
Patients died and the date of 
death is known
event
Date of death
Patients died and date of death 
is unknown
censored
Date of last contact 
when the patient is 
known to be alive
Patient alive
censored
Date of last contact 
Unknown
censored
Date of last contact 
when the patient is 
known to be alive
RANDOMISATION
7.6
No randomization is necessary since this is an uncontrolled, non-randomized trial. Eligible 
patients will be entered into the trial sequentially.


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DETERMINATION OF SAMPLE SIZE
7.7
Assuming the underlying objective response rate for the selected patient population is 40%. A
sample size of 40 patients are expected in order to obtain an exact binomial 95% CI for ORR 
with a lower bound greater than 24%, which is considered clinically meaningful (R14-4573). 
Table 7.7.1 provides the exact binomial 95% CI for various observed ORRs for the 40 
patients. The calculations above were performed in R version 3.0.3.
Table 7.7:1
Exact Binomial 95% Confidence Intervals for Various Observed 
ORRs (n=40)
Observed ORR
Number of Patients with Confirmed 
PR or CR
Exact 95% CI
35%
14
(20.6%, 51.7%)
40%
16
(24.9%, 56.7%)
45%
18
(29.3%, 61.5%)
50%
20
(33.8%, 66.2%)


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the ethical 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) and 
relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will 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 or of ICH 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 rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).”
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
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 Investigator must give a full explanation to trial patients including the items listed below 
in association with the use of the patient information form, which is prepared avoiding the 
use of technical terms and expressions. The patient is given sufficient time to consider 
participation in the trial. The Investigator obtains written consent of the patient’s own free 
will with the informed consent form after confirming that the patient understands the contents. 
The Investigator must sign (or place a seal on) and date the informed consent form. If a trial 


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collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC 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.
RECORDS
8.3
(e)CRF for individual patients will be provided by the Sponsor. See Section 4.1.5 for rules 
about emergency code breaks. 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 the CRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For the eCRF, all data need to be derived from source documents, eg:

Patient identification (gender, date of birth)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results (in validated electronic format, if available)

Completion of Patient’s Participation in the trial”

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records or testing conducted specific for a protocol) to support 
inclusion/exclusion criteria does not make the patient eligible for the clinical trial.


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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. 
CRF/eCRF 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. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRF / eCRF, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents 
described in Section 8.3.1.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil 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 afatinib this is the current version of the Investigator’s Brochure (c01802941-09).for the
non-investigational medicinal product paclitaxel, the reference document is the current 
version of SmPC. The current versions of these reference documents are to be provided in the 
ISF. 
8.4.2
Expedited reporting to health authorities and IEC / IRB
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IEC / IRB, will be done according to local 
regulatory requirements.
STATEMENT OF CONFIDENTIALITY
8.5
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.
END OF TRIAL
8.6
The trial will end when:

All patients have stopped the treatment because of disease progression or death or 
intolerant toxicity.
And 90% events for overall survival had been achieved.
The sponsor may decide to discontinue the trial earlier than this if the primary efficacy 


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analysis has been completed, sufficient PFS data has been collected, and all patients have 
either ended study treatment or are eligible to receive afatinib under the conditions listed in 
Section 3.3.4.1.


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9.
REFERENCES
PUBLISHED REFERENCES
9.1
P07-03251 Solca F, Baum A, Himmelsbach F, Meyer R, Amelsberg A, Adolf G. Efficacy of 
afatinib, an irreversible dual EGFR/HER2 receptor tyrosine kinase inhibitor, in 
combination with cytotoxic agents. 18th EORTC-NCI-AACR Symp on 
Molecular Targets and Cancer Therapeutics, Prague, 7 - 10 Nov 2006 (Poster) 
2006
P07-11507 Moy B, Goss PE. Lapatinib-associated toxicity and practical management 
recommendations. Oncologist 2007. 12(7):756-765.
P09-00886 Perera SA, et al. HER2YVMA drives rapid development of adenosquamous 
lung tumors in mice that are sensitive to BIBW2992 and rapamycin combination 
therapy. Proc Natl Acad Sci USA 2009. 106(2):474-479.
P09-05119 Spicer JF, Harris D, Ang J, Chau M, Vizor S, Shahidi M, Uttenreuther-Fischer 
M, Southey K, Chambers J, Bono JS de. A phase I study of daily afatinib, an 
irreversible EGFR/HER2 dual kinase inhibitor, in combination with weekly 
paclitaxel. Ann Oncol 2008. 19(Suppl 8):VIII157-VIII158. Abstr 474P
P09-10056 Ang J, Mikropoulos C, Stavridi F, Rudman S, Uttenreuther-Fisher M, Shahidi 
M, Pemberton K, Wind S, Bono J de, Spicer JF. A phase I study of daily 
afatinib, an irreversible EGFR/HER2 dual kinase inhibitor, in combination with 
weekly paclitaxel. 45th Ann Mtg of the American Society of Clinical Oncology 
(ASCO), Orlando, 29 May - 2 Jun 2009 J Clin Oncol 2009. 27(15S)(Suppl) 
Abstr e14541
P09-10062 Greve J de, Teugels E, Mey J de, in 'tveld P, Decoster L, Schallier D, Geers C, 
Galdermans D, Taton M, Shahidi M. Clinical activity of afatinib, an irreversible 
inhibitor of EGFR/HER1 and HER2 in adenocarcinoma of the lung with 
mutations in the kinase domain of HER2neu. 13th World Conf on Lung Cancer, 
San Francisco, 31 Jul - 4 Aug 2009 (Oral Presentation) 2009
P11-09424 Porta C, Osanto S, Ravaud A, Climent MA, Vaishampayan U, White DA, Creel 
P, Dickow B, Fischer P, Gornell SS, Meloni F, Motzer RJ. Management of 
adverse events associated with the use of everolimus in patients with advanced 
renal cell carcinoma. Eur J Cancer 2011. 47:1287-1298.
P12-01885 Greve J de, Teugels E, Geers C, Decoster L, Galdermans D, Mey J de, Everaert 
H, Umelo I, Veld P in't, Schallier D. Clinical activity of afatinib (BIBW 2992) in
patients with lung adenocarcinoma with mutations in the kinase domain of
HER2/neu. 4th Latin American Conf on Lung Cancer, Buenos Aires, 28 - 30 Jun 
2010; 2nd Eur Lung Cancer Conf, Geneva, 28 Apr - 1 May 2010; 13th World 
Conf on Lung Cancer, San Francisco, 31 Jul - 4 Aug 2009; Joint ECCO 15 -
34th ESMO, Biennial Multidisciplinary Cong of the European Cancer 
Organisation and the European Society for Medical Oncology, Berlin, 20 - 24 
Sep 2009 Lung Cancer, article in press, published online 13 February 2012, doi: 
10.1016/j.lungcan.2012.01.008 Lung Cancer (Neth) 2012. 76(1):123-127.


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P13-03658 Lacouture M, Schadendorf D, Chu CY, Uttenreuther-Fischer M, Stammberger 
U, O'Brien D, Hauschild A. Dermatologic adverse events associated with 
afatinib: an oral ErbB family blocker. Expert Review of Anticancer Therapy, 
Epub ahead of print, Posted online on March 18, 2013, doi: 10.1586/era.13.30 
Expert Rev Anticancer Ther 2013. 13(6)(Suppl):721-728.
P13-03659 Yang JCH, Reguart N, Barinoff J, Koehler J, Uttenreuther-Fischer M, 
Stammberger U, O'Brien D, Wolf J, Cohen EEW. Diarrhea associated with 
afatinib: an oral ErbB family blocker. Expert Review of Anticancer Therapy, 
Epub ahead of print, Posted online on March 18, 2013, doi: 10.1586/era.13.31 
Expert Rev Anticancer Ther 2013. 13(6):729-736.
P13-05288 Mazieres J, Peters S, Lepage B, Cortot AB, Barlesi F, Beau-Faller M, Besse B, 
Blons H, Mansuet-Lupo A, Urban T, Moro-Sibilot D, Dansin E, Chouaid C, 
Wislez M, Diebold J, Felip E, Rouquette I, Milia JD, Gautschi O. Lung cancer
that harbors a HER2 mutation: epidemiologic characteristics and therapeutic 
perspectives. Journal of Clinical Oncology, Published Ahead of Print on April 
22, 2013, doi: 10.1200/JCO.2012.45.6095 J Clin Oncol 2013. 31(16):1997-2003.
P14-00758 Wu YL, Zhou C, Hu CP, Feng J, Lu S, Huang Y, Li W, Hou M, Shi JH, Lee 
KY, Xu CR, Massey D, Kim M, Shi Y, Geater SL. Afatinib versus cisplatin plus
gemcitabine for first-line treatment of Asian patients with advanced non-small-
cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, 
randomised phase 3 trial. Lancet Oncology, Published Online January 15, 2014, 
doi:10.1016/S1470-2045(13)70604-1 Lancet Oncol 2014. 15(2):213-222.
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) 2007
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.
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, 
Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, 
Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009. 45:228-
247.
R11-0826
Potthoff K, Hofheinz R, Hassel JC, Volkenandt M, Lordick F, Hartmann JT, 
Karthaus M, Riess H, Lipp HP, Hauschild A, Trarbach T, Wollenberg A. 
Interdisciplinary management of EGFR-inhibitor-induced skin reactions: a 
German expert opinion. Ann Oncol 2011. 22(3):524-535
R13-1023
Spector NL, Blackwell KL. Understanding the mechanisms behind trastuzumab 
therapy for human epidermal growth factor receptor 2-positive breast cancer. J 
Clin Oncol 2009. 27(34):5838-5847.


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R14-4573
Kawaguchi T, Ando M, Asami K, Okano Y, Fukuda M, Nakagawa H, Ibata H, 
Kozuki T, Endo E, Tamura A, Kamimura M, Sakamoto K, Yoshimi M, Soejima 
Y, Tomizawa Y, Isa S, Takada M, Saka H, Kubo A. Randomized phase III trial
of erlotinib versus docetaxel as second- or third-line therapy in patients with
advanced non-small-cell lung cancer: Docetaxel and Erlotinib Lung Cancer
Trial (DELTA). J Clin Oncol 2014. 32(18):1902-1908
UNPUBLISHED REFERENCES
9.2
U08-1023-02
.  A Phase I open-label dose escalation study of 
continuous once-daily oral treatment with BIBW 2992 in patients with 
advanced solid tumours.  Trial 1200.3.  30 January 2008. Revised 25 February 
2010.
U12-1167 
. Phase III randomised trial of BIBW 2992 plus
weekly paclitaxel versus investigator’s choice of chemotherapy following
BIBW 2992 monotherapy in non-small cell lung cancer patients failing
previous erlotinib or gefitinib treatment (LUX Lung 5). 17 April 2012.
c01802941-09 Investigator’s brochure. Afatinib (BIBW 2992). Version 15, 1200.P1 -
1200.P10. 03 Jul 2014.


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10.
APPENDICES
RECIST 1.1 CRITERIA
10.1
The criteria below are based on RECIST 1.1 (R09-0262).
The preferred method of assessment is a spiral CT scan with IV and oral contrast, unless IV 
and/or oral contrast are medically contraindicated. CT scans of the chest, abdomen and other 
areas of known or newly suspected disease must be performed. Scans of the abdomen, pelvis 
and other areas of the body, but not chest, may be done with MRI instead of CT. 
Skin lesions followed as target lesions must be documented by colour digital photography 
and must include in the image a ruler with millimetre subdivisions and a label that includes 
the patients ID and date. 
Bone scans (using 99m-technetium polyphosphonate scintigraphy) are recommended at 
baseline if the patient has any signs and symptoms consistent with bone metastasis or a 
history of bone metastasis. Bone metastasis identified at baseline must be documented and 
assessed according to RECIST 1.1 at the times of the other tumour measurements indicated in 
the Flow Chart. During the study bone scans should be repeated as clinically indicated in 
patients without bone metastasis at Baseline. 
Follow-up tumour assessments must utilize the same CT/MRI/photographic method and 
acquisition technique (including use or non-use of IV contrast) as were used for screening 
assessments to ensure comparability. A chest x-ray or skeletal x-ray which clearly 
demonstrates a new metastatic lesion may be used to document progression in lieu of 
CT/MRI/bone scan.   
Only those patients who have measurable disease present at baseline, have received at least 3 
weeks of therapy, and have had their disease re-evaluated will be considered evaluable for 
response.  These patients will have their response classified according to the definitions stated 
below.
Measurability of the disease
Measurable lesions
Lesions that can be accurately measured in at least one dimension with longest diameter ≥ 10 
mm (by CT scan, MRI, caliper measurement) or ≥ 20 mm (by chest X-ray). Pathological 
lymph nodes, defined as lymph nodes with a short axis >15mm are also measurable.
Measurable disease
Measurable disease requires the presence of at least one measurable lesion. Measurable lesion 
if limited to either small (<2cm) solitary visceral lesion or scant (<5cm) lymph nodes only 


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metastasis should be evaluated for additional evidence of malignant nature and discussed 
with BI trial clinical monitor before enrolling.
Non-measurable disease
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 
mm with CT scan, MRI or caliper measurement or <20 mm with chest X-ray or pathological 
lymph nodes with shortest axis ≥10 and <15 mm) as well as truly non-measurable lesions. 
Lesions considered truly unmeasurable include leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/ abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.
New lesions in irradiated fields
Previously irradiated lesions should not be used as indicator lesions. However, new lesions 
occurring in previously irradiated fields can be used to assess the antitumour response.
Methods of measurement
All measurements must be recorded in metric notation, using a ruler or calipers. All baseline 
evaluations must be performed as close as possible to the treatment start and never more than 
4 weeks before the beginning of the treatment. If a lesion is considered too small to measure, 
a default measurement of 5mm should be applied. If the lesion is not visible, a default 
measurement of 0mm should be applied.
The same method of assessment and the same technique must be used to characterise each 
identified and reported lesion at baseline and during follow-up. 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). In the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is obligatory.
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 5 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to the chest, abdomen and 
pelvis.
Ultrasound, endoscopy and laparoscopy should not be used to measure tumour lesions or 
evaluate tumour response. However, these techniques can be useful to supplement 
information from other techniques.
Tumour markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, they must normalise for a patient to be considered in complete clinical 
response.


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Cytology and histology can be used to differentiate between PR and CR in rare cases (for 
example, residual lesions in tumour types such as germ cell tumours, where known residual 
benign tumours can remain).
Baseline Documentation of Target and Non-target Lesions
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs should be identified as target lesions and will be 
recorded, measured (longest diameter = LD) and numbered at baseline. Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their suitability 
for accurate repetitive measurements (either by imaging techniques or clinically). Lymph 
nodes must be ≥15mm in order to be considered as target lesions.
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference to further characterize 
the objective tumour response of the measurable dimension of the disease (see Table 10.1:1).
10.1.1
Table 10.1:1 Evaluation of target lesions
Complete Response (CR)
Disappearance of all target lesions.
Partial Response (PR) 
At least a 30% decrease in the sum of LD of target lesions 
taking as reference the baseline sum LD.
Progression (PD)
At least a 20% increase in the sum of LD of target lesions taking 
as reference the smallest sum LD recorded since the treatment 
started, together with an absolute increase in the sum of LD of at 
least 5mm. OR 
The appearance of one or more new lesions.
Stable Disease (SD) 
Neither sufficient shrinkage to qualify for PR, taking as 
reference the baseline sum LD, nor sufficient increase to qualify 
for PD taking as reference the smallest sum LD since the 
treatment started.
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements are not required and these lesions should be 
followed as “present” or “absent” (see Table 10.1:2).


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10.1.2
Table 10.1:2 Evaluation of non-target lesions and new lesions
Complete Response 
(CR)
Disappearance of all non-target lesions and normalisation of tumour 
marker level. All lymph nodes must be non-pathological in size 
(<10 mm short axis)
Non-CR/ Non-PD 
Persistence of one or more non-target lesions or/and maintenance of 
tumour marker level above normal limits.
Progression (PD)
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions.
Although a clear progression of non-target lesions only is exceptional, 
in such circumstances, the opinion of the treating physician should 
prevail and the progression status should be confirmed later by the 
review panel (or study chair).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status.
Confirmation
In case of tumour response (CR or PR), confirmation will be performed with a repeat 
assessment no less than 4 weeks after the RECIST criteria for response have been met. A 
confirmation of PR or CR should be conducted 4 weeks after the initial assessment, then 
continue the scheduled tumor assessments until PD occurs.
In the case of SD, measurement must have met the SD criteria at least once after 1st dose at an 
interval of not less than 6 weeks.
Evaluation of Best Response to Study Treatment
The best response to study treatment (Table 10.1:3) is the best response recorded from the 
start of treatment until disease progression or start of further anti-cancer treatment (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). In general, the patient’s best response assignment will depend on the achievement of 
both measurements and confirmation criteria (Table 10.1:3).
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment.


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10.1.3
Table 10.1:3 Algorithm for evaluation of overall best response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/ Non- PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not
evaluated
No
PR
SD
Non-PD or not
evaluated
No
SD
Not evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CLINICAL EVALUATION OF LIVER INJURY
10.2
10.2.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.3.5 (Protocol-specified 
Significant Events), are to be further evaluated using the following procedures:
10.2.2
Procedures
Any elevation of ALT/AST and bilirubin qualifying as laboratory alert should be confirmed 
using the initial sample if possible. 
If the alert is confirmed on initial sample, or it is not possible to repeat testing using initial 
sample, the following must be completed;
1) Evaluate the patient within 48 hours and,
2) Perform the following laboratory tests:
1. Repeat of AST, ALT, bilirubin (with fractionation to total and direct)
2. Haptoglobin
3. Complete blood count and cell morphology
4. Reticulocyte count
5. CK
6. LDH
7. Alkaline Phosphatase
The results of these laboratory tests must be reported to BI as soon as possible. 


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If the initial alert values (ie AST,ALT, and bilirubin) are confirmed on the second sample 
described as above, then an abdominal ultrasound or clinically appropriate alternate imaging 
(to rule out biliary tract, pancreatic or intrahepatic pathology, e.g. bile duct stones or
neoplasm) must be completed within 48 hours. 
The findings from the hepatic imaging (including comparison to prior imaging if available) 
must be made available as soon as possible as part of the adverse event reporting process. In 
the event the etiology of the abnormal liver tests results is not identified based on the imaging 
(e.g. biliary tract, pancreatic or intrahepatic pathology), then the “DILI checklist” must be 
completed. Details of the “DILI checklist” are provided in the ISF. The following 
assessments need to be performed in order to complete the “DILI checklist”. Any resulting 
diagnoses will be reported via the eCRF:
o
obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF;
o
obtain history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets according to the “DILI checklist” provided in the ISF;
o
obtain a history of exposure to environmental chemical agents (consider home and 
work place exposure) according to the “DILI checklist” provided in the ISF;
o
complete the following laboratory tests as detailed in the DILI checklist provided in 
the ISF: 

Clinical chemistry 
alkaline phosphatase, cholinesterase (serum)*, albumin, PT or INR, CK,
CK-MB, coeruloplasmin*, α-1 antitrypsin*, transferrin*, amylase, lipase, 
fasting glucose, cholesterol, triglycerides

Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs,DNA), 
Hepatitis C (Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-
IgM, Anti-IgG), Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti-
HEV IgM positive), Anti-Smooth Muscle antibody (titer), Antinuclear
antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-
mitochondrial antibody, Epstein Barr Virus (VCA IgG, VCA IgM),
cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, IgM)*, varicella
(IgG, IgM)*, parvovirus (IgG, IgM)*

Hormones, tumormarker
Thyroid-stimulating hormone (TSH)*

Haematology
Thrombocytes, eosinophils
*If clinically indicated (e.g immunocompromised patients) 


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Long term follow-up
o
Initiate close observation of subjects by repeat testing of ALT, AST, and bilirubin 
(with fractionation to total and direct) at least weekly until the laboratory ALT and or 
AST abnormalities stabilize or return to normal, then according to the protocol. 
Depending on further laboratory changes, additional parameters identified e.g. by 
reflex testing will be followed up based on medical judgement and Good Clinical 
Practices (GCP).
Report any resulting diagnoses via the eCRF.
COCKCROFT-GAULT FORMULA
10.3
Estimated creatinine clearance rate (eCCR) using Cockcroft-Gault formula
Or when serum creatinine is measured in µmol/L
Where Constant is 1.23 for men and 1.04 for women
eCCR =
(140-Age)X Mass (in kilograms) X [0.85 if 
Female]
72 X Serum Creatinine (in mg/dL)
(140-Age)X Mass (in kilograms) X Constant
eCCR =
Serum Creatinine (in µmol/L)


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NEW YORK HEART ASSOCIATION (NYHA) FUNCTIONAL 
10.4
CLASSIFICATION
NYHA 
Class
Symptoms
I
Cardiac disease, but no symptoms and no limitation in ordinary physical activity, 
e.g. no shortness of breath when walking, climbing stairs etc.
II
Mild symptoms (mild shortness of breath and/or angina) and slight limitation 
during ordinary activity.
III
Marked limitation in activity due to symptoms, even during less-than-ordinary 
activity, e.g. walking short distances (20–100 m).
Comfortable only at rest.
IV
Severe limitations. Experiences symptoms even while at rest. Mostly bedbound 
patients.


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LIST OF POTENT INHIBITORS AND INDUCERS OF PGP
10.5
List of potent inhibitors and inducers of P-glycoprotein (MDR1)
Inhibitors
Inducers
Amiodarone
Azithromycin
Captopril
Carvedilol
Clarithromycin
Conivaptan
Cyclosporine
Diltiazem
Dronedarone
Erythromycin
Felodipine
Itraconazole
Ketoconazole
Lopinavir
Nelfinavir
Ritonavir
Quinidine
Ranolazine
Saquinavir
Tacrolimus
Ticagrelor
Verapamil
Carbamazepine
Phenytoin
Rifampicin
St John’s Wort
Phenobarbital Salt
Tipranavir
Ritonavir
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 and in case of 
questions contact BI clinical monitor.


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ECOG PERFORMANCE STATUS
10.6
ECOG PERFORMANCE STATUS*
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair
5
Dead


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1.0
Date of CTP revision
05 Feb 2016
EudraCT number
NA
BI Trial number
1200.222
BI Investigational Product(s)
BIBW2992 (afatinib)/ Giotrif®/ GiotrifTM
Title of protocol
A phase II study of afatinib in patients with 
advanced NSCLC harboring HER2 mutations, 
previously treated with chemotherapy
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
Section to be changed
Trial Clinical Monitor information  in Title Page
Description of change
TCM was changed from 
 to 
Rationale for change
TCM was changed
Section to be changed
Flow Chart (Part A)  Screening Visit 
Description of change
Screening Visit is split  into SV1 and SV2
The previous footnote:
2. Documented test results from each investigator’s 
accredited labs are acceptable for eligibility. Other 
trial screening activities could be initiated after 
HER2 mutation positive result is available. 


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Was changed to:
2. For patient who has already tested positive for 
HER2 mutation as confirmed by AmoyDx® HER2 
Mutation Detection Kit before enrollment to this 
trial, the repeated HER2 Mutation testing is not 
required again.
For patients who have HER2 mutation tested 
negative in screening visit 1, no need proceed to 
screening visit 2.
Rationale for change
To lessen the unnecessary procedure in screening
visit for negative HER2 mutation and previous 
tested positive patients.
Section to be changed
FLOW CHART: PartA  (A-FU-x)  and  PartB
(Observation period)
Description of change
ECOG Performance Status was removed from A-
FU-x in Part A and  Observation period in Part B
Rationale for change
Not  necessary and feasible to record the ECOG 
Performance  status in this visit 
Section to be changed
3.3.3
Description of change
Previous text:
i.)
Palliative radiation to target organs other 
than chest may be allowed up to 2 weeks 
prior to randomization,
Was changed to:
i.)
Palliative radiation to target organs other 
than chest may be allowed up to 2 weeks 
prior to enter
Rationale for change
No randomization is applicable.
Section to be changed
6.2.1
Description of change
Previous text:
Documentation of HER2 Mutation Status, if HER2
mutation had been confirmed by the site with the 
same method, that means HER2 mutations as 
confirmed by AmoyDx® HER2 Mutation 
Detection Kit before enrollment to this trial (the 
specification of AmoyDx® HER2 Mutation 


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Detection Kit could be found in the investigator 
study folder), and solid documentation of test 
results are available, the repeating HER2 Mutation 
testing is not required again. One copy of archival 
tumor biopsy sample would be collected for future 
double confirmation of HER2 mutation at 
coordinator investigator’s site, the method of 
HER2 mutation double confirmation could be 
AmoyDx® kit testing or DNA sequencing.
Was changed to:
In screening visit 1, if HER2 mutation had been 
confirmed by AmoyDx® HER2 Mutation 
Detection Kit before enrollment to this trial (the 
specification of AmoyDx® HER2 Mutation 
Detection Kit could be found in the investigator
study folder), and solid documentation of test 
results are available, the repeated HER2 Mutation 
testing is not required again, other trial screening 
activities in screening visit 2 could be initiated after 
HER2 mutation positive result is available
For patients who have HER2 mutation tested 
negative in screening visit 1, no need proceed to 
screening visit 2.
Rationale for change
The double testing in central lab (Shanghai 
pulmonary hospital) for HER2 mutation 
confirmation is waived.
To lessen the unnecessary procedure in screening 
visit for negative HER2 mutation and previous 
tested positive patients.


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Number of global amendment
2.0
Date of CTP revision
16 Aug 2017
EudraCT number
NA
BI Trial number
1200.222
BI Investigational Product(s)
BIBW2992 (afatinib)/ Giotrif®/ GiotrifTM
Title of protocol
A phase II study of afatinib in patients with 
advanced NSCLC harboring HER2 mutations, 
previously treated with chemotherapy
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
Section to be changed 
Main criteriafor inclusion 1 in the title page and 
3.3.2
Description of change
“IIIb” is added in the stage, and “systemic” is 
added in the chemotherapy.
Rationale for change
1) The advanced NSCLC including IIIb and IV in 
common practice,cause IIIb patient may benefit 
from afatinib treatment.
2) The “systemic” is to clarify the general 
chemotherapy, and exclude other local therapy.
Section to be changed 
3.3.4.2
Description of change
Added: 4. At the discretion of the sponsor (BI) for 
other reason.
Rationale for change
To list other unexpected cause


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Section to be changed 
Flowchart in part A 
Description of change
1) SV1 is separated  from SV2; 
2) the X for study medication compliance check in 
A-FU1 was removed to concomitant medication in 
A-FU1;
3) should be done within 28 days prior to the start 
of treatment in Part A” is added in note 3;
4) * note is attached with physical examination, 
vital signs and ECOG Performance status ;
5)** note is attached with 12 Lead Digital ECG 
and safety lab;
6)*** note is attached with AE and concomitant 
medication.
Rationale for change
1) SV1 duration is not limited, to allow potential 
eligible patient in chemotherapy to join the trial 
2) This is an edit error in previous version.
3) The time limit for pregnancy test prior to study 
treatment is requested.
4) The time limit is requested to avoid the 
unnecessary repeated procedure but ensure the 
validity   prior to study treatment.
5) The time limit is requested to avoid the 
unnecessary repeated procedure but ensure the 
validity   prior to study treatment.
6) To decrease the undesired data collection for 
SV1 in EDC, waive the reporting of SAE not 
related with study procedure in SV1 prior to 
study treatment.
Section to be changed 
5.3.3
Description of change
The volum of blood drawing for safety lab testing
is added.
Rationale for change
To specify the blood volum to keep consistent with 
ICF
Section to be changed 
5.3.6
Description of change
Added: In SV1, only those SAE related with study 
procedure need to be reported; the AE and 
Concomitant Medication do not need to be 
collected in EDC.
Rationale for change
To be consistent with the note of flowchart in part 
A, decrease the undesired data collection for SV1


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in EDC, waive the reporting of SAE not related 
with study procedure in SV1 prior to study 
treatment.
Section to be changed 
6.1
Description of change
“Within 28 days”  is removed
Rationale for change
To be consistent with flowchart in Part A
Section to be changed 
7.3.1
Description of change
Added: The primary analysis of response will be 
done when all treated patients are evaluable for 
response, which is expected to be approximately 20
weeks after the last patient starts treatment.
Rationale for change
To specify the evaluation timepoint of primary 
endpoint 
Section to be changed 
7.3.2
Description of change
PFS2 is updated as PFS
Rationale for change
Edit error
Section to be changed 
7.3.4
Description of change
Removed :Tables that describe the frequency, 
intensity, time to onset, and clinical consequences 
will be produced for the following AE of special 
interest:

diarrhea 

rash/acne

stomatitis
Rationale for change
To consistent with the AESI in 5.3.5.1
Section to be changed 
7.4
Description of change
A Primary analysis and secondary analysis is 
planned.
Rationale for change
No interim analysis but the primary and secondary 
analysis is planned to show the analysis result 
before study end.
Section to be changed 
8.6
Description of change
Added: The sponsor may decide to discontinue the 
study earlier than this if the primary efficacy 
analysis has been completed, sufficient PFS data 


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has been collected, and all patients have either 
ended study treatment or are eligible to receive 
afatinib under the conditions listed in section
3.3.4.1.
Rationale for change
Clarify the other cause that sponsor discontinue the 
study.
Section to be changed 
10.1 confirmation 
Description of change
Added: A confirmation of PR or CR should be 
conducted 4 weeks after the initial assessment, then 
continue the scheduled tumor assessments until PD 
occurs.
“study entry” is updated as “1st dose”
Rationale for change
The confirmation of PR or CR is clarified.
The “study entry” is replaced by “1st dose” to 
make more accurate.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08988429
2.0
clinical-trial-protocol-revision-02
A phase II study of afatinib in patients with advanced NSCLC harboring HER2
mutations, previously treated with chemotherapy
Approval-Clinical Program 
17 Aug 2017 16:57 CEST
Approval–Clinical Monitor
18 Aug 2017 03:22 CEST
Author-Trial Statistician
18 Aug 2017 03:28 CEST
Approval-Therapeutic Area 
21 Aug 2017 09:59 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c08988429
2.0

SAP_000.pdf: 
Reference Document “Template Trial Statistical Analysis Plan – template”
001-MCG-40-415_RD-02 (1.0) / Saved on: 012 Oct 2016
TITLE PAGE
Trial Statistical Analysis Plan
c23337948
BI Trial No.:
1200.222
Title:
A phase II study of afatinib in patients with advanced NSCLC
harboring HER2 mutations, previously treated with chemotherapy
Investigational
Product(s):
Giotrif®/ Gilotrif™(afatinib)
Responsible trial 
statistician(s):
Phone: 
Fax: 
Date of statistical 
analysis plan:
16 APR 2018 SIGNED 
Version:
Final
Page 1 of 28
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2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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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
...................................................................................8
...................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................10
6.1
TREATMENT.....................................................................................................10
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................11
6.3
PATIENT SETS ANALYSED...........................................................................14
.....................................................................................................14
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........17
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................17
7.3
TREATMENT COMPLIANCE........................................................................17
7.4
PRIMARY ENDPOINT .....................................................................................18
7.5
SECONDARY ENDPOINTS.............................................................................18
7.5.1
Key secondary endpoint .....................................................................................18
7.5.2
Secondary endpoints...........................................................................................19
.................................................................................20
7.7
EXTENT OF EXPOSURE.................................................................................21
7.8
SAFETY ANALYSIS..........................................................................................22
7.8.1
Adverse events.....................................................................................................22
7.8.2
Laboratory data ..................................................................................................24
7.8.3
Vital signs.............................................................................................................25
7.8.4
ECG......................................................................................................................25
7.8.5
Others...................................................................................................................25
8.
REFERENCES....................................................................................................26
...............................................................................27
10.
HISTORY TABLE..............................................................................................28


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LIST OF TABLES
Table 6.2: 1
Important protocol violations ...........................................................................12
Table 10: 1
History table .....................................................................................................28


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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
OR
Objective response
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
PP
Per-protocol 
PT
Preferred term
SAE
Serious adverse event
SD
Standard deviation
SD
Stable disease
SOC
System organ class


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Term
Definition / description
TKI
Tyrosine kinase inhibitor
TS
Treated set
TSAP
Trial statistical analysis plan
TTP
Time to 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
There has been no change in the planned analyses from the statistical methods described in 
the CTP.


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5.
ENDPOINT(S)
5.1
PRIMARY ENDPOINT
Objective response in Part A, defined as patients with tumor size reduction of a predefined 
amount using RECIST 1.1 in part A. Objective responses include both confirmed partial 
responses (PR) plus complete responses (CR).
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
There are no key secondary endpoints.
5.2.2
Secondary endpoints
Disease control in Part A, defined as patients who have achieved confirmed complete
response, partial response and stable disease per RECIST 1.1 in part A.
Progression Free Survival (PFS) in Part A, defined as the time from the date of starting
treatment of afatinib to the date of disease progression per RECIST 1.1, or to the date of death 
no matter which happens first in part A.
Overall survival (OS) in Part A, defined as the time from start of treatment of afatinib until 
death from any cause.
Time to progression (TTP) in Part A, defined as the time from the date of starting treatment 
of afatinib to the date of disease progression per RECIST 1.1 in part A.
Duration of response (DoR) in part A, defined as the time from the first documented
response PR or CR to the date of tumor progression evaluated according to RECIST 1.1 or 
death in part A.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT
This is a single arm study, which consists two treatment parts, Afatinib monotherapy (Part A) 
and Afatinib combined with weekly paclitaxel (Part B). Part A and part B are conducted 
sequentially.
There is only one treatment group in this study in Part A, which is Afatinib monotherapy. The 
following study periods for Part A based on actual start and stop dates of study treatment 
administration are defined:

Part A Screening Visit 1:
Patients with positive HER2 Mutation Status= from day of informed consent to day that 
patient has the texted positive HER2 mutation status or day prior to the first assessment 
scheduled in screening visit 2 whichever comes late
Patients with negative HER2 Mutation Status= from day of informed consent to the day
that patient has the texted negative HER2 mutation status

Part A Screening Visit 2: from the first assessment scheduled in screening visit 2 to day 
prior to starting study treatment of Afatinib. 
The last day of Part A screening visit 1 can be prior to or at the same day as the first day 
of the screening visit 2.

Part A on-treatment: from day of first administration of afatinib to the day of last
administration of afatinib monotherapy.

Part A residual effect period (REP): from last day of part A on-treatment period + 1 day 
through the 30th day after last administration of afatinib monotherapy for patients not 
entered to Part B

Part A off-treatment: from 31st day after last administration of afatinib monotherapy for 
patients not entered to Part B
Part A REP and off-treatment periods are not defined for patients who are entered to Part B. 
Safety data recorded up to the 30th day after last administration of afatinib monotherapy 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).
There is also only one treatment in Part B, which is afatinib combined with weekly paclitaxel. 
The following study periods will be defined for Part B:

Part B screening: from last day of Part A on treatment period +1 day through the day 
prior to starting study treatment of paclitaxel plus afatinib.

Part B on-treatment: from day of first administration of combination treatment to the day 
of last administration of study medication. If the patient entered to Part B but did not 
receive paclitaxel, the date of administration of afatinib will be used as the start date of 
Part B on-treatment period.


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
Part B residual effect period (REP): from last day of part B on-treatment period + 1 day 
through the 30th day after last administration of study medication, for patients entered to 
Part B

Part B off-treatment: from 31st day after last administration of study medication to the last 
follow up visit or death, which occurs first, for patients entered to Part B
Safety data recorded up to the 30th day after last administration of study medication 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).
Adverse event with onset date prior to first administration of paclitaxel and afatinib combined 
therapy will be considered as Part A adverse event. Adverse events with onset date on or after 
first administration of paclitaxel and afatinib combined therapy will be considered as Part B 
adverse events.
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
Excluded 
from
A
Inclusion Criteria Not Met
A1
Inclusion Criteria Not Met for Part A
A1.1
Diagnosis of NSCLC questionable (or 
incorrect disease stage )
Inclusion criteria IN1 for 
part A not met
None
A1.2
No presence of HER2 mutation in tumor 
tissue as confirmed by AmoyDx® HER2
Mutation Detection Kit
Inclusion criteria IN2 for 
part A not met
or
HER2 mutation negative
None
A1.3
No measurable tumor lesion that can 
accurately be measured
by CT scan or MRI according to RECIST 1.1
Inclusion criteria IN3 for 
part A not met
None
A1.4
Age <=18 years
Inclusion criteria IN4 for 
part A not met
None
A1.5
ECOG performance score > 1
Inclusion criteria IN5 for 
part A not met
None
A1.6
Inadequate organ function
Inclusion criteria IN6 for 
part A not met
None
A1.7
Not recovered from any previous therapy 
related toxicity to ≤Grade 1 at study entry
(except for stable sensory neuropathy ≤Grade 
2 and alopecia)
Inclusion criteria IN7 for 
part A not met
None
A2
Inclusion Criteria Not Met for Part B
A2.1
Inadequate organ function before entering to 
Part B
Inclusion criteria IN1 for 
part B not met
None
A2.2
ECOG performance score > 1before entering 
to Part B
Inclusion criteria IN2 for 
part B not met
None
A2.3
Not enough clinical benefit in part A (that is, 
tumor response at week 8 and
week 12 is CR, PR or SD)
Inclusion criteria IN3 for 
part B not met
None
B
Exclusion Criteria Met
B1
Exclusion Criteria Met for Part A
B1.1
Prior treatment with EGFR or HER2 targeting 
small molecules or antibodies.
Exclusion criteria EX1 for 
part A met
None
B1.2
Any chemo-, or immune anticancer therapy 
within 4 weeks prior to start of study
treatment, Hormonal treatment within 2 weeks 
prior to start of study treatment,
Radiotherapy within 4 weeks prior to start of 
study treatment, except as follows:
i.) Palliative radiation to target organs other 
than chest may be allowed up to 2
weeks prior to enter, and
ii.) Single dose palliative treatment for 
symptomatic metastasis outside above
allowance to be discussed with sponsor prior 
to enrolling.
Exclusion criteria EX2 for 
part A met
None
B1.3
Major surgery within 4 weeks before starting 
study treatment or scheduled for
surgery during the projected course of the 
study
Exclusion criteria EX3 for 
part A met
None
B1.4
Known hypersensitivity to afatinib or the 
excipients of any of the trial drugs
Exclusion criteria EX4 for 
part A met
None


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Category / 
Code
Description
Comment/Example
Excluded 
from
B1.5
History or presence of clinically relevant 
cardiovascular abnormalities such as
uncontrolled hypertension, congestive heart 
failure NYHA classification of ≥3, unstable 
angina or poorly controlled arrhythmia as
determined by the investigator. Myocardial 
infarction within 6 months prior to first
Afatinib dose.
Exclusion criteria EX5 for 
part A met
None
B1.6
Any history of or concomitant condition that, 
in the opinion of the Investigator, would 
compromise the patient’s ability to comply 
with the study or interfere with the evaluation 
of the efficacy and safety of the test drug.
Exclusion criteria EX6 for 
part A met
None
B1.7
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
effectively treated malignancy that has been in 
remission for more than 3 years and is 
considered to be cured.
Exclusion criteria EX7 for 
part A met
None
B1.8
Requiring treatment with any of the prohibited 
concomitant medications listed in protocol
Section 4.2.2.1 that cannot be stopped for the 
duration of trial participation
Exclusion criteria EX8 for 
part A met
None
B1.9
Known pre-existing interstitial lung disease
Exclusion criteria EX9 for 
part A met
None
B1.10
Any history or presence of poorly controlled 
gastrointestinal disorders that could affect the 
absorption of the study drug (e.g. Crohn’s 
disease, ulcerative colitis, chronic diarrhoea,
malabsorption).
Exclusion criteria EX10 for 
part A met
None
B1.11
Active hepatitis B infection (defined as 
presence of HepB sAg and/ or Hep B DNA),
active hepatitis C infection (defined as 
presence of Hep C RNA) and/or known HIV
carrier.
Exclusion criteria EX11 for 
part A met
None
B1.12
Known Leptomeningeal carcinomatosis.
Exclusion criteria EX12 for 
part A met
None
B1.13
Symptomatic brain metastases; To be eligible 
patients must be asymptomatic from brain 
metastases at least 4 weeks without 
requirement for steroids or anti-epileptic
therapy
Exclusion criteria EX13 for 
part A met
None
B1.14
Women of child-bearing potential (WOCBP) 
and men who are able to father a child,
unwilling to be abstinent or use highly
effective methods of birth control that result in 
a low failure rate of less than 1% per year 
when used consistently and correctly prior to 
study entry, for the duration of study 
participation and for at least 2 weeks after 
treatment has ended.
Exclusion criteria EX14 for 
part A met
None
B1.15
Women who are pregnant, nursing, or who 
plan to become pregnant while in the
trial
Exclusion criteria EX15 for 
part A met
None
B2
Exclusion Criteria Met for Part B


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Category / 
Code
Description
Comment/Example
Excluded 
from
B2.1
Any known contraindication for paclitaxel 
treatment
Exclusion criteria EX1 for 
part B met
None
B2.2
Not able to tolerate lowest dose of 20 mg 
afatinib.
Exclusion criteria EX2 for 
part B met
None
B2.3
Peripheral polyneuropathy >Grade 2.
Exclusion criteria EX3 for 
part B met
None
C
Informed Consent
C1
Informed consent not given
Inclusion criteria IN8 not 
met
or
consent date is missing
None
C2
Informed consent given too late
Inclusion criteria IN8 not 
met
None
D
Trial medication and Concomitant medication
D1
Prohibited medication use
Review concomitant
medications for prohibited
medication use. Refer to
Section 4.2.2 of the CTP.
None
D2
Non-compliance of trial medication
e.g., compliance rate<80%
E
Others
E1
Subjects who met discontinuation criteria but 
still continue in the study
None
Note: Missing visits, evaluations, and tests will be considered missing data, not protocol deviations..
6.3
PATIENT SETS ANALYSED
Enrolled set 1 (ES1)
The enrolled set consists of all patients who signed informed consent and entered Screening 
Visit 1.
Enrolled set 2 (ES2)
The enrolled set consists of all patients who entered Screening Visit 2. .
Treated set (TS)
This patient set includes all patients who were dispensed with and documented to have taken 
at least one dose of study medication. This set of patients will be used for the evaluation of
efficacy and safety.
Part A and Part B will be analysed separately. 
6.5
POOLING OF CENTRES
This section is not applicable because there will be no pooling of centres or countries and no 
modelling thereof.


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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:
For PFS, duration of tumour response and duration of disease control, if a patient is known to 
have progressed, but the date of progression (progymd) is not attainable, the following 
sequence for imputation of progression date will be followed:

Use the date of cancer related symptoms assessment or visit date in which the progression 
was recorded (whichever is earliest)

If this is missing, use the last known visit date or cancer related symptom assessment date 
prior to the recorded progression (regardless of the disease assessment result at that visit).

If any such patient has no visit date or cancer related symptoms assessment date recorded 
at all, the date of first administration of study medication will be used as the date of 
disease progression
For overall survival, if a patient is known to have died (due to any cause), but date of death is 
not attainable, the last date when the patient is known to be alive will be used as date of death.
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

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 for Part A and prior to first administration of afatinib or 
paclitaxel for Part B.
Except for Cycle 1 (see CTP Flowchart: Part A), the time windows for subsequent clinic visits 
is 28 -2/+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 first follow-up visit should be between 27 and 33
days after the EoT visit.
Nominal visit numbers as recorded in the eCRF will be used where required and there will be
no windowing.


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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 appendix tables, the set of summary statistics is: N/Mean/SD/Min/Q1(lower 
quartile)/Median /Q3(Upper quartile) /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, all patients in the respective patients set 
whether they have non-missing values or not). 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

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)

Alcohol status

Baseline ECOG score

Oncology history

Previous therapies
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics using standard summary tables for the Treated Set (TS) are planned 
for this section of the report. 
For baseline conditions and signs and symptoms of the trial disease also only descriptive
statistics will be presented.
7.3
TREATMENT COMPLIANCE
There is no analysis planned for treatment compliance.


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7.4
PRIMARY ENDPOINT
The primary endpoint of the study is Objective Response (OR) to study treatment in Part A, 
which is defined as patients with tumour size reduction of a predefined amount, includes CR 
(Complete Response) or PR (Partial Response), judging by the investigator per RECIST 1.1 
in part A. The Objective response rate (ORR) is defined as the proportion of patients with 
objective response of confirmed CR or PR in part A.
The maximum percentage decrease from baseline in the sum of target lesion diameters will be 
summarized descriptively, the mean, sd, median, and range will be reported. And a waterfall 
plot of it will be provided. Besides, the patient percentage change from baseline of the sum of 
target lesion diameter over time will be plotted. 
Number of patients in each of below categories of maximum percentage change from baseline 
in the sum of target lesion diameters will be provided in the table:
1. Missing;
2. >=20% increase;
3. >=0 - <20% increase;
4. >0 - < 30% decrease;
5. >=30% decrease
The primary analysis of response will be done when all treated patients are evaluable for
response, the two-sided 95% confidence intervals will be given for the calculated objective 
response rate using the exact 95% Clopper-Pearson confidence interval.
In addition, at each tumor assessment visit, patient will be assigned to one of the following 
RECIST categories based on Investigator assessment, irrespective of protocol violations or 
missing data:
1. CR
2. PR
3. SD
4. Progressive disease (PD)
5. Unknown
Then n(%) of patients tumour response category will be tabulated by tumour assessment visit 
(objective response without confirmation, CR without confirmation, PR without confirmation, 
SD, PD, unknown). The total number of patients assessed at the visit will be used as 
denominator.
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.


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7.5.2
Secondary endpoints
Disease Control Rate in Part A
Patients whose best assessment is confirmed CR, PR or SD according to the treating 
investigator’s assessment per RECISIT 1.1 criteria will be considered to have achieved 
disease control.
The Disease Control Rate (DCR) is defined as the proportion of patients who have achieved 
disease control. Its estimation and the exact 95% Clopper-Pearson confidence interval will be 
calculated.
Progression-free survival (PFS) in Part A
Disease progression will be evaluated according to the RECIST 1.1 criteria. 
PFS with regard to Part A is defined as the time (number of days) from the date of the first 
administration of afatinib to the date of progression or to the date of death (due to any cause), 
whichever occurs first. 
PFS in Part A will be derived as:
PFS [days] = (the earliest of: date of progression or death due to any cause under Afatinib 
monotherapy) – (date of first administration of Afatinib in Part A) + 1
For patients known to be alive and without progression by the end of study or follow-up visit,
they will be censored at the date of last imaging without progression. For patients that are 
known to have progressed, but with unknown date of progression, refer to Section 6.6 for 
more detail.
Kaplan-Meier estimates and 95% confidence intervals for the 25th, median, and 75th 
percentiles of the survival distribution will be calculated for progression-free survival, using 
Greenwood’s standard error estimate. Kaplan-Meier curves will also be produced.
Censoring rules for PFS:

For patients who have definitely not progressed or died whilst on study treatment, these 
patients will be censored at the last known visit date or cancer related symptoms 
assessment date (up to and including the EOT visit).

For patients with unknown progression status (no tumour assessment reported or ‘not 
evaluable’ assessment) at the final on treatment or EOT visit, these patients will be 
censored at the last known visit or cancer related symptoms assessment date, where the 
tumour assessment was SD, PR or CR.

For patients with no on treatment tumour assessments (either missing or ‘not evaluable’), 
these patients will be censored at the date of first administration of afatinib.
Overall survival (OS) in Part A
OS (months), defined as the time from the date of first administration of Afatinib to the date 
of death due to any cause. 
OS will be derived as:


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Overall Survival [days]=date of death-(date of first administration of Afatinib in Part A) +1; 
For patients known to have died (due to any cause), with the date of death missing, refer to  
Section 6.6 for more detail.
Kaplan-Meier estimates and corresponding 95% confidence intervals for the 25th, median, 
and 75th percentiles of the survival distribution will be calculated for overall survival, using 
Greenwood’s standard error estimate. Kaplan-Meier curves will also be produced. 
Censoring rules for OS: 
Patients know to be alive by the end of the trial or follow-up visit (ignoring secondary 
treatment)  will be censored at the last date the patient is known to be alive. 
Time to progression (TTP) in Part A
TTP in part A is defined as the time (number of days) from the date of starting treatment of 
afatinib to the date of disease progression in part A. 
TTP will be derived as:
TTP [days]=date of progression-date of start first administration of Afatinib in Part A +1
For patients that are known to have progressed, but with unknown date of progression, refer 
to Section 6.6 for more detail. 
Kaplan-Meier estimates and corresponding 95% confidence intervals for the 25th, median, 
and 75th percentiles of the TTP distribution will be calculated, using Greenwood’s standard 
error estimate. Kaplan-Meier curves will also be produced. 
Duration of response (DoR) in part A
Defined as the number of months from first documented objective response (latest of: cancer 
related symptoms assessment date or visit date where first documented OR recorded) to the 
time of tumor progression or death (due to any cause) in Part A.
For patients with confirmed objective response only, Kaplan-Meier estimates and 95% 
confidence intervals for the 25th, median, and 75th percentiles of the survival distribution will 
be calculated for duration of objective tumour response. Greenwood’s standard error estimate 
will be used. Kaplan-Meier curves will also be produced.
Censoring rules for duration of objective tumour response (progression date):

For patients who have definitely not progressed or died whilst on study treatment, these 
patients will be censored at the last known visit date or cancer related symptoms 
assessment date (up to and including the EOT visit). 

For patients with unknown progression status (no tumour assessment reported or ‘not 
evaluable’ assessment) at the final on treatment or EOT visit, these patients will be 
censored at the last known visit or cancer related symptoms assessment date, where the 
tumour assessment was CR, PR or SD.


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7.7
EXTENT OF EXPOSURE
Treatment exposure for Treatment A and B will be calculated separately. 
Afatinib
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.
Paclitaxel
Total treatment period 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 paclitaxel treatment, date of death) + 1 day
Standard descriptive summaries of these data will be provided for the treated set of patients.


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7.8
SAFETY ANALYSIS
All patients who receive at least one dose of trial medication will be included in the safety
analysis. All safety analysis described below will be performed for patients in part A and part
B separately. (see CTP Section 7.3.4).
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 4.0 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.
Adverse events will be coded using the Medical Dictionary for Regulators Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All
adverse events with an onset between start of treatment and end of the residual effect period
(REP), a period of 30 days after the last dose if trial medication, will be assigned to the
treatment period for evaluation.
Standard tabulations arranged by MedDRA SOC and PT will include (see CTP Section 7.3.4):

the overall incidence and intensity of adverse events,

AE judged to have been related to afatinib

AE leading to dosage reduction

AE leading to permanent treatment discontinuation

SAE

Fatal outcome
These standard tables will be supplemented with tables in which MedDRA SMQ and HLT
(with some modifications) will be used to group MedDRA PT for the following:

rash/acne

stomatitis

paronychia

fatigue
Listings will be prepared of patients who are identified as having experienced any of the
following AE. For AE other than dehydration, identification will be based upon modified
MedDRA SMQ and HLT groupings.

dehydration

renal insufficiency

hepatic impairment

ILD-like events

heart failure

Keratitis

Pancreatitis


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
Severe skin reaction

Gastrointestinal perforation

Hypersensitivity reaction
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 
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.

AE of special interest
As per protocol AESI (CTP Sect 5.3.5) hepatic injury is considered as AESI. Some other pre-
defined AEs are considered of special interest for the safety analysis too including diarrhea, 
rash/acne, renal insufficiency, stomatitis, interstitial lung disease, keratitis, severe skin 


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reactions, pancreatitis, heart failure, gastrointestinal perforation, and hypersensitivity 
reactions. 
For Part B, drug related AE will be displayed separately for afatinib plus paclitaxel. 
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/acne, stomatitis, paronychia, fatigue, acute renal failure with 
severe diarrhea, severe cutaneous AEs, ILD, keratitis, hepatic impairment, pancreatitis, heart 
failure, gastrointestinal perforation, and hypersensitivity reactions).
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 the AEs of special interest, 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
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(8). CTCAE version 4.0 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’ (9).
Primary laboratory tests are defined as:
• Low values (-): haemoglobin, total WBC, platelets, neutrophils(only at baseline), potassium, 
magnesium, sodium, and GFR
• High values (+): AST, ALT, alkaline phosphatase, aPTT, INR, creatinine, and total bilirubin
The following analyses will be presented for the primary laboratory tests:
• descriptive statistics at each planned assessment,
• frequency of patients with transitions in CTCAE grade from baseline to worst and last 
values during treatment, and
• frequency of patients with possible clinically significant abnormalities.


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Possible clinically significant abnormalities are defined as CTCAE grade of 2 or greater, with 
an increase of at least one grade from baseline.
Frequency and time of onset of liver enzyme elevations will be tabulated. Additional, more 
in-depth analyses will be performed as needed. These analyses will examine the influence of 
extent of exposure and time to event onset.
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.
A listing for pregnancy test results of patients with child bearing potential will be provided.
7.8.4
ECG
A 12-lead resting ECG will be performed at the time points specified in the Flow Charts.  
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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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
16-Apr-18
None
This is the final TSAP.