Clinical trial NCT02208843
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim
Start date: 2014-10-02; Completion date: 2017-06-13
Enrollment: 60 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objectives of this single-arm, open-label trial are to assess the efficacy and safety of afatinib as second line treatment for patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring a common EGFR mutation who have failed first-line platinum-based chemotherapy and to demonstrate that the efficacy and safety are comparable to the results seen in previous trials.

Detailed description:

Arms: arm 1: Afatinib tablet once daily until progression
Interventions: intervention 1: Afatinib
Intervention descriptions: intervention 1: Afatinib tablet once daily until progression

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: c02156918-02
EudraCT No.:
BI Trial No.:
2014-001077-14
1200.217
BI Investigational
Product(s):
Giotrif®/ GilotrifTM (Afatinib)
Title:
An open label, single-arm phase IV study to assess the efficacy and 
safety of afatinib as second-line therapy for patients with locally 
advanced or metastatic non-small cell lung cancer (NSCLC) harbouring 
an EGFR mutation (Del19 or L858R) who have failed first-line 
treatment with platinum-based chemotherapy
Clinical Phase:
IV
Trial Clinical 
Monitor:
Phone: 
Fax: 
Co-ordinating 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol
Version and Date:
Version:
1
         
Date:    10 April 2014
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TITLE PAGE


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Doc. No.: c02156918-02
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Giotrif®/ GilotrifTM
Name of active ingredient:
Afatinib
Protocol date:
Trial number:
Revision date:
10 Apr 2014
1200.217
Title of trial:
An open label, single-arm phase IV study to assess the efficacy and safety of afatinib 
as second-line therapy for patients with locally advanced or metastatic non-small cell 
lung cancer (NSCLC) harbouring an EGFR mutation (Del19 or L858R) who have 
failed first-line treatment with platinum-based chemotherapy.
Co-ordinating 
Investigator:
Trial site(s):
Multi-centre trial
Clinical phase:
IV
Objective(s):
To assess the efficacy and safety of afatinib as second line treatment for patients with 
locally advanced or metastatic non-small cell lung cancer (NSCLC) harbouring a 
common EGFR mutation who have failed first-line platinum-based chemotherapy and 
to demonstrate that the efficacy and safety are comparable to the results seen in 
previous trials (P12-03681, P13-07382).
Methodology:
Single-arm, open-label
No. of patients: 
total entered:
60
each treatment:
N/A
Diagnosis :
Stage IIIB (with cytologically proven pleural effusion or pericardial effusion) or Stage 
IV adenocarcinoma of the lung harbouring an EGFR mutation.
Main criteria
for inclusion:

Pathologically confirmed diagnosis of Stage IIIB (with cytologically proven 
pleural effusion or pericardial effusion) or Stage IV adenocarcinoma of the 
lung. 

Documented common EGFR mutation (L858R and/or Deletion 19).

Measureable disease according to RECIST 1.1.

Radiologically confirmed progression or recurrence of disease during or 
following first-line therapy with a platinum-based chemotherapy regimen.

Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Giotrif®/ GilotrifTM
Name of active ingredient:
Afatinib
Protocol date:
Trial number:
Revision date:
10 Apr 2014
1200.217
Test product(s):
Afatinib
dose:
Starting dose 40mg/day
mode of admin.:
Oral, once daily continuous 
Comparator products:
Not applicable
dose:
Not applicable
mode of admin.:
Not applicable
Duration of treatment: Continuous treatment in the absence of disease progression or unacceptable treatment-
related adverse events.
Criteria for efficacy:
Objective tumour response (complete response (CR), partial response (PR)), 
progression-free survival (PFS) and disease control (CR, PR and stable disease (SD)) 
according to Response Evaluation Criteria in Solid Tumours (RECIST 1.1).
Criteria for safety:
Intensity and incidence of adverse events, graded according to US National Cancer 
Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE Version 
3.0).
Statistical methods:
Descriptive statistics will be provided for efficacy and safety evaluation.


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FLOW CHART
Screening
Treatment
courses***
End of 
Treatment****
Follow-up
Follow-up 
progression
*****
Visit abbreviation
SV1*
SV2**
CxV1a
C1V2
EOT
FU
FUPDxb
Days
Any 
time 
before 
SV2
Up to 28 
days 
before 
treatment
Day 1 
(± 2 days)
Course 1
Day 15 
(± 2 days)
0-14 days after 
permanent 
discontinuation 
of afatinib
28-35 days after 
discontinuation 
of afatinib 
Every 60
days after 
follow-up (±
15 days)
Tissue analysis consent
x1
EGFR mutation analysis
x1
Informed consent (trial 
participation)
x
Demographics
x
Medical history
x
Physical examination
x
x
x
Vital signs
x
x
x
x
Height
x
Weight
x
x
x
ECOG performance status
x
x
x
x
Safety laboratory tests 
x
x
x
Serum pregnancy test
x
Review of incl/exclusion criteria
x
Review medication compliance
x
x
Dispense medication
x
Administration of afatinib
Continuous
Adverse events
x2
x
x
x
x
x
x3
Concomitant therapy
x
x
x
x
x4
Tumour assessment5
x
Every 8 weeks (±7 days) from start of treatment until documented progression5
Termination of trial medication
x
Trial completion timepoint
x6
x6
Collect patient status information
x7
*Screening visit 1 is not required if the patient has already tested positive for a common EGFR mutation.
**Only patients who have tested positive for a common EGFR mutation should proceed to screening visit 2. Procedures which have been 
performed as part of routine clinical care do not need to be repeated at screening visit 2 if they are within the allowed time window (28 days 
prior to treatment).
*** All treatment courses are 28 days in duration. Patients may continue on treatment for unlimited courses, until criteria for stopping 
medication are met (see section 3.3.4)
****If the decision to permanently discontinue afatinib is taken during a scheduled visit, the EOT visit should be performed instead of the 
scheduled visit.
***** Follow-up progression is only for patients who have no documented disease progression at the follow-up visit.
a The visit is performed on the first day of each 28-day course and x is the number of the treatment course
bx is the number of the follow-up PD assessment
1
Not required if the patient has already tested positive for a common EGFR mutation and a written copy of the result is available.
2
Between tissue analysis consent and trial informed consent, AEs will only be reported if related to trial procedures.
3
From 28 days after last trial drug administration, new AEs will only be collected, documented and reported if they are considered
related to trial drug or design.
4
After end of treatment, concomitant therapies will only be recorded if indicated for the treatment of an AE (see section 4.2).
5
Tumour assessment should be performed every 8 weeks (every 12 weeks after week 56) calculated from start of treatment until 
documented progression. If treatment continues after progression, tumour assessment should continue according to the schedule 
until the decision to stop treatment. In the event of early discontinuation or an interruption/delay to treatment, the tumour 
assessment schedule should not be changed. See section 5.1.2 for further details.
6
Trial completion occurs at the follow-up visit, unless progression has not been documented, in which case tumour assessment 
should continue according to the trial schedule until progression or start of further treatment and the trial completion date is the 
date on which progression was documented or further anti-cancer treatment commenced.
7
Clinical assessments should be performed in accordance with institution practice; trial specific assessments are not required. 
Status information will include documentation of start of further treatment and/or clinical progression.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................5
ABBREVIATIONS.............................................................................................8
1.
INTRODUCTION.................................................................................... 10
1.1
MEDICAL BACKGROUND............................................................................10
1.2
DRUG PROFILE...............................................................................................10
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 12
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................12
2.2
TRIAL OBJECTIVES.......................................................................................12
2.3
BENEFIT - RISK ASSESSMENT ...................................................................12
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 14
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................14
3.1.1
Administrative structure of the trial...................................................15
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................15
3.3
SELECTION OF TRIAL POPULATION ......................................................15
3.3.1
Main diagnosis for study entry............................................................16
3.3.2
Inclusion criteria...................................................................................16
3.3.3
Exclusion criteria ..................................................................................17
3.3.4
Removal of patients from therapy or assessments.............................19
4.
TREATMENTS........................................................................................ 21
4.1
TREATMENTS TO BE ADMINISTERED....................................................21
4.1.1
Identity of BI investigational product and comparator 
product(s)...............................................................................................21
4.1.2
Method of assigning patients to treatment groups ............................21
4.1.3
Selection of doses in the trial................................................................21
4.1.4
Drug assignment and administration of doses for each patient .......21
4.1.5
Blinding and procedures for unblinding ............................................23
4.1.6
Packaging, labelling, and re-supply ....................................................23
4.1.7
Storage conditions.................................................................................23
4.1.8
Drug accountability ..............................................................................24


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................24
4.2.1
Rescue medication, emergency procedures, and additional 
treatment(s) ...........................................................................................24
4.2.2
Restrictions............................................................................................30
4.3
TREATMENT COMPLIANCE.......................................................................31
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 33
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................33
5.1.1
Endpoint(s) of efficacy..........................................................................33
5.1.2
Assessment of efficacy...........................................................................33
5.2
SAFETY..............................................................................................................33
5.2.1
Endpoint(s) of safety.............................................................................33
5.2.2
Assessment of adverse events...............................................................34
5.2.3
Assessment of safety laboratory parameters......................................37
5.2.4
Electrocardiogram................................................................................38
5.2.5
Assessment of other safety parameters...............................................38
5.3
OTHER...............................................................................................................38
5.3.1
EGFR mutation analysis ......................................................................38
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................39
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................39
6.
INVESTIGATIONAL PLAN.................................................................. 40
6.1
VISIT SCHEDULE............................................................................................40
6.1.1 Treatment beyond progression...............................................................40
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................41
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 42
7.1
STATISTICAL DESIGN – MODEL ...............................................................42
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................42
7.3
PLANNED ANALYSES....................................................................................42
7.3.1
Primary analyses...................................................................................42
7.3.2
Secondary analyses ...............................................................................42
7.3.3
Safety analyses.......................................................................................42
7.3.4
Interim analyses ....................................................................................43
7.3.5
Pharmacokinetic analyses ....................................................................43
7.3.6
Pharmacodynamic analyses.................................................................43
7.3.7
Pharmacogenomic analyses..................................................................43
7.4
HANDLING OF MISSING DATA ..................................................................43


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7.5
RANDOMISATION ..........................................................................................44
7.6
DETERMINATION OF SAMPLE SIZE ........................................................44
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 45
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................45
8.2
DATA QUALITY ASSURANCE .....................................................................45
8.3
RECORDS..........................................................................................................46
8.3.1
Source documents .................................................................................46
8.3.2
Direct access to source data and documents.......................................46
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................46
8.4.1
Listedness...............................................................................................46
8.4.2
Expedited reporting to health authorities and IECs/IRBs................46
8.5
STATEMENT OF CONFIDENTIALITY.......................................................47
8.6
COMPLETION OF TRIAL..............................................................................47
9.
REFERENCES......................................................................................... 48
9.1
PUBLISHED REFERENCES...........................................................................48
9.2
UNPUBLISHED REFERENCES.....................................................................50
10. APPENDICES .......................................................................................... 51
10.1
APPENDIX 1 COCKCROFT-GAULT FORMULA......................................51
10.2
APPENDIX 2 PGP INHIBITORS AND INDUCERS ....................................52
10.3
APPENDIX 3 RECIST 1.1................................................................................53
10.4
APPENDIX 4  ECOG PERFORMANCE STATUS.......................................58
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 59


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ABBREVIATIONS
ADL
Activities of Daily Living
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALT
Alanine Amino Transferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Amino Transferase
AUC
Area under the Concentration-time curve
BI
Boehringer Ingelheim
BSA
Body Surface Area
CA
Competent Authority
CI
Confidence Interval
CK
Creatinine Kinase
CML
Local Clinical Monitor 
CPK
Creatinine Phosphokinase
CR
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organisation
CT
Computed Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
DNA
Deoxyribonucleic Acid
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EGFR
Epidermal Growth Factor Receptor
EMA
European Medicines Agency
EOT
End of Treatment
EU
European Union
EudraCT
European Clinical Trials Database
FU
Follow Up
GCP
Good Clinical Practice
GFR
Glomerular Filtration Rate
HER
Human Epidermal Growth Factor Receptor
HIV
Human Immunodeficiency Virus
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
ILD
Interstitial Lung Disease
INR
International Normalised Ratio
IRB
Institutional Review Board
ISF
Investigator Site File


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IUD
Intrauterine device
i.v.
intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web-based Response System
LD
Longest Diameter
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
NSCLC
Non-small Cell Lung Cancer
NYHA
New York Heart Association
OPU
Operative Unit
OS
Overall Survival
PD
Progressive Disease
PFS
Progression-free survival
P-gp
P-glycoprotein
PK
Pharmacokinetic
PR
Partial Response
PS
Performance Status
PTT
Partial Thromboplastin Time
RDC
Remote Data Capture
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual Effect Period
SAE
Serious Adverse Event
SD
Stable Disease
SoD
Sum of Diameters
SOP
Standard Operating Procedure
SPC
Summary of Product Characteristics
SUSAR
Suspected Unexpected Serious Adverse Reaction
SV
Screening Visit
TKI
Tyrosine Kinase Inhibitor
ULN
Upper Limit of Normal
WBC
White Blood Cell
WOCBP
Woman of Child Bearing Potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
A subset of patients with non-small cell lung cancer (NSCLC) have a mutation in the tumour 
Epidermal Growth Factor Receptor (EGFR) gene which drives the growth of the tumour.
Standard first-line treatment for patients with locally advanced or metastatic NSCLC
harbouring an activating EGFR mutation is with agents targeting EGFR Tyrosine Kinase, 
such as EGFR Tyrosine Kinase Inhibitors (TKI) (gefitinib/erlotinib) or ErbB receptor family 
blocker afatinib. Despite this, many patients receive first-line treatment with chemotherapy. 
The purpose of this trial is to evaluate the efficacy and safety of afatinib as second-line 
treatment in this latter group of patients.
1.2
DRUG PROFILE
For the latest information on the drug profile of afatinib, please refer to the current 
Investigator’s Brochure (IB) (U03-3218).  All references in this protocol concerning afatinib 
refer to the free base compound afatinib BI 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 
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 seen. Afatinib is highly 
distributed out of the blood and has a moderate to high clearance. The overall gMean terminal 
half-life at steady state was 37.2 hours in cancer patients. Steady state was reached no later 
than 8 days after the first administration. The major route of elimination of afatinib was via 
faeces. After food intake, a decreased systemic exposure was observed compared to 
administration under fasted conditions. The pharmacokinetic (PK) characteristics in 
Caucasian cancer patients were comparable to those observed in Japanese cancer patients. 
Afatinib is bound covalently to proteins to a variable extent and covalent protein adducts 
were the major circulating metabolites in the plasma. Afatinib did not show relevant 
inhibition or induction of cytochrome P450 isoenzymes, and it appears unlikely that drug-
drug interactions based on this mechanism will occur. 
Afatinib is a substrate of the P-glycoprotein (P-gp) transporter. Concomitant administration 
of the potent P-gp inhibitor ritonavir did not relevantly change the exposure to 40 mg afatinib 
when taken simultaneously with or 6 h after afatinib but increased the bioavailability of 
afatinib (single dose of 20 mg) by 48% and 39% for AUC0-∞ and Cmax when given 1 h before 
afatinib, respectively. Pretreatment with the potent P-gp inducer rifampicin decreased the 


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plasma exposure of 40 mg afatinib by 34 % afatinib (AUC0-∞) 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 phase I open label dose-escalation studies determined the Maximum Tolerated Dose 
(MTD) with continuous dosing of afatinib in patients with advanced solid tumours at 40mg 
and 50mg daily, respectively [U07-3128-02 and U08-1023-02]. Adverse events (AE) 
observed with afatinib are consistent with those reported for other EGFR and dual 
EGFR/HER2 inhibitors. The most frequent investigator defined drug-related AEs were 
associated with gastrointestinal disorders (including diarrhoea, and stomatitis), skin and 
subcutaneous tissue disorders (rash, dry skin, pruritus, acneiform rash, acne), nail effects, 
epistaxis, 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].
Afatinib is approved in many countries for the treatment of EGFR TKI-naïve adult patients 
with locally advanced or metastatic non-small cell lung cancer with activating EGFR 
mutation. Previous studies with afatinib indicate that it is efficacious as a second-line therapy 
in patients who have received first line chemotherapy. In a phase II study (P12-03681), 68 
patients with EGFR mutations received second-line therapy with afatinib (starting dose 40mg 
or 50mg). Of these, 41 patients (60%) achieved an objective response based on investigator 
assessment, and 39 (57%) by independent review. Median progression-free survival (PFS) 
was 8.0 months by independent review and 10.5 months by investigator assessment, with a 
median overall survival of 23.3 months. 


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
This trial is being conducted at the request of the European Medicines Agency (EMA) as a 
condition of their favourable approval of afatinib for treatment of EGFR TKI-naïve patients 
with locally advanced or metastatic non-small cell lung cancer (NSCLC) with activating 
EGFR mutation(s).
The European Medicines Agency (EMA) recognised that the main biological predictor of 
response to afatinib is the presence of an activating EGFR mutation in the tumour, which 
takes precedence over the line of treatment in which afatinib is being used. As the submission 
package included limited safety and efficacy data for afatinib at a daily dose of 40mg in the 
EGFR mutation-positive chemotherapy pre-treated population (P12-03681), this study has 
been requested to confirm the efficacy and safety of afatinib with a starting dose of 40mg in 
the second line (post-chemotherapy) setting in a larger cohort of patients.
2.2
TRIAL OBJECTIVES
The objectives of this single-arm, open-label trial are to assess the efficacy and safety of 
afatinib as second line treatment for patients with locally advanced or metastatic non-small 
cell lung cancer (NSCLC) harbouring a common EGFR mutation who have failed first-line 
platinum-based chemotherapy and to demonstrate that the efficacy and safety are comparable 
to the results seen in previous trials (P12-03681, P13-07382). The primary and secondary 
endpoints are documented in section 5.
2.3
BENEFIT - RISK ASSESSMENT
According to the evolving global diagnostic and treatment standard, patients with 
adenocarcinoma of the lung should undergo testing of their tumour to determine the presence 
of EGFR mutations which in turn determines their treatment strategy. Patients with EGFR 
mutation positive disease should receive first-line treatment with an agent targeting EGFR 
(erlotinib, gefitinib or afatinib). Where first-line treatment with an EGFR TKI is not possible, 
patients become eligible to receive the targeted therapy as their second-line treatment, after 
initial chemotherapy treatment.
A previous phase II study (P12-03681) has shown that afatinib at a starting dose of 40mg or 
50mg is efficacious in this setting, with 57% of patients achieving an objective response (by 
independent review), median progression-free survival (PFS) of 8.0 months (by independent 
review) and median overall survival of 23.3 months. The demonstrated activity exceeded the 
historical performance of chemotherapy agents (docetaxel, pemetrexed) in the second line 
treatment of unselected NSCLC population (R05-1054) and compared favorably to the 
limited historical data available for EGFR TKIs in second line treatment of EGFR mutation 
positive patients (R11-1316, R08-5614).


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The side effects of afatinib are well documented (R13-4780) and are manageable with 
proactive intervention and dose reduction when indicated. The most common side effects are 
gastrointestinal disorders (including diarrhoea, and stomatitis), skin and subcutaneous tissue 
disorders (rash, dry skin, pruritus, acneiform rash, acne), nail effects (including paronychia), 
epistaxis, fatigue and decreased appetite. The standard guidance for management of these 
side effects is followed in this trial (section 4.1.4.1, section 4.2) and the drug is expected to be 
well tolerated. Interstitial lung disease (ILD) has been observed during treatment with 
afatinib but is uncommon (0.7% of treated patients, R13-4780). Careful assessment of all 
patients with an acute onset and/or unexplained worsening of pulmonary symptoms will be 
performed to exclude ILD (see section 4.2.1).
Regular and frequent assessment of clinical benefit throughout the trial will ensure that any 
patient not deriving clinical benefit will be withdrawn from the trial treatment.
Considering the expected efficacy of afatinib in this group of patients, and the expected side 
effects, it is anticipated that the benefits of second-line therapy with afatinib will outweigh 
the risks.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a single-arm open-label phase IV trial for patients with locally advanced or metastatic 
non-small cell lung cancer (NSCLC) harbouring a common EGFR mutation. 
The diagram below illustrates the trial design.
Figure 3.1.1 Trial design


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3.1.1
Administrative structure of the trial
The coordinating investigator has been designated by Boehringer Ingelheim and will sign the 
clinical trial report. There will be no steering committee or data monitoring committee for 
this trial. The trial will be performed by investigators experienced in the treatment of non-
small cell lung cancer (NSCLC).
On-site monitoring will be performed by BI or a Contract Research Organisation (CRO) 
appointed by BI.
Boehringer Ingelheim will appoint CROs for special services such as central laboratory 
analyses (testing for EGFR mutation), provision of Interactive Voice/Web Response System 
(IVRS/IWRS) and trial medication logistics.
All trial relevant documentation will be stored in the clinical trial master file (CTMF) at BI. 
In addition each site will have an Investigator Site File (ISF) containing all trial documents 
relevant for the site.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This is an exploratory study to assess the efficacy and safety of afatinib given as second-line 
treatment after chemotherapy and confirm previously reported results using a starting dose of 
40mg afatinib. All patients will receive the same treatment and therefore the trial is open-
label.
3.3
SELECTION OF TRIAL POPULATION
The trial will be conducted in multiple centres worldwide. A log of all patients included into 
the study (i.e. having given informed consent) will be maintained in the ISF at the 
investigational site irrespective of whether they have been treated with investigational drug or 
not.
The trial explores the use of afatinib as a second-line therapy after first-line chemotherapy 
and therefore the inclusion/exclusion criteria have been designed to ensure that the trial 
population reflects this, whilst also accounting for variations in first-line therapy.
Patients who do not have an EGFR test result available will be asked to sign consent to tissue 
analysis and a sample of their tumour will be sent for EGFR testing. There are no inclusion 
and exclusion criteria for tissue analysis except that the patient must have tissue available for 
analysis and must be expected, as far as is possible to determine, to meet all inclusion and 
exclusion criteria at some point in the future.
The study will include patients who have one (or both) of the most common EGFR 
mutations; L858R or Deletion 19, with no other documented mutations of EGFR. Patients 
with less common mutations are excluded because the group of patients with these mutations 
is expected to be too small for meaningful analysis.


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3.3.1
Main diagnosis for study entry
The study will recruit patients with locally advanced or metastatic non-small cell lung cancer 
(NSCLC) harbouring a common EGFR mutation. Patients must have experienced disease 
progression during or after completion of first-line platinum-based chemotherapy.
Patients who do not meet all of the inclusion criteria or who meet any of the exclusion criteria 
are not eligible for study participation and are not eligible to receive study drug.
3.3.2
Inclusion criteria
1. Pathologically confirmed diagnosis of Stage IIIB (with cytologically proven pleural 
effusion or pericardial effusion) or Stage IV adenocarcinoma of the lung. Patients with 
mixed histology are eligible if adenocarcinoma is the predominant histology.
2. Documented EGFR mutation (L858R and/or Deletion 19) with no other known EGFR 
mutation.
3. Measureable disease according to RECIST 1.1 (R09-0262).
4. Radiologically confirmed progression or recurrence of disease during or following first-
line therapy with a platinum-based chemotherapy regimen.*
5. Age >18 years.
6. Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1.
7. Adequate organ function, defined as all of the following:
-
Absolute neutrophil count (ANC) > 1500 / mm3.
-
Platelet count >75,000 / mm3.
-
Estimated creatinine clearance > 45ml / min. Refer to APPENDIX 10.1.
-
Total Bilirubin < 1.5 times upper limit of institution normal.
-
Aspartate amino transferase (AST) and alanine amino transferase (ALT) < 
three times the upper limit of institution normal (ULN) (if related to liver 
metastases < five times ULN).
8. Recovered from any previous therapy-related toxicity to ≤CTCAE Grade 1 at study entry 
(except for alopecia and stable sensory neuropathy which must be ≤CTCAE Grade 2). 
9.    Life expectancy of at least three months.
10.  Written informed consent that is consistent with ICH-GCP guidelines.
* Additional guidance on prior therapy;

Patients may have received maintenance chemotherapy (continuous or switch 
maintenance) following completion of 1st line platinum-based chemotherapy.


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
Patients who previously received platinum-based chemoradiotherapy and had a 
recurrence and evidence of stage IIIB-IV disease within 1 year of completing 
chemoradiotherapy will be eligible. Those patients who have received 2-3 cycles of 
further consolidation chemotherapy with the same or different agents will also be 
eligible if they progressed within 1 year of completion of consolidation treatment. 

Patients who received adjuvant/ neoadjuvant platinum-based chemotherapy and had a 
recurrence and evidence of stage IIIB-IV disease within 1 year of completing 
chemotherapy will be eligible.

Patients who progress more than 1 year after completing chemoradiotherapy, adjuvant 
or neoadjuvant treatment may be suitable for re-challenge with platinum-based 
therapy as a first-line treatment for advanced disease and thus are ineligible for this 
trial. However, if in the opinion of the investigator such patient is eligible to receive 
second-line treatment, their participation in the study can be discussed on a case-by-
case basis with the BI clinical monitor.
3.3.3
Exclusion criteria
1.
More than one line of prior therapy for disease. 
o
Radiotherapy alone is not counted as a line of therapy. 
o
Radiosensitisers and/or intrapleural administration of anti-cancer agents are 
not counted as a line of therapy.
2.
Previously received less than 3 cycles of platinum-based chemotherapy due to toxicity 
and/or intolerance of treatment.
3.
Previous treatment with any EGFR targeting TKI or antibody.
4.
Chemotherapy, biological therapy or investigational agents within three weeks prior 
to the start of study treatment.  
5.
Hormonal treatment within two weeks prior to start of study treatment. 
6.
Radiotherapy within 4 weeks prior to study treatment, except as follows:
i.) Palliative radiation to target organs other than chest is allowed up to 2 weeks prior 
to study treatment.
ii.) Single dose palliative treatment for symptomatic metastasis which is outside the 
above allowance may be allowed but must be discussed with sponsor prior to 
enrolling.
7.
Major surgery within 4 weeks before starting study treatment or surgery scheduled 
during the projected course of the study.
8.
Known hypersensitivity to afatinib or the excipients of afatinib.
9.
History or presence of clinically relevant cardiovascular abnormalities such as 
uncontrolled hypertension, congestive heart failure NYHA classification of 3, 


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unstable angina or poorly controlled arrhythmia as determined by the investigator. 
Myocardial infarction within 6 months prior to study treatment.
10.
Women of child-bearing potential (WOCBP) and men who are able to father a child, 
unwilling to be abstinent or use adequate contraception prior to study entry, for the 
duration of study participation and for at least 28 days after treatment has ended. 
Adequate methods of contraception and Women of Child-Bearing Potential are 
described in Section 4.2.2.3.
11.
Female patients of childbearing potential (see Section 4.2.2.3) who are nursing or 
pregnant or do not agree to submit to pregnancy testing required by this protocol.
12.
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.
13. 
Previous or concomitant malignancies at other sites, except;
a) effectively treated non-melanoma skin cancers
b) effectively treated carcinoma in situ of the cervix
c) effectively treated ductal carcinoma in situ
d) other effectively treated malignancy that has been in remission for more than 3 years 
and is considered to be cured.
14.
Requiring treatment with any of the prohibited concomitant medications listed in 
Section 4.2.2 that cannot be stopped for the duration of trial participation.
15.
Known pre-existing interstitial lung disease
16.
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 
diarrhea, malabsorption).
17.
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.
18.
Prior participation in an afatinib clinical study, even if not assigned to afatinib 
treatment.
19.
Meningeal carcinomatosis.
20.
Presence or history of brain or subdural metastases, unless patient has completed local 
therapy and has discontinued the use of corticosteroids or has been on stable dose of 
corticosteroids for at least 4 weeks before starting study treatment. Any symptoms 
attributed to brain metastases must be stable for at least 4 weeks before starting study 
treatment. 


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3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
The investigator or patient may stop study treatment at any time for safety or personal 
reasons.  
If a patient is entered in violation of inclusion/exclusion criteria, the sponsor, in discussion 
with the investigator, will determine the medical risk/benefit on a patient-by-patient basis and 
can require such a patient be discontinued from the study treatment.
A patient is to discontinue study medication if they:
1
Withdraw consent to further study treatment.
2
Have radiologic (or clinical) documentation of progressive disease (section 5.1.2) 
unless the investigator agrees with the sponsor that the patient may continue treatment 
beyond progression due to clinical benefit (section 6.1.1).
3
Become pregnant (section 4.2.2.3).
4
Are diagnosed with interstitial lung disease (ILD).
5
Are required to stop treatment due to adverse events as described in section 4.1.4.
6
Have a significant deviation from the protocol or eligibility criteria. The decision to 
continue or withdraw treatment will be made by the sponsor in agreement with the 
investigator.
The EOT visit should be performed 0-14 days after permanent discontinuation of treatment 
and wherever possible patients should be encouraged to return for a follow-up visit 28-35 
days after discontinuation of treatment. Patients who have not progressed prior to the follow-
up visit should be encouraged to return for regular follow-up assessments until progression or 
start of further treatment.
If a patient withdraws consent to any further trial procedures and follow-up activities, no 
additional study assessments will be completed.  This will be documented in the eCRF.
Patients who withdraw from the trial after commencing treatment will not be replaced.
After completion of the primary efficacy analysis, the sponsor may remove patients from the 
study treatment if the patient has access to afatinib through marketed product, an expanded-
access program, named patient use program, compassionate use protocol or other means 
based on local regulation. The cost of any ongoing supply of afatinib will be incurred by the 
sponsor. If a patient is removed from the study treatment, an end of treatment and follow-up 
visit will be performed to ensure all adverse events are followed up and patients with no 
documented progression will then enter the Follow-up PD phase. If the sponsor decides that 
sufficient PFS data has already been collected at the point of transfer, patients will have a 
follow-up visit but will not enter the Follow-up PD phase (see also 3.3.4.2 and 8.6).


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3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site,

Emergence of any efficacy/safety information that could significantly affect 
continuation of the trial.

Violation of GCP, the protocol, or the contract by a trial site or investigator, 
disturbing the appropriate conduct of the trial.

The primary efficacy 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.
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
4.1
TREATMENTS TO BE ADMINISTERED
Eligible patients will receive once daily treatment with afatinib until progression or until 
other criteria for stopping medication are met (see section 4.1.4).
4.1.1
Identity of BI investigational product and comparator product(s)
Substance (INN)
Afatinib 
Brand name:
Giotrif®/ GilotrifTM
Pharmaceutical form:
Film-coated tablet
Source:
Boehringer-Ingelheim Pharma GmbH & Co. KG
Unit strength:
20, 30 and 40mg film-coated tablets (the dose of afatinib in the 
film-coated tablets is related to the free base equivalent to 
afatinib)
Route of administration:
Oral
Posology
Once daily
4.1.2
Method of assigning patients to treatment groups
Patients who have given their written informed consent will be enrolled sequentially on a first 
come first enrolled basis and will be registered in IVRS/IWRS. Patients who meet all 
eligibility criteria will be entered into the study and the start of treatment will be registered in 
IVRS/IWRS. The trial will continue to enrol patients until the goal of approximately 60
entered into the study is reached. Following registration, patients should begin treatment 
within 2 days.
4.1.3
Selection of doses in the trial
The starting dose and the dose reduction schedule are based on the current summary of 
product characteristics (SPC) for afatinib (R13-4780). Dose escalation will not be allowed 
during this study.
4.1.4
Drug assignment and administration of doses for each patient
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 (unless treatment beyond 
progression has been agreed) or until other criteria for stopping medication are met. The dose 
of afatinib must be reduced if certain adverse events occur (see sections 4.1.4.1).
The medication should be taken at approximately the same time each day without food (at 
least one hour before a meal and at least three hours after a meal).  


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Missed doses of afatinib can be made up during the same day.  Otherwise, the dose must be 
skipped and patients should take the next scheduled dose at the usual time. 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 course. For administrative purposes, a treatment course is defined as 28 days.  
Treatment will start when the patient takes the first dose of medication and will stop when the 
patient is diagnosed with disease progression (unless treatment beyond progression has been 
agreed) or for any reason detailed in section 3.3.4.  Study drug will be prescribed by the 
investigator and may be dispensed either by the investigator, site staff or affiliated pharmacy.
A new bottle of medication will be dispensed on day 1 of each course, regardless of the 
number of tablets remaining in the bottle from the previous course. The patient will initially 
receive one bottle of 40mg tablets and in the event that dose reduction is necessary the patient 
will return to the clinic and new medication will be dispensed.
4.1.4.1 Dose reduction for afatinib
Treatment related toxicities will be managed by treatment interruptions and subsequent dose 
reductions of afatinib according to the schedule described in Table 4.1.4.1: 1 which is based 
on the SPC for afatinib (R13-4780). Should the guidance in the SPC change during the study, 
the latest SPC will take precedence. 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 proactively as described in Section 
4.2. 
Table 4.1.4.1: 1 Dose reduction scheme for afatinib
CTCAEa Adverse Events
related to afatinib
Action
Dose reduction scheme
Grade 1 or Grade 2
No interruptionb
No dose adjustment
Grade 2 (prolongedc or intolerable)
or
Grade ≥ 3
Interrupt until Grade 0/1b
Resume treatment with dose 
reduction by 10mg 
decrementsd
a NCI Common Terminology Criteria for Adverse Events v3.0 (R04-0474)


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b In case of diarrhoea, anti-diarrhoeal medicinal products (e.g. loperamide) should be taken 
immediately and continued for persistent diarrhoea until loose bowel movements ease.
c >48 hours of diarrhoea and/or >7 days of rash
d If patient cannot tolerate 20mg/ day, afatinib should be permanently discontinued
Interstitial Lung Disease (ILD) should be considered if a patient develops acute or worsening 
of respiratory symptoms in which case treatment should be interrupted pending evaluation. If 
ILD is diagnosed, afatinib should be discontinued and appropriate treatment initiated as 
necessary.
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 for any reason, the decision to continue 
with afatinib will be made by the BI clinical monitor in agreement with the investigator.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Not applicable
4.1.5.2
Procedures for emergency unblinding
Not applicable
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF.
Afatinib will be supplied as film-coated tablets. Available dosage strengths will be 20 mg, 30 
mg and 40 mg.
Trial drug bottles will have unique medication numbers which will be used for tracking 
purposes only. 
4.1.7
Storage conditions
Drug supplies, which will be provided by the sponsor and/or a CRO appointed by the 
sponsor, must be kept in a secure, limited access storage area under the storage conditions 
defined by the sponsor. Where necessary, temperature logs must be maintained to make 
certain that the drug supplies are stored at the correct temperature. If storage temperature is 
out of range at any time, this has to be reported in the ISF and the sponsor must be notified.
Afatinib must be stored in the original package in order to protect from light. Film-coated 
tablets are humidity-sensitive; therefore, bottles must be kept tightly closed to protect from 
moisture. 


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4.1.8
Drug accountability
The investigator or delegate (e.g. pharmacist or investigational drug storage manager) will 
receive the investigational drugs delivered by the sponsor when the following requirements 
are fulfilled:

approval of the study protocol by the institutional review board (IRB) / ethics 
committee,

availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre,

approval/notification of the regulatory authority, e.g. competent authority,

availability of the curriculum vitae of the principal investigator,

availability of a signed and dated clinical trial protocol or immediately imminent 
signing of the clinical trial protocol, 

availability of the proof of a medical licence for the principal investigator (if 
applicable).
The investigator or delegate must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or alternative 
disposition of unused product(s). 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) and trial patients. The 
investigator or delegate will maintain records that document adequately that the patients were 
provided the doses specified by the protocol and reconcile all investigational product(s) 
received from the sponsor. At the time of return to the sponsor and/or appointed CRO, the 
investigator or delegate must verify that all unused or partially used drug supplies have been 
returned by the clinical trial patient and that no remaining supplies are in the investigator’s 
possession.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Rescue medication
Rescue medications to reverse the actions of afatinib are not available. There is no specific 
antidote for overdosage with afatinib. Potential adverse events should be treated 
symptomatically. Common adverse events of treatment with afatinib with specified 
management recommendations and/or requirements include diarrhoea, 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.


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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.  Patients who are dose interrupted for 
>28 days due to palliative radiotherapy must be permanently discontinued from study 
medication.
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 to trial participation
(SV2), 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.
Emergency procedures
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude interstitial 
lung disease (ILD). Afatinib should be interrupted pending investigation of these symptoms. 
If interstitial lung disease is diagnosed, study drug must be permanently discontinued and 
appropriate treatment instituted as necessary. 
Patients who present with symptoms of keratitis, such as acute or worsening eye 
inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be 
referred promptly to an ophthalmic specialist. If a diagnosis of ulcerative keratitis is 
confirmed, treatment with afatinib should be interrupted or discontinued. If keratitis is 
diagnosed, the benefits and risks of continuing treatment with afatinib should be carefully 
considered. Afatinib should be used with caution in patients with a history of keratitis, 
ulcerative keratitis or severe dry eye. Contact lens use is a risk factor for keratitis and 
ulceration.
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.


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4.2.1.1 Management of diarrhoea and hydration status following treatment with afatinib
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 require
treatment modification or discontinuation, so early management is essential (Table 4.2.1.1: 
1). At the time of initiation of treatment with afatinib, patients should be given a supply of 
loperamide to keep with them at all times 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 fluid to make up for the fluid lost 
through diarrhoea. 
Table 4.2.1.1: 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 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.


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4.2.1.2 Management recommendations for dermatological AEs following treatment with 
afatinib
Dermatologic AEs of afatinib include rash, acne, dermatitis acneiform, and dry skin. General 
recommendations for prophylaxis are summarized in Table 4.2.1.2: 1 and grade-specific 
treatment recommendations are summarized in Table 4.2.1.2: 2. For dose adjustment of 
afatinib refer to Table 4.1.4.1:1.  
Specific interventions should be reassessed at least after 2 weeks or at any worsening of 
symptoms, in which case the specific intervention should be adjusted and, depending on own 
clinical experience, early involvement of a dermatologist should be considered (adapted from 
R11-0826).
Table 4.2.1.2: 1  General recommendations for prophylaxis while receiving afatinib
Personal hygiene
Use of gentle soaps and shampoos for the body, e.g. pH5 neutral bath and 
shower formulations and tepid water.
Use of very mild shampoos for hair wash.
Only clean and smooth towels are recommended because of potential risk of 
infection. The skin should be patted dry after a shower, whereas rubbing the skin 
dry should be avoided.
Fine cotton clothes should be worn instead of synthetic material.
Shaving has to be done very carefully.
Manicure, i.e. cutting of nails, should be done straight across until the nails no 
longer extend over the fingers or toes. Cuticles are not allowed to be trimmed 
because this procedure increases the risk of nail bed infections
Sun protection
Sunscreen should be applied daily to exposed skin areas regardless of season. 
Hypoallergenic sunscreen with a high SPF (at least SPF30, 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 4.2.1.2: 2 Grade specific treatment recommendations of skin reactions to afatinib
Severity 
(CTCAE Grading)
Description
Specific intervention
ACNEIFORM RASH
Mild (Grade 1)
Macular or papular eruptions or 
erythema without associated 
symptoms
Consider topical antibiotics, 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 
body surface area (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)
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


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Table 4.2.1.2: 2 Grade specific treatment recommendations of skin reactions to afatinib 
(continued)
4.2.1.3
Management of mucositis/stomatitis 
General and grade specific recommendations are described in Table 4.2.1.3:1. For dose 
adjustment refer to Section 4.1.4 and for restrictions on concomitant therapies refer to 
Sections 4.2.2 and 10.2.
Treatment is supportive and aimed at symptom control. These may include atraumatic 
cleansing and rinsing with non-alcoholic solutions such as normal saline, diluted salt and 
baking soda solution (e.g. one-half teaspoonful of salt and one teaspoon of baking soda in one 
quart of water every four hours); avoidance of agents containing iodine, thyme derivatives 
and prolonged use of hydrogen peroxide; dietary 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 4.2.1.3:1 include: topical analgesics –
viscous lidocaine 2%; mucosal coating agents - topical kaolin/pectin; oral antacids, 
maltodextrin, sucralfate; topical antifungals – nystatin suspension. (Adapted from P11-
09424)
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
Moderate (Grade 2)
Symptomatic, not interfering with 
ADL
See Grade 1. 
Consider oral antibiotics.
Severe (Grade 3)
Symptomatic,
Interfering with ADL
See Grade 2.
If Grade 2 rash persists for >7 days despite treatment and is poorly tolerated by the patient, the investigator 
may choose to pause treatment up to 14 days followed by a reduction in the dose of afatinib according to the 
dose reduction scheme in Table 4.1.4.1: 1


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Table 4.2.1.3: 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.
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
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
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 
afatinib. 
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 
10.2.
4.2.2.2
Restrictions on diet and life style
Patients should be advised to avoid any foods known to aggravate diarrhoea.


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To prevent skin related adverse events it is recommended to avoid intense irradiation with 
UV light and harsh detergents, see also Section 4.2.1.2.
4.2.2.3
Women of Child-Bearing Potential & Pregnancy Prevention
Patients who are not of childbearing potential due to being postmenopausal (1 year without 
menstruation and at least 2 years without menstruation following chemotherapy) (R11-1406) 
or surgical sterilisation (oophorectomy, hysterectomy and/or tubal ligation) do not need to 
use contraception to be eligible for the trial.
All other patients (male or female) are considered to have childbearing potential and must use 
adequate contraception throughout the trial (from screening until end of trial participation or 
28 days after last dose of trial medication, whichever is later).
Acceptable methods of contraception include surgical sterilisation and double barrier method, 
and must be in accordance with local regulations where applicable. Double barrier method of 
contraception is defined as two barrier methods used simultaneously each time the patient has 
intercourse. Accepted barrier methods include diaphragm, female condom, cervical cap, male 
condom and intrauterine device (IUD) (the diaphragm and cervical cap must be used in 
conjunction with spermicidal jelly/cream). Those using hormonal contraceptives, or with 
partners using hormonal contraceptives, must also be using an additional approved method of 
contraception (as described above).  Partner vasectomy, natural "rhythm" and spermicidal 
jelly/cream are not acceptable methods of contraception.
Women who become pregnant while participating in the study must discontinue study 
medication immediately.  The pregnancy must be reported following procedures detailed in 
section 5.2.2.2.
4.3
TREATMENT COMPLIANCE
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 28 days of treatment will be provided to 
patients to be self-administered at home.
Patients will be asked to bring the remaining trial medication at the end of each 28 day period 
to the investigator site for a compliance check. The remaining film-coated tablets will be 
counted by the investigator/site staff and recorded at the investigator site. Discrepancies 
between the number of tablets remaining and the calculated number of tablets the patients 
should have taken must be documented and explained. At the end of each 28 day period, any 
remaining medication will be collected. If the patient is eligible for further treatment, a new 
bottle of study medication must be dispensed. 
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. 


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Patients repeatedly missing scheduled on-treatment study visits, unless due to exceptional 
circumstances, should be discussed with the BI trial monitor and be evaluated for 
compliance. 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
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoint(s) of efficacy
The efficacy endpoints will be assessed at the time points specified in the flowchart. The time 
frame will last from start of treatment until the trial completion timepoint. 
The primary endpoint will be objective tumour response (Complete response (CR), Partial 
Response (PR)) according to RECIST 1.1 (R09-0262).
The secondary endpoints are;

Progression free survival (PFS) according to RECIST 1.1 (R09-0262).

Disease control (CR, PR, Stable Disease (SD)) according to RECIST 1.1 (R09-0262).
5.1.2
Assessment of efficacy
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 review.
See APPENDIX 10.3, RECIST 1.1 Criteria for details on lesion measurements and response 
assessment.
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 (CT scan or MRI). 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 every tumour assessment. 
Assessment will be performed every 8 weeks until week 56 and then every 12 weeks
calculated from start of treatment until documented progression. In the event of early 
discontinuation or an interruption/delay to treatment, the tumour assessment schedule should 
not be changed. If treatment continues after progression, tumour assessment should continue 
according to the schedule until the decision to stop treatment.
5.2
SAFETY
5.2.1
Endpoint(s) of safety
Safety of afatinib as indicated by intensity and incidence of adverse events, graded according 
to US National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events 
(CTCAE) Version 3.0 (R04-0474). Safety is an ‘other’ endpoint.


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5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions.
Intensity of adverse event
The intensity of adverse events should be classified according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 3.0 and recorded in the eCRF.
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms. 
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
Worsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the eCRF.
If progressive disease occurs and is associated with symptoms , the term “Progressive 
Disease” should not be reported as AE, however, signs and symptoms of progressive disease 
will be reported as an (S)AE (if applicable). Exception to this: Death due to progressive 
disease and where no signs or symptoms are available should be reported as “malignant 
neoplasm progression (grade 5, outcome fatal).”


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Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the (e)CRF, if they are judged clinically relevant by the investigator.
Protocol-specified adverse events of special interest (AESIs)
There are no Protocol-specified Adverse Events of Special Interest for this study.
Expected Adverse Events
For expected (listed) AEs of afatinib, see the current version of the IB (U03-3218). 
5.2.2.2
Adverse event and serious adverse event reporting
The Residual Effect Period (REP) for afatinib is 28 days. All adverse events, serious and non-
serious, occurring during the course of the clinical trial (i.e., from signing the informed 
consent to trial participation (SV2) onwards through the residual effect period (REP) (28 days 
after the last drug administration, Table 5.2.2.2:1)) will be collected, documented and 
reported to the sponsor by the investigator on the appropriate CRF(s) / eCRFs / SAE 
reporting forms. Reporting will be done according to the specific definitions and instructions 
detailed in the ‘Adverse Event Reporting’ section of the Investigator Site File. 
For each adverse event, the investigator will provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in 
Section 5.2.2.1. 
All events reported within 28 days after the last trial medication will be considered on drug. 
All adverse events will be reported up until 28 days after the last dose of trial medication. If a 
patient continues on the trial after this point (e.g. for follow-up PD) the investigator should 
report any SAEs/AEs which are considered related to trial treatment or design. The 
investigator does not need to actively monitor patients for adverse events once the clinical 
trial has ended. However, if the investigator becomes aware of an SAE that occurred after the 
patient has completed the clinical trial it should be reported by the investigator to the sponsor 
if considered relevant by the investigator.


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Table 5.2.2.2:1 AE/SAE reporting requirements
Time period
Reporting requirements
From signing of tissue analysis consent
(SV1) to signing of informed consent to trial 
participation (SV2)
Report only AEs and SAEs which are 
considered related to trial procedures.
For screen failures; From signing of informed 
consent to trial participation (SV2) to the 
timepoint where ineligibility is confirmed.
Report all AEs and SAEs. This includes all 
deaths.
For treated patients; From signing of 
informed consent to trial participation (SV2)
to the end of the REP (28 days after last trial 
drug administration).
Report all AEs and SAEs regardless of 
relatedness. This includes all deaths.
After the end of the REP (>28 days after last 
trial drug administration) until the patient 
completes the study.
Report only AEs and SAEs which are 
considered related to trial treatment or trial 
design.
Death should be reported as an SAE only 
when considered related to trial treatment or 
trial design.
After the patient has completed the study
Active monitoring for adverse events is not 
required. If the investigator becomes aware of 
an SAE that occurred after the patient has 
completed the clinical trial it should be 
reported to the sponsor if considered relevant 
by the investigator.
The investigator must report the following events immediately (within 24 hours) to the 
sponsor: SAEs and non-serious AEs relevant for the SAEs.
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non serious 
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the event.  If the event description is correct, the 
item “serious” needs to be ticked and an SAE has to be reported in expedited fashion 
following the same procedure as above.
The list of these adverse events can be found via the Remote Data Capture (RDC) system.
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the Investigator Site File) or by using the 


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electronic submission process. This immediate report is required irrespective of whether the 
investigational product has been administered or not and irrespective of causal relationship. It 
also applies if new information to existing SAEs becomes available. 
Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female patient has been 
enrolled into the clinical trial, after having taken study medication, the investigator must 
report immediately any drug exposure during pregnancy to the sponsor. Drug exposure 
during pregnancy has to be reported immediately (within 24 hours or next business day 
whichever is shorter) to the defined unique entry point for SAE forms of the respective BI 
OPU (country-specific contact details will be provided in the Investigator Site File). The 
outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical 
Trials and not the SAE form is to be completed. The ISF will contain the Pregnancy 
Monitoring Form for Clinical Trials (Part A and Part B).
5.2.3
Assessment of safety laboratory parameters
Safety laboratory samples will be analyzed at the investigator’s local laboratory. Safety 
laboratory examinations will include hematology and biochemistry examinations. Table 
5.2.3: 1 presents the laboratory tests to be performed.
Table 5.2.3:1
Clinical Laboratory Tests
Clinical Laboratory Tests
Category
Parameters
Hematology
Haemoglobin, haematocrit, platelet count, white 
blood cell count (WBC), neutrophils, bands
Coagulation
International Normalized Ratio (INR), activated 
Partial Thromboplastin Time (aPTT)
Chemistry
Electrolytes
Sodium, potassium, calcium, magnesium
Liver function tests
Alkaline phosphatase, aspartate aminotransferase 
(AST), alanine aminotransferase (ALT), γ-
glutamyltransferase (GGT), total bilirubin
Renal function parameters
Blood urea (preferred) or blood urea nitrogen 
(BUN), creatinine; Creatinine clearance (see 
Appendix 10.1).
Other
Glucose, albumin
Pregnancy test
β-HCG testing in urine or serum in women of 
childbearing potential (WOCBP)


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The investigator should complete additional evaluations of laboratory tests as clinically 
indicated.  Any abnormal and clinically relevant findings from these investigations need to be 
reported as an Adverse Event.
5.2.4
Electrocardiogram
Electrocardiogram (ECG) is not required for the purposes of the trial. If an ECG is performed 
as part of routine clinical care and clinically significant results are found, this will be 
documented in accordance with the adverse event process. 
5.2.5
Assessment of other safety parameters
5.2.5.1 Physical examination, vital signs, height and weight
A full physical exam must include cardiopulmonary examination, examination of the regional 
lymph nodes, and examination of the abdomen and an assessment of the mental and 
neurological status. Additional symptoms which have not been reported during a previous 
examination must be clarified. Wherever possible the same investigator should perform this 
examination.
A complete physical examination will be done at Screening visit 2, on Day 1 of each 
treatment course and at the End of Treatment visit. A symptom-directed examination is to be 
performed at all other visits. 
5.2.5.2 Vital Signs
Vital sign measurements should include blood pressure [systolic blood pressure, diastolic 
blood pressure], pulse rate, temperature and measurement of height (in cm, at screening) and 
body weight (in kg). Evaluation of the ECOG performance status (see appendix 4) will be 
performed at the times specified in the flowchart.  
5.3
OTHER
5.3.1
EGFR mutation analysis
The presence of a common EGFR mutation (Deletion 19 and/or L858R) is mandatory for 
study enrolment. 
The results of prior local analysis of EGFR mutation status using the institution’s local testing 
methodology will be accepted for study enrolment as long as documentation of the result is 
available. In this case, patients will not have a Screening Visit 1 (SV1) and will proceed 
directly to Screening Visit 2 (SV2).


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If prior analysis of EGFR mutation status has not been performed, patients will sign informed 
consent to tissue analysis and EGFR mutation analysis will be performed on tumour biopsy 
material. The expectation is that this test will use existing material and that a new biopsy will 
not be required. The EGFR mutation analysis may be performed locally using a validated 
technique or, if local analysis of EGFR mutation status is not possible, tumour sample may be 
sent to the central laboratory for analysis as described in the Laboratory Manual and in the 
Investigator Site File (ISF).
EGFR mutation analysis may be performed at any time prior to Screening Visit 2 as long as 
the patient is expected to meet the inclusion/exclusion criteria at some point in the future. 
This allows testing to take place at diagnosis or during first line therapy so that a result is 
available at the appropriate time. Patients must not proceed to Screening Visit 2 until a 
positive test result (Deletion 19 and/or L858R) has been documented.
5.4
APPROPRIATENESS OF MEASUREMENTS
All methods used are standard.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Not applicable.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Please refer to the flowchart and figure 3.1.1 for the visit schedule. A description of the 
patient’s progress through the trial is given below.
Patients who do not have an EGFR mutation test result available will be asked to sign 
informed consent to tissue analysis (tissue analysis consent), and analysis of their EGFR 
mutation status will be performed prior to any further assessments. During this period, 
adverse events will only be reported if related to trial procedures.
Patients with a documented common EGFR mutation will be asked to sign informed consent 
to trial participation and will undergo screening. Eligible patients will be administered 
afatinib once daily until criteria for treatment discontinuation are met (see section 3.3.4). At 
the time of discontinuing afatinib treatment the End of Treatment visit will be performed. 
From the signature of the informed consent to trial participation, during the treatment period, 
and for 28 days after the last dose of afatinib, all adverse events will be documented. The 
follow-up visit is performed 28-35 days after the last dose of afatinib and is primarily to 
collect follow-up safety information. For the majority of patients, progression will already be 
documented at this point, and this will also be the trial completion timepoint for such 
patients. 
If a patient does not have documented progression prior to the follow-up visit he/she will 
continue to have regular tumour assessments in accordance with the trial schedule (every 8 
weeks until week 56 and every 12 weeks thereafter). Clinical assessments will be performed 
in accordance with local institution practice, and patient status will be collected every 60 
days. Trial completion will occur at the timepoint of disease progression or start of further 
anti-cancer treatment, whichever occurs first. During this phase, new adverse events will only 
be documented if they are considered to be related to afatinib or the trial design.
6.1.1 Treatment beyond progression
Patients may continue trial treatment until disease progression as confirmed by imaging or 
clinical assessment if imaging could not be performed. However, in case of clinical benefit as 
judged by the investigator and based on careful clinical assessment, patients may be allowed 
to continue afatinib beyond disease progression as defined by RECIST 1.1 criteria after 
discussion with the BI clinical monitor. Clinical benefit can include, but will not be restricted 
to, significant symptom control of originally symptomatic tumours. Patients who continue as 
described will continue to follow the trial schedule for treatment visits (see flowchart) 
including the imaging and clinical tumour evaluations. Trial treatment may be continued as 
long as judged beneficial by the investigator. The date of documented progression will not 
change if the decision is taken to continue the treatment.


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Please refer to the flowchart and section 5 for details of the procedures performed at each 
visit.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
This trial follows a single-arm, open-label design. The aim is to provide more data on 
efficacy and safety in the second-line (chemotherapy pre-treated) patients with EGFR 
mutation positive NSCLC. Efficacy and safety will be evaluated in a descriptive manner.
7.2
NULL AND ALTERNATIVE HYPOTHESES
No formal statistical hypotheses.
7.3
PLANNED ANALYSES
All treated patients will be included in the analysis of efficacy and safety.
The primary analysis of response data will occur when all treated patients are evaluable for 
response, which is expected to be approximately 16 weeks (the second tumour imaging 
assessment per flowchart) after the last patient starts treatment. 
After all patients reach the point of ‘trial completion’, the final trial database lock will occur 
and all endpoints will be analysed based on this final lock.
7.3.1
Primary analyses
The primary analysis will estimate the proportion of patients who achieve confirmed 
objective response (CR or PR) according to RECIST 1.1. An exact 95% confidence interval 
will be calculated based on the Clopper-Pearson formula (R06-1080). 
7.3.2
Secondary analyses
Similar to the response rate, proportion and 95% confidence interval will be calculated for 
patients who achieve disease control (i.e. best overall response is CR, PR or SD). 
PFS is defined as the time from start of treatment to the earlier date of disease progression or 
death of any cause. Kaplan-Meier curve will be calculated, from which the median PFS and 
the PFS probability at specified timepoints will be derived. 
7.3.3
Safety analyses
All patients who received at least one dose of afatinib will be included in the analysis of 
safety. Adverse events within an onset date within the time period from the date first dose of 
afatinib until 28 days after the last dose of afatinib will be analysed as ‘on-treatment’ AE. 
Adverse events are graded according to CTCAE, v3.0 (R04-0474). Safety analysis will be 
descriptive, in most cases, in the form of frequency tables. 


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Key safety measures will include: The overall incidence and intensity (CTCAE grade) of 
AEs, as well as relatedness of AEs to treatment and seriousness

AEs leading to dose reduction or treatment discontinuation

Gastrointestinal events (vomiting, nausea, diarrhoea)

Skin reaction (rash, acne)

Other serious or significant AEs according to ICH E3

Potential clinical significance in selected laboratory tests (CTCAE grade >=2 with 
increase by at least one grade from baseline)

(low values) haemoglobin, leukocytes (total WBC), neutrophils, lymphocytes, 
platelets, potassium

(high values) PTT, creatinine, AST, ALT, bilirubin, alkaline phosphatase, proteinuria

Descriptive statistics for change from baseline for all laboratory tests
7.3.4
Interim analyses
In the event that primary analysis of response cannot occur in Q2 2016, a preliminary 
analysis of response and safety data will be provided to EMA in Q2 2016 as agreed. 
7.3.5
Pharmacokinetic analyses
Not applicable.
7.3.6
Pharmacodynamic analyses
Not applicable.
7.3.7
Pharmacogenomic analyses
Not applicable.
7.4
HANDLING OF MISSING DATA
In general, missing values will not be imputed. For efficacy data, every reasonable effort will 
be undertaken to determine patients’ best overall response status and disease progression. 
Missing baseline laboratory values (on the date of first dose) will be imputed by the value 
from the screening visit. For adverse events, every effort will be made to obtain complete 
information. 


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7.5
RANDOMISATION
Not applicable.
7.6
DETERMINATION OF SAMPLE SIZE
As explained in previous sections of this protocol, the phase II trial (P12-03681) had total 68 
patients treated with afatinib as second-line treatment (7 on 40mg starting dose and 61 on 
50mg). The agreement with EMA as post-marketing commitment was to provide more 
efficacy and safety data on afatinib as second-line treatment with 40mg starting dose. The 
sample size of 60 is based on how many patients can be recruited within a reasonable time
frame, rather than on statistical considerations. 
In the phase II trial, the overall confirmed response rate was reported as 60% based on 
investigator assessment in the total 68 second-line patients (P12-03681).
Given the observed response rate of 60%, with 60 patients, the 95% confidence interval of 
the response rate would be (46.5%, 72.4%) based on the Clopper-Pearson exact method. In 
other words, this sample size will provide reasonable precision to the estimation of response 
rate. 


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study patients against any immediate hazard, and also of any serious breaches 
of the protocol/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 general rule, no trial results should be 
published prior to finalisation of the Clinical Trial Report.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File).
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 


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auditor will have access to all medical records, the investigator’s trial-related files and
correspondence, and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, either on 
paper or via remote data capture. 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 entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current
medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents 
described in Section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To 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 (U03-3218) The current 
version of this reference document is to be provided in the ISF. No AEs are classified as 
listed for study design or invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.


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8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
8.6
COMPLETION OF TRIAL
The trial will be completed when all patients have either completed the study (Figure 3.1.1) 
or withdrawn from the study prior to documented progression (see section 3.3.4.1). The 
sponsor may decide to complete the trial earlier than this if the primary efficacy 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.
The IEC/competent authority in each participating EU member state needs to be notified
about the end of the trial (last patient/patient out) or early termination of the trial. 


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P07-11507
Moy B, Goss PE. Lapatinib-associated toxicity and practical management 
recommendations.  Oncologist 2007;12(7):756-765.
P11-09424
Porta C, Osanto S, Ravaud A, Climen MA, Vaishampayan U, White DA et al.  
Management of adverse events associated with use of everolimus in patients 
with advance renal cell carcinoma.  Eur J Cancer 2011:  47:  1287-1298.
P12-03681
Yang JCH, Shih JY, Su WC, Hsia TC, Tsai CM, Ou SHI, Yu CJ, Chang GC, 
Ho CL, Sequist LV, Dudek AZ, Shahidi M, Cong XJ, Lorence RM, Yang PC, 
Miller VA. Afatinib for patients with lung adenocarcinoma and epidermal 
growth factor receptor mutations (LUX-Lung 2): a phase 2 trial. Lancet 
Oncology, Published Online March 26, 2012, doi:10.1016/S1470-
2045(12)70086-4 Lancet Oncol 2012. 13(5):539-548.
P13-03658
Lacouture M, Schadendorf D, Chu CY, et al. Dermatologic adverse 
eventsassociated with afatinib: an oral ErbB family blocker. Expert Rev 
Anticancer Ther 2013; 6: 721-728.
P13-03659
Yang JCH, Reguart N, Barinoff J, et al. Diarrhea associated with afatinib: an 
oral ErbB family blocker. Expert Rev Anticancer Ther 2013; 6: 729-736.
P13-07382
Sequist LV, Yang JCH, Yamamoto N, O'Byrne K, Hirsh V, Mok T, Geater 
SL, Orlov S, Tsai CM, Boyer M, Su WC, Bennouna J, Kato T, Gorbunova V, 
Lee KH, Shah R, Massey D, Zazulina V, Shahidi M, Schuler M. Phase III 
study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung 
adenocarcinoma with EGFR mutations. J Clin Oncol 2013. 31(27):3327-3334.
R01-0787
Oken, M.M., Creech, R.H., Tormey, D.C., Horton, J., Davis, T.E., McFadden, 
E.T., Carbone, P.P.: Toxicity And Response Criteria Of The Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655.
R04-0474
Common terminology criteria for adverse events Version 3.0 (CTCAE) 
(Publish Date: 12 December 2003). 
Website: ctep.cancer.gov/forms/CTCAEv3.pdf; Cancer therapy evaluation 
program, common terminology criteria for adverse events, Version 3.0, 
DCTD, NCI, NIH, DHHS, 31 March 2003, Publish Date:12 December 2003.
R05-1054
Hanna N, Shepherd FA, Fossella FV, Pereira JR, Marinis P de, Pawel J von, 
Gatzemeier U, Tsao TCY, Pless M, Muller T, Lim HL, Desch C, Szondy K, 
Gervais R, Shaharyar, Manegold C, Paul S, Paoletti P, Einhorn L, Bunn PA. 
Randomized phase III trial of pemetrexed versus docetaxel in patients with 
non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 
2004. 22(9):1589-1597.


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R06-1080
Clopper CJ, Pearson ES.  The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrika 1934;26: 404-413
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, Lacoutoure ME.  Epidermal 
growth factor inhibitor-associated toxicities:  an evolving paradigm in clinical 
management.  Oncologist 2007; 12(5): 610-621.
R08-5614
Kim ES, Hirsh V, Mok T, Socinski MA, Gervais R, Wu YL, Li LY, Watkins 
CL, Sellers MV, Lowe ES, Sun Y, Liao ML, Osterlind K, Reck M, Armour 
AA, Shepherd FA, Lippman SM, Douillard JY. Gefitinib versus docetaxel in 
previously treated non-small-cell lung cancer (INTEREST): a randomised 
phase III trial. Lancet 2008. 372(22):1809-1818.
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D et al., New 
response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer 2009;45:228-247.
R11-0826
Potthoff K, Hoffheinz R, Hassel JC, Volkenandt M, Lordick F, Hartman JT, et 
al.  Interdisciplinary management of EGFR-inhibitor-induced skin reactions:  a 
German expert opinion.  Ann Oncol 2011;22(3):524-535.
R11-1316
Addison CL, Ding K, Zhao H, Maitre A le, Goss GD, Seymour L, Tsao MS, 
Shepherd FA, Bradbury PA. Plasma transforming growth factor alpha and 
amphiregulin protein levels in NCIC Clinical Trials Group BR.21. J Clin 
Oncol 2010. 28(36):5247-5256.
R11-1406
NCCN Clinical Practice Guidelines in Oncology:  breast cancer, v2.2011.  
website: nccn.org: National Comprehensive Cancer Network; 2011.
R13-4780
Giotrif 20 mg, 30 mg, 40 mg, 50 mg film-coated tablets (Boehringer Ingelheim 
International) (summary of product characteristics, manufacturer(s) 
responsible for batch release, conditions or restrictions regarding supply and 
use, other conditions and requirements of the marketing authorisation, 
conditions or restrictions with regard to the safe and effective use of the 
medicinal product, labelling and package leaflet, first published: 16/10/2013). 
2013


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9.2
UNPUBLISHED REFERENCES
U03-3218
Afatinib (BIBW2992) Investigator's Brochure
U07-3128-02
  A Phase I open-label dose escalation study of 
continuous once-daily oral treatment with BIBW 2992 in patients with 
advanced solid tumours.  Trial 1200.4.  30March 2007.  Revised 23 April 
2010.
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.


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10.
APPENDICES
10.1
APPENDIX 1 COCKCROFT-GAULT FORMULA
The following formula may be used for estimated creatinine clearance rate (eCCR) using 
Cockcroft-Gault formula.  The use of on-line calculators or formulas which are institution 
standards for eCCR and differ slightly may also be used.  The calculations and results must be 
filed in the patient’s chart.
When serum creatinine is measured in mg/dL;







mg/dL
in 
Creatinine
Serum
72
85
.0
kilograms
in 
Mass
Age
140
eCCR





Female
if
When serum creatinine is measured in µmol/L;






µmol/L
in 
Creatinine
Serum
Constant
kilograms
in 
Mass
Age
140
eCCR




Where Constant is 1.23 for men and 1.04 for women.


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10.2
APPENDIX 2 PGP INHIBITORS AND INDUCERS
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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10.3
APPENDIX 3
RECIST 1.1
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 flowchart. During the study bone scans should be performed as clinically indicated in 
patients without bone metastasis at baseline. 
For the purposes of this study, patients should be evaluated for response at week 8 and then 
every 8 weeks until week 56. After week 56, response should be evaluated every 12 weeks. 
In the event of a treatment delay, interruption or discontinuation of treatment, tumour 
assessment should continue to follow the original schedule. 
Follow-up tumour assessments must utilise 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.   
Paitents will have their response classified according to the definitions stated below.  
Measurability of tumour at baseline
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 
metastasis should be evaluated for additional evidence of malignant nature and discussed 
with BI trial clinical monitor before enrolling.


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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.
Lesions in irradiated fields
At baseline, previously irradiated lesions should not be used as indicator lesions unless they 
have progressed since irradiation. New lesions occurring in previously irradiated fields can be 
used as indicator lesions
Methods of measurement
All measurements must be recorded in metric notation, using a ruler or callipers. 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.
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).


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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) for all lesions except lymph nodes, where shortest 
diameter (ShD) is used) 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 measured in the short axis in order to be considered as target lesions. 
A sum of diameters (SoD) for all target lesions will be calculated (using ShD for lymph 
nodes and LD for all other lesions) and reported as the baseline SoD. The baseline SoD will 
be used as reference to further characterise the objective tumour response of the measurable 
dimension of the disease (see Table 10.3:1).
Table 10.3: 1
Evaluation of target lesions
Complete Response 
(CR)
Disappearance of all target lesions.
Partial Response 
(PR)
At least a 30% decrease in the SoD of target lesions taking as 
reference the baseline SoD.
Progression (PD)
At least a 20% increase in the SoD of target lesions taking as 
reference the smallest SoD recorded since the treatment started, 
together with an absolute increase in the SoD 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 SoD, nor sufficient increase to qualify for PD taking as 
reference the smallest SoD 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 10.3:2).


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Table 10.3: 2
Evaluations of non-target lesions and new lesions
Complete Response 
(CR)
Disappearance of all non-target lesions and normalisation of tumour 
marker level.
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 the case of SD, follow-up measurements must have met SD criteria at least once after
study entry at a minimum interval of six weeks.
Evaluation of best response to study treatment
The best response to study treatment (Table 10.3: 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 10.3: 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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Table 10.3: 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
* In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a minimum
interval of six (6) weeks.


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10.4
APPENDIX 4
ECOG PERFORMANCE STATUS
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
R01-0787


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
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
Description of change
Rationale for change


 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Version Number:
Document Name: 
 
 
 
                                                                                                                      
 
Title: 
 
 
 
 
                                                                                                                     
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02156918
2.0
clinical-trial-protocol
An open label, single-arm phase IV study to assess the efficacy and safety of afatinib
as second-line therapy for patients with locally advanced or metastatic non-small cell
lung cancer (NSCLC) harbouring an EGFR mutation (Del19 or L858R) who have
failed first-line treatment with platinum-based chemotherapy
Author-Trial Statistician
11 Apr 2014 15:27 CEST
Approval-Clinical 
11 Apr 2014 17:03 CEST
Approval-Therapeutic Area 
14 Apr 2014 13:29 CEST
Author-Trial Clinical Monitor
22 Apr 2014 22:40 CEST


Boehringer Ingelheim 
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Document Number: 
 
Version Number:
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02156918
2.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c04649761-01
BI Trial No.:
1200.217
Title:
An open label, single-arm phase IV study to assess the efficacy and 
safety of afatinib as second-line therapy for patients with locally 
advanced or metastatic non-small cell lung cancer (NSCLC) 
harbouring an EGFR mutation (Del19 or L858R) who have failed 
first-line treatment with platinum-based chemotherapy
Investigational
Product:
Afatinib
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
22 September 2015 SIGNED
Version:
Final
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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.
ENDPOINTS ..........................................................................................8
5.1
PRIMARY ENDPOINT ......................................................................................8
5.2
SECONDARY ENDPOINTS..............................................................................8
5.2.1
Key secondary endpoint..................................................................................8
5.2.2
Other secondary endpoints.............................................................................8
5.3
FURTHER ENDPOINTS....................................................................................8
5.4
OTHER VARIABLES.........................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS.............................................9
6.1
TREATMENT......................................................................................................9
6.2
IMPORTANT PROTOCOL VIOLATIONS ....................................................9
6.3
PATIENT SETS ANALYSED..........................................................................11
6.4
SUBGROUPS .....................................................................................................11
6.5
POOLING OF CENTRES ................................................................................11
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................12
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................12
7.
PLANNED ANALYSIS.......................................................................13
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........13
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................14
7.3
TREATMENT COMPLIANCE .......................................................................14
7.4
PRIMARY ENDPOINT ....................................................................................14
7.5
SECONDARY ENDPOINTS............................................................................15
7.5.1
Key secondary endpoint................................................................................15
7.5.2
Other secondary endpoints...........................................................................15
7.6
FURTHER ENDPOINTS..................................................................................16
7.7
EXTENT OF EXPOSURE................................................................................16
7.8
SAFETY ANALYSIS.........................................................................................16
7.8.1
Adverse events ...............................................................................................16
7.8.2
Laboratory data.............................................................................................17
7.8.3
Vital signs.......................................................................................................18
7.8.4
ECG ................................................................................................................18
7.8.5
Others .............................................................................................................18
8.
REFERENCES.....................................................................................19
9.
ADDITIONAL SECTIONS ................................................................20
10.
HISTORY TABLE...............................................................................21


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LIST OF TABLES
Table 6.2: 1
Important protocol violations..........................................................................10
Table 10: 1
History table ....................................................................................................21


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2.
LIST OF ABBREVIATIONS
Include a list of all abbreviations used in the TSAP
Term
Definition / description
AE
Adverse event
BRPM
Blinded report planning meeting
CR
Complete response
CTC
Common Terminology Criteria  
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
ES
Enrolled set
ICH
International Conference on Harmonisation
Max
Maximum
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligram
Min
Minimum
N
Denotes number of patients
NSCLC
Non-small cell lung cancer
IPV
Important protocol violation
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
PT
Preferred term
REP
Residual effect period
SAE
Serious adverse event
SD
Stable disease
SOC
System organ class


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Term
Definition / description
TS
Treated set
TSAP
Trial statistical analysis plan


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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 Trial Statistical Analysis Plan (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 or a newer version will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY

Confirmation requirement of PR and CR has been specified in Section 7.4 as per 
RECIST 1.1 (1).

Time to objective response, duration of objective response, best overall response has 
been defined with analyses specified in Section 7.4.

Duration of disease control has been defined with analysis specified in Section 7.5.2.

Proteinuria which is mentioned in Section 7.3.3 of CTP, is not included in Section 
7.8.2 of TSAP because it is not collected in the study.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT

Objective response (CR, PR) assessed by investigator review according to RECIST 
1.1.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint 
There are no key secondary endpoints.
5.2.2
Other secondary endpoints

Progression free survival (PFS) assessed by investigator review according to RECIST 
1.1.

Disease control (CR, PR, SD) assessed by investigator review according to RECIST 
1.1.
5.3
FURTHER ENDPOINTS
There are no further endpoints. 
5.4
OTHER VARIABLES

 

Safety endpoints as specified in CTP Section 5.2.1.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENT
Eligible patients will receive afatinib once daily treatment until progression or until other 
criteria for stopping medication are met. The following study periods based on actual start 
and stop dates of study treatment administration are defined:
The following study periods based on key visit dates and actual start and stop dates of study 
treatment administration are defined:

Screening: day of informed consent to day prior to starting study treatment. The day 
of informed consent is defined as the day of consent to tissue analysis if such analysis 
is required, or the day of consent to study participation otherwise. 

On-treatment: From day of first administration of study treatment to the day of last 
administration of study treatment.

Residual effect period: From day after last administration of study treatment to the 
28th day after last administration of study treatment.

Post-study: From 29th day after last administration of study treatment onwards.
For safety summaries data recorded up to 28 days after last administration of study treatment 
will be considered as on-treatment (i.e. the actual on-treatment and residual effect period
periods defined above will be combined into one ‘on-treatment’ analysis period).
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
Requirements
A
Entrance Criteria Not Met
A1
Diagnosis of NSCLC questionable (or 
incorrect disease stage/no measureable 
disease).
Refers to IN 1, 3 and 4, also 
check oncological history 
and baseline tumour 
measurement details from 
investigator
A2
Prior treatment for NSCLC does not meet 
entrance criteria
Refers to EX 1, 2, 3, 4, 5, 6, 
and 7 also check previous 
therapy details.
A3
Genotypic tumour characteristics do not meet 
entrance criteria
Refer to IN 2 also check 
tumour biopsy details.
A4
Laboratory values do not meet entrance 
criteria
Refers to IN 7, also check 
against screening laboratory 
values.
A5
Chronic diarrhoea or other pre-existing event 
that might exacerbate expected Afatinib 
events
Refers to EX 8 and 16 also 
check baseline conditions.
A6
Other deviation from entrance criteria
Refers to IN 5, 6, 8 and 9 
and EX 9, 10, 11, 12, 13, 
14, 15, 17, 18, 19, and 20. 
Also check baseline 
demographics, oncological 
history, pregnancy test, 
ECOG score and baseline 
conditions.
B
Informed Consent
B1
Patient’s written informed consent not 
available
Refers to IN10.  Date of 
written informed consent  
must be available. The day 
of informed consent is 
defined as the day of 
consent to tissue analysis if 
such analysis is required, or 
the day of consent to study 
participation otherwise.
B2
Patient’s written informed consent too late
Date of written informed 
consent to tissue analysis
must be on or before 
Screening Visit 1.  Date of 
written informed consent to 
study participation must be
on or before Screening Visit 
2.


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Table 6.2: 1
Important protocol violations (cont.)
C
Trial medication and randomisation
C1
Incorrect trial medication taken
Incorrect starting dose or 
incorrect route of 
administration; Dose 
reduction not performed 
when indicated by the 
protocol (note that if dose 
reduction if performed 
when not indicated, this is 
not considered an IPV as it 
does not affect patient 
safety).
C2
Non-compliance
Check medication 
compliance details for 
extreme non-compliance 
only.
D
Concomitant medication
D1
Prohibited medication use
Review concomitant 
medications for prohibited 
medication use, refer to 
Section 4.2.2 of the CTP.
E
Trial specific
E1
Procedure not performed according to 
protocol
Procedure performed prior 
to written informed consent
and not part of routine 
clinical assessments
Note: Missing visits, evaluations, and tests will be considered missing data, not protocol deviations.
6.3
PATIENT SETS ANALYSED
Enrolled set (ES)
The enrolled set consists of all patients who signed informed consent at screening Visit 2.
Treated set (TS)
All planned analyses will be based on the Treated set (TS) which includes all patients who 
were dispensed trial medication and are documented to have taken at least one dose of 
investigational treatment (afatinib).
6.4
SUBGROUPS
There are no subgroup analyses planned for this study.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.


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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”).(2)
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 is not attainable, but the date of 
visit with the disease progression recorded as the physician’s assessment, then the 
date of the visit will be used as the progression date. If the assessment is recorded as 
disease progression, but both progression and the visit (when the assessment was 
made) dates are missing, the last date when the patient was assessed will be used as 
progression (even if the assessment was not a disease progression at that time). If the 
assessment is recorded as disease progression, both progression and visit dates are 
missing and a patient has no previous visit dates recorded, then the date of first 
administration of study medication will be used as the date of disease progression
In addition, time since diagnosis of NSCLC will be calculated from the date of diagnosis and 
the date of the start of the study.  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 and 
combine with date of Screen Visit 2 to calculate time since diagnosis

If only year is present, set to January 1st and combine with date of Screen Visit 2 to 
calculate time since diagnosis
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Where a baseline value is required, this will be the Screening Visit 2 value.  
Nominal visit numbers as recorded in the eCRF will be used where required and there will be 
no windowing. Study day will be calculated relative to the date of the first administration of 
study drug.  The day prior to first administration of study drug will be ‘Day -1’ and the day of 
first administration of study drug will be ‘Day 1’; therefore ‘Day 0’ will not exist.
For presentation of tumour response data which will follow a calculated visit approach based 
on the protocol specified tumour assessment schedule at Week 8, 16, 24, 32, 40, 48, 56, and 
in 12-weekly intervals thereafter; images will be assigned to corresponding visits (i.e., Week 
8, 16, 24, 32, 40, 48, 56, …, etc.) based on their study day and using a ±4 or ±6 week window 
as appropriate (images taken within the first 4 weeks from treatment start will be assigned to 
Week 8). In case two or more images for a patient are assigned to one interval then the last 
assessment will be used to ensure progressive disease is not missed.


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7.
PLANNED ANALYSIS
Unless otherwise stated, for EoT tables, the set of summary statistics is: N / Mean / SD / Min 
/ Median / Max.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group, unless otherwise stated. Percentages will be rounded to one 
decimal place. The category missing will be displayed only if there are actually missing 
values. 
Subject Data Listings will be presented for the Treated Set except for

Disposition (based on Enrolled Set)
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report. Demographic data 
collected and to be presented include:

Age [years]

Age class  (<65, ≥65 years)

Gender  (Male, Female)

Race (as defined in the eCRF)

Ethnicity (as defined in the eCRF)

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)

Baseline ECOG score (0, 1)

Common EGFR mutation type (Yes, No)

Oncology history

Previous therapies:
o
Systemic chemotherapies
o
Other anti-cancer therapies
o
Radiotherapies

Previous surgeries for trial disease


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7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. This will include
concomitant therapies for rash and diarrhoea only.
7.3
TREATMENT COMPLIANCE
There is no analysis planned for treatment compliance.
7.4
PRIMARY ENDPOINT
Objective response according to RECIST 1.1
Each patient will be assigned to one of the following categories of the Tumour response:
1. Complete response (CR)
2. Partial response (PR)
3. Stable disease (SD)
4. Progressive disease (PD)
5. Not evaluable for response, reasons to be specified (e.g. early death, tumour assessments 
incomplete, etc.)
Objective Response is defined as having a complete or partial response according to RECIST 
1.1.
The proportion of patients in each response category will be tabulated by each week (with 
confirmation of response required). The total number of patients assessed at the week will be 
used as denominator.
For patients with objective response, time to objective response is defined as the time from 
the start of treatment to the date of the first objective response. Cumulative frequencies will 
be calculated for time to objective response by 8-week periods.
Duration of objective response is measured from the time of first objective response to the 
time of progression or death (or date of censoring for PFS, i.e., patients will be censored as 
for the PFS analysis). Kaplan-Meier estimates and 95% confidence intervals for the 25 th, 
median, and 75th percentiles of the survival distribution will be calculated for duration of 
objective response. Kaplan-Meier curves will be produced without confidence intervals.
Best overall response is defined as the best individual response including: CR, PR, SD, PD, 
Not evaluable from the date of the first administration until the earliest recording of PD, 
death or end of treatment (as long as no other anti-cancer therapy has been given). Two-sided 
95% Clopper-Pearson confidence intervals will be given for the calculated best response rate.
As per RECIST 1.1 guideline, confirmation of CR and PR is required to ensure responses 
identified are not result of measurement error in non-randomised trials where response is the 


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primary endpoint, that is, CR or PR may be claimed only if the criteria for each are met at a 
subsequent time point as specified in the protocol. In case of SD, measurements must have 
met SD criteria at least once after study entry at a minimum interval of 6 weeks.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoints have been specified in the 
protocol.
7.5.2
Other secondary endpoints
The secondary endpoint will be analysed as described below:
Progression-free survival (PFS) according to RECIST 1.1
Progression-free survival is the time from start of treatment to the date of disease progression 
or date of death, whichever comes first (or the date of censoring for PFS).
For patients with known date of progression:
Progression-free survival [days] = date of progression (or of death if no earlier progression) –
(date of start of treatment) + 1
For patients that are known to have progressed, but with unknown date of progression, refer 
to Section 6.6 for more detail.
Censoring 
For patients known not to have progressed, i.e., those remaining on trial drug: 
Progression-free survival (censored) [days] = date of last assessment showing no disease
progression or death - (date of start of treatment) + 1.
Patients with unknown progression status (no progression reported) will be censored at the 
date of last assessment, where the assessment was: stable disease, partial response or 
complete response. If a disease progression was not reported and all tumour assessments are 
missing or “not evaluable”, patient will be censored for PFS at date of first administration of 
afatinib.
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. 
Kaplan-Meier curves will be produced without confidence intervals.  
Disease control according to RECIST 1.1
Patients whose best assessment is SD, PR, or CR will be considered to have achieved disease 
control. Duration of disease control is defined as the time from the start of treatment to the 


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date of progression or death (or date of censoring for PFS), but is restricted to patients who 
achieve disease control.
Kaplan-Meier estimates and 95% confidence intervals for the 25th, median, and 75th
percentiles of the survival distribution will be calculated for duration of disease control.
Kaplan-Meier curves will be produced without confidence intervals.
7.6
FURTHER ENDPOINTS
There are no further endpoints. 
7.7
EXTENT OF EXPOSURE
Total treatment time (days and number of courses) will be calculated for each patient; off-
drug periods due to non-compliance or toxicity prior to permanent discontinuation will be 
included as treatment time.  Standard descriptive summaries of these data will be provided 
for the treated set of patients. Summary of exposure by dose level will also be provided. 
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. 
7.8.1
Adverse events
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.
The adverse events will be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 3.0. 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' (3)
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 drug intake until 28 days 
after last 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 include the first 
5 categories from the list below 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), primary system organ class 
(SOC) and preferred term (PT) for each of the following AE tables:

Any AEs,


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
Drug related AEs,

AEs leading to dose reduction,

AEs leading to treatment discontinuation,

Serious AEs,

Drug related AEs leading to treatment discontinuation,

Drug related serious AEs,

AEs leading to death,

Drug related AEs leading to death.
All tables will be sorted by SOC according to the standard sort order specified by the 
European Medicines Agency (EMA); PTs will be sorted by frequency (within SOC).
In order to most accurately characterize those adverse events related to different mechanism, 
MedDRA SMQ and HLT (with some modification) will be used to group MedDRA PT for 
rash/acne, stomatitis, ocular effects, lip effects, nail effects and fatigue. As a first step in the 
analysis of grouped AE, all constituent PT will be presented in a separate table for each 
grouped AE. The first 5 standard tables will be supplemented with tables using the grouped 
AE. Grouping will follow the project standard and details 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 
project defined groupings and MedDRA PTs within each grouping will also be produced.
Additional AE tables will be prepared to describe the frequency, intensity, clinical 
consequences for patients who are identified as having experienced any of the following AE:

Gastrointestinal events (vomiting, nausea, diarrhea)

Skin reaction (rash, acne)
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards [see DM&SM: Display and Analysis of Laboratory Data (4)].  CTC grades will be 
applied to laboratory parameters using the current BI oncology standard as detailed in the 
document ‘Conversion of laboratory parameters to CTCAE grades within BI’ (5).
Descriptive statistics of all laboratory values by visit will be provided including changes from 
baseline.  Frequency tables of transitions relative to the reference range and of possible 
clinically significant abnormalities will be produced.  For those parameters that have CTC 
grading possible clinically significant abnormalities are defined as those laboratory values 
with a CTC grade ≥ 2 that have had an increase of ≥ 1 grade from baseline.  For those 
parameters for which no CTC grade has been defined standard BI project definitions will be 


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used to decide on clinical significance.  Further frequency tables will show the transition of 
CTC grade from baseline to worst value and last value on treatment.
Summaries will be produced of laboratory data recorded prior to treatment, on-treatment and 
28 days after last study drug intake.
The focus of the laboratory data analysis will be on the following laboratory parameters:

Low values: haemoglobin, leukocyte (total WBC), neutrophils, lymphocyte, platelet
count, potassium.

High values: aPTT, creatinine, AST, ALT, total bilirubin, alkaline phosphatase.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
Only the date of the tracing is collected. 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.
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D et al., New response 
evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J 
Cancer 2009; 45:228-247 [R09-0262].
2.
001-MCG-156_RD-01, ‘Handling of missing and incomplete AE dates’, current 
version; IDEA for CON.
3.
001-MCG-156, ‘Handling and summarisation of adverse event data for clinical trial 
reports and integrated summaries’, current version; IDEA for CON.
4.
001-MCG-157, ‘Display and Analysis of Laboratory Data’, current version, IDEA for 
CON.
5.
BI Guidance document ‘Conversion of laboratory values to CTCAE grades within 
Boehringer Ingelheim’.


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9.
Additional sections
Not applicable.


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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
22-Sep-15
None
This is final TSAP without any 
modification