A Randomised, Open-label, Phase III Study to Evaluate the Efficacy and Safety of Oral Afatinib (BIBW 2992) Versus Intravenous Methotrexate in Patients With Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma Who Have Progressed After Platinum-based Therapy.
Phase: PHASE3
Conditions: Head and Neck Neoplasms
Sponsor: Boehringer Ingelheim

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Clinical Trial Protocol
Doc. No.: c02089607-05
TITLE PAGE
BI Trial No.:
1200.161
BI Investigational
Product:
Afatinib (BIBW 2992)
Title:
LUX-Head & Neck 3
A randomised, open-label, phase III study to evaluate the efficacy and 
safety of oral Afatinib (BIBW 2992) versus intravenous methotrexate in 
patients with recurrent and/or metastatic head and neck squamous cell 
carcinoma who have progressed after platinum-based therapy
Clinical Phase:
III
Sponsor contacts
Trial Clinical Monitor:
Team Member 
Medicine:
Phone: +
Phone: +
Co-ordinating 
Investigator:
Phone: +
Status:
Final Protocol (Revised Protocol based on global amendment 4)
Version and Date:
Version
Date
5
03 January 2019
Page 1 of  127
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission
I@\ Boehringer 
\J1llluJ lngelheim 

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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
Afatinib (BIBW 2992)
Protocol date:
Trial number:
Revision date: 
03 January 2019
07 Feb 2013
1200.161
Title of trial:
LUX-Head & Neck 3
A randomised, open-label, phase III study to evaluate the efficacy and safety of oral 
Afatinib (BIBW 2992) versus intravenous methotrexate in patients with recurrent 
and/or metastatic head and neck squamous cell carcinoma who have progressed after 
platinum-based therapy.
Co-ordinating 
Investigator:
Phone: +
Trial sites:
Multi-centre trial
Clinical phase:
III
Objectives:
To investigate the efficacy and safety of Afatinib versus methotrexate therapy in 
patients with recurrent and/or metastatic (R/M) head and neck squamous cell 
carcinoma (HNSCC) who have progressed after platinum-based therapy given for 
R/M HNSCC.
Methodology:
Randomised, multicentre, open-label, active-control study with two parallel arms. 
Eligible patients will be stratified by their Eastern Cooperative Oncology Group 
(ECOG) performance score (0 vs. 1) and prior use of EGFR-targeted antibody therapy 
in the recurrent/metastatic setting (yes vs. no) at baseline. Within each stratum, 
patients will be randomised to either Afatinib or methotrexate with a 2:1 
randomization ratio.
No. of patients: 
total randomised: 330
each treatment:

Afatinib: 220

methotrexate: 110
Diagnosis :
Recurrent and/or metastatic head and neck squamous cell carcinoma.

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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
Afatinib (BIBW 2992)
Protocol date:
Trial number:
Revision date: 
03 January 2019
07 Feb 2013
1200.161

Main inclusion 
criteria:

Histologically or cytological confirmed squamous cell carcinoma of the oral 
cavity, oropharynx, hypopharynx or larynx, which has recurred/metastasised and 
is not amenable for salvage surgery or radiotherapy.

Documented progressive disease based on investigator’s assessment according to 
Response Evaluation Criteria in Solid Tumours (RECIST) following receipt of a 
cisplatin and/or carboplatin based regimen (minimum doses described below) 
administered for recurrent and/or metastatic disease independent of whether 
patient progressed during or after platinum based therapy.
-
Cisplatin, minimum dose: at least two cycles of cisplatin, ≥60 mg/m2/cycle 
or a total cumulative dose of ≥120 mg/m2 within eight weeks
-
Nedaplatin minimum dose: at least two cycles of Nedaplatin, ≥60 
mg/m2/cycle or a total cumulative dose of ≥160 mg/m2 during eight weeks.
-
Carboplatin, minimum dose: at least two cycles of carboplatin area under the 
concentration-time curve (AUC) ≥4/cycle or a total cumulative dose of 
AUC ≥8 within eight weeks.

Measurable disease according to RECIST (version 1.1).

ECOG performance status 0 or 1 at the time of randomization visit (Visit 2).
Main exclusion criteria: 
Progressive disease within three months of completion of curatively intended 
treatment for locoregionally advanced HNSCC or for metastatic HNSCC.

Primary tumour site nasopharynx (of any histology), sinuses, and/or salivary 
glands

Any other than one previous platinum-based systemic regimen given for recurrent 
and/or metastatic disease with the exception of immunotherapy used either before 
or after platinum based treatment. Re-challenge with the platinum based regimen 
after a temporary break is considered an additional line regimen only in case of 
progression within the break.

Prior treatment with EGFR-targeted small molecules.

Unresolved chronic toxicity, other than hearing loss, tinnitus or dry mouth, 
CTCAE grade >2 from previous anti-cancer therapy or unresolved skin toxicities 
CTCAE grade >1 and/or diarrhoea CTCAE grade >1 caused by prior treatment 
with EGFR targeted antibodies.
Test product:
Afatinib
dose:
Starting dose 40 mg daily, escalation to 50 mg/day and/or reduction to 40, 30 then 20 
mg according to absence or presence of drug related adverse events.
Mode of admin. :
Oral

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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
Afatinib (BIBW 2992)
Protocol date:
Trial number:
Revision date: 
03 January 2019
07 Feb 2013
1200.161
Comparator products:
Methotrexate
dose:
40 mg/m2/ week with an option to escalate to 50 mg/m2/ week and/or to reduce to 40, 
30 then 20 mg/m2/ week according to drug related adverse events.
Mode of admin. :
Intravenous bolus injection
Duration of treatment: Both treatment arms: continuous treatment until disease progression confirmed by 
imaging or adverse events requiring permanent discontinuation from treatment. After 
primary analysis, duration of treatment may be limited to one year after the last 
patient randomised.
Criteria for efficacy
and pharmacokinetics:
Primary Endpoint:

Progression free survival (PFS) based on RECIST version 1.1
Secondary Endpoints:

Overall survival (OS)

Objective response rate based on RECIST version 1.1

Health related quality of life (HRQOL)
Pharmacokinetics: Pharmacokinetics of Afatinib (i.e. plasma concentrations)
Criteria for safety:
Incidence and intensity of adverse events (CTCAE, version 3.0), and changes in 
safety laboratory parameters, vital signs, ECOG status and ECG.
Statistical methods:
This study will be powered to demonstrate the PFS benefit of Afatinib over 
methotrexate. The total progression (or death) events needed is 274 to detect a 43% 
improvement in median PFS (Afatinib 3.0 months vs. methotrexate 2.1 months; 
hazard ratio=0.70) with one-sided type-I error α=0.025 and 80% power. Overall 330
patients will be randomised.
A stratified log-rank test will be used to test PFS. All safety endpoints and Afatinib
plasma concentrations will be analysed descriptively.

Boehringer Ingelheim                                                                                                                                                    03 Jan 2019
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FLOW CHART
Flow Chart for Visits 1 - 26 (until and including week 24)
Study Period
Screen
Treatment period
EOT
FUV
OP
Visit
1
2
3
4
5
6
7
8
9 to 26
EOT
FUV
OP1 etc
Weeks after randomization
-2
0
1
2
3
4
5
6
7 to 24
Day1
-14 to -1
1
8
(+/-2)
15
(+/-2)
22
(+/-2)
29
(+/-2)
36
(+/-2)
43
(+/-2)
Repeat visits 
3 to 8
0-7 after 
last dose
+28
(+7)
after EOT
Every 4 
weeks
(+/-7 days)
Informed consent2
X
Demographics, height, smoking 
status, alcohol consumption
X
Medical history
X
Body weight
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
Physical, skin and H&N exam3
X
X
X
X
X
Tumour imaging4
X
X
X5
X5
X5
ECOG Performance status
X
X
X
X
X
12 Lead ECG
X
X6
X6
X7
HRQOL8
X
X
X
X
Health care resource use/Home care
X
X
X
Review of In-/Exclusion criteria
X
X
Randomization9
X
Dispense Afatinib
X
every 4 weeks
Afatinib treatment10
Continuous
Compliance check (Afatinib)11
when dispensing new study medication
X
Methotrexate treatment
X
X
X
X
X
X
X
Termination of study medication
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X12
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X13
Safety laboratory testing14
X
X
X15
X
X
X
X
Pregnancy testing16
X
X
Archival tumour tissue17
X
Serum and plasma sampling 17
X
X
Pharmacogenetics18
X

Boehringer Ingelheim                                                                                                                                                    03 Jan 2019
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Study Period
Screen
Treatment period
EOT
FUV
OP
Visit
1
2
3
4
5
6
7
8
9 to 26
EOT
FUV
OP1 etc
Weeks after randomization
-2
0
1
2
3
4
5
6
7 to 24
Day1
-14 to -1
1
8
(+/-2)
15
(+/-2)
22
(+/-2)
29
(+/-2)
36
(+/-2)
43
(+/-2)
Repeat visits 
3 to 8
0-7 after 
last dose
+28
(+7)
after EOT
Every 4 
weeks
(+/-7 days)
Vital status19
X
Blood sampling for 
pharmacokinetic analysis
X20
X21
Screen
Screening visit; is performed within 14 days prior to first drug administration.
Treatment period
Patients may continue on treatment for unlimited visits, until the criteria for stopping medication are met (see Section 3.3.4).
Visits 3-8 are repeated when a patient continues beyond Visit 8. After week 24, the visits should follow the next Flow Chart table.
EOT
End of treatment; EOT visit is done within 7 days after last drug administration.
If a patient permanently discontinues study treatment at a scheduled visit, the EOT visit should be performed instead of this visit.
FUV
Follow-up visit; all patients should have a follow-up visit 28 days (+7days) after the EOT visit.
OP
Observational Period; All patients will be followed-up for overall survival at 4 week intervals after the last follow-up for 
progression visit until death, withdraw of consent, lost to follow-up or completion of the whole trial whatever occurs earlier. See 
section 5.2.2.2. After database lock for primary analysis, frequency will be every 3 months.
1)
Recommended day for visit.
2)
Written informed consent must be obtained before any study-specific 
screening assessments are performed.
3)
In case progression is detected, this should be confirmed by imaging
within 14 days.
4)
Tumour imaging should include CT scans or MRI of the head and 
neck, chest, upper abdomen to include the liver, and if clinically 
indicated, imaging of any other known or suspected sites of disease.
The same radiographic procedure must be used throughout the study, 
and imaging guidelines must be followed. Imaging will be performed 
until progression at the following time points:

At screening (within 21 days prior to start of treatment (Visit 2) is 
accepted if compliant with central imaging requirements)

Every 6 weeks after Visit 2

Every 8 weeks after treatment week 24.
A 7-day interval before a scheduled tumour assessment is generally 
acceptable, except for the first imaging time point, which has to be at 
least 6 weeks from randomization date. In the event of early 
discontinuation or an interruption/delay of study medication, the 
tumour imaging schedule should not be changed. After the database 
lock for primary analysis, the imaging intervals can change to follow 
local site standard (if no standard; every 16 weeks).
5)
Only for patients permanently discontinuing study medication without 
disease progression: Follow imaging schedule every 6 weeks until PD 
or start of new anti-cancer therapy. After the database lock for primary 
analysis, the requirement to continue imaging will be removed.
6)
During the treatment period, ECG will be assessed at Visit 4, 14, 26, 
and then every 16 weeks.
7)
If not performed in the previous 8 days.
8)
HRQOL: EORTC QLQ-C30, EORTC QLQ-H&N35, and EQ-5D, till 
the FUV. After database lock for primary analysis, collection of 
HRQOL will stop.
9)
Treatment must commence as soon as possible after randomization, 
but within four days of randomization.

Boehringer Ingelheim                                                                                                                                                                 03 Jan 2019
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10) Continuous daily dosing, starting at Visit 2. For dosing, see Section 
4.1.3.
11) After one week of Afatinib treatment, treatment compliance should be 
discussed with the patient, to ensure that the medication is being taken 
correctly. When new medication is dispensed, treatment compliance is 
calculated and entered in the eCRF.
12) All adverse events, serious and non-serious, occurring from signing 
the informed consent onwards through the end of the follow up period 
will be collected, documented and reported to the sponsor by the 
investigator on the appropriate eCRFs/SAE reporting forms. Please 
refer to section 5.2.2.2.
13) Only anti-cancer therapy will be collected in the observational period.
14) Includes haematology, serum biochemistry, and urinalysis. Urinalysis 
only at screening and EOT.
15) Only Visit 3 (i.e. not when Visit 3 is repeated as Visit 9, 15, and 21)
16) Pregnancy test is mandatory for female patients of childbearing 
potential prior to treatment start and at EOT. Repeat as necessary 
during the treatment period according to local law.
17) Provision of samples for biomarker testing (blood and archival tumour 
tissue) is mandatory and samples are sent to central laboratory for 
exploratory biomarker analyses. For randomized patients who 
consented for biomarker testing before implementation of this 
amendment but tumour samples have not yet been collected, every 
effort should be made to collect tumour tissue samples. For 
randomized patients whom the investigator did not check consent at 
screening for biomarker testing, re-consent is necessary.
18) Pharmacogenetic testing is optional, and the sampling is only 
performed if the patient has given written informed consent to this.
19) All patients will be followed-up for overall survival at 4 week 
intervals after the last follow-up for progression visit until death, 
withdraw of consent, lost to follow-up or completion of the whole trial 
whatever occurs earlier. See section 5.2.2.2. Observational contacts 
may be performed by telephone interview if patients are unable to visit 
the investigator. Deaths must be recorded in the eCRF within 48 hours 
of a site becoming aware of a patient death. After database lock for 
primary analysis, these Observational contacts will be at 3 month 
intervals.
20) Pre-dose and post-dose blood samples will be collected from Afatinib
patients only at Visit 3 (refer to Section 5.6 for detailed PK sampling 
schedule). 
21) Pre-dose blood sample will be collected from Afatinib patients only at 
Visit 6 (refer to Section 5.6 for detailed PK sampling schedule).

Boehringer Ingelheim                                                                                                                                                                 03 Jan 2019
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Flow Chart for Visit 27 and onwards (i.e. from week 25)
Study Period
Treatment period
EOT
FUV
OP
Visit
27
28
29
30
31
32
33
34
35,36 etc.
EOT
FUV
OP1 
etc.
Weeks after randomization
25
26
27
28
29
30
31
32
33,34 etc.
Day1
176
(+/-2)
183
(+/-2)
190
(+/-2)
197
(+/-2)
204
(+/-2)
211
(+/-2)
218
(+/-2)
225
(+/-2)
Repeat 
visits 
27 to 34
0-7 after 
last dose
+28
(+7)
after EOT
Every 4 
weeks
(+/-7 days)
Body weight
X
X
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
X
X
Physical, skin and H&N exam2
X
X
X
X
Tumour imaging3
X
X4
X4
X4
ECOG Performance status
X
X
X
X
12 Lead ECG
X5
X6
HRQOL7
X
X
X
Health care resource use/Home care
X
X
Dispense Afatinib
every 4 weeks
Afatinib treatment8,14
Continuous
Compliance check (Afatinib)
when dispensing new study medication
X
Methotrexate treatment
X
X
X
X
X
X
X
X
Termination of study medication
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X9
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X10
Safety laboratory testing11
X
X
X
X
Pregnancy testing12
X
Vital status13
X
Treatment period
Patients may continue on treatment for unlimited visits, until the criteria for stopping medication are met (see Section 3.3.4).
Visits 27-34 are repeated when a patient continues beyond Visit 34.
EOT
End of treatment; EOT visit is done within 7 days after last drug administration.
If a patient permanently discontinues study treatment at a scheduled visit, the EOT visit should be performed instead of this visit.
FUV
Follow-up visit; all patients should have a follow-up visit 28 days (+7days) after the EOT visit.
OP
Observational Period; All patients will be followed-up for overall survival at 4 week intervals after the last follow-up for 
progression visit until death, withdraw of consent, lost to follow-up or completion of the whole trial whatever occurs earlier. See 
section 5.2.2.2. After database lock for primary analysis, frequency will be every 3 months until one year after last patient 
randomized.

Boehringer Ingelheim                                                                                                                                                                 03 Jan 2019
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1)
Recommended day for visit.
2)
In case progression is detected, this should be confirmed by imaging 
within 14 days.
3)
Tumour imaging should include CT scans or MRI of the head and 
neck, chest, upper abdomen to include the liver, and if clinically 
indicated, imaging of any other known or suspected sites of disease. 
The same radiographic procedure must be used throughout the study, 
and imaging guidelines must be followed. Imaging will be performed 
until progression at the following time points:

Every 8 weeks after treatment week 24.
A 7-day interval before a scheduled tumour assessment is generally 
acceptable. In the event of early discontinuation or an 
interruption/delay of study medication, the tumour imaging schedule 
should not be changed. After the database lock for primary analysis, 
the imaging intervals can change to follow local site standard (if no 
standard; every 16 weeks).
4)
Only for patients permanently discontinuing study medication without 
disease progression: Follow imaging schedule every 8 weeks until PD 
or start of new anti-cancer therapy. After the database lock for primary 
analysis, the requirement to continue imaging will be removed.
5)
During the treatment period, ECG will be assessed every 16 weeks.
6)
If not performed in the previous 8 days.
7)
HRQOL: EORTC QLQ-C30, EORTC QLQ-H&N35, and EQ-5D till 
the FUV. After database lock for primary analysis, collection of 
HRQOL will stop.
8)
Continuous daily dosing. For dosing, see Section 4.1.3.
9)
All adverse events, serious and non-serious, occurring from signing 
the informed consent onwards through the end of the follow up period 
will be collected, documented and reported to the sponsor by the 
investigator on the appropriate eCRFs/SAE reporting forms. Please 
refer to section 5.2.2.2.
10) Only anti-cancer therapy will be collected in the observational period.
11) Includes haematology, serum biochemistry, and urinalysis. Urinalysis 
only at screening and EOT.
12) Pregnancy test is mandatory for female patients of childbearing 
potential prior to treatment start and at EOT. Repeat as necessary 
during the treatment period according to local law.
13) All patients will be followed-up for overall survival at 4 week 
intervals after the last follow-up for progression visit until death, 
withdraw of consent, lost to follow-up or completion of the whole trial 
whatever occurs earlier. See section 5.2.2.2. Observational contacts 
may be performed by telephone interview if patients are unable to visit
the investigator. Deaths must be recorded in the eCRF within 48 hours 
of a site becoming aware of a patient death. After database lock for 
primary analysis, these Observational contacts will be at 3 month 
intervals until one year after last patient randomized.
14) The patients that are still on treatment at one year after last patient 
randomized can continue drug administration from the trial, until 
disease progression or earlier if stop of treatment for other reasons is 
considered the best interest for the patient per investigator’s judgment. 
An interim database lock will occur at around one year after last 
patient randomized. After this interim lock, only AE, dose change, 
drug termination date and cause of termination are required to be 
collected in RDC or BRAVE, and all the other trial procedures will be 
waived.

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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ................................................................................ 10
ABBREVIATIONS.......................................................................................... 15
1.
INTRODUCTION.................................................................................... 17
1.1
MEDICAL BACKGROUND ........................................................................... 17
1.1.1
Head and neck squamous cell carcinoma .......................................... 17
1.1.2
Treatment of incurable HNSCC......................................................... 17
1.2
DRUG PROFILE .............................................................................................. 18
1.2.1
Afatinib.................................................................................................. 18
1.2.2
Preclinical data..................................................................................... 19
1.2.3
Previous clinical experience................................................................. 19
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 22
2.1
RATIONALE FOR PERFORMING THE TRIAL ....................................... 22
2.2
TRIAL OBJECTIVES...................................................................................... 22
2.3
BENEFIT – RISK ASSESSMENT.................................................................. 23
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 25
3.1
OVERALL TRIAL DESIGN AND PLAN...................................................... 25
3.1.1
Administrative structure of the trial .................................................. 27
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP ......................................................................................... 28
3.3
SELECTION OF TRIAL POPULATION...................................................... 28
3.3.1
Main diagnosis for trial entry ............................................................. 29
3.3.2
Inclusion criteria .................................................................................. 29
3.3.3
Exclusion criteria.................................................................................. 30
3.3.4
Removal of patients from this trial or assessments........................... 31
3.3.4.1
Removal of individual patients ............................................... 31
3.3.4.2 Discontinuation of the trial by the sponsor ............................. 32
4.
TREATMENTS........................................................................................ 34
4.1
TREATMENTS TO BE ADMINISTERED ................................................... 34
4.1.1
Identity of BI investigational product and comparator product..... 34
4.1.2
Method of assigning patients to treatment groups............................ 34

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4.1.3
Selection of doses in the trial............................................................... 35
4.1.4
Drug assignment and administration of doses for each patient....... 35
4.1.4.1
Afatinib treatment ................................................................... 35
4.1.4.2
Methotrexate treatment ........................................................... 38
4.1.5
Blinding and procedures for unblinding............................................ 39
4.1.5.1
Blinding................................................................................... 39
4.1.5.2
Procedures for emergency unblinding..................................... 39
4.1.6
Packaging, labelling, and re-supply.................................................... 40
4.1.7
Storage conditions ................................................................................ 40
4.1.8
Drug accountability.............................................................................. 41
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT ................................................................................................... 41
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ............................................................................................. 42
4.2.2
Restrictions ........................................................................................... 43
4.2.2.1
Restrictions regarding concomitant treatment......................... 43
4.2.2.2 Restrictions on diet and life style............................................ 43
4.2.3
Management of expected adverse events ........................................... 43
4.2.3.1
Management of diarrhoea following treatment with Afatinib 43
4.2.3.2
Management of dermatological AEs following treatment with 
Afatinib.................................................................................... 44
4.2.3.3
Management of mucositis/stomatitis....................................... 47
4.3
TREATMENT COMPLIANCE ...................................................................... 48
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 50
5.1
EFFICACY - PHARMACODYNAMICS....................................................... 50
5.1.1
Endpoints of efficacy............................................................................ 50
5.1.2
Assessment of efficacy.......................................................................... 50
5.1.2.1
Tumour imaging...................................................................... 50
5.1.2.2
Central image review .............................................................. 51
5.1.2.3
Health-related quality of life ................................................... 52
5.2
SAFETY ............................................................................................................. 53
5.2.1
Endpoints of safety............................................................................... 53
5.2.2
Assessment of adverse events .............................................................. 53
5.2.2.1
Definitions of adverse events.................................................. 53
5.2.2.1.1Adverse event.......................................................................... 53
5.2.2.1.2Serious adverse event.............................................................. 53
5.2.2.1.3Intensity of adverse event........................................................ 54
5.2.2.1.4Causal relationship of adverse event....................................... 54
5.2.2.1.5Worsening the underlying disease or other pre-existing 
conditions ................................................................................ 54

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5.2.2.1.6Changes in vital signs, ECG, physical examination, and laboratory 
test results................................................................................ 54
5.2.2.1.7Protocol Defined Adverse Event of Special Interest [AESI].. 55
5.2.2.1.8Expected adverse events.......................................................... 55
5.2.2.2
Adverse event and serious adverse event reporting ................ 55
5.2.2.2.1Pregnancy................................................................................ 57
5.2.3
Assessment of safety laboratory parameters ..................................... 57
5.2.4
Assessment of other safety parameters .............................................. 58
5.2.4.1
Physical examination............................................................... 58
5.2.4.2
Clinical head and neck examination........................................ 59
5.2.4.3
Performance status score......................................................... 59
5.2.4.4
Electrocardiogram ................................................................... 59
5.2.4.5
Vital signs and body weight.................................................... 59
5.3.2
Other assessments ................................................................................ 60
5.3.2.1
Demographics, medical history, smoking, and alcohol status 60
5.3.2.2
Concomitant therapies and diagnoses ..................................... 60
5.3.2.3
Assessment of healthcare resource use and home care........... 61
5.3.3 Pharmacogenomic evaluation ............................................................. 61
5.3.3.1
Methods and timing of sample collection ............................... 61
5.4
APPROPRIATENESS OF MEASUREMENTS ............................................ 62
5.5
ASSESSMENT OF EXPLORATORY BIOMARKERS............................... 62
5.5.1 Biomarker Assessments.......................................................................... 62
5.5.1.1
Tumour Biomarker Assessments ............................................ 62
5.5.1.2
Blood-based Biomarker Assessments..................................... 63
5.5.2
Endpoints based on biomarkers ......................................................... 63
5.5.3. Handling of Samples and Biomarker Results.................................... 63
5.6
DRUG CONCENTRATION MEASUREMENTS – PHARMACOKINETICS
............................................................................................................................. 64
5.6.1
Methods and timing of sample collection........................................... 64
6.
INVESTIGATIONAL PLAN.................................................................. 66
6.1
VISIT SCHEDULE........................................................................................... 66
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS................ 66
6.2.1
Screening and randomization ............................................................. 66
6.2.2
Treatment period.................................................................................. 67
6.2.3
End of treatment and follow-up period.............................................. 68
6.2.3.1
End of treatment visit.............................................................. 68

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6.2.3.2
Follow-up visit ........................................................................ 68
6.2.3.3
Observational period ............................................................... 68
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 70
7.1
STATISTICAL DESIGN - MODEL ............................................................... 70
7.2
NULL AND ALTERNATIVE HYPOTHESES.............................................. 70
7.3
PLANNED ANALYSES ................................................................................... 70
7.3.1
Primary analyses .................................................................................. 70
7.3.1.1
Primary endpoint PFS ............................................................. 71
7.3.2
Secondary analyses............................................................................... 72
7.3.2.1
OS............................................................................................ 72
7.3.2.3
Objective response .................................................................. 73
7.3.2.6
Health related quality of life.................................................... 74
7.3.3
Safety analyses...................................................................................... 74
7.3.4
Interim analyses.................................................................................... 75
7.3.5
Pharmacogenomic analyses................................................................. 75
7.3.6
Pharmacokinetic methods ...................................................................... 75
7.4
HANDLING OF MISSING DATA.................................................................. 76
7.5
RANDOMIZATION ......................................................................................... 77
7.6
DETERMINATION OF SAMPLE SIZE ....................................................... 77
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 79
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT.......................................................................................................... 79
8.2
DATA QUALITY ASSURANCE .................................................................... 80
8.3
RECORDS ......................................................................................................... 80
8.3.1
Source documents................................................................................. 80
8.3.2
Direct access to source data and documents...................................... 81
8.3.3
Storage period of records .................................................................... 81
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS81
8.4.1
Listedness.............................................................................................. 82
8.4.2
Expedited reporting to health authorities and IECs/IRBs............... 82
8.5
STATEMENT OF CONFIDENTIALITY...................................................... 82
8.6
TRIAL MILSTONES ....................................................................................... 82
9.
REFERENCES......................................................................................... 83

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9.1
PUBLISHED REFERENCES.......................................................................... 83
9.2
UNPUBLISHED REFERENCES .................................................................... 88
10. APPENDICES .......................................................................................... 89
10.1
APPENDIX 1 RECIST 1.1 CRITERIA .......................................................... 89
10.2
APPENDIX 2 COCKCROFT-GAULT FORMULA..................................... 93
10.3
APPENDIX 3 ECOG PERFORMANCE STATUS ....................................... 94
10.4
APPENDIX 4 CLINICAL EVALUATION OF LIVER INJURY................ 95
10.4.1 Introduction.......................................................................................... 95
10.4.2 Procedures............................................................................................. 95
10.5
APPENDIX 5 P-GLYCOPROTEIN INHIBITORS AND INDUCERS....... 97
11. DESCRIPTION OF GLOBAL AMENDMENTS................................. 98
11.1
GLOBAL AMENDMENT 1............................................................................. 98
11.2
GLOBAL AMENDMENT 2........................................................................... 105
11.3
GLOBAL AMENDMENT 3........................................................................... 121
11.4
GLOBAL AMENDMENT 4........................................................................... 128

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ABBREVIATIONS
ADL
Activity of Daily Life
AE
Adverse Event
ALT
AESI
Alanine Amino Transferase
Adverse Event of Special Interest
ANC
Absolute Neutrophil Count
AST
Aspartate Amino Transferase
AUC
Area Under the Concentration-time curve
BI
Boehringer Ingelheim
BSA
Body Surface Area
BSC
Best Supportive Care
CI
Confidence Interval
CML
Clinical Monitor Local
CR
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Contract Research Organisation
CT
Computerised Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
DILI
Drug Induced Liver Injury
DMC
Data Monitoring Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EGFR
Epidermal Growth Factor Receptor
EORTC
European Organisation for Research and Treatment of Cancer
EOT
End of Treatment
ErbB
Epidermal Growth Factor family of receptors
(ErbB1/EGFR/HER1, ErbB2/HER2, ErbB3/HER3, ErbB4/HER4)
EudraCT
European Union Drug Regulating Authorities Clinical Trials
FDA
Food & Drug Administration
FFPE
Formalin-Fixed Paraffin-Embedded
5-FU
5-Fluorouracil
FUV
Follow Up Visit
GCP
Good Clinical Practice
HB-EGF
Heparin Binding EGF-like Growth Factor
HER
Human Epidermal Growth Factor Receptor
HNSCC
Head and Neck Squamous Cell Carcinoma
HPV
Human Papillomavirus
HRQLQ
Health Related Quality of Life
IB
Investigator’s Brochure
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee

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IHC
Immunohistochemistry
ILD
Interstitial Lung Disease
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
ISF
Investigator Site File
i.v.
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web-based Response System
LLN
Lower Limit of Normal
LVEF
Left Ventricular Ejection Fraction
mAb
MENA
Monoclonal Antibody
Middle East and North Africa
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
MUGA
Multiple Gated Acquisition Scan
NCI
National Cancer Institute
NSCLC
Non-Small Cell Lung Cancer
OP
Observational Period
ORR
Overall Response Rate
OS
Overall Survival
p16
p16 protein, a cyclin-dependent kinase (CDK) inhibitor
PBMC
Peripheral Blood Mononuclear Cells
PET
Positron Emission Tomography
PD
Progressive Disease
PFS
Progression Free Survival
P-gp
P-glycoprotein
PI
Package Insert
PK
Pharmacokinetics
PR
Partial Response
PS
Performance Status
PTT
Partial Thromboplastin Time
QLQ
Quality of Life Questionnaire
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual Effect Period
R/M
Recurrent and/or Metastatic
RS
Randomised Set
SAE
Serious Adverse Event
SD
Stable Disease
SPC
Summary of Product Characteristics
SSQ
Subjective Significance Questionnaire
SUSAR
Suspected Unexpected Serious Adverse Reaction
TKI
Tyrosine Kinase Inhibitor
TMA
Tissue Microarray
ULN
Upper Limit of Normal

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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
1.1.1
Head and neck squamous cell carcinoma
Head and neck cancers constitute a group of cancers originating in the upper aerodigestive tract, 
including oral cavity, oropharynx, hypopharynx, larynx, paranasal sinuses, and nasal cavity and 
vestibule. Most head and neck cancers (>90%) are squamous cell carcinomas (SCC) arising 
from epithelial cells of the mucosa. Head and neck squamous cell carcinoma (HNSCC) is the 6th
most common type of cancer with an incidence of approximately 650,000 new cases worldwide 
each year, and its incidence is rising rapidly in developing countries (R06-1650).
It’s noted that nasopharyngeal carcinoma (NPC) is a unique type of head and neck malignancy 
that shows a clear regional and racial prevalence. NPC occurs most commonly in Asians who 
inhabit in the southern Chinese provinces and southern Asia (Ma and Cao, 2009). Since the 
biological behaviour of NPC differs significantly from other types of HNSCC, the below 
statement focuses on HNSCC (non-NPC) only.
Over expression of the epidermal growth factor receptor (EGFR) is seen in the overwhelming 
majority of HNSCC. The EGFR is a member of the human epidermal receptor (HER)/Erb-B 
family of tyrosine kinase receptors that are responsible for signal transduction (R10-5898). 
EGFR activation plays an important role in malignant cell proliferation, angiogenesis, metastasis 
and inhibition of apoptosis. Both EGFR over expression and EGFR gene amplification are 
prognostic factors for shorter progression free survival (PFS) and overall survival (OS) (R10-
5919).
The major known risk factors are alcohol and tobacco consumption, mediating frequent p53 
mutations and over expression of the EGFR (R10-5931). Recently, the human papillomavirus 
(HPV) has emerged as a new cause of oropharyngeal carcinoma. These patients have a better 
prognosis as compared to HNSCC caused by tobacco and alcohol use (R10-5847). 
1.1.2
Treatment of incurable HNSCC
The multimodal curative treatment of locally advanced HNSCC includes radiation therapy 
and/or surgery and/or chemotherapy. Despite this aggressive approach more than 50% of these 
patients will relapse (R06-1650) (R06-0221). The most frequent chemotherapy regimens used 
for R/M HNSCC include a platinum agent combined either with a taxane or 5-fluorouracil (5-
FU). Doublet chemotherapy yields objective response rates in approximately 30% of the patients 
treated in first line therapy. Median survival remains low, between 6-8 months (R01-0555). 
Recently, several therapies involving biologically targeted molecules against receptors, such as 
the EGF receptor, have been developed and tested in clinical trials in HNSCC. Inhibition of the 
EGFR by cetuximab (Erbitux®), a chimeric monoclonal antibody (mAb) targeting the EGFR, 
has demonstrated a survival benefit across HNSCC treatment lines i.e. for locally advanced 
HNSCC in combination with radiotherapy (R06-1657) and in the first-line setting of R/M 
disease in combination with platinum and 5-FU (R10-5937).

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Effective second-line therapeutic options after platinum failure are limited. Weekly methotrexate 
monotherapy is a treatment option for these patients not eligible for polychemotherapy (R10-
5909). Methotrexate is approved in several countries, and has been used as a single-agent 
comparator for phase III trials (R10-5848, R10-5850). Cetuximab is approved as monotherapy in 
the US and most countries in Asia for patients for whom prior platinum-based therapy has failed 
based on the response rate of 13% in 103 patients with R/M HNSCC (R08-1660). Recently 
pembrolizumab and nivolumab were approved (by FDA) in the same setting. Pembrolizumab 
and nivolumab are humanised and fully human anti-PD-1 monoclonal antibodies respectively. 
Pembrolizumab was approved based on a durable response rate of 18%, while nivolumab was 
approved based on a benefit in OS compared to investigator’s choice (7.5 vs 5.1 months) with an 
ORR of 13% (R16-4089, R16-5709).
A randomised phase III study (ZALUTE) compared zalutumumab, a fully human mAb against 
the EGFR, versus best supportive care (BSC) in platinum-refractory HNSCC patients (R11-
0801). There was no significant difference in OS between the two treatment groups; 6.7 months 
with zalutumumab versus 5.2 months with best supportive care (BSC). It is notable that optional 
methotrexate was used in 78% of patients on BSC.
Gefitinib, a reversible tyrosine kinase inhibitor (TKI) targeting the EGFR, has demonstrated 
complete response (CR) in locally advanced HNSCC when given concurrent with 
chemoradiotherapy, and survival rates that compare favourably with prior experience (R10-
5924). In a phase III study (IMEX), gefitinib was compared with methotrexate in R/M HNSCC 
(R10-5936). No obvious difference in OS between methotrexate and either gefitinib at 250 or 
500 mg/day was observed.
Lapatinib, a novel, dual EGFR ErbB2 TKI has shown anti-tumour activity in various solid 
tumours, including HNSCC (R07-1160, R10-5849). 
Afatinib is a second generation irreversible EGFR-TKI. Proof of concept of Afatinib in R/M 
HNSCC has been established in a Boehringer Ingelheim (BI) phase II study of Afatinib versus 
cetuximab, where the anti-tumour activity of Afatinib was at least comparable to the activity of 
cetuximab (P10-12525). This, combined with the convenience of oral administration of a TKI 
targeting the EGFR pathway, supports further development of Afatinib in patients with R/M 
HNSCC.
1.2
DRUG PROFILE
For the latest information on the drug profile, please refer to the latest Investigator’s Brochure 
(IB) (U03-3218). All references in this protocol concerning Afatinib (BIBW 2992) refer to the 
free base compound Afatinib BS, which is used as the oral formulation.
1.2.1
Afatinib
Afatinib is a highly selective and potent low molecular weight, irreversible inhibitor of the 
ErbB-family tyrosine kinase receptors EGFR (ErbB1/HER1) and HER 2 (ErbB2).

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1.2.2
Preclinical data
In preclinical models, it was shown that Afatinib can effectively inhibit ligand-induced EGFR-
and constitutive HER2 phosphorylation resulting in tumour growth inhibition and regression. 
Afatinib binds covalently to the targeted enzymes.
The efficacy and potency of Afatinib was demonstrated in vitro in receptor phosphorylation and 
cell proliferation assays in various human cancer cell models. The potency of Afatinib was 
determined in enzymatic assays using recombinant human wild-type EGFR and HER2 that 
revealed IC50 values of 0.5 nM and 14 nM, respectively (U02-1391, U03-3218). In vitro
experiments (U03-3218) have shown inhibitory activity of Afatinib on the erlotinib/gefitinib 
resistant EGFR L858R/T790M double mutant NSCLC cell line, and investigations of xenograft 
models and transgenic mice have confirmed the results (P08-06904). In addition, Afatinib
inhibits growth of cells harbouring other clinically relevant mutations of the EGFR, such as 
EGFRvIII. The in vivo activity of Afatinib against EGFR was investigated in different mice 
xenograft models, and Afatinib at tolerated doses was shown to induce almost complete 
regression of established subcutaneous tumours derived from human cell lines know to co-
express ErbB receptors.
1.2.3
Previous clinical experience
Afatinib was tested in phase I and phase II trials with solid tumours, and phase III trials in 
several indications are ongoing. At the time of data cut-off 25 March 2015, 6673 cancer patients 
had been exposed to Afatinib monotherapy or in combination with other anti-cancer agents 
across various Phase I-III trials and expanded-access program. In addition there are 265 patients 
in a double-blind Phase III trial in head and neck cancer. A compassionate use/named patient use 
program was initiated for Afatinib in 2010, and by 24 March 2015, overall 5607 treatment 
requests had been authorised. In investigator-initiated trials, 808 patients have been treated with 
Afatinib as monotherapy or in combination therapy as of 24 May 2015.
Afatinib showed moderately fast absorption after oral administration, with median tmax values 
approximately 3 hours after drug administration. The overall geometric mean terminal half-life 
at steady state was 37.2 hours in cancer patients after single dose administration. Steady state 
was reached no later than 8 days after the first administration. The major route of elimination of 
Afatinib was via the faeces. After food intake, a decreased systemic exposure was observed 
compared to administration of Afatinib under fasted conditions.
Afatinib is a substrate of P-glycoprotein (P-gp) drug efflux pump and the results from a phase I 
trial showed that the rate and extent of absorption of Afatinib was increased by co-treatment 
with ritonavir, indicating that an effect of potent P-gp inducers on the pharmacokinetic 
characteristics of Afatinib cannot be excluded.
Adverse events (AE) observed with Afatinib predominantly include diarrhoea and skin rash, and 
these are dose-dependent. Apart from gastrointestinal disorders, the AE pattern observed with 
Afatinib is consistent with that reported for other EGFR and dual EGFR/HER2 inhibitors (R06-
1657). Diarrhoea generally begins within two weeks of exposure to Afatinib, and early 
intervention and effective management is mandated to manage diarrhoea. Other common AEs 
(regardless of assessment of relatedness) include fatigue, nausea, vomiting, anorexia, epistaxis, 

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stomatitis, mucosal inflammation, dry skin, dyspnoea and pruritus. AEs observed less frequently 
are: cough, constipation, dehydration, dry mouth and pyrexia, dermatitis acneiform, back pain, 
urinary tract infection, abdominal pain, acne, dyseusia, upper abdominal pain and dyspepsia. 
The majority of these events were either CTCAE grade 1 or 2. The two most common CTCAE 
grade 3 events with Afatinib were diarrhoea and rash/acne. Life threatening SAEs and fatal 
SAEs were observed, however, most were judged to have been non-related to treatment with 
Afatinib.
Related cases of suspected interstitial lung disease (ILD) or ILD-like events have been reported. 
As this is a rare but serious adverse event (SAE) reported with other EGFR TKIs, patients with 
known ILD will be excluded from clinical trials with Afatinib. Careful assessment of all patients 
with an acute onset and/or unexplained worsening of pulmonary symptoms (including dyspnoea, 
cough, and fever), interruption of study drug pending investigations, and permanent 
discontinuation if ILD has been diagnosed, are emphasised (see Section 3.3.4).
The efficacy of Afatinib has been investigated in a variety of malignancies. Available evidence 
of activity has been observed in NSCLC patients progressing after first generation EGFR-TKI 
(erlotinib or gefitinib). In addition, proof of concept has been observed in EGFR mutation 
positive advanced NSCLC patients who are EGFR-TKI naïve with high anti-tumour response 
and tumour control rate and long progression free survival. Furthermore, phase II data have 
shown anti-tumour activity of Afatinib in HER2 positive breast cancer.
In the completed global phase II cross-over trial 1200.28 in HNSCC, 124 patients with R/M 
disease were randomised to monotherapy with either Afatinib or cetuximab until tumour 
progression or undue AEs. The primary endpoint, tumour shrinkage of target lesions, per 
investigator review (IRR) and independent central imaging review (ICR) did not differ 
significantly between Afatinib and cetuximab treated patients. Objective response rate with 
Afatinib and cetuximab was 16.1%/8.1% with Afatinib and 6.5%/9.7% with cetuximab (IR/ICR).
The starting dose of Afatinib used in trial 1200.28 was 50 mg once daily, which is the maximum 
tolerated dose (MTD), established in phase I continuous dosing monotherapy trials. Based on the 
data on tolerability of Afatinib in 1200.28, the starting dose chosen for trial 1200.161 will be 40 
mg. Dose modifications will be based on tolerability of the patient.
In trial 1200.43 (global trial with similar design as 1200.161), 483 were randomized (2:1) to 
receive a daily oral dose of Afatinib (n=322) or a weekly intravenous bolus injection of 
methotrexate (n=161).
Treatment with Afatinib significantly prolonged PFS compared to methotrexate, meeting the
primary endpoint of the trial. The median PFS for the Afatinib arm was of 2.63 months
compared to 1.74 months (HR = 0.797; 95% CI 0.646, 0.983; p = 0.0296). The treatment effect 
was comparable across most of the subgroups tested. Median OS was 6.80 months on Afatinib
vs 6.18 months on methotrexate (HR of 0.940 (95% CI 0.749, 1.181; p = 0.5955)). The objective 
response rate based on central independent review was 10.2% in the Afatinib arm and 5.6% in 
the methotrexate arm (odds ratio: 1.91; 95% CI 0.88, 4.14; p = 0.1010). Disease control rate 
based on central independent review was significantly higher in the Afatinib arm (49.1%) 
compared with the methotrexate arm (38.5%) (Odds ratio: 1.52; 95% CI 1.03, 2.26; p = 0.0353). 

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The median duration of disease control was 4.14 months (95% CI 3.98, 4.24) in the Afatinib arm 
and 3.58 months (95% CI 2.86, 4.17) in the methotrexate arm. 34.8% of patients in the Afatinib
arm experienced a decrease in the tumour size compared with 22.4% of patients in the 
methotrexate arm.
Compared with methotrexate, Afatinib delayed the time to deterioration in pre-defined scores of 
global health status (HR 0.74; 95% CI 0.56, 0.97; p = 0.0268), pain (HR 0.73; 95% CI 0.55, 
0.96; p = 0.0217), and swallowing (HR 0.67; 95% CI 0.50, 0.89; p = 0.0040). Similar
proportions of patients showed improvements for pain, swallowing, and global health status.
Over time, patients taking Afatinib reported significantly less pain compared with methotrexate 
(p=0.0330) but no significant differences were seen for swallowing (p = 0.9773) or global health 
status (p = 0.7767).

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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Patients with HNSCC progressing after having received standard platinum-based therapy for 
R/M disease are left with few opportunities for treatment, and median life expectancy is 
estimated to be approximately six months (R10-5848, R11-0801, R10-5936).
The tyrosine kinase EGFR has been implicated in supporting oncogenesis and progression of 
human solid tumours, and the receptor has been the target for recently developed molecules. The 
introduction of the EGFR inhibiting antibody cetuximab has improved the survival when added 
to platinum based therapy in patients with previously untreated R/M HNSCC as compared to 
chemotherapy alone (R10-5937). As a single agent, cetuximab has also showed activity in 
patients with platinum-refractory HNSCC, although no survival benefit was shown (R08-1660). 
However, cetuximab has not been assessed in comparison with other agents or with best 
supportive care in patients with previously treated R/M HNSCC. Small molecule inhibitors, such 
as gefitinib, have been explored, however when compared to methotrexate in the R/M setting, no 
survival benefit has yet been shown (R10-5936). Methotrexate or taxanes are frequently used in 
routine clinical practice after platinum failure, although no phase III trials have formally 
demonstrated that these chemotherapeutics increase survival. Cetuximab is still the only targeted 
agent approved (by FDA) in this setting and the approval was achieved based on a response rate 
of 13% from a single-arm Phase II study (R08-1660). Recently the immunotherapy agents 
pembrolizumab and nivolumab have been approved (by FDA) for the treatment of patients with 
R/M HNSCC with disease progression on or after platinum containing chemotherapy (see 
Section 1.1.2). Despite the emergence of new agents, it is evident that most patients do not 
respond to treatment and that there is still a high unmet medical need in second-line R/M 
HNSCC.
Afatinib is a second generation irreversible EGFR-TKI. Proof of concept of Afatinib in R/M 
HNSCC has been established in a BI phase II study of Afatinib versus cetuximab, where the 
anti-tumour activity of Afatinib was at least comparable to the activity of cetuximab (P10-
12525).
The promising anti-tumour efficacy of Afatinib in R/M HNSCC supports further development in 
this population. If Afatinib shows superior efficacy over methotrexate in trial 1200.161, it may 
offer a new efficacious treatment alternative to recurrent/metastatic HNSCC patients failing 
platinum based chemotherapy in addition to offering a convenient oral alternative to an 
infusional therapy.
2.2
TRIAL OBJECTIVES
The objective of this trial is to investigate the efficacy and safety of Afatinib versus 
methotrexate in the treatment of patients with R/M HNSCC who have progressed after platinum 
based therapy given for R/M HNSCC. The main objective of the trial is to investigate the 
favourable trend of Afatinib to methotrexate in terms of PFS improvement as the second line 

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treatment for this trial patient population. Patients on both treatment arms will be allowed to 
receive best supportive care in addition to study medication.
The secondary objectives are to compare OS, objective response rate (ORR), health related 
quality of life (HRQOL), and safety of two treatment arms. For details on endpoints and their 
assessments, see Section 5.
PFS is chosen as the primary endpoint because additional anti-cancer therapy after disease 
progression dilutes the potential increase in survival afforded by the treatments under 
investigation. For example, two recent trials have investigated the efficacy of EGFR targeting 
drugs in the R/M setting: the IMEX trial (R10-5936) and the ZALUTE trial (R11-0801). In these 
trials, up to 38% of patients received further treatment after progression. Also, this primary 
endpoint is consistent with global pivotal study 1200.43.
Study 1200.161 is phase III trial with a design similar to the global phase III trial 1200.43 
(NCT01345682), but to be conducted in the Asian/Middle East and North African (MENA) 
region.
2.3
BENEFIT – RISK ASSESSMENT
Despite considerable progress in understanding the biological characteristics of cancer as well as 
the development of more effective treatment regimens, prognosis of R/M HNSCC remains poor. 
US-FDA approved agents include platinum compounds, methotrexate and cetuximab 
(Erbitux®). In clinical practice, after the failure of approved agents, other non-approved agents 
are frequently used such as taxanes and platinum derivatives. Cytotoxic therapies carry a 
substantial risk of side effects including leukopenia, fatigue, and nausea/vomiting.
During recent years, biological agents targeted against molecules involved in crucial pathways 
of cancer growth have been developed and some have proven clinical efficacy in different 
cancer indications. These therapies include mAbs against the EGFR and small molecules 
inhibiting intracellular pathways. Afatinib as a novel oral EGFR/HER2 TKI has shown anti-
tumour activity in NSCLC, breast cancer and HNSCC. It offers the possibility to control disease 
on an outpatient basis and could, therefore, be experienced as more convenient for patients as 
compared to intravenous chemotherapy.
The most common AEs with Afatinib treatment are expected to be primarily gastrointestinal 
(including diarrhoea, nausea and vomiting) and skin related AEs (such as skin rashes, pruritus 
and acne). The severity of AEs is dose-dependent, and potential AEs are expected to be 
manageable with treatment pauses, dose reductions, and administration of anti-diarrhoeal 
medication. ILD or ILD-like events are a known and infrequent risk associated with EGFR 
inhibitor therapy and suspected rare cases have been reported as AEs associated with Afatinib
available data. Recently, several cases of ILD have been reported with administration of EGFR 
TKIs in NSCLC patients that had been previously treated with Nivolumab (R16-4467). Patients 
with known ILD will not be included in this trial. Careful monitoring of pulmonary symptoms 
with sudden onset will be implemented during this trial.  For AE details please refer to the IB 
(U03-3218). 

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Based on the experience from previous Afatinib studies, a continuous oral daily dose of 40 mg 
Afatinib, together with proactive management of common side effects and the proposed dose 
reduction scheme, is expected to be well tolerated. If no or minimal AE is observed in the first 
four weeks of treatment, the dose of Afatinib could be escalated to 50 mg. This will give the 
patients an opportunity to receive the highest dose of Afatinib based on their tolerability.
Methotrexate is chosen as the comparator in this trial because it has been approved in EU and 
the US as the second-line chemotherapy for HNSCC (R10-5909, R10-5936).  Its most common 
side effects are stomatitis, leukopenia and nausea. Similar to all other cytotoxic agents, these 
side effects are not always reversible, which could lead to less adherence to treatment and/or 
early interruption of treatment.
Although rare, a potential of drug-induced liver injury (DILI) is under constant surveillance by 
sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and follow-up 
of laboratory alterations of selected liver laboratory parameters to ensure patients’ safety.
In the present trial, there will be regular and frequent assessment of clinical benefit (including
early imaging with first radiological tumour assessment after 6 weeks of treatment). All patients 
will have weekly visits to ensure close monitoring of AEs. An independent data monitoring 
committee (DMC) will oversee the trial and will advise on the further trial conduction based on 
the ongoing assessment of efficacy and safety data (see Section 3.1.1).
In conclusion, the risk benefit assessment for Afatinib and methotrexate in the treatment of R/M 
HNSCC in the proposed setting is positive. The potential benefits for trial patients on either 
treatment arm outweigh treatment-associated risks.

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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This phase III open-label, multi-centre randomised trial is designed to evaluate the efficacy and 
safety of Afatinib versus methotrexate as the second-line treatment of patients with R/M 
HNSCC who have progressed after prior platinum based chemotherapy for R/M disease in 
Asia/MENA region. Prior treatment with immunotherapy will be allowed. The primary endpoint 
of the trial is progression free survival (PFS).
Eligible patients will be stratified into four strata based on two stratification factors: ECOG 
performance score (0 vs. 1) and prior use of EGFR-targeted antibody therapy in the 
recurrent/metastatic setting.
Figure 3.1: 1   Trial design
Patients randomised to Afatinib treatment will receive continuous daily treatment with Afatinib
until tumour progression, unacceptable adverse events or other reasons necessitating treatment 
permanent discontinuation (refer to Section 3.3.4). The starting dose of Afatinib will be 40 mg 
once daily. In the event of no or minimal AEs after the first four weeks of treatment or later, the 
dose will be increased to 50 mg (see Section 4.1.4.1 for details). The dose will be reduced in the 
Observational period
until death
Platinum-refractory 
R/M HNSCC
Treatment until PD
or intolerable AE(s)
Methotrexate
N= 110
Afatinib
N= 220
R
2:1
EOT & Follow-up visit
I 
I 
• 
t 
t 
1.-------------'-------I ~I 
i 
! 
1 

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event of certain drug-related AEs. The dose reduction will be in decrement of 10 mg, with the 
lowest dose being 20 mg. Patients receiving 20 mg will be permanent discontinued from 
treatment if a drug reduction AE still occurs (Section 4.1.4.1).
Patients randomised to methotrexate treatment will receive methotrexate weekly until 
progression, unacceptable AEs or other reasons necessitating treatment permanent 
discontinuation (refer to Section 3.3.4). The treatment will be administered as intravenous bolus 
injections at the starting dose of 40 mg/m2 once a week with the option to increase the dose to 50 
mg/m2 in the event of no or minimal drug-related AEs after at least two-week treatment (see 
Section 4.1.4.2 for details). The dose of methotrexate should be reduced in decrements of 10 
mg/m2 in case of drug-related AEs, see Section 4.1.4.2, but should not be below 20 mg/m2.
All patients will visit the investigational site weekly for assessment of safety parameters and 
AEs. Tumour response will be assessed regularly by CT scan/MRI (see Flow Chart) until 
progression. At disease progression, confirmed by tumour imaging, patients will be discontinued 
from the study medication.
The end of treatment (EOT) is defined as permanent discontinuation of Afatinib or methotrexate. 
Related EOT information needs to be obtained. Patients who permanently discontinue the study 
medication for any other reason than progression of disease (or withdrawal of consent) should 
continue the scheduled tumour imaging visits until progression as described in Section 6.2.3.
The requirement to continue imaging for study purposes for such patients will be removed 
following the database lock for primary analysis.
Following the EOT visit, patients should come to a follow-up visit (FUV) and then continue in 
the observational period. During the observational period, data of survival (vital status), related 
SAEs/AESIs and concomitant anti-cancer therapy will be collected. For patients who progressed 
on treatment, the observation period for overall survival starts after the FUV (end of residual 
effect) visit. For patients who have not progressed on treatment, this period starts after the last 
additional FU visit. A patient is considered to have completed the trial following death, 
withdrawal of consent or lost to follow-up.
Primary statistical analyses will be performed when the required number of progression free 
survival events has occurred as described in Section 7.6. The clinical trial report will be written
based on primary analysis results. An addendum to the clinical trial report may be used to 
summarise data collected beyond database lock for the primary analysis.
In this study the median PFS is assumed to be 2.1 months in the methotrexate arm and 3.0 
months in the afatinib arm based on previous studies in same indication (see Section 7.6). 
Patients will continue treatment until tumour progression or other reasons necessitating 
permanent treatment discontinuation. The study will end when the primary analysis has been 
performed, however if any patients are still on study medication at this time point, the study will 
continue up to one year after last patient randomized. The study will be considered completed 
after all patients have permanently discontinued study medication based on above criteria and 
completed the follow-up visit. If allowed by local regulations, for patients who continue to 
benefit from study treatment the cost of ongoing supply of randomised medication outside the 
study will be incurred by the sponsor (see Section 3.3.4).

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Tumour response and progression will be assessed using RECIST 1.1 (R09-0262, Appendix 1). 
Investigator’s assessment will be sufficient to decide on continuation of treatment. The central 
imaging unit (see Section 5.1.2.2) will perform an independent analysis of response for the 
primary analysis.
Pharmacokinetic (PK) analysis will be carried out for patients on Afatinib only. PK blood 
samples will be collected at Visit 3 (Day8) and Visit 6 (Day 29) on treatment (refer to Section 
5.6.1 for detailed PK sampling schedule).
3.1.1
Administrative structure of the trial
The coordinating investigator has been designated by BI and will sign the clinical trial report. 
The trial will be performed by investigators specialised in the treatment of HNSCC.
A steering committee including the coordinating investigator, experienced experts in HNSCC 
treatment and BI representatives will monitor the trial on a regular basis (all operational aspects, 
recruitment issues, data quality, etc.). The objective of the steering committee will be specified 
in the charter, which will be filed in the investigator site file (ISF).
The DMC will represent an independent multidisciplinary group consisting of three experienced 
and independent members, including two clinicians and one biostatistician who, collectively, 
have expertise in the management of patients with head and neck cancer and in the conduct and 
monitoring of randomised clinical trials. The DMC will meet regularly and their responsibilities 
are to continuously assess the trial data to ensure overall safety and efficacy in the treated 
patients, monitor the quality, and provide the trial steering committee with advice about the 
conduct of the trial and the integrity of the data. The DMC responsibilities are detailed in the 
DMC charter, which will be filed in the ISF. Patient recruitment will continue during the 
scheduled meetings of the DMC. Decisions on trial termination, amendment, or cessation of 
patient recruitment, based on safety or outcome findings will be made after recommendations 
from the DMC have been assessed by the sponsor.
On-site monitoring will be performed by Clinical Research Associate (CRA) from BI or 
appointed Contract Research Organisation (CRO).
BI will appoint CROs for special services such as central independent review of CT scans and 
MR images, central laboratory analyses (including analyses of tumour tissue and, blood and 
urine samples) and interactive voice/web response system (IVRS/IWRS) for randomization and 
trial medication logistics.
All trial relevant documents will be stored in the clinical trial master file (CTMF) at BI and 
investigational sites according to ICH-GCP or regulation of local Health Authority of Ethical 
Committee.

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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
The trial is designed with two parallel arms in order to assess efficacy and safety of Afatinib
versus methotrexate, administered as monotherapy in combination with BSC. Patients will be 
randomised to either treatment arm in a 2:1 ratio since this will enhance controlled collection of 
safety data for Afatinib for the investigated patient population. Following progression after 
standard platinum-based therapy for R/M HNSCC, there is no world-wide standard treatment. 
Erbitux® has been approved for this indication in the US based on response rate in a single arm 
trial without comparison to an active control. Methotrexate is mentioned as one of active single 
chemotherapeutical agents in the National Comprehensive Cancer Network (NCCN) guidelines. 
Weekly methotrexate administration is an acceptable treatment choice for R/M HNSCC patients 
who have failed to platinum-based therapy (R10-5909). Methotrexate is therefore selected as 
comparator for this trial.
The trial is open-label, partly due to the substantial differences in the safety profiles of the two 
investigational products, which could potentially reveal the blinding. The main reason for 
choosing an open-label design is the different administration routes of Afatinib and 
methotrexate, where blinding would mean that two thirds of the patients would receive placebo 
intravenous bolus injections weekly, which might not be ethical. Efforts are made to minimize 
bias, e.g., the primary analysis will be based on assessments of an independent, central imaging 
review committee who will evaluate tumour scans/images for each patient in a blinded manner.
The first disease evaluation will be done after 6 weeks of treatment in order to allow sufficient 
time to observe benefit from either drug. Six week duration is considered adequate to assess 
response although maximal tumour shrinkage may be seen later. To better assess any potential 
differences in the primary endpoint, PFS, tumour imaging assessments are required every 6 
weeks for the first 24 weeks on treatment. Subsequent tumour evaluation will be done every 
8 weeks. After the database lock for primary analysis, the imaging intervals can be changed to 
follow local site standard (if no standard; every 16 weeks).
Although there is no world-wide accepted standard treatment for R/M HNSCC patients failed to 
the first line chemotherapy, they often receive several sequential anti-cancer treatments. It is 
expected that the trial medication will not be the last anti-cancer treatment of study subjects. The 
subsequent treatment(s) may impact on the survival. This situation was observed in the IMEX 
and ZALUTE trials (R10-5936, R11-0801) where 30-40% and 20-30% subjects of respective 
study received subsequent anti-cancer therapies. Therefore, PFS is selected as the primary 
endpoint in order to assess the efficacy of the trial medications as accurate as possible.
3.3
SELECTION OF TRIAL POPULATION
It is estimated that 375 patients will be screened for the trial in order to randomise approximately 
330 eligible patients.
This trial will be conducted in about 60 sites mainly in Asia/MENA region. Each site is expected 
to randomize at least 3 subjects. Enrolment is competitive. When the required number of patients 

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has entered the study, recruitment will stop. Patients who have already signed informed consent 
form and meet all eligibility criteria can continue in the trial.
A patient enrolment log will be maintained in the ISF at the investigational site irrespective 
patients are randomised or not.
3.3.1
Main diagnosis for trial entry
All patients who are included into the trial must have confirmed HNSCC and have progressed 
after treatment with platinum-based chemotherapy for R/M HNSCC.
3.3.2
Inclusion criteria
1. Histologically or cytological confirmed squamous cell carcinoma of the oral cavity, 
oropharynx, hypopharynx or larynx, which has recurred/metastasised and is not 
amenable for salvage surgery or radiotherapy.
2. Documented progressive disease based on investigator assessment according to RECIST, 
following receipt of a cisplatin and/or carboplatin and/or Nedaplatin based regimen 
(minimum doses described below*) administered for recurrent and/or metastatic disease 
independent of whether patient progressed during or after platinum based therapy.

Cisplatin, minimum dose: at least two cycles of cisplatin, ≥60 mg/m2/cycle or a total 
cumulative dose of ≥120 mg/m2 during eight weeks.

Nedaplatin minimum dose: at least two cycles of Nedaplatin, ≥80 mg/m2/cycle or a 
total cumulative dose of ≥160 mg/m2 during eight weeks.

Carboplatin, minimum dose: at least two cycles of carboplatin area under the 
concentration-time curve (AUC) ≥4/cycle or a total cumulative dose of AUC ≥8 
during eight weeks.
* If cisplatin is switched to carboplatin (or vice versa, e.g. due to intolerance), the 
following conversion should be used for calculation of minimum cumulative platinum 
dose: carboplatin 1 AUC = cisplatin 15 mg/m2.
* If cisplatin is switched to Nedaplatin (or vice versa, e.g. due to intolerance), the 
following conversion should be used for calculation of minimum cumulative platinum 
dose: cisplatin 1 mg/m2 = Nedaplatin 1.3 mg/m2.
3. Measurable disease according to RECIST (version 1.1).
4. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 at Visit 2.
5. Male and female patients age >18 years.
6. Signed and dated written informed consent that is in compliance with ICH-GCP and 
local law.

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3.3.3
Exclusion criteria
1. Progressive disease within three months after completion of curatively intended 
treatment for locoregionally advanced or for metastatic HNSCC.
2. Primary tumour site nasopharynx (of any histology), sinuses, and/or salivary glands.
3. Any other than one previous platinum based systemic regimen given for recurrent and/or 
metastatic disease, with the exception of immunotherapy used either before or after 
platinum based treatment. Re-challenge with the platinum based regimen after a 
temporary break is considered an additional line regimen only in case of progression 
within the break.
4. Prior treatment with EGFR-targeted small molecules.
5. Treatment with any investigational drug less than four weeks or anti-cancer therapy less 
than three weeks prior to randomization (except palliative radiotherapy to bones to
alleviate pain).
6. Unresolved chronic toxicity, other than hearing loss, tinnitus or dry mouth, CTCAE 
grade >2 from previous anti-cancer therapy or unresolved skin toxicities CTCAE grade 
>1 and/or diarrhoea CTCAE grade >1 caused by prior treatment with EGFR targeted 
antibodies.
7. Previous tumour bleeding CTCAE grade ≥3.
8. Requirement for treatment with any of the prohibited concomitant medications listed in 
Section 4.2.2.
9. Major surgical or planned procedure less than four weeks prior to randomization 
(isolated biopsies are not considered as major surgical procedures).
10. Any other malignancy unless free of disease for at least five years except for:

Other HNSCC of a location as described in inclusion criterion number 1

Appropriately treated superficial basal cell skin cancer

Surgically cured cervical cancer in situ

For Korea: endoscopically cured superficial esophageal and/or gastric cancer is 
allowed
11. Known lesion or signs of brain metastasis.
12. Known pre-existing interstitial lung disease (ILD).
13. Clinically relevant cardiovascular abnormalities, as judged by the investigator, such as, 
but not limited to, uncontrolled hypertension, congestive heart failure NYHA

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classification ≥III, unstable angina, myocardial infarction within six months prior to 
randomization, or poorly controlled arrhythmia.
14. Significant or recent acute gastrointestinal disorders with diarrhoea as a major symptom 
in the opinion of the investigator, e.g. Crohn's disease, malabsorption or CTCAE grade 
>1 diarrhoea of any aetiology at randomization.
15. Known HIV, active hepatitis B, active hepatitis C, and/or other known severe infections, 
including but not limited to tuberculosis, as judged by the investigator.
16. Other significant disease that in the investigator's opinion would exclude the subject 
from the trial.
17. Screening laboratory values:
a) Absolute neutrophil count (ANC) <1.5x109/l
b) Platelet count <75x109/l
c) Total bilirubin >1.5 times the upper limit of normal (ULN)
d) Aspartate amino transferase (AST) or alanine amino transferase (ALT) >3 times 
the ULN (if related to liver metastases >5 times the ULN)
e) Calculated creatinine clearance <50 ml/min (as evidenced by using the 
Cockcroft-Gault formula, see Appendix 2).
18. Women of child-bearing potential and men who are able to father a child, unwilling to be 
abstinent or to use adequate contraception during the trial and for at least six months 
after end of treatment. Adequate methods of contraception and definition of child-
bearing potential are described in Section 5.2.2.2.1.
19. Pregnancy or breast feeding.
20. Known or suspected hypersensitivity to any of the study medications or their excipients.
21. Patients unable to comply with the protocol, in the opinion of the investigator. 
3.3.4
Removal of patients from this trial or assessments
3.3.4.1
Removal of individual patients
A patient is to be permanently discontinued from study medication if:
1. The patient withdraws consent to further study medication.
2. Radiologically documented progressive disease (refer to Section 5.1.2).
3. Pregnancy (refer to Section 5.2.2.2.1).
4. Diagnosis of ILD.
5. Need further dose reductions but not allowed according to the protocol (see Section 
4.1.4).

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6. The patient is no longer able to receive the study medication (e.g. adverse events, 
concomitant diagnoses, concomitant therapies interfering with Afatinib or methotrexate, 
or administrative reasons), significant deviation from the protocol. 
At the time of study medication withdrawal the patient should return for a complete EOT visit. 
The information, including the reason for treatment discontinuation, will be recorded in the 
electronic Case Report Form (eCRF). See also Section 6.2.3 and the Flow Chart.
For safety reasons, the patient should come to the FUV four weeks after the EOT visit. 
Following the FUV, the patient will continue in the observational period. During this period vital 
status information, anti-cancer therapy, and related SAEs and AESIs will be collected every four 
weeks. For patients who progressed on treatment, the observation period for overall survival 
starts after the FUV (end of residual effect) visit. For patients who have not progressed on 
treatment, this period starts after the last additional FU visit. The observational period ends when 
the patient deceases.
A patient should be withdrawn from trial if:
1. The patient withdraws consent for any further trial procedures and follow-up activities.
Data of a withdrawn patients, regardless the patient received study medication or not, and the 
reason of withdrawal must be recorded in the eCRF.
Unless a randomised patient withdraws consent to be followed up, vital status information will 
be collected (e.g. by phone contact or check of medical records) until the entire trial has ended.
Patients who withdraw from the trial after randomization will not be replaced.
After completion of the primary analyses (see Section 7.3) and one year after last patient 
randomised, if there is still any patient on treatment, the sponsor may decide to conduct another 
interim DBL. The patients who are off treatment and have completed FU1 will be considered to 
have complete the study and will not be further followed in observational period.
The patients that are still on treatment at one year after last patient randomized can continue 
drug administration from the trial until disease progression or earlier if stop of treatment for 
other reasons is considered the best interest for the patient per investigator’s judgment.    
3.3.4.2 Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial overall or terminate a particular trial site at any time 
for the following reasons:
1. Fail to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the trial.
3. A trial site or investigator significantly violate GCP, the clinical trial protocol (CTP), or 
the clinical contract, which prevent the appropriate conduct of the trial. 
4. All the patients have discontinued study treatment by site or other cause by sponsor.

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The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except the third reason).

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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
Patients will be randomised to receive either Afatinib or methotrexate. 
4.1.1
Identity of BI investigational product and comparator product
Table 4.1.1: 1
Afatinib (investigational medicinal product, IMP)
Substance (INN):
Afatinib (BIBW 2992)
Pharmaceutical form:
Film-coated tablets
Source:
Boehringer Ingelheim Pharma GmbH and Co. KG.
Unit strength:
50 mg, 40 mg, 30 and 20 mg film-coated tablets
Daily dose:
Starting dose 40 mg. The dose is escalated to 50 mg and/or 
reduced to 40 mg, 30 mg, or 20 mg, see Section 4.1.4.1
Duration of use:
Continuous daily dosing in the absence of PD, unacceptable 
AEs or other reason necessitating permanent discontinuation
Route of administration:
Oral (swallowed)* For details refer to Section 4.1.4.1
Dose regimen:
Once daily
*
Afatinib should not be chewed nor crushed, but can be administered as a drinking suspension or via a feeding 
tube (e.g. gastric tube) after dispersing the tablet, see Section 4.1.4.1.
Table 4.1.1: 2
Methotrexate (active comparator)
Substance (INN):
Methotrexate 
Pharmaceutical form:
Injection solution
Source:
Boehringer Ingelheim will provide commercially available 
methotrexate
Unit strength:
50 mg/2 ml vial
Daily dose:
Starting dose 40 mg/m2 once a week (5.7 mg/m2 per day). 
The dose can be escalated to 50 mg/m2 and/or reduced to 40 
mg/m2, 30 mg/m2, or 20 mg/m2, see Section 4.1.4.2
Duration of use:
Continuous weekly dosing in the absence of PD, 
unacceptable AEs or other reason necessitating permanent 
discontinuation
Route of administration:
Intravenous bolus injection according to package insert (PI) 
or summary of product characteristics (SPC)
Dose regimen:
Once weekly
4.1.2
Method of assigning patients to treatment groups
After confirming that the patient meets all the eligibility criteria at Visit 2, the patient will be 
randomly assigned to Afatinib or methotrexate arm (with a randomization ratio of 2:1 for 
Afatinib: methotrexate). The randomization will be stratified according to ECOG performance 

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status (0 vs. 1) and prior treatment with EGFR-targeted antibodies for R/M HNSCC (yes vs. no). 
Details of stratification can be found in Section 7.5.
Randomization will be carried out centrally using an IVRS/IWRS. The company that provides 
the IVRS/IWRS will receive the randomization list from BI Clinical Trial Support Group or a 
CRO appointed by BI. The BI standard validated random number generating system will be used 
to generate the randomization list, which will be verified by an independent statistician who is 
not involved in the trial. The access to the randomization code will be supervised by the Clinical 
Trial Support Group. Any personnel directly involved in the conduct and analysis of the trial 
will have no access to the randomization schedule prior to the database lock.
The investigators will receive a manual describing how to access and use the IVRS/IWRS.
4.1.3
Selection of doses in the trial
Based on previous clinical trials, the MTD of Afatinib was identified as 50 mg once daily 
continuous dosing and this was used as a starting dose in the HNSCC proof of concept trial 
1200.28 (P10-12525). However, higher incidences of CTCAE grade 3 AEs (especially 
diarrhoea) were observed in this trial, and there seemed to be no loss of efficacy in patients dose 
reduced to 40 mg in the same trial. In a phase II trial in NSCLC patients, CTCAE grade 3 
diarrhoea (7%) and rash/acne (7%) was approximately one third of what was reported for 
patients starting on 50 mg once daily (24% diarrhoea and 25% rash/acne) (P10-12524). In other 
indications (including NSCLC) durable responses (>20 months) have been observed with daily 
doses of 40 mg and less (P10-09678). For an extensively pre-treated HNSCC population, it is 
considered that starting Afatinib treatment from 40 mg/day can optimise the efficacy/tolerability 
balance in this patient population. The daily dose will be modified following careful monitoring 
of patients side effects, as depicted in Table 4.1.4.1: 1. For patients with no or minimal AEs, 
Afatinib dose must be escalated to 50 mg/day. For patients experiencing drug-related AEs, dose 
should be reduced to 40 mg, 30 mg, or 20 mg. (see Section 4.1.4).
The recommended dose for the comparator, methotrexate, is 40 mg/m2 once weekly as bolus 
injections, which is considered adequate for HNSCC because this dose was effective  in several 
clinical trials (R10-6484, R10-5936). The option to increase the dose to 50 mg/m2 is based on 
common clinical practice and has also been integrated in previous clinical trials. Methotrexate 
dose should be reduced if the patient experiences drug-related AEs (see Section 4.1.4.2).
4.1.4
Drug assignment and administration of doses for each patient
4.1.4.1
Afatinib treatment
One bottle of 30 tablets will be dispensed to the patient at Visit 2 and then every four weeks 
regardless of any tablets remaining in the previous bottle. If dose reduction is necessary, the 
patient will return to the site to receive a new bottle of tablets. Patients should return old bottle 
before receive a new one.

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Treatment will start on Visit 2 (Day 1). Patients will take a single oral dose of Afatinib every 
day. The very first tablet should preferably be taken at the investigational site under the 
supervision of the investigator or delegate.
The Afatinib tablet should be swallowed with a glass of water (~250 ml). Afatinib tablets should 
not be chewed nor crushed, but may be administered after dispersing the Afatinib tablets 
according to the following procedure:
Place the tablet into a glass containing approximately 100 ml of non-carbonated drinking water 
or isotonic sodium chloride solution. Without crushing it, stir occasionally until the tablet is 
broken up into very small particles (may take up to 15 minutes), and drink the suspension 
immediately. Rinse the glass with another 100 ml of water and drink (to pick up any drug 
remaining in the glass). The Afatinib suspension can also be administered via a feeding tube 
(e.g. gastric tube).
Route of Afatinib administration is recorded in the eCRF. 
Afatinib should be taken around the same time (+/-2 hours) on each treatment day and at least 
one hour before food intake, and at least three hours after food intake.
Missed doses of Afatinib can be made up during the same day, if taken within 12 hours of the 
regularly scheduled time. Otherwise, the dose should be skipped and patients should take the 
next scheduled dose at the usual time. Afatinib tablet should not, under any circumstances, be 
taken more than once a day.  Patients with emesis should not take a replacement dose.
Each day, patients will take a single oral dose of Afatinib, starting on 40 mg. If a patient, at any 
time point during the treatment, experiences AEs necessitating dose reduction, the current dose 
should be paused and re-introduced at reduced dose (or treatment withdrawn) as described in 
Table 4.1.4.1: 1.
Dose escalation, Afatinib
The dose of Afatinib must be escalated to 50 mg (at the earliest after 28 days on study 
medication) if all the following criteria are met:

CTCAE grade ≤ 1 skin rash (any aetiology/relation)

Absence of diarrhoea, mucositis, and/or any drug-related event (any grade) other than skin 
rash CTCAE grade 1 and  

Compliance of  Afatinib intake is in 80~100% as described in Section 4.3

Dose was not previously reduced due to any of the AEs depicted in the dose reduction 
scheme (see Table 4.1.4.1: 1)
Dose escalation is prohibited in any situation other than that described above. The patient should 
remain on 50 mg unless dose reduction becomes necessary (see Table 4.1.4.1: 1).
Dose reduction, Afatinib
Treatment related AEs will be managed by treatment interruptions and subsequent dose 
reductions of Afatinib according to the schedule described in Table 4.1.4.1: 1. Dose reductions 

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will apply to individual patients only. Once the dose has been reduced, it may not be increased 
later.
Table 4.1.4.1: 1
Afatinib dose reduction scheme
AE type and CTCAE grade
Events related to study medication;

Any drug related AE grade ≥3.

Diarrhoea grade ≥2 persisting for 2 or more consecutive days (≥48 hours) despite 
adequate anti-diarrhoeal medication/hydration. 

Nausea and/or vomiting grade ≥2 persisting for 3 or more consecutive days despite 
anti-emetic treatment/hydration.

Reduced renal function to grade ≥1 as measured by serum creatinine, proteinuria, or 
glomerular filtration rate.
Action
Interrupt Afatinib treatment until patient has recovered to grade ≤1 (note for reduced renal 
function, recovered to grade <1) or to the CTCAE grade present at baseline1.
If patient has not recovered within 14 days, study medication should be permanently 
discontinued2.
Dose reduction scheme 
Resume treatment at reduced dose according to;
40 mg if the dose prior to the interruption was 50 mg.
30 mg if the dose prior to the interruption was 40 mg.
20 mg if the dose prior to the interruption was 30 mg.
No dose reduction is allowed below 20 mg.
1
Baseline is defined as the CTCAE grade prior to start of treatment
2
In the event that the patient is deriving obvious clinical benefit in the opinion of the investigator, but has 
not recovered within 14 days, the further treatment with Afatinib will be decided in agreement between the 
sponsor and the investigator.
In the event of a treatment pause, subsequent visits should not be delayed.
In the event of a prolonged (≥7 consecutive days) CTCAE grade 2 drug-related event not listed 
in Table 4.1.4.1: 1, which is poorly tolerated by the patient, the investigator may interrupt the 
medication for up to 14 days to allow the patient to recover followed by a dose reduction 
according to the scheme in Table 4.1.4.1: 1.

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In the event of any AEs other than listed in Table 4.1.4.1: 1, the investigator may choose to 
interrupt the medication for up to 14 days to allow the patient to recover, but no dose reduction 
should occur. 
If the investigator chooses to interrupt the study medication for more than 14 days but believes 
that the patient would derive clinical benefit from continuing medication, the decision to 
continue will be made by the sponsor in agreement with the investigator.
In case of major surgery, as judged by the investigator, it is recommended to interrupt Afatinib
treatment around one week prior to the surgery, and to resume treatment after complete wound 
healing. If the medication is interrupted for more than 14 days, the decision to continue with 
Afatinib will be made by the sponsor in agreement with the investigator.
4.1.4.2
Methotrexate treatment
Treatment will start on Visit 2 (Day 1). Patients randomised to the methotrexate arm will be 
administered intravenous bolus injections once a week. See methotrexate SPC/PI for warnings 
and precautions before initiating methotrexate treatment.
Patients will start on 40 mg/m2 methotrexate and continue (see Table 4.1.4.2: 1) on this dose in 
the absence of AEs necessitating dose reduction (see Table 4.1.4.2: 2). If no evidence of drug-
related AEs, the methotrexate dose may be escalated to 50 mg/m2 after two weeks of treatment 
at the discretion of the investigator.
In case the dose has been reduced once, it should not be escalated again.
Dose continuation and escalation, methotrexate
Table 4.1.4.2: 1
Methotrexate dose continuation and escalation criteria
Parameter
Recommended 
dose
After at least two 
consecutive weeks (only if 
current dose is 40 mg/m2)1
Neutrophil count ≥1.5x109/l, and Platelet 
count ≥75x109/l, and Calculated 
creatinine clearance2 ≥50 ml/min, and
Mucositis CTCAE grade ≤1, and
Other drug-related AE CTCAE grade ≤1
Continue current 
dose
Escalate to 50 mg/m2
1
At the discretion of the investigator
2
Calculated according to Cockcroft-Gault formula, see Appendix 2.
Dose reduction, methotrexate
Dose reductions will apply to individual patients only, as described in Table 4.1.4.2: 2. Once the 
dose has been reduced, it may not be increased later.

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Table 4.1.4.2: 2
Methotrexate dose reduction scheme
Event
Any of the following;

Neutrophil count <1.5x109/l

Platelet count <75 x109/l

Mucositis CTCAE grade > 1

Calculated creatinine clearance <50 ml/min

Any drug-related CTCAE grade ≥2
Action
Interrupt methotrexate treatment until patient has recovered or reaches the baseline1 values.
Discontinue study medication if:

Drug-related AEs requiring a treatment pause of more than three consecutive weeks

Any CTCAE grade ≥2 when treated with a dose of 20 mg/m2 per week.
Dose reduction scheme
Resume treatment at reduced dose according to:

40 mg/m2 if the dose prior to the interruption was 50 mg/m2

30 mg/m2 if the dose prior to the interruption was 40 mg/m2

20 mg/m2 if the dose prior to the interruption was 30 mg/m2
No dose reduction is allowed below 20 mg/m2.
1
Baseline is defined as the CTCAE grade prior to start of treatment
In the event of a treatment pause, subsequent visits should not be delayed.
In the event of any unrelated AE, the investigator may choose to skip one administration to 
allow the patient to recover, but no dose reduction should occur. If the investigator chooses to 
interrupt the study medication longer than 3 consecutive weeks but believes that the patient 
would derive clinical benefit from continuing medication, the decision to continue will be made 
by the sponsor in agreement with the investigator.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
There will be no blinding as discussed in Section 3.2. The eCRF will contain information on 
randomised treatment.
4.1.5.2
Procedures for emergency unblinding
Not applicable.

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4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF.
Trial drug packages will have unique medication numbers, which will be used for tracking 
purposes only. The medication numbers are different from the randomization numbers.
Afatinib will be supplied as film-coated tablets. Available dosage strengths will be 50 mg, 
40 mg, 30 mg, and 20 mg. Tablets will be supplied in child-resistant, tamper-evident bottles. 
Each bottle will contain 30 film-coated tablets of identical dosage strength.
Methotrexate will be supplied as vials containing 2 ml of 25 mg/ml solution.
Afatinib bottles and methotrexate vials will be labelled according to local regulations and will 
include the following as a minimum;

Trial number (1200.161)

Product name

Contents of the bottle/vial

Strength

Batch number

Medication number

Use-by date

Storage information

Instructions for use

Sponsor name and address

A statement that the medication is for clinical trial use only.
4.1.7
Storage conditions
Trial medication, which will be provided by the sponsor, must be kept in a secure, access-
controlled storage area under the storage conditions defined below until administered to patient. 
A temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. For facilities with a central alarm system, a print out of the temperature 
curves can be used and filed in the ISF. 
Afatinib tablets may be stored according to the storage conditions defined on the medication 
label. Any temperature excursion has to be reported to BI. BI needs to decide whether the 
impacted Afatinib is usable or not and inform site the decision. Documentation of this event 
should be filed in the ISF. Tablets 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. 
Methotrexate will be stored in accordance with the instruction on the label.

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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 from the sponsor when the following requirements are fulfilled:

approval of the trial protocol by the institutional review board (IRB) / ethics committee,

availability of a signed and dated clinical trial contract by related parties

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 CTP or immediately imminent signing of the CTP,

if applicable, availability of the proof of a medical licence for the principal investigator,
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 – upon check of the Clinical Research 
Associate (CRA) – the disposition of used and unused product(s) or alternative return to the 
sponsor. Upon completion of the trial, the investigator or delegate submits to BI a copy of the 
investigational drug dispensing and return log. 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the study medication and trial patients. The investigator or 
delegate will maintain records that document adequately that the patients were provided the 
doses specified in the CTP and reconcile all investigational products received from the sponsor. 
At the time of local destruction by site, 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
All concomitant (non-oncological) therapies (except for those listed in Section 4.2.2) are 
allowed. No additional oncological concomitant therapies are allowed during the treatment 
period with Afatinib or methotrexate. The exception is palliative radiotherapy to bones (see 
Section 4.2.1, Additional treatments).
All concomitant therapy, except for vitamins or appetite stimulants (with the exception of 
megesterol acetate; megesterol acetate is recorded in the eCRF), which are taken between the 
screening visit and 28 days after the last administration of Afatinib/methotrexate, should be 
recorded in the eCRF: Trade name, reason for use, and dates of administration must be 
documented.
For anti-cancer treatment (see Section 5.3.2.2), anti-emetic and anti-diarrhoeal also total daily 
dose and the respective unit must be documented.
If patients receive parenteral nutrition during the trial, the components do not need to be 
specified in detail. It is sufficient to report as “parenteral nutrition”. If a patient requires 
anaesthesia, it will be sufficient to indicate “anaesthesia” without specifying the drug. 

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Concomitant therapy for treatment of an AE, which has to be documented after the end of active 
treatment (i.e. AE which persists after the end of active treatment or which is drug related), have 
to be documented as long as the AE is reported.
4.2.1
Rescue medication, emergency procedures, and additional treatments

Rescue medication
Rescue medications to reverse the actions of Afatinib are not available. Side effects of these 
treatments should be treated symptomatically.
The current version of the IB lists the AEs expected with Afatinib Suggested treatments for 
diarrhoea, mucositis/stomatitis and dermatological AEs are described in Section 4.2.3.
Side effects of methotrexate should be treated symptomatically and according to SPC/PI and 
local practice. In case of over dosage with methotrexate, calcium folinate which can diminish the 
toxicity and counteract the effects of methotrexate should be administered according to 
recommendations in the SPC/PI or local practice.

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 ILD (Afatinib) 
or non-specific pneumonitis (methotrexate). Study medication should be interrupted pending 
investigation of these symptoms. If ILD (Afatinib treated patients) or methotrexate induced lung 
disease is diagnosed, study medication should be permanently discontinued and appropriate 
treatment should be administrated as necessary.
For patients treated with Afatinib: 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.

Additional treatments
During trial participation symptomatic treatment of tumour associated symptoms is allowed. 
Concomitant medications or therapy to provide adequate care may be given as clinically 
necessary. In this trial, best supportive care (BSC) in both treatment arms will be defined as the 
best care available judged by the attending physicians, according to the institutional standards 
for each centre. BSC includes e.g. nutritional support, antibiotics, analgesics, oxygen, anti-
emetics, transfusions, or any other symptomatic therapy (with the exception of cytotoxic 
chemotherapy) and/or assistance of a psychotherapist and/or physiotherapist. Localised radiation 
therapy to bones to alleviate pain is allowed provided that the total dose delivered is in a 
palliative range according to institutional standards and does not involve a target lesion(s) for 

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response evaluation. Study medication should be delayed during palliative radiotherapy and may 
be resumed once the patient has recovered from any radiation associated toxicity.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Additional experimental treatment is not allowed concomitantly with the administration of study 
medication, nor any additional anti-cancer therapy between four weeks prior to randomization 
and until EOT (with the exception of megestrol acetate and palliative short-course radiotherapy 
to bone lesions for pain relief).
Afatinib is a substrate of the P-glycoprotein (P-gp) transporter. Caution should be exercised 
when combining Afatinib with P-gp modulators (U03-3218). For a list of potent P-gp inhibitors 
and inducers (see Appendix 10.5). Patients treated with methotrexate should not receive any of 
the prohibited medications as listed in the current SPC/PI for methotrexate therapy.
4.2.2.2 Restrictions on diet and life style
For Afatinib: Patients should be advised to avoid lactose-containing products or any foods 
known to aggravate diarrhoea, see Section 4.2.3.1.
To prevent skin related adverse events intense irradiation with UV light should be avoided, see 
also Section 4.2.3.2.
For methotrexate: Compare SPC/PI.
4.2.3
Management of expected adverse events
Dermatologic AEs and diarrhoea are the most common side effects associated with treatment 
with Afatinib. Treatment of these side-effects should be proactive e.g. should be started as early 
as possible after onset of symptoms, and side effect management material will be given out to 
patients. Recommendations for management are described below. For dose modifications of 
Afatinib, see Section 4.1.4.1.
The most common undesirable effects of methotrexate treatment are ulcerative stomatitis, 
leukopenia, nausea, and abdominal discomfort. For further information, see the SPC/PI. For 
dose modifications of methotrexate, see Section 4.1.4.2.
4.2.3.1
Management of diarrhoea following treatment with Afatinib
Diarrhoea occurs at a high frequency and generally begins within two weeks of exposure to 
Afatinib. Although usually mild to moderate, diarrhoea may compel treatment modification or 
discontinuation, so early management is essential (see Table 4.2.3.1: 1). At the time of Afatinib
initiation, patients should be given anti-diarrhoeal agents (such as loperamide). Investigator 
should ask patients to keep anti-diarrhoeal agents with them at all times, and instruct the 

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appropriate use. Patients should also be advised to drink adequate an amount of fluids during 
diarrhoea. For the use of anti-diarrhoeal medication, please refer to local SPC/PI.
Table 4.2.3.1: 1
Grade specific treatment of Afatinib related diarrhoea
Severity
(CTCAE grade)
Description
Intervention concerning 
Afatinib dose
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 sufficient 
water or clear fluids per 
day
4 mg (2 tablets) of 
loperamide to be taken 
immediately, followed by 
2 mg (1 tablet) after each 
loose stool 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 activity 
of daily life (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 i.v. fluids and 
electrolyte replacement
Severe
(grade 3)
Increase of ≥7 stools per day 
over baseline
Incontinence
i.v. fluids >24 hours
Hospitalisation
Severe increase in ostomy 
output compared with 
baseline
Interfering with ADL
Dose interruption until 
recovered to grade ≤1 
followed by dose 
reduction1
See grade 2, plus:
An infectious process 
should be ruled out with 
stool cultures
Aggressive i.v. fluid 
replacement ≥24 hours
Hospitalisation 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 
reduction1
See grade 3
1.
If despite optimal supportive care and a treatment interruption, diarrhoea does not resolved to CTCAE 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.
4.2.3.2
Management of dermatological AEs following treatment with Afatinib
Dermatologic AEs of Afatinib include rash, acne, dermatitis acneiform, and dry skin. 
A proactive and early approach to the management is crucial, and depending on own clinical 
experience, early involvement of a dermatologist should be considered.

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Dermatologic events can be managed with a variety of treatment options to relieve symptoms 
and reduce the skin reaction. General recommendations for prophylaxis are summarised in Table 
4.2.3.2: 1 and grade-specific treatment recommendations are summarised in Table 4.2.3.2: 2
(adapted from Potthoff et al (R11-0826)). For dose adjustment refer to Section 4.1.4.1.
Table 4.2.3.2: 1
General recommendations for dermatological 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 is recommended.

Patients should be encouraged to consequently stay out of the sun.

Protective clothing for sun protection and wearing a hat should be 
recommended.
Moisturizer treatment

It is important to moisturize the skin as soon as anti-EGFR therapy is started.

Hypoallergenic moisturizing creams, ointments and emollients should be 
used once daily to smooth the skin and to prevent and alleviate skin dryness. 

Note: avoid greasy creams (e.g. petrolatum, soft paraffin, mineral oil based) 
and topical acne medications.
Prevention of paronychia

Patients should keep their hands dry and out of water if ever possible.

They should avoid friction and pressure on the nail fold as well as picking or 
manipulating the nail.

Topical application of petrolatum is recommended around the nails due to its 
lubricant and smoothing effect on the skin.

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Table 4.2.3.2: 2
Grade specific treatment recommendations of skin reactions to Afatinib
Severity
(CTCAE grade)
Description
Specific intervention
ACNEIFORM RASH (adapted from CTCAE version 3.0)
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. Caution should be 
exercised when combining Afatinib with 
strong P-gp modulators
Life threatening
(grade 4)
Generalized exfoliative, ulcerative, or 
bullous dermatitis
See grade 3
Systemic steroids are recommended. Caution 
should be exercised when combining Afatinib
with strong P-gp modulators
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 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 4.2.3.2: 2
Grade specific treatment recommendations of skin reactions to Afatinib,
continued
Severity
(CTCAE grade)
Description
Specific intervention
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
4.2.3.3
Management of mucositis/stomatitis
General and grade specific suggestions are described in Table 4.2.3.3: 1. For dose adjustment 
refer to Section 4.1.4.1 and for restrictions on concomitant therapies refer to Section 4.2.2.1.
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 approximately one 
litre (one quart) of water every four hours); avoidance of agents containing iodine, thyme 
derivatives and prolonged use of hydrogen peroxide; dietary manoeuvres such as promotion of 
soft, non-irritating foods like ice-creams, mashed/cooked vegetables, potatoes and avoidance of 
spicy, acidic or irritating foods such as peppers, curries, chillies, nuts and alcohol. If the patient 
is unable to swallow foods or liquids, parenteral fluid and/or nutritional support may be needed. 
Examples of some of the agents suggested in Table 4.2.3.3: 1 include: topical analgesics –
viscous lidocaine 2%; mucosal coating agents – topical kaolin/pectin; oral antacids, 
maltodextrin, sucralfate; topical antifungals – nystatin suspension (adapted from Porta et al
(P11-09424).

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Table 4.2.3.3: 1
Grade specific treatment recommendations of Afatinib related 
mucositis/stomatitis
Severity 
(CTCAE grade)
Description 
Treatment Suggestions
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 
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
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 
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 
4.3
TREATMENT COMPLIANCE
Study medications should be taken / administered according to the trial protocol. As per Section 
4.1.4, treatment interruptions for up to 14 days are allowed. For patients on Afatinib, treatment 
adherence will be calculated, see below. Patients who are not adherent according to the protocol 
should be carefully interviewed and re-informed about the purpose and the conduct of the trial. 
However, non-adherent patients with prolonged (>14 days) treatment interruptions not 
necessitated by AEs will not automatically be withdrawn from treatment. The investigator 
and/or the sponsor can, however, withdraw a patient from the study in the event of serious and 
persistent non-adherence, which jeopardizes the patient’s safety or renders study results for this 
patient unacceptable.
Afatinib: Patients randomised to Afatinib should take the first dose of Afatinib at the trial site 
and subsequent doses at home. On day 8, the site personnel should discuss treatment compliance 
with the patient, to ensure that the medication is taken correctly. The patients will be asked to 
bring all remaining tablets to the site at every visit when a new bottle is dispensed. The 
remaining tablets (if any) will be counted by the investigator or delegate. Treatment adherence 
will be calculated based on pill count, days since last pill count, and cumulative number of 
treatment interruption days due to AEs (see Table 4.1.4.1: 1). Compliance needs to be recorded 
on source note. Treatment compliance should be above 80%. Missed doses will be documented 
and explained, e.g. in the medical records. 
Compliance will be calculated according to the
formula:
%
100
period
same
in the
been taken
have
should
 which 
 tablets
of
Number 
count
t 
last table
since
aken 
actually t
 tablets
of
Number 
(%)
Compliance



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Methotrexate will be administered as an intravenous bolus injection at the investigational site. 
Date of administration will be recorded in the eCRF. In the event that a patient does not receive 
the full dose of methotrexate, its reason should be documented.

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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - PHARMACODYNAMICS
5.1.1
Endpoints of efficacy
The primary endpoint of this trial is progression free survival (PFS), defined as the time from the 
date of randomization to the date of progression evaluated according to RECIST 1.1 or to the 
date of death, whichever occurs first.
Secondary efficacy endpoints are:

Overall survival (OS), defined as the time from the date of randomization to the date of 
death (regardless of the cause of death).

Objective response defined as complete response (CR) or partial response (PR) 
determined by RECIST 1.1 according to the best response to study medication.

Health related quality of life (HRQOL).
5.1.2
Assessment of efficacy
5.1.2.1
Tumour imaging
Tumour response will be evaluated according to RECIST 1.1 (R09-0262). CR, PR, stable 
disease (SD) or progressive disease (PD) will be assessed by the investigator and also by an 
independent central review (see Section 5.1.2.2). After database lock for primary analysis, the 
requirement for independent central review will be removed.
The assessments should include imaging by computed tomography (CT) or magnetic resonance 
imaging (MRI) of the head and neck, chest and upper abdomen to include the liver and, if 
clinically indicated, imaging of any other known or suspected sites of disease using an 
appropriate method according to clinical practice at the site. The examinations should be 
performed at screening and every 6 weeks during the first 24 weeks after randomization, then 
every 8 weeks. After the database lock for primary analysis, the imaging intervals can change to 
follow local site standard (if no standard; every 16 weeks).

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The investigational site should strive to objectively evaluate tumour response and confirm 
tumour progression with radiological tumour imaging for all patients who enter into the trial, 
including those who discontinue study medication prematurely.
As per RECIST (version 1.1), one to five target lesion(s), not exceeding two lesions per organ, 
should be identified at screening by CT or MRI. Lesions will be individually recorded in the 
eCRF at screening and the size of the target lesions will be recorded in millimetres. The lesions 
must be followed up with the same method(s) used at screening. If a patient develops an allergy 
to contrast media, CT scans may be performed without contrast media or may be substituted by 
MRI.
If PET-CT is used, the CT part of the images must be of diagnostic quality.
Tumour imaging does not need to be performed at the screening visit if there are valid results 
available from assessments, which were performed as part of routine clinical practice within the 
allowed time window (within 21 days prior to randomization). However, in case the available 
image does not meet specifications in the central image manual, the exam must be repeated. 
Target lesions should be selected based on their size according to RECIST (1.1) and suitability 
for accurate repeated measurements. All other lesions should be identified as non-target lesions 
and will be recorded at baseline. The non-target lesions need to be followed during the patient’s 
scheduled imaging and will be taken into consideration when determining the patient’s response.
Details regarding imaging-assessment according to RECIST (version 1.1) are provided in the 
central image review guideline (see also Appendix 1).
In the event of a delay, interruption or discontinuation of treatment, tumour assessment should 
continue to follow the original schedule, until progressive disease is confirmed by imaging. In 
case patients who have no progression commence other anti-cancer therapies, tumour imaging 
should be performed in close proximity to the start of this other therapy.
5.1.2.2
Central image review
All image data will be sent to a blinded central image review unit to obtain an independent 
systematic interpretation of radiographic image data for all images. Upon receipt, the central 
review unit will log all image data into a tracking system and perform quality control of digitised 
radiographic images. An independent review of radiographic images including (i) sequential 
lesion selection and measurement, and (ii) incremental radiological response assessment 
followed by (iii) global review of tumour response or progression will be performed by two 
independent radiologists who are otherwise not affiliated with the trial and who are blinded with 
regard to patient, treatment, and visit. In the case of disagreement on the radiological assessment 
between the two primary reviewers, a third adjudicating radiologist will select one of the 
primary reviewer’s interpretations for all time points (details regarding adjudication will be 
clarified in the imaging charter).
All procedures will be done according to the specifications provided in the ISF and central 
image review charter.

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The results of the central image review will not be communicated to the investigator. Patient 
management including treatment decision will be based on the assessment of disease by the 
investigator.
After database lock for primary analysis, it will no longer be required to send any image data to 
the central imaging unit.
5.1.2.3
Health-related quality of life
Health-related quality of life (HRQOL) will be assessed with the following multidimensional 
patient reported outcome (PRO) measures:

EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer (EORTC) 
Quality of Life Questionnaire (QLQ-C30) (R09-0566).

EORTC Head and Neck cancer specific supplementary module (EORTC QLQ-H&N35) 
(R10-6455) 

EQ-5D health status questionnaire (R07-1314).
These questionnaires are widely used and validated (R07-4290, R09-5497, R09-5584, R10-
6456, R99-1213, R99-1214, R99-1216).
The EORTC QLQ-C30 comprises 30 questions. It incorporates both multi-item scales and 
single-item measures. These include one global health status / HRQOL scale, five functional 
scales (physical, role, cognitive, emotional, and social), three symptoms scales (fatigue, 
nausea/vomiting, and pain), and six single items to assess dyspnoea, insomnia, appetite loss, 
constipation, diarrhoea, and financial difficulties. Each of the multi-item scales includes a 
different set of items, i.e. no item occurs in more than one scale (R07-2064).
The EORTC QLQ-H&N35 module contains 35 questions of relevance to assess the HRQOL of 
patients with head & neck cancer varying in disease stage and treatment modality (i.e. surgery, 
radiotherapy and chemotherapy). The QLQ-H&N 35 module includes seven multi-item scales 
that assess pain, swallowing, senses (taste and smell), speech, social eating, social contact, and 
sexuality (R07-2064).
The EQ-5D is a standardised non-disease-specific measure of HRQOL designed for self-
completion by respondents, and it was developed for clinical and economic appraisal (R96-2382, 
R07-1314). The EQ-5D comprises the following two questionnaires:

Five dimensions of health (mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression). Each dimension comprises three levels (no problems, some/moderate 
problems, extreme problems).

The visual analogue scale (VAS) in which the respondent records self-rated health status on 
a vertical graduated (0-100) visual analogue scale.
According to research by Osoba et al. (R99-1223), where transformed QLQ-C30 raw scores 
ranging from 0-100 were compared to perceived changes as reported on the Subjective 
Significance Questionnaire (SSQ), patients who reported ‘little change’ had mean QLQ-C30 

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changes of 5-10 points. The change classifications of ‘moderate’ and ‘very much’ on the SSQ 
were reflected by changes of 10-20 points or more than 20 points on the QLQ-C30 respectively.
HRQOL will be assessed at the time points specified in the Flow Chart. The questionnaire will 
be filled in by the patients at a quiet area before any clinical assessment, treatment and provision 
of any new information about their disease status so that the responses are not influenced 
(biased). Once completed, the site staff should check for any unsolicited information provided 
by the patient on the questionnaire.
The questionnaire data are entered to the CRF.
HRQOL will be assessed in countries where validated translations are available and patients will 
receive the questionnaire in their native language till the FUV.
After database lock for primary analysis, the completion of the questionnaires is no longer 
required at any visit.
5.2
SAFETY
5.2.1
Endpoints of safety
Safety of Afatinib/methotrexate will mainly be evaluated by incidence and intensity of AEs, 
graded according to United States National Cancer Institute (NCI) CTCAE version 3.0 (R04-
0474). Safety endpoints include:

the overall incidence and intensity of adverse events 

gastrointestinal events (vomiting, nausea, diarrhoea)

skin reactions (rash, acne)

Change from baseline for all laboratory tests.
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
5.2.2.1.1 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.
5.2.2.1.2 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

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
requires or prolongs patient hospitalisation

is a congenital anomaly / birth defect

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.
Patients may be hospitalised for administrative reasons during the trial, including hospitalisation 
for respite care. These as well as hospitalisations, which were planned before the patient signed 
informed consent, need not be reported as SAEs if they have been documented at or before 
signing of the informed consent and have been performed as planned.
5.2.2.1.3 Intensity of adverse event
The intensity of AEs should be classified and recorded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 3.0 (R04-0474).
5.2.2.1.4 Causal relationship of adverse event
Medical judgement 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 CRF. 
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. 
5.2.2.1.5 Worsening 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 (e)CRF.
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)”.
5.2.2.1.6 Changes in vital signs, ECG, physical examination, and laboratory test results 
Changes in vital signs, ECG, physical examination, and laboratory tests will be recorded as an 
(S)AE in the (e)CRF, if they are judged clinically relevant by the investigator.

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5.2.2.1.7 Protocol Defined Adverse Event of Special Interest [AESI]
Although rare, drug-induced liver injury (DILI) is under constant surveillance by sponsors and 
regulators and is considered a protocol-defined adverse event of special interest (AESI). Timely 
detection, evaluation, and follow-up of laboratory alterations of selected liver laboratory 
parameters to distinguish an effect of the underlying malignancy on liver function from other 
causes are important for patient safety. The following are considered as AESI:

For patients with normal liver function (ALT, AST, bilirubin within normal limits) at 
baseline an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of 
bilirubin ≥2 fold ULN measured in the same blood draw sample and/or marked peak   
aminotransferase (ALT, and/or AST) elevations ≥ 10 fold ULN.

For patients with abnormal liver function at baseline an elevation of AST and/or ALT ≥5 
fold ULN combined with an elevation of bilirubin ≥2 fold ULN measured in the same blood 
draw sample and/or marked peak aminotransferase (ALT, and/or AST) elevations ≥ 10 fold 
ULN.
Patients showing these lab abnormalities need to be followed up according to Appendix 5 of this 
clinical trial protocol and the “DILI checklist” provided in the ISF.
Protocol-defined AESIs are to be reported in an expedited manner similar to SAEs, even if they 
do not meet any of the seriousness criteria – for details see Section 5.2.2.2.
If the investigator determines any protocol-defined AESI is related to study drug, the 
administration of the study drug must be managed according to Section 4.1.4 of the protocol. 
5.2.2.1.8 Expected adverse events
For expected (listed) AEs of Afatinib, see the current version of the IB (U03-3218). For 
methotrexate, see the adverse drug reaction section of the current SPC/PI.
5.2.2.2
Adverse event and serious adverse event reporting
The residual effect period (REP) for both Afatinib and methotrexate is 28 days.
All AEs will be collected starting from the signing of informed consent through the first per 
protocol visit following the REP. During this period the investigator is responsible for reporting 
to the sponsor all non-serious adverse events, serious adverse events and protocol defined 
adverse events of special interest (AESI) occurring in subjects treated by the investigator in the 
clinical trial.
After the end of treatment (including the REP) until the individual patient’s end of trial: collect 
all related SAEs and related AESIs.
After the individual patient’s end of trial, the investigator does not need to actively monitor 
subjects for AEs but should only report relevant SAEs and relevant AESIs which the 
investigator may become aware of.

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All AEs, including those persisting after end of study medication must be followed up until they 
have resolved or have been sufficiently characterised, unless the sponsor and the investigator 
agree not to pursue them further.
Reporting will be done according to the specific definitions and instructions detailed in the 
adverse event reporting section of the ISF. A summary of the AE reporting requirements is given 
in Table 5.2.2.2: 1.
Table 5.2.2.2: 1
AE/SAE reporting requirements
Period
Reporting requirements
Signing of informed consent to at least 28 
days after last administration of study 
medication.
Report all AEs and SAEs regardless of 
relatedness. This includes all deaths.
Post-treatment (>28 days after last 
administration of study medication) until 
completion of trial.
Collect all related SAEs and related AESIs.
Refer to Section 5.2.2.2 for details.
For each AE, the investigator should provide the onset date, end date, CTCAE grade, 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 
5.2.2.1.4.
The investigator must report the following events via fax using the SAE form immediately 
(within 24 hours) to the sponsor:

SAEs

non-serious AEs which are relevant for the reported SAE/AESI

protocol-defined AESIs
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.
The list of these AEs can be found in the RDC system.
With receipt of any further information to these events, a follow-up SAE report has to be 
provided. SAEs and non-serious AEs must include a causal relationship assessment made by the 
investigator.
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 or protocol-defined AESIs becomes available. 

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5.2.2.2.1 Pregnancy
Patients who are not of childbearing potential due to being postmenopausal (one year without 
menstruations without any other medical reasons) or surgical sterilisation (oophorectomy, 
hysterectomy) do not need to use contraception in order to be eligible for the trial.
All other patients who are considered to have childbearing potential should be abstinent or use 
adequate contraception throughout the trial (from screening until at least 28 days (patients 
treated with Afatinib) / at least six months (patients treated with methotrexate) after last dose of 
study medication).
Acceptable methods of contraception include surgical sterilisation, tubal ligation, 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.
In rare cases, pregnancy might occur in clinical trials. If a female subject becomes pregnant 
during treatment stage, the study medication must be permanently stopped.  Drug exposure 
during pregnancy has to be reported immediately (within 24 hours) to the defined unique entry 
point for SAE forms (country-specific contact details will be provided in the ISF). 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. Only if pregnancy is accompanied with a SAE, the SAE form 
must 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
Blood and urine samples will be collected at the time points specified in the Flow Chart and 
analysed in a laboratory facility at (or close to ) the investigational site. The sampling details are 
recorded in the eCRF. The laboratory report should be reviewed, signed and dated by the 
investigator.
Safety laboratory assessments may be performed according to local practice but must include at 
least the following parameters:
Haematology
Red blood cell count (RBC), haemoglobin, haematocrit, white blood cell 
count (WBC) and differential, platelet count, reticulocyte number.
Biochemistry
Serum glucose, sodium, potassium, calcium (including ionized calcium), 
magnesium, creatinine, urea, aspartate amino transferase (AST), alanine 
amino transferase (ALT), alkaline phosphatase, lactate dehydrogenase, 

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total bilirubin, γ-glutamyltransferase (GGT), albumin, creatine 
phosphokinase (CPK).
In case CPK is higher than ULN, further evaluation (e.g., by Troponin I 
assays, CPK isoenzymes and ECG exam) should be performed.
Glomerular Filtration Rate (GFR) will be estimated by the Cockcroft-
Gault Formula utilising serum creatinine values (see Appendix 2).
Coagulation
Prothrombin time (PT), partial thromboplastin time (PTT).
Urinalysis
pH, glucose, erythrocytes, leukocytes, protein, nitrite will be analysed at 
baseline and EOT only. In case of values out of range, further evaluation 
should be performed.
Pregnancy test
β-HCG testing in serum (alternatively in urine) will be performed in 
women of childbearing potential.
In case there is an obvious reason (for instance dehydration) for the laboratory results being 
abnormal at the screening visit, the laboratory sample(s) may be repeated.
The screening laboratory sampling must be done within two weeks before randomization. If the 
randomization is delayed beyond this, then the screening laboratory sampling must be repeated.
In case of neutropenia CTCAE grade 4, blood will be examined as clinically indicated at the 
discretion of the investigator until recovery.
Local lab results will be collected in the eCRF. Any AEs detected will be reported, see Section 
5.2.2.1.6.
5.2.4
Assessment of other safety parameters
5.2.4.1
Physical examination
A physical examination will be performed at screening and at the time points specified in the 
Flow Chart.
The physical examination should include the following;

cardiopulmonary examination

examination of the abdomen

skin examination

assessment of the mental and neurological status.
Additional symptoms or signs, which have not been reported during a previous examination, 
should be clarified. Wherever possible the same investigator should perform this examination.

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In case of cutaneous metastases, lesion(s) should be measured with caliper. If possible, 
photographic documentation should be performed.
5.2.4.2
Clinical head and neck examination
A head and neck examination will be performed at the time points specified in the Flow Chart. 
The examination should include the following;

inspection of the tumour site in order to document mucosal abnormalities and induration

oral and throat examination (pharyngolaryngoscopy should be included if deemed necessary)

palpation neck/regional lymph nodes

evaluation of cutaneous tumour/breakthrough of skin and local complications

sequelae of surgery, neck dissection, chemo-radiation, and size, location including level, 
fixation noted of palpable neck nodes should be documented.
If signs of progressive disease are observed at the head and neck examination, tumour imaging 
should be performed within two weeks.
5.2.4.3
Performance status score
Evaluation of the ECOG performance status will be performed at the time points specified in the 
Flow Chart. The ECOG performance status grading is found in Appendix 3.
5.2.4.4
Electrocardiogram
A 12-lead resting ECG will be performed at the time points specified in the Flow Chart. 
The investigator should review the ECG at the time of the assessment. The screening ECG will 
be used to make decisions on eligibility for the trial.
5.2.4.5
Vital signs and body weight
Vital signs (blood pressure and pulse after 5 minutes seated rest), and body weight (without 
overcoat and shoes) will be recorded at the time points specified in the Flow Chart.

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5.3.2
Other assessments
5.3.2.1
Demographics, medical history, smoking, and alcohol status
Demographics (sex, birth date, and race if allowed by local law), information on smoking and 
alcohol history, baseline conditions will be collected, and height will be measured during the 
screening visit.
The smoking history will be documented as follows;

smoking status; never smoker (<100 cigarettes/lifetime), current smoker or former 
smoker

number of pack years = (number of cigarettes (or equivalent) smoked per day × number 
of years smoked) / 20 (R08-4072)

date of last cigarette.
Weight changes within three months prior to randomization will be documented. Body weight at 
Visit 2 will be recorded as the baseline. Medical history (oncological and relevant non-
oncological) will be collected and recorded in the eCRF. History of HNSCC will be obtained 
during screening and the following information will be documented:

date of first histological/cytological diagnosis

primary tumour site

tumour histology and characteristics

stage according to the tumour, (lymph) node, metastasis (TNM) classification (as 
obtained at diagnosis)

previously administered chemotherapy, radiotherapy, immunotherapy and anti-EGFR 
targeted therapy; including start and end dates, reason for stopping, the treatment 
regimen, total dose (chemotherapy), best overall response to platinum based regimen for 
R/M disease, total radiation dose and radiation field (radiotherapy)

previous tumour surgery (date and location).
5.3.2.2
Concomitant therapies and diagnoses
Concomitant diagnoses and/or therapies present during trial participation (between the screening 
visit and at least until 28 days after the last administration of study medication) will be recorded 
in the eCRF. In case of medical or surgical procedures that would affect the assessment of the 
radiology findings, the investigator has to describe the type and location of intervention as well 
as the results from biopsy or cytology assessment in the eCRF.
Any anti-cancer therapy (including radiotherapy) administered after EOT and throughout the 
observational period, will be recorded in the eCRF with the same information as mentioned in 
Section 5.3.2.1.

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5.3.2.3
Assessment of healthcare resource use and home care
In case patients would be hospitalised due to AEs, the duration of hospital stay as well as the 
duration of staying in the intensive care unit, if any, will be documented in the eCRF.
Information on caregiver support (home care), GP, outpatient and hospital visits (other than 
scheduled visits) will be collected in the eCRF to inform on resource use required to treat the 
trial indication and adverse events observed during the trial. The data collected will be used for a 
health economic (cost effectiveness) analysis.
Information on healthcare resource use will be collected according to the Flow Chart.
5.3.3 
Pharmacogenomic evaluation
Pharmacogenetics investigates genetic variations in patients in order to explain and to predict 
their individual response to drugs. 
Participation in the pharmacogenetics part of the study is voluntary and not a prerequisite for 
participation in the clinical trial. A separate informed consent to allow pharmacogenetic analyses 
must be given in accordance with local ethical and regulatory requirements. After signing of the 
pharmacogenetic informed consent form, a blood sample will be collected from the randomized 
patient for DNA banking.
The blood sample (DNA-banking sample) will be completely anonymised. The anonymisation 
procedure will guarantee a very high level of data protection for the donor. The anonymised 
DNA may be analysed at a later time to identify whether there are genetic factors that could 
contribute to a better therapeutic outcome or a higher risk of developing treatment-related 
adverse drug reactions. These analyses may include genes related to efficacy and safety.
After anonymisation, this sample (or the DNA derived thereof) will be stored at BI Germany for 
maximum 15 years after the end of the clinical trial or until there is no more material available 
for tests.
The results of the pharmacogenetic analyses will not be directly reported to investigators.
5.3.3.1
Methods and timing of sample collection
For those patients who signed the pharmacogenetics informed consent, the blood sample will be 
taken after randomization at Visit 2 (or at any subsequent visit).
A maximum of 8.5 ml blood will be collected per PaxGene DNA blood sampling tube.
Detailed instructions for sampling, handling, and shipment of the pharmacogenetic samples are 
provided in the ISF.

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5.4
APPROPRIATENESS OF MEASUREMENTS
RECIST is used for evaluation of tumour response in solid tumours. These criteria are well 
established and well received by the regulatory authorities and scientific community. The patient 
reported outcomes questionnaires EORTC QLQ-C30, EORTC QLQ-H&N35, and EQ-5D used 
in the present trial are validated and have been widely used in cancer trials. The CTCAE criteria 
are used in the assessment of AEs in cancer patients. In the present trial version CTCAE version 
3.0 will be used although an updated version is published, however, since several pivotal
oncology trials are currently ongoing with the investigational product it is considered more 
appropriate to continue to collect safety data using the same criteria.
5.5
ASSESSMENT OF EXPLORATORY BIOMARKERS
The evaluation of several biomarkers will be performed in an exploratory way as a means of 
identifying patient subgroups with differential prognosis or response to treatment. This may 
include, but is not limited to, the determination of HPV infection status, the expression of the 
PTEN and Her3 genes and the assessment of the chromosomal amplification of the EGFR gene. 
Participation in the biomarker assessments is mandatory and the provision of samples for these 
assessments is thus a prerequisite for participation in the clinical trial. 
The collection of fresh tumour biopsies is viewed as not being generally feasible in this trial. 
Therefore, biomarker analyses will be normally based on archival tumour tissue and also fresh 
blood samples from which plasma and serum will be prepared. 
After signing of the biomarker informed consent, patients will be asked for archival tumour 
tissue samples. If archival tumour tissues are available from more than one occasion, the latest 
obtained sample should be used wherever possible. 
If no archival tumour tissue is available, a new tumour biopsy should be obtained. The site of 
biopsy (primary tumour, recurrent, lymphoid node, or metastatic site) will be recorded in the 
eCRF.
A brief description of the biomarker analyses to be performed is provided here.
5.5.1 Biomarker Assessments 
5.5.1.1
Tumour Biomarker Assessments
Exploratory assessments in tumour tissue include but not limited to:
HPV Infection Status will be assessed by a combination of indirect detection via measurement of 
p16 expression by immunohistochemistry (IHC) and by direct, in-situ, detection of HPV mRNA.
This information is important in the prognostication of Head and Neck SCC, particularly those 
originating in the oropharynx (R10-5928, R10-6444).

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Expression of EGFR, Her3 and PTEN will be measured by immunochemistry (IHC). This is to 
determine whether the expression of the EGFR and Her3 receptors, which are targets for 
Afatinib, and the downstream signalling partner gene PTEN are prognostic or predictive of 
improved response to the medications used in this trial. 
Amplification of the EGFR gene will be determined by means of fluorescence in-situ 
hybridisation (FISH) in order to determine whether activation of the EGFR by increase in gene 
copy number is prognostic or predictive of improved response to the medications used in this 
trial. 
mRNA Expression of the Target Receptors of Afatinib and the corresponding ligands may be 
performed by means of a multiplexed Nanostring assay, or any other suitable methodology such 
as TaqMan. This assessment will be performed discretionally and is intended to determine 
whether patients’ responses the trial medications are correlated to the mRNA expression, prior to 
treatment, of Afatinib’ s target receptors and their ligands. 
Somatic Mutations may be detected in the tumours by means of targeted assays or by DNA 
sequencing.  This assessment will be performed discretionally and is intended to determine 
whether the patients’ responses to the trial medications are correlated to the presence, prior to 
treatment, of specific somatic mutations within the tumours. These assessments may be 
performed in one or more of the target receptor genes, in a selected set of genes by means of a 
gene panel assay or in all genes using a technique such as Whole Exome Sequencing. 
5.5.1.2
Blood-based Biomarker Assessments
A blood sample will be collected from each patient prior to administration of the study 
medication as per the flow charts. This sample will be used to prepare plasma and serum in order 
to enable the assessment of blood based biomarkers. An additional blood sample will also be 
collected from each patient at the end of treatment (EOT) visit for the same purpose. 
In addition, the tumour and blood samples collected for biomarker assessments may be used for 
testing of other disease related tissue- or serum/ plasma-derived biomarkers that may be of 
scientific interest for understanding mechanisms of the disease after initiation/completion of this 
trial.
All exploratory analyses described above will be performed only if considered both feasible and 
clinically and/or scientifically justified at the time of the planned analyses. More detail 
information regarding analyte stability will be included in lab manual.
5.5.2
Endpoints based on biomarkers
No endpoints in this trial are based on biomarkers.
5.5.3.
Handling of Samples and Biomarker Results
Detailed instructions for handling, storage, and shipment of the biomarker samples will be 
provided in the laboratory manual included in the ISF. All required materials and labels will be 
provided. Date of sampling will be recorded in the eCRF.

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Further information on tissue slide preparation and storage conditions for measuring exploratory 
biomarkers via IHC will be given in the lab manual. 
10 slides of 5 m of FFPE tumour tissue from archival material will be needed for p16, 
Nanostring (mRNA) and somatic mutation analyses. One, but preferably two, core biopsies of 
approximately 1mm will be punched from archival tissue (if available) for TMA construction for 
all of the other analyses in tumour tissue material. 
A total of 9 mL blood will be collected comprising about 4.5 mL for the preparation of serum 
and about 4.5 mL for the preparation of plasma. The samples will be used for the exploratory 
analysis of biomarkers of relevance to response to the study medication, for example the levels 
in blood of the ligands of the ErbB receptor family (e.g. Heregulin 3).If local regulations allow, 
any excess materials at the central lab will be shipped and stored at BI’s central lab until all 
required validations have taken place or until it is decided that there is no requirement for 
validation. 
Samples will be destroyed no later than 15 years after trial completion
The analyses will be performed either by a CRO or by research collaborators within academic 
groups.
The results of the analyses will not be directly reported to investigators.
5.6
DRUG CONCENTRATION MEASUREMENTS – PHARMACOKINETICS
5.6.1
Methods and timing of sample collection
For patients randomized to Afatinib arm, blood sampling will be performed to determine the 
Afatinib pre-dose and 3 h post-dose plasma concentration at steady state.
Four (4) ml of venous blood samples will be collected in K-EDTA tubes at the time-points
specified in the table below, respectively.
Table 5.6.1:1
Time schedule for pharmacokinetic (PK) sampling
Visit
Day on 
treatment
Time of
sampling
Allowed time 
window
Planned time on 
CRF*
No. of sampling
V3
8
Just before 
Afatinib
intake
None
Hour -0:05
1: pre-dose
2-4hours after 
Afatinib
intake
+/-1:00 hour
Hour +3:00
2: post-dose
V6
29
Just before 
Afatinib
intake
None 
Hour -0:05
3: pre-dose
*: the time of Afatinib intake is considered as Hour 0:00.

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On Visit 2, site should remind patient NOT to take Afatinib tablet on the day of Visit 3 (Day 8) 
at home and also NOT take any food at least 3 hours before Visit 3. Instead, the patient should 
take the Afatinib bottle to site at Visit 3 (Day 8) and take Afatinib under the supervision of site 
personnel AFTER pre-dose PK sampling. The patient should also have no meal for at least 1 
hour after Afatinib intake. 
On Visit 5, site should remind patient again NOT to take Afatinib tablet on the day of Visit 6 
(Day 29) at home. Instead, it will be taken at site AFTER pre-dose PK sampling. 
Investigator and patients are strongly recommended to follow PK sampling schedule. Correct 
and complete documentation for drug administration and blood sampling is mandatory to ensure 
high quality data for pharmacokinetic analysis.
Date and time of pharmacokinetic blood sampling should be recorded on the eCRF. In addition, 
the dose, date, Afatinib medication time, and food time before / after Afatinib medication in the 
four (4) days prior to each PK sampling visit should be recorded in the eCRF.
A blank Patient Diary and PK sampling worksheet will be provided in ISF.
PK blood samples will be processed at site according to instruction in lab manual. Plasma 
derived from PK blood will be shipped to central lab for storage, and then forwarded to bio-
analytical lab on agreed shipment frequency for analysis. 

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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Written informed consent must be obtained before any protocol specific screening assessments 
are performed, and may be obtained prior to the screening visit. Separate written informed 
consents must be obtained before the collection of samples for pharmacogenetic and biomarker 
analyses.
Eligible patients will receive the randomised study medication for unlimited number of weeks, 
until any of the criteria for stopping medication are met (see Section 3.3.4). During the treatment 
phase, visits should be performed weekly, but within two days of the scheduled date. The 
scheduled time interval for each visit is relative to the date of randomization. Following the 
permanent discontinuation of study medication (EOT visit) and the follow-up visit, patients will 
be followed until death by contacts every four weeks.
In case a patient missed a visit and the patient reports to the investigator between the missed 
visit and the next scheduled visit, the date of the report and the reason for the delayed visit 
should be noted in the patient’s chart. The next visit, however, should take place at the 
scheduled time. In the event of any interruption/delay of treatment, the tumour assessment 
schedule should not be changed.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The assessments to be performed at the respective visits are outlined in the Flow Chart and the 
procedures for each assessment are described in Section 5.
6.2.1
Screening and randomization
The screening visit should be performed within 14 days before the first administration of study 
medication. Patients who meet the eligibility criteria will be randomised and treatment should 
commence on the same day the patient is randomised, but at least within four calendar days after 
randomization.
Baseline tumour images, obtained maximum 21 days prior to start of treatment, are acceptable if 
the same technique can be used for the following visits and the images fulfil the central imaging 
review requirements. If the screening images were obtained for routine assessment before 
informed consent, a clarification that the imaging was not performed for the purpose of the 
present trial must be clearly documented on source note.
If a patient is screened and screening images do not show progression after platinum based 
therapy, patient can be kept in screening until new images are obtained that can confirm PD 
according to RECIST. Visit 1 procedures must be repeated after PD is confirmed to ensure 
eligibility criteria are fulfilled before randomization.
HRQOL questionnaires should be filled in by the patient as the first activity at the relevant visits 
prior to receiving any new information about their disease status in order to avoid bias.

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6.2.2
Treatment period
Patients randomised to Afatinib will receive continuous daily oral treatment.
A Patient Diary will be dispensed to patients randomised to Afatinib to record study medication. 
Whenever dispensing a new Afatinib bottle, a new diary should be dispensed and the completed 
diary should be collected from the patient.  In case a patient is illiterate, site should aim to train 
the patient’s relative or care-giver how to complete the Patient Diary, if at all possible.
Patients randomised to methotrexate will receive weekly bolus injections.
The treatment period will continue for unlimited number of weeks, until disease progression is 
confirmed by tumour imaging or any of the other criteria for stopping medication are met (see 
Section 3.3.4).
There will be weekly visits during the treatment period, and for the first 24 weeks of treatment, 
the Flow Chart entitled “Visits 1-26” should be adhered to. Patients continuing beyond 24 weeks 
should then be followed according to the Flow Chart entitled “Visit 27 and onwards”.
Tumour imaging
Tumour imaging will be performed every 6 weeks during the first 24 weeks of treatment, and 
hereafter every 8 weeks until disease progression or start of subsequent anti-cancer therapy. As 
the primary endpoint of the trial is based on the tumour imaging evaluation, it is important that 
the imaging schedule is held. After the database lock for primary analysis, the imaging intervals 
can change to follow local site standard (if no standard; every 16 weeks).
Health related quality of life
To avoid potential bias, HRQOL questionnaires should be filled in by the patient as the first 
activity when the patient comes to the clinic prior to seeing the clinician and prior to receiving 
any new information about their disease state. After database lock for primary analysis, the 
completion of the questionnaires is no longer required at any visit.
Biomarkers and pharmacogenetics
The tumour tissue slides and core punch biopsies should be sent to the central laboratory as soon 
as possible as described in the investigator lab manual. The serum sample should be drawn at 
Visit 2 (see Flow Chart) and sent to the central laboratory as described in the investigator lab 
manual.
For patients consenting to the pharmacogenetic part of the trial, blood sampling should be 
performed, preferably at Visit 2, and sent to the central laboratory.

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6.2.3
End of treatment and follow-up period
6.2.3.1
End of treatment visit
The end of treatment (EOT) visit will be performed when the patient permanently discontinues 
the study medication.
The decision to permanently discontinue study medication due to disease progression must be 
based on the evaluation of tumour imaging. If the decision to permanently discontinue the study 
medication is taken during a scheduled visit, the EOT visit procedures should be performed 
instead of the scheduled visit. If the decision is taken between scheduled visits, the EOT visit 
should be performed no later than seven days after the last treatment administration.
In the case study medication is permanently discontinued due to reasons other than disease 
progression or withdrawal of consent, the EOT visit will be performed, and the patient should 
continue the tumour imaging according to the pre-defined schedule until disease progression or 
start of other anti-cancer therapy. If a patient who did not have disease progression needs 
commence of other anti-cancer therapy, tumour imaging should be performed close to the start 
of new anti-other therapy. After the database lock for primary, the requirement to continue 
imaging for patients who permanently discontinued study medication due to other reasons than 
disease progression will be removed.
The investigator will, in consultation with the patient, decide the future treatment.
The patients that are still on treatment at one year after last patient randomized can continue 
drug administration from the trial, until disease progression or earlier if stop of treatment for 
other reasons is considered the best interest for the patient per investigator’s judgment. An 
interim database lock will occur at around one year after last patient randomized. After this 
interim lock, only AE, dose change, drug termination date and cause of termination are required 
to be collected in RDC or BRAVE, and all the other trial procedures will be waived.
6.2.3.2
Follow-up visit
All patients should have a follow-up visit (FUV) 28 days (+7 days) after the EOT visit.
Patients who stopped the study medication in spite of no disease progression should continue the 
tumour imaging according to the protocol defined schedule until progression or start of other 
anti-cancer therapy. If the time window (7 days) allows, the FUV visit should be performed on 
the same day of the tumour imaging. After the database lock for primary analysis, the 
requirement to continue imaging will be removed.
6.2.3.3
Observational period
For patients who progressed on treatment, the observation period for overall survival starts after 
the FUV (end of residual effect) visit. For patients who have not progressed on treatment, this 
period starts after the last additional FU visit.

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During the observational period, i.e., after the FUV and until death, withdrawal of consent or 
lost to follow-up, the following information will be collected;

vital status

Related SAEs/related protocol-defined AESIs

Anti-cancer therapy, including radiotherapy (type, dose, start and stop dates, and reason for 
stopping).
A formal visit is not required, and the method of contact as well as the date will be recorded in 
the eCRF.
Besides collecting vital status as per the schedule in the Flow Chart, the sites will contact 
patients and/or their health care providers to collect the most up-to-date vital status so that the 
latest information can be available before pre-specified data analysis as specified in Section 
7.3.1. Death information from public sources, e.g. death registry, obituary listing, etc. can also 
be used when it is available and verifiable. This approach is referred to as an endpoint in the 
literature (R10-5907).
Patients who stopped the study medication without disease progression should continue the 
tumour imaging during the observational period according to the protocol defined schedules 
until progression or start of other anti-cancer therapy. After the database lock for primary 
analysis, the requirement to continue imaging will be removed.

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7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE 
SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a randomised, multicentre, open-label, active-controlled study with two parallel arms. 
Eligible patients will be stratified by their ECOG performance score (0 vs. 1) and prior use of 
EGFR-targeted antibodies for R/M HNSCC (yes vs. no) at baseline. Within each stratum, they 
will be randomised to either the Afatinib arm or the methotrexate arm with a randomization ratio 
2:1. The primary endpoint PFS is a time-to-event endpoint. Based upon these design 
considerations, the trial will be analysed using stratified logrank test with baseline ECOG score 
and prior use of EGFR-targeted antibodies for R/M HNSCC being the stratification factors.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The null hypothesis is that Afatinib and methotrexate are equally effective in terms of PFS:
H0: Saftinib(t) = SMTX(t), for t > 0,
Where S(t) is the probability that a patient has no disease progression or death up to time t.
The alternative hypothesis is that Afatinib is more effective than methotrexate in terms of PFS:
H1: Saftinib(t) > SMTX(t), for t > 0.
7.3
PLANNED ANALYSES
Two analysis data sets will be used.
Randomised Set (RS): this data set includes all patients who are randomised, regardless of 
taking investigational treatment.
Treated Set (TS): the data set includes all randomised patients who take at least one dose of 
investigational treatment.
7.3.1
Primary analyses
Primary analyses will be based on Randomised Set and patients will be analysed as randomised.
When the required number of progression (or death) events (see Section 7.6) is achieved,
primary analysis will be performed. Updated analysis if needed will be performed at interim 
DBL (if any) after primary analyses and at study completion.

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7.3.1.1
Primary endpoint PFS
The primary endpoint of this study is PFS, defined as time from the date of randomization to the 
earlier date of progression or death. For the primary analysis, disease progression is evaluated 
according to RECIST 1.1 by independent central review.
For a patient with known date of progression (or death), the event date will be the date of 
progression or the date of death, whichever comes first:
PFS [days] = min (date of progression, date of death) – date of randomization + 1.
For patients known to be alive and without progression by the time of database lock for the 
primary analysis, they will be censored at the date of last imaging when the patient is known to 
be progression-free and alive:
PFS (censored) [days] = date of last imaging when the patient is known to be 
progression-free and alive – date of randomization + 1.
Stratified logrank test, with two strata baseline ECOG score (0 vs. 1) and prior use of EGFR 
antibodies for R/M HNSCC (yes vs. no), will be used to test H0 and obtain p-value. 
The Kaplan-Meier method will be used to estimate the 25th percentile, median, and 75th
percentile PFS for each treatment group. For the median PFS point estimate, the 95% CI will be 
constructed using the Greenwood variance estimate.
Stratified Cox proportional-hazards model will be used to derive hazard ratio between the two 
treatment groups using methotrexate as the reference and its 95% CI. The two stratification 
factors will be included in the Cox model as strata. 
Table 7.3.1.1: 1 describes rules of determining PFS for the primary analysis.

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Table 7.3.1.1: 1 Determination of PFS for the primary analysis
Situation
Date of progression or censoring
Outcome
Without post-baseline radiological assessments
1. Alive 
Date of randomization
Censored
2a. Death prior to the second 
scheduled image
Date of death
Progressed
2b. Death beyond the second 
scheduled image
Date of randomization
Censored
With post-baseline radiological assessments BUT no other anti-cancer therapy
3. Alive and no progression
Date of last radiological assessment 
of measured lesions 
Censored
4a. Death but no progression, zero or 
one missed image prior to death
Date of death
Progressed
4b. Death but no progression, two or 
more missed images prior to death
Date of last radiological assessment 
of measured lesions
Censored
5a. Progression, zero or one missed 
image prior to progression
Date of radiological assessment of 
progression
Progressed
5b. Progression, two or more missed 
images prior to progression
Date of last radiological assessment 
of measured lesions prior to 
progression
Censored
With post-baseline radiological assessments AND other anti-cancer therapy
6. New anti-cancer therapy started 
before progression (or death)  
Date of last radiological assessment 
before other new anti-cancer 
therapy 
Censored
7a. Progression before new anti-
cancer therapy, zero or one missed 
image prior to progression
Date of radiological assessment of 
progression
Progressed
7b. Progression before new anti-
cancer therapy, two or more missed 
image prior to progression
Date of last radiological assessment 
of measured lesions prior to 
progression
Censored
7.3.2
Secondary analyses
7.3.2.1 OS
One of the secondary endpoint of this study is OS, defined as time from the date of 
randomization to the date of death.
For patients with known date of death (regardless of the cause of death):
OS [days] = date of death – date of randomization +1. 
For patients known to be alive by the end of trial or the last follow-up visit:

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OS (censored) [days] = the last date when the patient is known to be alive – date of 
randomization +1.
OS will be analysed similarly to PFS, including using the stratified logrank test, the Kaplan-
Meier method and the stratified Cox proportional hazards model.
Primary analyses will be based on Randomised Set and patients will be analysed as randomised. 
7.3.2.3
Objective response
Each patient will be assigned to one of the following RECIST categories in terms of best overall 
response based on independent central review, irrespective of protocol violations or missing 
data:
1 = CR (complete response)
2 = PR (partial response)
3 = SD (stable disease)
4 = PD (progressive disease)

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9 = unknown (not assessable, insufficient data)
Objective response is defined as CR or PR. Cochran’s statistic will be used to test difference 
between two treatment groups for the proportion of patients with objective response adjusting 
for two baseline stratification factors.
7.3.2.6
Health related quality of life
The main analysis of HRQOL questionnaires will focus on the change in score from baseline in 
the following scales measured on the EORTC QLQ-C30 (R09-0566) and EORTC QLQ-H&N35 
(R10-6455):

Pain Scale (composite of items 31-34 of the QLQ-H&N35)

Swallowing Scale (composite of items 35-38 of the QLQ-H&N35)

Global Health Status/QOL Scale (composite of items 29 and 30 of the EORTC QLQ-C30)
Scoring of the symptom scales/items will follow the EORTC scoring algorithm. For ease of 
interpretation, a linear transformation will be used to standardise the raw scores of all items and 
scales, so that scores range from 0 to 100 (R07-2064). A higher score represents a higher 
(‘better’) level of functioning (functional scales, global health status/QOL), or a higher (‘worse’) 
level of symptoms (symptom scale/item).
Status change (improved, stable, or worsened) from baseline in Global Health Status/QOL scale, 
functional scale and symptom scale will be tabulated by treatment group.
HRQOL data collected using the EQ-5D questionnaire will be analysed descriptively including 
the changes over time by treatment group.
7.3.3
Safety analyses
Safety analyses will be based on Treated Set, i.e., all patients who receive at least one dose of 
study medication will be included in the analysis of safety. The safety analysis will be 
descriptive and exploratory in nature. Adverse events will be graded according to United States 
NCI CTCAE, Version 3.0 (R04-0474).

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Key safety measures will include:

the overall incidence and intensity of AEs, as well as relatedness of AEs to treatment and 
seriousness of AEs

AEs leading to dose reduction or permanent treatment discontinuation

gastrointestinal events (vomiting, nausea, diarrhoea)

skin reactions (rash, acne)

other serious or significant AEs according to ICH E3

decreased cardiac left ventricular function (reduction to below LLN and ≥20% decrease 
compared to baseline)

CTCAE grade 2 with increase by at least one CTCAE grade from baseline, for selected 
laboratory tests:

(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

causes of death.
7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacogenomic analyses
Pharmacogenomic data will be analysed separately.
7.3.6
Pharmacokinetic methods
Afatinib plasma concentrations will be summarized by descriptive statistics and graphically 
inspected. 
Objectives of this analysis will be:

to describe the pre-dose (Cpre,ss,N) and 3 h post-dose (Ct,N) Afatinib plasma concentrations 
at steady state

to estimate the inter-individual and intra-individual variability of Afatinib plasma 
concentrations

to explore potential impact of mode of Afatinib administration (oral administration as tablet 
versus oral administration as drinking suspension after dispersing the tablet versus 
administration as suspension via a feeding tube (e.g. gastric tube) after dispersing the tablet) 
on exposure if feasible
The derivation of pharmacokinetic parameters is described in detail in the relevant Corporate 
Procedure of the Sponsor.
All evaluable subjects who received at least one dose of Afatinib and with at least one valid 
Afatinib plasma concentration available will be included in the pharmacokinetic analysis. 

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Subjects who are considered as not evaluable will be listed with their individual plasma 
concentrations and individual pharmacokinetic parameters, however, will not be included in 
descriptive statistics for plasma concentrations, pharmacokinetic parameters or other statistical 
assessment.
Concentrations will be used for graphs and calculations in the format that is reported in the 
bioanalytical report. Only concentrations within the validated concentration range will be used 
for the calculation of pharmacokinetic parameters. For pre-dose samples, the actual sampling 
time will be set to zero.
Plasma concentrations will be plotted graphically versus time for all evaluable subjects as listed 
in the drug plasma concentration-time tables. For the presentation of the mean profiles, the 
geometric and arithmetic mean and the planned blood sampling times will be used.
The following descriptive statistics will be calculated for analyte concentrations as well as for all 
pharmacokinetic parameters: N, arithmetic mean, standard deviation, minimum, median, 
maximum, arithmetic coefficient of variation, geometric mean, and geometric coefficient of 
variation. The data format for descriptive statistics of concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of pharmacokinetic 
parameters will be calculated using the individual values with the number of decimal places as 
provided by the evaluation program. Then the individual values as well as the descriptive 
statistics will be reported with three significant digits in the clinical trial report.
7.4
HANDLING OF MISSING DATA
All reasonable efforts will be undertaken to determine the date and cause of death for each 
patient in the study, including, but not limited to, telephone follow-up and search of death 
registry databases.
The independent central review unit will work with the clinical sites towards a standard 
implementation of RECIST. This will include development of a charter detailing all procedures. 
The charter will include extensions to the criteria needed to handle missing values, such as target 
lesions that become non-evaluable, or are not evaluable at a single point. In addition to the 
standardized imaging and reporting procedures enforced by the independent central review unit, 
all patients will undergo follow-up for progression (based on tumour imaging) until they (1) 
receive any other anti-cancer therapy, (2) experience progression of disease and no benefit of 
continuing current therapy in the opinion of investigator, or (3) die.
Handling of missing PK data will be performed according to the relevant Corporate Procedure of 
the Sponsor.
Drug concentration data identified with NOS (no sample available), NOR (no valid result), NOA 
(not analyzed), BLQ (below the lower limit of quantification), or NOP (no peak detectable) will 
be displayed as such and not replaced by zero at any time point.

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7.5
RANDOMIZATION
After screening, eligible patients will be stratified by their ECOG performance score (0 vs. 1) 
and prior use of EGFR-targeted antibody therapy in the recurrent/metastatic setting (yes vs. no). 
There will be four strata:
Stratum 1: ECOG score 0 and no prior use of EGFR-targeted antibody therapy in the R/M 
setting;
Stratum 2: ECOG score 0 and prior use of EGFR-targeted antibody therapy in the R/M setting;
Stratum 3: ECOG score 1 and no prior use of EGFR-targeted antibody therapy in the R/M 
setting;
Stratum 4: ECOG score 1 and prior use of EGFR-targeted antibody therapy in the R/M setting;
Within each stratum, patients will be randomised (2:1) to receive either Afatinib or 
methotrexate.
The process of randomization is done via an IVR/IWR system (see Section 4.1.2).
7.6
DETERMINATION OF SAMPLE SIZE 
The median PFS for methotrexate is assumed to be 2.1 months based on a study by Machiels et 
al (R11-0801); the median PFS for Afatinib is assumed to be 3.0 months based on a BI phase II 
trial 1200.28 by Seiwert et al (P10-12525). With the assumption of Exponential distribution for 
time to progression (or death), this transforms to a hazard ratio of 2.1/3.0 = 0.70. Given a 
randomisation rate of 9.5 patients per month (2:1 ratio for Afatinib: methotrexate) and one-sided 
type-I error α=0.025, this trial requires a total of 274 progression events and approximate 330
randomised patients to have 80% power. Total randomized patients might be adjusted to ensure 
274 PFS events can be observed at primary analyses.
If the true hazard ratio is 0.65 (2.1 months median PFS for methotrexate and 3.23 months 
median PFS for Afatinib), a total of 274 progression events would yield a power of 92.3% given 
that all other parameters remain constant.

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Table 7.6: 1
Number of events and randomised patients needed with one-sided 
α = 0.025 and randomisation ratio 2:1*
Endpoint
Median (month)
Hazard 
Ratio
Power 
(%)
Total 
number of 
events 
needed
Total number of 
randomised 
patients needed
methotrexate
Afatinib
PFS
2.1
3.0
0.7
80
274
330
PFS
2.1
3.23
0.65
92.3
274
330
*Assuming a randomisation rate of 12.5 patients per month and Exponential distribution for time to death. 
Calculation performed using EAST version 5.3 software using the module of “Two-Sample Test - Logrank 
Test: Basic” for survival superiority Trials.
Table 7.6: 1 summarises sample size calculation for PFS. This study will power for PFS (80%)! 
"#$%$&'%$ 
(%')*+ ,,-
.("/$*"0 1/22 3$ %(*+'4/5$+ "' (6#/$7$ "#$ 8'(29

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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.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of the 
protocol or of ICH GCP*.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor 
with regard to publication of the results of this trial are described in the Investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
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 or an impartial witness) according to ICH 
GCP and to the regulatory and legal requirements of the participating country. Each signature 
must be personally dated by each signatory. A signed and dated copy of the informed consent 
and any additional patient information must be given to each patient or the patient’s legally 
accepted representative. The other copy will be retained by the investigator as part of trial 
records.
The Investigator must give a full explanation to trial patients based on the patient information 
form. A language understandable to the patient should be chosen, technical terms and 
expressions avoided, if possible. The patient must be given sufficient time to consider 
participation in the trial. The Investigator obtains written consent of the patient’s own free will 
with the informed consent form after confirming that the patient understands the contents. The 
Investigator must sign (or place a seal on) and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or places a 
seal on) and dates the informed consent.
The patient must be informed that his/her personal trial-related data will be used by BI in 
accordance with the local data protection law. The level of disclosure must also be explained to 
the patient.

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The patient must be informed that his/her medical records may be examined by BI’s 
representative such as CRA, Clinical Monitor Local (CML), Compliance Manager, Clinical 
Quality Assurance auditors, or appropriate IRB/IEC members, or 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 auditor will have 
access to all medical records, the investigator’s trial-related files and correspondence, and the 
informed consent documentation of this clinical trial.
8.3
RECORDS
Case report forms (CRFs) for individual patients will be provided by the sponsor via remote data 
capture. For drug accountability, refer to Section 4.1.8.
The data management procedures to ensure the quality of the data are described in detail in the 
trial data management and analysis plan (TDMAP) available in the CTMF. Coding of the data 
obtained will be done by using the medical dictionary for regulatory activities (MedDRA) and 
the world health organisation drug dictionary (WHO-DD).
8.3.1
Source documents
In accordance with regulatory requirements the Investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and other 
data pertinent to the investigation on each trial subject. Source data as well as reported data 
should follow good documentation practices and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail). Data reported on the 
CRF must be consistent with the source data or the discrepancies must be explained.
The current medical history of the subject may not be sufficient to confirm eligibility for the trial 
and the Investigator may need to request previous medical histories and evidence of any 
diagnostic tests. In this case the Investigator must make three documented attempts to retrieve 
previous medical records. If this fails a verbal history from the patient, documented in their 
medical records, would be acceptable.
Before providing any copy of patients’ source documents to the sponsor the investigator must 
ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, social 
security number) have properly been removed or redacted to ensure patient confidentiality.
If the patient is not compliant with the protocol, any corrective action e.g. re-training must be 
documented in the patient file.
For the CRF, data must be derived from source documents, for example:

Patient identification: gender, date or year of birth (in accordance with local laws and 
regulations)

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
Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

Completion of Patient’s Participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).
Prior to allocation of a patient to a treatment into a clinical trial, there must be documented
evidence in the source data (e.g. medical records) that the trial participant meets all inclusion 
criteria and does not meet any exclusion criteria. The absence of records (either medical records, 
verbal documented feedback of the patient or testing conducted specific for a protocol) to 
support inclusion/exclusion criteria does not make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of on-site monitoring will be determined by assessing 
all characteristics of the trial, including its nature, objective, methodology and the degree of any 
deviations of the intervention from normal clinical practice.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). The CRA and auditor may review all CRFs and informed consents. The accuracy of 
the data will be verified by direct comparison with the source documents described in section 
8.3.1. The sponsor will also monitor compliance with the protocol and ICH GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.

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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). For 
methotrexate this is an EU SPC. The current versions of these reference documents are to be 
provided in the ISF. No AEs are classified as listed for matching 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 
ISF.
8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered confidential 
and should not be disclosure to third parties with the exceptions below. When information of a 
patient is cited, patient’s confidentiality will be assured by using patient identification number 
only.
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
TRIAL MILSTONES
The start of the trial is defined as the date of the enrolment of the first patient in the whole trial.
The end of the trial is defined as after all patients have terminated investigational treatments 
and have completed one follow-up visit, and number of required PFS events has occurred.
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the last 
patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of SUSARs occurring with the trial 
medication until 30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.

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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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10(8):1245-1251
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Harrington KJ, EI-Hariry IA, Holford CS, Lusinchi A, Nutting CM, Rosine D, et 
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locally advanced squamous cell carcinoma of the head and neck. J Clin Oncol 
2009; 27(7):1100-1107
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Schornagel JH, Mulder PHM de, Cognetti F, Vermorken JB, Cappelaere P, 
Armand JP, et al. Randomized phase III trial of edatrexate versus methotrexate in
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Kalyankrishna S, Grandis JR. Epidermal growth factor receptor biology in head 
and neck cancer. J Clin Oncol 2006:24(17); 2666-2672
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Experience collecting interim data on mortality: an example from the RALES 
study. Curr Control Trials Cardiovasc Med 2001; 2(1):59-62
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Gregoire V, Lefebvre JL, Licitra L, Felip E, EHNS-ESMO-ESTRO Guidelines 
Working Group. Squamous cell carcinoma of the head and neck: EHNS-ESMO-
ESTRO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann 
Oncol 2010; 21(Suppl 5):V184-V186
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Chung CH, Ely K, McGavran L, Varella-Garcia M, Parker J, Parker N, et al. 
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poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol 2006;
24(25):4170-4176
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et al. Epidermnal growth factor receptor inhibitor gefitinib added to 
chemoradiotherapy in locally advanced head and neck cancer. J Clin Oncol 2010;
28(20):3336-3343
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Human papillomavirus and survival of patients with oropharyngeal cancer. N 
Engl J Med 2010; 363(1):24-35
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Kumar B, Cordell KG, Lee JS, Worden FP, Prince ME, Tran HH, et al. EGFR, 
p16, HPV Titer, Bcl-xL and p53, sex, and smoking as indicators of response to 
therapy and survival in oropharyngeal cancer. J Clin Oncol 2008; 26:3128-3137
R10-5936
Stewart JSW, Cohen EEW, Licitra L, Herpen CML van, Khorprasert C, Soulieres 
D, et al. Phase III study of gefitinib compared with intravenous methotrexate for 
recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 2009;
27(11):1864-1871
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Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J 
Med 2008; 359(11):1116-1127
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hybridization and p16 immunohistochemistry in the detection of human 
papillomavirus-associated head and neck cancer based on a prospective clinical 
experience. Cancer 2010:116; 2166-2173
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(access date: 1 December 2010) 1994
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of Life Head and Neck Module (QLQ-H&N35). Arch Otolaryngol Head Neck 
Surg 2000; 126:459-467
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comparison of high-dose infusion methotrexate versus standard-dose weekly 
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patients with recurrent or metastatic squamous-cell carcinoma of the head and 

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neck after failure of platinum-based chemotherapy: an open-label, randomised 
phase 3 trial. Lancet Oncol, 2011;12:333-343
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German expert opinion. Ann Oncol 2011:22(3); 524-535
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Seiwert TY, Burtness B, Mehra R, Weiss J, Berger R, Eder JP, et al. Safety and
clinical activity of pembrolizumab for treatment of recurrent or metastatic 
squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, 
multicentre, phase 1b trial. Lancet Oncol 2016;17:956-965
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combined with durvalumab in EGFR-mutant non-small cell lung cancer: results 
from the TATTON phase lb trial. 6th Eur Lung Cancer Conf (ELCC), Geneva, 
13-16 Apr 2016, J Thorac Oncol 11 (4) (Suppl), S115, Abstr 1360
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al. Nivolumab for recurrent squamous cell carcinoma of the head and neck. N 
Engl J Med 2016;375(19);1856-1867
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EORTC Study Group on Quality of Life. The European Organization for 
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in international clinical trials in oncology. J Natl Cancer Inst 1993; 85(5):365-376
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Bjordal K, Ahlnwe-Elmqvist M, Tollesson E, Jensen AB, Razavi D, Maher EJ, et 
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Bjordal K, Hammerlid E, Ahlner-Elmqvist M, Graeff A de, Boysen M, Evensen 
JF, et al. EORTC Quality of Life Study Group. Quality of life in head and neck 
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Treatment of Cancer quality of life questionnaire-H&N35. J Clin Oncol 1999;
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changes in health-related quality-of-life scores. J Clin Oncol 1998; 16(1):139-144

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9.2
UNPUBLISHED REFERENCES
U02-1391
 and 
 Nonclinical Pharmacology Study Reports: Effects of 
BIBW 2992 on endogenous EGFR and HER2 phosphorylation states and on 
proliferation in various cell lines, 23 June 2002
U03-3218
Investigator’s brochure, BIBW 2992 (Afatinib). Version 17, 05 July 2016

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10.
APPENDICES
10.1
APPENDIX 1
RECIST 1.1 CRITERIA
The criteria below are based on RECIST 1.1 (R09-0262).
Measurability of the disease
Measurable disease
Measurable disease requires the presence of at least one measurable lesion. 
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). Longest diameter 
will be recorded.
For a lymph node to be considered pathologically enlarged and measurable, the short axis must 
be ≥15 mm (by CT scan). The short axis will be recorded.
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 short axis ≥10 and <15 mm) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include leptomeningeal disease, ascites, pleural or pericardial 
effusion, and 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 with prior local therapy
Standard of care in locally advanced HNSCC includes local therapies such as radiotherapy or 
surgery and the vast majority of patients eligible for this trial would have received local therapy. 
According to RECIST 1.1, target lesions in previously irradiated area or areas subjected to other 
local-regional therapy, are allowed if they are growing or new.
Methods of measurement
All measurements must be recorded in metric notation, using a ruler or calipers. All baseline 
evaluations must be performed as close as possible to the treatment start and within 4 weeks 
before the beginning of the treatment. If a lesion is considered too small to measure, a default 
measurement of 5 mm 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.

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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 suggested.
CT and MRI are the best currently available and reproducible methods to measure target lesions 
selected for response assessment. Conventional CT and MRI should be performed with cuts of 5 
mm or less in slice thickness contiguously. Spiral CT should be performed using a 5 mm 
contiguous reconstruction algorithm. This applies to the chest, abdomen and pelvis.
Ultrasound, endoscopy and laparoscopy should not be used to measure tumour lesions or 
evaluate tumour response. However, these techniques can be useful to supplement information 
from other techniques.
Tumour markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, they must normalise for a patient to be considered in complete clinical 
response.
Cytology and histology can be used to differentiate between PR and CR in rare cases (for 
example, residual lesions in tumour types such as germ cell tumours, where known residual 
benign tumours can remain).
Baseline Documentation of Target and Non-target Lesions
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs should be identified as target lesions and will be recorded, 
measured and numbered at baseline. The longest diameter will be recorded, except for lymph 
nodes, which will be measured by their short axis. 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).
The sum of diameters for all target lesions will be calculated and reported as the baseline sum of 
diameters. The baseline sum of diameter will be used as reference to further characterise the 
objective tumour response of the measurable dimension of the disease (see Table 10.1: 1).
Table 10.1: 1
Evaluation of target lesions
Complete Response (CR)
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have a reduction in short axis 
to <10mm)
Partial Response (PR)
At least a 30% decrease in the sum of diameters of target lesions, 
taking as reference the baseline sum diameters.

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Table 10.1: 1 Evaluation of target lesions, continued
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. Measurements are not required and these lesions should be followed as 
“present” or “absent” (see Table 10.1: 2).
Table 10.1: 2
Evaluations of non-target lesions and new lesions
Complete Response 
(CR)
Disappearance of all non-target lesions and normalisation of tumour 
marker level. All lymph nodes must be non-pathological in size (<10mm 
short axis)
Non-CR / Non-PD
Persistence of one or more non-target lesions 
Progression (PD)
Unequivocal progression (see comments below) of existing non-target 
lesions. (Note: the appearance of one or more new lesions is also 
considered progression).
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.
Progression (PD)
At least a 20% increase in the sum of diameters of target lesions, 
taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm. (Note: The appearance of one 
or more new lesions is also considered progression.)
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum 
diameters while on study.

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Evaluation of Best Response to Study Treatment
The best response to study treatment (Table 10.1: 3) is the best response recorded from the start 
of treatment until disease progression or start of further anti-cancer treatment (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). In general, the patient’s best response assignment will depend on the achievement of 
both measurements and confirmation criteria.
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.
Table 10.1: 3
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 all 
evaluated
No
PR
SD
Non-PD or not all 
evaluated
No
SD
Not all 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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10.2
APPENDIX 2
COCKCROFT-GAULT FORMULA
Estimated creatinine clearance rate (eCCR) using Cockcroft-Gault formula (rounded up to a 
whole number without decimals).
When serum creatinine is measured in mg/dl;







mg/dl
in 
Creatinine
Serum
72
85
,0
kilograms
in 
Mass
Age
140
eC CR





Female
if
When serum creatinine is measured in µmol/L;
Where Constant ≈1.23 for men and 1.04 for women.
(140 - Age)· Ma s (in kifogr3.111S) • Constant 
eCCR = 
. 
. . 
. 
Se1u1n Creatmme (m ~uno 1) 

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10.3
APPENDIX 3
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
* As published in Am. J. Clin. Oncol. (R01-0787)

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10.4
APPENDIX 4
CLINICAL EVALUATION OF LIVER INJURY
10.4.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1.7 (protocol-defined 
adverse events of special interest (AESIs)), are to be further evaluated using the following 
procedures.
10.4.2
Procedures
Investigator must pay attention to results of ALT/AST/bilirubin tests. Any elevation of 
ALT/AST and bilirubin qualifying as laboratory alert in Section 5.2.2.1.7 would be confirmed 
by local laboratory on initial sample. If due to technical error, the laboratory is not able to 
complete the confirmatory testing, an alert will be generated if possible.
If a site receives a potential DILI alert notice from the local laboratory or if the investigator 
notices the elevated ALT/AST/bilirubin reach the level in Section 5.2.2.1.7, the following must 
be completed:

Evaluate patient within 48 hours AND

Perform the following laboratory tests locally for confirmation:
1. Repeat of AST, ALT, bilirubin (with fractionation to total and direct) 
2. Haptoglobin
3. Complete blood count and cell morphology
4. Reticulocyte count
5. CPK
6. Lactate dehydrogenase
7. Alkaline phosphatase
If the initial alert values (i.e. AST, ALT, and bilirubin) are confirmed on the second sample 
described as above, then an abdominal ultrasound or clinically appropriate alternate imaging  (to 
rule out biliary tract, pancreatic or intrahepatic pathology, e.g. bile duct stones or neoplasm) 
must be completed within 48 hours.
The findings from the hepatic imaging (including comparison to prior imaging if available) must 
be made available as soon as possible as part of the AE reporting process. In the event the 
aetiology of the abnormal liver tests results is not identified based on the imaging (e.g. biliary 
tract, pancreatic or intrahepatic pathology), then the “DILI checklist” must be completed.  
Details of the “DILI checklist” are provided in the ISF. The following assessments need to be 
performed in order to complete the “DILI checklist” and results will be reported via the eCRF:

obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF;

obtain history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets according to the “DILI checklist” provided in the ISF;

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
obtain a history of exposure to environmental chemical agents (consider home and work 
place exposure) according to the “DILI checklist” provided in the ISF;

complete the following laboratory tests as detailed in the DILI checklist provided in the 
ISF:

Clinical chemistry
alkaline phosphatase, cholinesterase (serum)*, albumin, PT or INR, CPK, CPK-MB, 
coeruloplasmin*, α-1 antitrypsin*, transferrin*, amylase, lipase, fasting glucose, 
cholesterol, triglycerides

Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C 
(Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis 
E (Anti-HEV, Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth 
Muscle antibody (titer), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney 
microsomes) antibody, Anti-mitochondrial antibody, Epstein Barr Virus (VCA IgG, 
VCA IgM), cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, IgM)*, varicella 
(IgG, IgM)*, parvovirus (IgG, IgM)*

Hormones, tumourmarker
TSH*

Haematology
Thrombocytes, eosinophils
*If clinically indicated (e.g immunocompromised patients)
Long term follow-up

Initiate close observation of subjects by repeat testing of ALT, AST, and bilirubin (with 
fractionation to total and direct) at least weekly until the laboratory ALT and/or AST 
abnormalities stabilise or return to normal, then according to the protocol. Depending on 
further laboratory changes, additional parameters identified e.g. by reflex testing will be 
followed up based on medical judgement and GCP and report these via the (e)CRF.

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10.5
APPENDIX 5
P-GLYCOPROTEIN INHIBITORS AND INDUCERS
Examples of P-gp modulators that can be considered as potent inhibitors and/or potent inducers 
of the P-gp (P-gp is also known as MDR1) are listed in Table 10.5: 1.
Table 10.5: 1   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
Carbamazepine
Phenytoin
Rifampicin
St John's wort
Phenobarbital salt
Tipranavir
Ritonavir
As the information on potent inhibitors and inducers of P-gp may evolve, it is important for the 
investigator to assess such status on concomitant therapies and in case of questions contact 
sponsor/sponsor representative.

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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Summary of Clinical Trial Protocol Modifications Sheet (SOMS)
11.1
GLOBAL AMENDMENT 1
Number of CTP modification
1
Date of CTP modification
20 Jun 2014
BI Trial number
1200.161
BI Investigational Product
BIBW2992 (Afatinib)
Title of protocol
LUX-Head & Neck 3
A randomised, open-label, phase III study to 
evaluate the efficacy and safety of oral Afatinib
(BIBW 2992) versus intravenous methotrexate in 
patients with recurrent and/or metastatic head and 
neck squamous cell carcinoma who have 
progressed after platinum-based therapy
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
criteria for efficacy in synopsis
Description of change
PK of Afatinib is added as other endpoints
Rationale for change
To reflect the additional PK endpoint in the 
synopsis.
Section to be changed
Statistical methods in synopsis
Description of change
Add Afatinib plasma concentrations as analytical 
parameters
Rationale for change
To specify parameters for PK assessment.
Section to be changed
Schedule of 12 lead ECG on flow chart for visit 
1-26

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Description of change
Remove ECG testing on Visit 8, and add Note 6 
for Visit 9-26
Rationale for change
According to Footnote 6, ECG testing is not 
needed on Visit 8.
Section to be changed
LVEF testing of EOT in two flowcharts
Description of change
Add Footnote 7 for LVEF testing at EOT in two
flowcharts
Rationale for change
LVEF at EOT is only performed for those who 
have no yet done in the previous 8 days. 
Otherwise, will not repeat.
Section to be changed
Flowchart for Visit 1-26
Description of change
Procedure of collecting PK blood samples is 
added. Accordingly Footnote 21, 22 are added.
Rationale for change
To instruct the procedure of collecting PK blood 
samples.
Section to be changed
Body weight frequency for Visit 27 onwards
Description of change
Change the frequency to once every week
Rationale for change
To be consist with the flowchart for Visit 1-26
Section to be changed
Footnote 3 of the Flowchart for visit 27 onwards
Description of change
Remove the specification for after Visit 2.
Rationale for change
This flowchart is for Visit 27 onwards. 
Specification for Visit 2 to 26 is not applicable.
Section to be changed
Footnote 7 of flowchart for visit 27 onwards.
Description of change
Remove LVEF at screening visit.
Rationale for change
Remove the redundant specification.
Section to be changed
Table of content 5.2.2.1.7
Description of change
Change the term of protocol specified significant 
events to AESI
Rationale for change
To follow the term change according to SOP.
Section to be changed
Table of content 5.6
Description of change
Add title of new section for PK procedure
Rationale for change
To reflect the new sections about PK procedure
Section to be changed
Table of content 7.3.6
Description of change
Add the title of new section 7.3.6
Rationale for change
To reflect the analysis methods of PK
Section to be changed
Abbreviations

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Description of change
Abbreviations AESI and PK are added
Rationale for change
To reflect the new content in the amendment
Section to be changed
Section 1.2.3
Description of change
Change “In the ongoing global phase II cross-
over trial 1200.28 in HNSCC, 124 patients with 
R/M disease were randomised to start 
monotherapy with either Afatinib or cetuximab 
until tumour progression. Objective response rate 
with Afatinib and cetuximab was, At the time of 
the interim analysis, tumour images showed 11 
confirmed responders (PR); 9 (15%) in the 
Afatinib and 2 (3%) in the cetuximab arm (P10-
12526).”  to “In the completed global phase II 
cross-over trial 1200.28 in HNSCC, 124 patients 
with R/M disease were randomised to 
monotherapy with either Afatinib or cetuximab 
until tumour progression or undue AEs. The 
primary endpoint, tumour shrinkage of target 
lesions, per investigator review (IRR) and 
independent central imaging review (ICR) did not 
differ significantly between Afatinib and 
cetuximab treated patients. Objective response 
rate with Afatinib and cetuximab was 
16.1%/8.1% with Afatinib and 6.5%/9.7% with 
cetuximab (IR/ICR).”
Rationale for change
To reflect the progress of phase II trial 1200.28.
Section to be changed
Section 3.1
Description of change
Change the phase of 1200.161 from IIb to III
Rationale for change
To correct the typo error.
Section to be changed
Footnote 13 & 20, Section 3.1, 3.3.4.1, 5.2.2.1.7, 
5.2.2.2,  6.2.3.3, Secion 10.5.1
Description of change
Change the requirement of reporting drug related 
AE in observational period to reporting 
AEs/AESIs considered relevant by the 
investigator.
Rationale for change
To reflect the updated SOP of reporting AEs in 
clinical trial.
Section to be changed
Section 3.1
Description of change
In the last paragraph of Section 3.1, add general 
information that PK analysis will be carried out.
Rationale for change
To reflect the new procedure of PK

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Section to be changed
Section 3.3
Description of change
Change word continute and enrollment to 
continue and enrolment
Rationale for change
To correct the typo error
Section to be changed
Section 4.1.4.1
Description of change
Change the specification of Afatinib intake time 
from “at least 1 hour before food intake or at least 
3 hours after food intake” to “ at least 1 hour 
before food intake and at least 3 hours after food 
intake”
Rationale for change
To correct the typo error
Section to be changed
Table 4.1.4.2.1
Description of change
Change the cut-off value of neutrophil count, 
platelet count, and calculated creatinine clearance. 
Rationale for change
To correct the typo error
Section to be changed
Section 4.1.6
Description of change
Remove the specification HDPE about Afatinib
bottle
Rationale for change
To reflect the instruction from clinical trial supply 
unit (CTSU)
Section to be changed
Section 4.2.1
Description of change
In second paragraph of recue medication, add 
mucositis/stomatitis. 
Rationale for change
To reflect the updated IB.
Section to be changed
Section 4.2.1
Description of change
Add additional paragraph of treat side effects of 
Afatinib
Rationale for change
To provide clearer guidance to treat side effects of 
Afatinib
Section to be changed
Section 4.2.1
Description of change
In the paragraph of additional treatment, add word 
“e.g.” and phrase “short term (<14 days)” to the 
specification of base supportive care. 
Rationale for change
Add e.g. to indicate the listed BSCs are just 
examples. 
To specify the allowed duration of corticosteroids
use.
Section to be changed
Table 4.2.3.1:1

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Description of change
Add stop laxatives and advise patient to drink 
sufficient water or clear fluids per day to treat 
mild diarrhoea.
Rationale for change
To provide more guidance to treat mild diarrhoea
Section to be changed
Section 5.1.2.1
Description of change
Change the specification about completing 
HRQOL
Rationale for change
Reflect the updated alignment of Head and Neck 
program. 
Section to be changed
Section 5.2.2.1.5
Description of change
Add “malignant” to neoplasm progression
Rationale for change
To be more specific
Section to be changed
Section 5.2.2.2 
Description of change
Add the specification about the REP of Afatinib
and methotrexate. Update the instruction of 
reporting S/AE. 
Rationale for change
To reflect the alignment of Head & Neck program 
and also update SOP about reporting AEs in 
clinical trial. 
Section to be changed
Biochemistry lab testing in Section 5.2.3
Description of change
Specify ionized calcium is included for calcium 
testing
Rationale for change
To be more specific
Section to be changed
Section 5.2.3
Description of change
Remove the requirement that sponsor’s approval 
is needed for repeated lab testing
Rationale for change
Investigator can decide to repeat of lab testing as 
needed.
Section to be changed
Section 5.2.3
Description of change
Change the interval between screening lab testing 
and randomization from 3 weeks to 2 weeks. 
Rationale for change
To be consistent with the flowchart for Visits 1-
26
Section to be changed
Description of change
Rationale for change
Section to be changed
Last paragraph of Section 5.5

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Description of change
revise some wording in the last paragraph
Rationale for change
To be more accurate
Section to be changed
Section 5.5.2 
Description of change
Change the number of slides for tumour tissue 
needed from 4 to 5
Rationale for change
To be consistent with message on informed 
consent form
Section to be changed
Section 5.6
Description of change
Add PK measurement procedures. Flowchart and 
description in Section 3.1 are updated 
accordingly.
Rationale for change
PK measurement is added to support registration 
of this indication.
Section to be changed
Section 6.2.2
Description of change
Adding the instruction of dispensing/collection 
Patient Diary.
Rationale for change
Patient diary will be dispensed to Afatinib patient. 
This instruction is added to guide sites the 
appropriate way of dispensing/collection the 
diary.
Section to be changed
Section 7.3.6
Description of change
New Section 7.3.6 is added.
Rationale for change
To describe the methods for PK analysis
Section to be changed
Section 7.4
Description of change
Add the specification of handling missing PK 
data
Rationale for change
To specify the methods of handling missing PK 
data
Section to be changed
Section 8.4.1
Description of change
Remove the US PI of methotrexate as the 
reference document for the listedness of this trial. 
Rationale for change
Only EU SPC is used per instruction from 
corporate pharmacovigilance
Section to be changed
Section 9.1
Description of change
Remove reference P10 12526
Rationale for change
With the result update for 1200.28 in Section 
1.2.3, the reference document P10 12526 is not 
applicable anymore. 

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Section to be changed
Section 9.1
Description of change
Remove reference P11 09424
Rationale for change
To remove the duplicated reference document
Section to be changed
Section 9.1
Description of change
Add version date to reference U03-3218
Rationale for change
To provide more specific information about this  
reference document
Section to be changed
Table 10.1:3
Description of change
Change “no” to “yes” in the last row.
Rationale for change
To correct the typo error
Section to be changed
Appendix 2
Description of change
Add more specification to the result of calculated
creatinine clearance rate
Rationale for change
To provide clearer instruction
Section to be changed
Appendix 4
Description of change
Update the flowchart of reporting AEs
Rationale for change
To reflect the updated SOP of reporting AEs in 
clinical trial 

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11.2
GLOBAL AMENDMENT 2
Number of CTP modification
2
Date of CTP modification
03 Mar 2016
BI Trial number
1200.161
BI Investigational Product
BIBW2992 (Afatinib)
Title of protocol
LUX-Head & Neck 3
A randomised, open-label, phase III study to 
evaluate the efficacy and safety of oral Afatinib
(BIBW 2992) versus intravenous methotrexate in 
patients with recurrent and/or metastatic head and 
neck squamous cell carcinoma who have 
progressed after platinum-based therapy
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
Cover page
Description of change
Both TCM and TMM contact information was 
updated.
Rationale for change
Administrative changes
Section to be changed
Throughout the protocol
Description of change
The number of randomised patients have been 
changed from 300 to 330
Rationale for change
Increase the sample size in order to have 274 
events due to high discontinuation rate.
Section to be changed
Clinical protocol synopsis
Description of change
Objective response
Was changed to:
Objective response rate
Other endpoints

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Was changed to :
Pharmacokinetics
Vital signs, ECOG status and ECG.
Added to:
Criteria for safety
Rationale for change
Clarification
Section to be changed
Flowchart
Section 6.2.3.2
Description of change
FUV 28 (+/-7) days after EOT
Was changed to :
FUV 28 (+7) days after EOT
Rationale for change
Remove “-“ in order to cover 28-day REP
Section to be changed
Flowchart
Description of change
“X” sign
Added to: 
Screening visit, Visit 9 to 27 and onwards column
for Adverse Events reporting
Rationale for change
Correction to be consistent with section 5.2.2.2
Section to be changed
Flowchart
Description of change
Footnote 13 was changed from OP column to 
FUV column for visit 1-26
Footnote 10 was changed from OP column to 
FUV column for visit 27 and onwards
Rationale for change
Correction to be consistent with footnote.
Section to be changed
Flowchart
Description of change
Plasma
Added to 
Biomarker sampling
Rationale for change
To reflect the update in Section 5.5.
Section to be changed
Flowchart for visit 1-26
Description of change
Footnote 13 SAEs/AESIs to be reported if 
considered relevant by the investigator
Was changed to :
All adverse events, serious and non-serious, 
occurring from signing the informed consent 
onwards through the end of the follow up period 
will be collected, documented and reported to the 
sponsor by the investigator on the appropriate 
eCRFs/SAE reporting forms. Please refer to 

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section 5.2.2.2.
Footnote 20: Collection of information on vital 
status, anti-cancer therapy, and relevant 
SAEs/AESIs
Was changed to :
All patients will be followed-up for overall 
survival at 4 week intervals after the last follow-
up for progression visit until death, withdraw of 
consent, lost to follow-up or completion of the 
whole trial whatever occurs earlier. See section 
5.2.2.2.
Rationale for change
To reflect the update in Section 5.2.2.2 due to 
updated AE reporting requirement
Section to be changed
Flowchart for visit 27 and onwards
Description of change
Footnote 10 SAEs/AESIs to be reported if 
considered relevant by the investigator
Was changed to :
All adverse events, serious and non-serious, 
occurring from signing the informed consent 
onwards through the end of the follow up period 
will be collected, documented and reported to the 
sponsor by the investigator on the appropriate 
eCRFs/SAE reporting forms. Please refer to 
section 5.2.2.2.
Footnote 14: Collection of information on vital 
status, anti-cancer therapy, and relevant 
SAEs/AESIs
Was changed to :
All patients will be followed-up for overall 
survival at 4 week intervals after the last follow-
up for progression visit until death, withdraw of 
consent, lost to follow-up or completion of the 
whole trial whatever occurs earlier. See section 
5.2.2.2.
Rationale for change
To reflect the update in Section 5.2.2.2 due to 
updated AE reporting requirement
Section to be changed
Flowchart for visit 1-26
Description of change
Footnote 18 Provision of samples for biomarker 
testing (serum and archival tumour tissue) is 
optional
Was changed to :

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Provision of samples for biomarker testing (serum 
blood and archival tumour tissue) is mandatory.
Added
For randomized patients who consented for 
biomarker testing before implementation of this 
amendment but tumour samples have not yet been 
collected, every effort should be made to collect 
tumour tissue samples. For randomized patients 
whom the investigator did not check consent at 
screening for biomarker testing, re-consent is 
necessary.
Rationale for change
To reflect the updates in Section 5.5 in order to 
collect more biomarker samples.
Section to be changed
Flowchart
Description of change
AE reporting requirement during observational 
period (OP) 
Collection of vital status information, anti-cancer 
treatment and relevant SAEs/AESIs every 4 
weeks after FUV.
Was changed to
All patients will be followed-up for overall 
survival at 4 week intervals after the last follow-
up for progression visit until death, withdraw of 
consent, lost to follow-up or completion of the 
whole trial whatever occurs earlier. See section 
5.2.2.2.
Rationale for change
To reflect the update in Section 5.2.2.2 due to 
updated AE reporting requirement.
Section to be changed
The first paragraph of Section1.2.3 
Description of change
More than 1797 subjects have been administered 
with Afatinib
Was change to 
At the time of data cut-off 25 March 2015, 6673 
cancer patients had been exposed to Afatinib
monotherapy or in combination with other anti-
cancer agents across various Phase I-III trials and 
expanded-access program. In addition there are 
265 patients in a double-blind Phase III trial in 
head and neck cancer. A compassionate 
use/named patient use program was initiated for 
Afatinib in 2010, and by 24 March 2015, overall 
5607 treatment requests had been authorised. In 
investigator-initiated trials, 808 patients have 

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been treated with Afatinib as monotherapy or in 
combination therapy as of 24 May 2015.
Added 
In trial 1200.43 (global trial with similar design as 
1200.161), 483 were randomized (2:1) to receive 
a daily oral dose of Afatinib (n=322) or a weekly 
intravenous bolus injection of methotrexate 
(n=161).
Treatment with Afatinib significantly prolonged 
PFS compared to methotrexate, meeting the
primary endpoint of the trial. The median PFS for 
the Afatinib arm was of 2.63 months compared to 
1.74 months (HR = 0.797; 95% CI 0.646, 0.983; p 
= 0.0296). The treatment effect was comparable 
across most of the subgroups tested. Median OS 
was 6.80 months on Afatinib vs 6.18 months on 
methotrexate (HR of 0.940 (95% CI 0.749, 1.181; 
p = 0.5955)). The objective response rate based 
on central independent review was 10.2% in the 
Afatinib arm and 5.6% in the methotrexate arm 
(odds ratio: 1.91; 95% CI 0.88, 4.14; p = 0.1010).
Disease control rate based on central independent 
review was significantly higher in the Afatinib
arm (49.1%) compared with the methotrexate arm 
(38.5%) (Odds ratio: 1.52; 95% CI 1.03, 2.26; p = 
0.0353). The median duration of disease control 
was 4.14 months (95% CI 3.98, 4.24) in the 
Afatinib arm and 3.58 months (95% CI 2.86, 
4.17) in the methotrexate arm. 34.8% of patients 
in the Afatinib arm experienced a decrease in the 
tumour size compared with 22.4% of patients in 
the methotrexate arm.
Compared with methotrexate, Afatinib delayed 
the time to deterioration in pre-defined scores of 
global health status (HR 0.74; 95% CI 0.56, 0.97; 
p = 0.0268), pain (HR 0.73; 95% CI 0.55, 0.96; p 
= 0.0217), and swallowing (HR 0.67; 95% CI 
0.50, 0.89; p = 0.0040). Similar proportions of 
patients showed improvements for pain, 
swallowing, and global health status. Over time, 
patients taking Afatinib reported significantly less 
pain compared with methotrexate (p=0.0330) but 
no significant differences were seen for 

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swallowing (p = 0.9773) or global health status (p 
= 0.7767).
Rationale for change
To reflect the update in Section 6 (Effects in 
Humans) of updated IB (Version 16, 6 July 2015)
Section to be changed
Section 2.3, section 3.1
Description of change
Delete
Rapid tumor growth after the discontinuation of 
TKIs has been described in NSCLC patients 
(R09-1569). This phenomenon has not been 
described in patients with HNSCC, but the 
possibility cannot be excluded. In order to prevent 
such a potential rapid tumor growth, patients who 
have PD as per RECIST  but  clinically benefit 
from this trial as per investigator’s discretion  and 
for whom no other systemic treatment with 
potential for clinical benefit is possible, may still 
continue on investigational medication (see
Section 3.2).
Rationale for change
Only a small fraction of the patients continued 
randomized treatment beyond disease progression
based on 1200.43 study, the number of patients is 
too small to be able to draw any conclusions 
regarding benefit and/or rapid tumor growth.
Section to be changed
Section 3.1
Description of change
During the observational period, data of survival 
(vital status), SAEs/AESIs considered relevant by 
the investigator and concomitant anti-cancer 
therapy will be collected.
Was changed to 
During the observational period, data of survival 
(vital status), related SAEs/AESIs and 
concomitant anti-cancer therapy will be collected.
Added
For patients who progressed on treatment, the 
observation period for overall survival starts after 
the FUV (end of residual effect) visit. For patients 
who have not progressed on treatment, this period 
starts after the last additional FU visit.
Rationale for change
To reflect the update in Section 5.2.2.2 due to 
updated AE reporting requirement.
Section to be changed
Section 3.1

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Description of change
The clinical trial report will be written following 
database lock and statistical analyses when the 
required number of progression free survival 
events has occurred as described in Section 7.6.
Was changed to
Primary statistical analyses will be performed 
when the required number of progression free 
survival events has occurred as described in 
Section 7.6. The clinical trial report will be 
written based on primary analysis results.
The trial is considered completed after all patients 
have progressed and the required number of death 
events has occurred.
Was changed to
The trial is considered completed after all patients 
have terminated investigational treatments and 
have completed one follow-up visit, and the 
required number of PFS events has occurred. 
Rationale for change
Clarification to be consistent with updates in 
section 7.3.1 and 8.6.
Section to be changed
Section 3.2
Description of change
Delete
Usually, patients should discontinue study 
medication if disease progression is confirmed 
with tumour imaging because treatment appears 
not to give the desired effect. However, there 
have been reports where continued use of TKI 
beyond disease progression has indicated a 
benefit (R09-1569). Hence disease-progressed 
patients in this trial may be allowed to continue 
the allocated treatment in case of clinical benefit 
as per investigator’s careful clinical assessment. 
Clinical benefit will be evaluated on a case by 
case basis, e.g., patients who demonstrate tumour 
shrinkage or improvement in symptoms such as 
improved swallowing and decreased pain. Such 
patients will follow the initial  visit schedule and 
procedures (see Flow Chart), including the 
imaging and clinical tumour evaluations to ensure 
adequate care of patients, collection of safety 
information, and discontinuation in case of further 
progression. Study medication may be continued 
as long as judged beneficial by the investigator. 
However, the original time to progression has 

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been defined by investigator or independent 
review will not change. The continued treatment 
should not compromise the administration of 
approved subsequent treatments if available later.
Rationale for change
Only a small fraction of the patients continued 
randomized treatment beyond disease progression
based on 1200.43 study, the number of patients is 
too small to be able to draw any conclusions 
regarding benefit and/or rapid tumor growth.
Section to be changed
Section 3.3.2
Description of change
Added
Nedaplatin minimum dose: at least two cycles of 
Nedaplatin, ≥80 mg/m2/cycle or a total 
cumulative dose of ≥160 mg/m2 during eight 
weeks.
If cisplatin is switched to Nedaplatin (or vice 
versa, e.g due to intolerance), the following 
conversion should be used for calculation of 
minimum cumulative platinum dose: cisplatin 1 
mg/m2 = Nedaplatin 1.3 mg/m2.
Rationale for change
Allow Nedaplatin in the 1st line setting of RM 
HNSCC to comply with Chinese practice.
Section to be changed
Section 3.3.3
Description of change
Treatment with any investigational drug or anti-
cancer therapy less than four weeks prior to 
randomization
Was changed to
Treatment with any investigational drug less than 
four weeks or anti-cancer therapy less than three 
weeks prior to randomization
Rationale for change
Clarification
Section to be changed
Section 3.3.4
Description of change
Following the FUV, the patient will continue in 
the observational period. During this period vital 
status information, anti-cancer therapy, and SAEs 
and AESIs considered relevant by the investigator 
will be collected every four weeks.
Was changed to
During this period vital status information, anti-
cancer therapy, and related SAEs and AESIs will 
be collected every four weeks.

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Added
For patients who progressed on treatment, the 
observation period for overall survival starts after 
the FUV (end of residual effect) visit. For patients 
who have not progressed on treatment, this period 
starts after the last additional FU visit.
Rationale for change
To reflect the update in Section 5.2.2.2 due to 
updated AE reporting requirement.
Section to be changed
Section 4.1.1
Description of change
Delete
In specific cases where the patient gains clinical 
benefit of Afatinib, as judged by the investigator, 
Afatinib may be continued in spite of PD based 
on imaging (see Section 3.2).
Rationale for change
Only a small fraction of the patients continued 
randomized treatment beyond disease progression
based on 1200.43 study, the number of patients is 
too small to be able to draw any conclusions 
regarding benefit and/or rapid tumor growth.
Section to be changed
Section 4.1.7
Description of change
Afatinib tablets may not be stored above 25°C 
(77°F).
Was changed to 
Afatinib tablets may be stored according to the 
storage conditions defined on the medication 
label.
Rationale for change
Clarification
Section to be changed
Section 4.2.1
Description of change
Delete
short term (<14 days) corticosteroids
Rationale for change
Deleted “short term (<14 days) corticosteroids” as 
the international treatment regimens vary.
Section to be changed
Table 4.2.3.2: 2
Description of change
Added
Caution should be exercised when combining 
Afatinib with strong P-gp modulators
Rationale for change
Clarification
Section to be changed
Section 5.1.1
Description of change
Added
Disease control, defined as the best overall 

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response of CR, PR, SD. SD should be observed 
for at least 6 weeks (>=42 days) after 
randomisation.
Rationale for change
Pre-defined efficacy endpoint
Section to be changed
Section 5.1.2
Description of change
….including those who discontinue prematurely.
Was changed to
….including those who discontinue study 
medication prematurely.
HRQOL will be assessed in countries where 
validated translations are available and patients 
will receive the questionnaire in their native 
language till the FUV.
Was changed to 
HRQOL will be assessed in countries where 
validated translations are available and patients 
will receive the questionnaire in their native 
language till the FUV.
Rationale for change
Clarification
Section to be changed
Section 5.2.2.1.7
Description of change
Added
…and/or marked peak   aminotransferase (ALT, 
and/or AST) elevations ≥ 10 fold ULN.
Rationale for change
To follow updated BI procedure, where criterion 
qualifying as AESI for patients
Section to be changed
Section 5.2.2.2
Description of change
Added
After the end of treatment (including the REP) 
until the individual patient’s end of trial: collect 
all related SAEs and related AESIs.
Delete
Serious adverse events and AESIs experienced by 
a subject after the treatment of that subject has 
ended (first per protocol visit following the REP) 
should be reported to the sponsor if the 
investigator becomes aware of them and considers 
the reported serious adverse events or AESI 
relevant. Examples of relevant SAEs/AESIs 

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include, but are not limited to:

events such as a subsequent occurrence of an 
infrequent event that has immediate health 
implications 

an event that is uncommon in a specific study 
population (e.g., stroke in young adults) 

events of delayed toxicity
The investigator does not need to actively monitor 
subjects for AEs once their treatment period 
(including protocol-defined residual period) has 
ended, unless provided otherwise in the CTP.
Was changed to 
After the individual patient’s end of trial, the
investigator does not need to actively monitor 
subjects for AEs but should only report relevant 
SAEs and relevant AESIs which the investigator 
may become aware of.
Delete
…and an overview of the AE reporting process is 
provided in Appendix 4Appendix4.
Added
AESI
eCRF 
Was changed to
RDC.
Rationale for change
Clarification due to updated AE reporting 
requirement and correction.
Section to be changed
Table 5.2.2.2:1
Description of change
For Post-treatment (>28 days after last 
administration of study medication) until 
completion of trial.
Report AEs/ AESIs if considered relevant by the 
investigator. 
Was changed to
Collect all related SAEs and related AESIs. Refer 
to Section 5.2.2.2 for details.
Rationale for change
Clarification due to updated AE reporting 
requirement.

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Section to be changed
Section 5.2.3
Description of change
In case CPK is out of range
Was changed to 
In case CPK is higher than ULN
Rationale for change
CPK lower than LLN is not clinically meaningful.
Section to be changed
Section 5.5
Description of change
Delete
All paragraphs under section 5.5
Added
The evaluation of several biomarkers will be 
performed in an exploratory way as a means of 
identifying patient subgroups with differential 
prognosis or response to treatment. This includes 
but is not limited to, the determination of HPV 
infection status, the expression of the PTEN and 
Her3 genes and the assessment of the 
chromosomal amplification of the EGFR gene. 
Participation in the biomarker assessments is 
mandatory and the provision of samples for these 
assessments is thus a prerequisite for participation 
in the clinical trial. 
The collection of fresh tumour biopsies is viewed 
as not being generally feasible in this trial. 
Therefore, biomarker analyses will be normally 
based on archival tumour tissue and also fresh 
blood samples from which plasma and serum will 
be prepared. 
After signing of the biomarker informed consent, 
patients will be asked for and archival tumour 
tissue samples. If archival tumour tissues are 
available from more than one occasion, the latest 
obtained sample should be used wherever 
possible. 
If no archival tumour tissue is available, a new 
tumour biopsy should be obtained. The site of 
biopsy (primary tumour, recurrent, lymphoid
node, or metastatic site) will be recorded in the 
eCRF.
A brief description of the biomarker analyses to 

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be performed is provided here. 
Added
Section 5.5.1 Biomarker Assessments
Rationale for change
Biomarker section was re-written based on LUX 
Head Neck 1 results. The biomarker assessments 
became mandatory process for participation in the 
study in order to collect more biomarker samples.
Section to be changed
Section 5.5.3 Handling of Samples and Biomarker 
Results
Description of change
Title of section 5.5.3 was changed from Methods 
of sample collection to Handling of Samples and 
Biomarker Results. Previous section 5.5.3 
Analytical determinations were deleted.
Delete
Samples should be sent to the central laboratory, 
which will forward these to the laboratories 
responsible for biomarker analyses.
For the serum sampling, approximately 5 ml 
blood will be obtained. Four Five slides of 5 m 
of FFPE tumour tissue from archival material will 
be needed for p16 analyses.
Was changed to 
10 slides of 5 m of FFPE tumour tissue from 
archival material will be needed for p16, 
Nanostring (mRNA) and somatic mutation 
analyses.
Added
Further information on tissue slide preparation 
and storage conditions for measuring exploratory 
biomarkers via IHC will be given in the lab 
manual. 
A total of 9 mL blood will be collected 
comprising about 4.5 mL for the preparation of 
serum and about 4.5 mL for the preparation of 
plasma. The samples will be used for the 
exploratory analysis of biomarkers of relevance to 
response to the study medication, for example the 
levels in blood of the ligands of the ErbB receptor 
family (e.g. Heregulin 3).If local regulations 

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allow, any excess materials at the central lab will 
be shipped and stored at BI’s central lab until all 
required validations have taken place or until it is 
decided that there is no requirement for 
validation. 
Samples will be destroyed no later than 15 years 
after trial completion
Rationale for change
Update for biomarker samples handling.
Section to be changed
Section 6.2.2
Description of change
Added
…every 8 weeks until disease progression or start 
of subsequent anti-cancer therapy.
Rationale for change
Clarification
Section to be changed
Section 6.2.3.3
Description of change
Added
For patients who progressed on treatment, the 
observation period for overall survival starts after 
the FUV (end of residual effect) visit. For patients 
who have not progressed on treatment, this period 
starts after the last additional FU visit.
SAEs/protocol-defined AESIs that are considered 
relevant by the investigator
Was changed to
Related SAEs/related protocol-defined AESIs
Rationale for change
Updates to reflect updated AE reporting 
requirements
Section to be changed
Section 7.3.1
Description of change
When the required number of progression (or 
death) events (see Section 7.6) is achieved,
database lock will be performed. 
Was changed to 
When the required number of progression (or 
death) events (see Section 7.6) is achieved,
primary analysis will be performed. The final 
analysis will be performed at study completion.
Rationale for change
Clarification
Section to be changed
Description of change

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Rationale for change
Section to be changed
Description of change
Rationale for change
Section to be changed
Section 7.6
Description of change
Added
Total randomized patients might be adjusted to 
ensure 274 PFS events can be observed at primary 
analyses.
Rationale for change
Clarification for the required patient numbers.
Section to be changed
Section 8
Description of change
Section 8: The second to last paragraph was 
added to section 8.
Section 8.1: The third paragraph was added to 
section 8.1
Section 8.3.1: The first two paragraphs were 
deleted and another 3 paragraphs were added.
Section 8.3.2: The first paragraph was deleted and 
another 1 paragraph was added.
Section 8.3.3: The first paragraph was deleted and 
another 1 paragraph was added.
Section 8.6: New milestones definitions were 
added.
Rationale for change
Update based on current CTP template
Section to be changed
9.2
UNPUBLISHED REFERENCES
Description of change
U03-3218
Shahidi, M. and Uttenreuther-
Fischer, M. Investigator’s brochure. BIBW 2992 
(Afatinib). Version 14, 04 July 2013
Was changed to:
Shahidi, M. and Uttenreuther-Fischer, M. 
Investigator’s brochure. BIBW 2992 (Afatinib). 
Version 16, 06 July 2015
Rationale for change
To reflect the update IB version
Section to be changed
Section 10.4 Appendix 4 Adverse event reporting 
process
Description of change
Delete
Appendix 4

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Rationale for change
The AE reporting process was updated in section 
5.2.2.2. To avoid confusion, this appendix was 
deleted.

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11.3
GLOBAL AMENDMENT 3
Number of CTP modification
3
Date of CTP modification
28 March 2017
BI Trial number
1200.161
BI Investigational Product
BIBW 2992 (Afatinib)
Title of protocol
LUX-Head & Neck 3
A randomised, open-label, phase III study to 
evaluate the efficacy and safety of oral Afatinib 
(BIBW 2992) versus intravenous methotrexate in 
patients with recurrent and/or metastatic head and 
neck squamous cell carcinoma who have 
progressed after platinum-based therapy
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
Cover page
Description of change
TCM and TMM information updated, address of 
Co-ordinating investigator.
Rationale for change
Administrative changes, correction of typo
Section to be changed
Synopsis; Main inclusion criteria
Description of change
Deletion (last in 2nd bullet):
*if cisplatin is switched to carboplatin (or vice 
versa, e.g. due to intolerance), the following 
conversion should be used for calculation of 
minimum cumulative platinum dose: carboplatin 
1 AUC = cisplatin 15 mg/m2
Changed to superscript where appropriate.
Rationale for change
Synopsis includes the main criteria, and do not 
need to have the conversion guidance included. 

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This is still part of the Inclusion criterion No. 2 in 
Section 3.3.2.
Administrative: change to superscript.
Section to be changed
Synopsis; Main exclusion criteria
Section 3.3.3: Exclusion criterion No. 3
Section 1.1.2 Treatment of incurable HNSCC
Section 2.1 Rationale for performing the trial
Section 2.3 Benefit – risk assessment
Section 3.1 Overall trial design and plan
Section 5.3.2.1 Demographics, medical history, 
smoking, and alcohol status
Description of change

Current criterion: Any other than one previous 
platinum-based systemic regimen given for 
recurrent and/or metastatic disease. Re-
challenge with the first line regimen after a 
temporary break is considered a second line 
regimen only in case of progression within the 
break.
Was changed to:

Any other than one previous platinum-based 
systemic regimen given for recurrent and/or 
metastatic disease with the exception of 
immunotherapy used either before or after 
platinum based treatment. Re-challenge with 
the platinum based regimen after a temporary 
break is considered an additional line regimen 
only in case of progression within the break.
The other sections were updated to include 
background on immunotherapy alternatives 
(Section 1.1.2), to address prior use of 
immunotherapy into context of this study 
(Sections 2.1 and 2.3), where necessitated to 
describe study population (Section 3.1) and data 
collection (Section 5.3.2.1).
Rationale for change
To allow patients who received immunotherapy 
(e.g. PD-1, PD-L1) in any line before inclusion. 
This is considered appropriate since 
immunotherapy agents have recently been 
approved for the treatment of HNSCC patients in 
the same as the study setting. Most patients do not 
respond to immunotherapy treatments. Overall 
immunotherapy is relatively well tolerated, so 
patients that progress on immunotherapy are 
usually in a rather good condition and could be 
eligible for further treatment.

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Section to be changed
Synopsis; Main exclusion criteria
Section 3.3.3: Exclusion criterion No. 22
Description of change
Criterion removed (Any past or present history of 
areca/betel-nut chewing or its derivatives for a 
cumulative duration of more than 3 months).
Rationale for change
In some of the participating countries the habit of 
areca/betel-nut chewing is common especially in 
HNSCC patients. Not allowing areca/betel nut 
chewing has been an important recruitment 
barrier and it considered acceptable at this time 
point in the study to allow such patients to 
participate. 
Section to be changed
Synopsis; Duration of treatment
Section 3.1 Overall trial design and plan
Section 3.3.4.1 Removal of individual patients
Section 3.3.4.2 Discontinuation of the trial by the 
sponsor
Description of change
The study will end one year after last patient 
randomised if the required number of PFS events 
has occurred. If a patient is removed from the 
study medication at end of study, an end of 
treatment and follow-up visit will be performed to 
ensure all AEs are followed up and then the 
patient will be considered to have completed the 
trial.
If allowed by local regulation, patients may 
switch to the randomised study medication via 
marketed product supply or other means. The cost 
of any ongoing supply of the treatment will be 
incurred by the sponsor until disease progression 
occurs (or earlier, if stop of treatment for other 
reason if this judged in the best interest for the 
patient).
Rationale for change
The study has one full analysis, which is the 
primary analysis. Data collected beyond this will 
not be re-analysed to full extent. Based on the 
study population and experience from other 
similar studies, only few patients are likely to still 
be on study medication at time of primary 
analysis (example from study 1200.43 in same 
population but other countries; median PFS 1.7-
2.6 months). It is considered appropriate to not 
keep patients on the study after the primary 
analysis for unlimited time. A one year time 
frame after last patient randomized is considered 

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realistic based on study population to allow all, or 
at least the vast majority, of patients to stop study 
medication due to PD. Should it be allowed by 
local regulation, sponsor is willing to reimburse 
the investigator for continued supply of the 
randomised medication.
Section to be changed
Flow Charts, footnotes “Tumour imaging…”
Description of change
Deletion: (or until end of treatment if patient 
continues study medication beyond progression)
Rationale for change
Administrative, should have been removed with 
previous amendment.
Section to be changed
Flow Charts, footnotes “Tumour imaging…”
Section 3.2 Discussion of trial design…
Section 5.1.2.1 Tumour imaging
Section 6.6.2 Treatment period
Description of change
Imaging intervals can change to follow local site 
standard (if no standard: every 16 weeks) after 
database lock for primary analysis.
Rationale for change
Since primary endpoint analysis is conducted at 
primary analysis, the requirement to continue 
imaging with the current frequency is not
considered to add additional value once the 
database lock for the primary analysis is 
complete. Therefore it is considered adequate to 
allow investigators to follow site standard.
Section to be changed
Flow Charts, footnotes “Only for patients 
permanently…”
Section 3.1 Overall trial design and plan
Section 6.2.3.1 End of treatment
Section 6.2.3.2 Follow-up visit
Section 6.2.3.3 Observational period
Description of change
The requirement to continue imaging for patients 
who permanently discontinued study medication 
due to other reasons than disease progression will 
be removed after database lock for primary 
analysis. Sentence to address this is added to 
applicable Flow Chart footnotes and Sections.
Rationale for change
Since primary endpoint analysis is conducted at 
primary analysis, the requirement to continue 
imaging for patients who stop study medication 
without PD is not considered to add additional 
value once the database lock for the primary 
analysis is complete.

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Section to be changed
Flow Charts, footnotes relating to ECG “During 
the treatment period, ECG…”
Description of change
Clarifying that ECG assessments after Visit 26 
are every 16 weeks (instead of indicating every 
2nd imaging).
Rationale for change
Administrative (clarification)
Section to be changed
Flow Charts; LVEF including footnote
Section 3.3.3; Exclusion criterion No. 14
Section 5.2.4.4; Left Ventricular Ejection Fraction
Description of change
Eligibility criterion for LVEF and post-baseline 
LVEF assessments removed.
Rationale for change
LVEF monitoring was initially included in the 
protocol to investigate potential effects of afatinib 
on the myocardium as are seen with other HER2 
inhibitors. Sponsor has over the years collected
extensive clinical data of patients treated with 
afatinib, which allows us to dismiss this as a 
potential ADR related to afatinib. It is therefore 
considered adequate to remove this type of 
assessment throughout the study.
Section to be changed
Flow Charts; HRQOL footnote
Section 5.1.2.3 Health-related quality of life
Section 6.2.2 Treatment period
Description of change
Collection of questionnaires for assessment of 
HRQOL will stop after database lock for primary 
analysis. Sentence to address this is added to 
applicable Flow Chart footnotes and Sections.
Rationale for change
Primary analysis will include all analysis, 
including analysis of HRQOL data. Therefore 
continued collection is not considered to add 
additional value once the database lock for the 
primary analysis is complete.
Section to be changed
Flow Charts; Below tables (item OP) and footnote
Description of change
Frequency of contacts in the Observational Period 
will be every 3 months instead of every 4 weeks
after database lock for primary analysis.
Rationale for change
Primary analysis will include all analysis and 
therefore less frequent collection of data is 
considered adequate.
Section to be changed
Abbreviations
Description of change
Addition: REP – Residual effect period
Rationale for change
Administrative

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Section to be changed
Section 3.1 Overall trial design and plan
Description of change
Deletion: For details on treatment beyond 
progression, see Section 3.2.
Rationale for change
Administrative, should have been removed with 
previous amendment.
Section to be changed
Section 3.1 Overall trial design and plan
Description of change
Addition at end of 8th paragraph (Primary 
statistical analysis…):
An addendum to the clinical trial report may be 
used to summarise data collected beyond database 
lock for the primary analysis.
Rationale for change
Clarification on reporting of data.
Section to be changed
Section 3.1 Overall trial design and plan
Section 5.1.2.1 Tumour imaging
Section 5.1.2.2 Central image review
Description of change
It will no longer be required to send any image 
data to the central imaging unit after database 
lock for primary analysis. Text added to clarify 
and address this.
Rationale for change
The central independent review of image data is 
applicable for the primary analysis and will not 
add value for data collected beyond this.
Section to be changed
Section 5.2.2.2.1 Pregnancy
Description of change
Tubal ligation is no longer considered to render a 
woman to be of non-childbearing potential, but is 
instead considered an acceptable method of 
contraception. Text updated to reflect this.
Rationale for change
To follow sponsor SOP.
Section to be changed
Section 5.5 Assessment of exploratory biomarkers
Description of change

1st paragraph:
This includes but is not limited to …
Was changed to:
This may include, but is not limited to …

4th paragraph: Deleted “and” to read: 
…patients will be asked for...
Rationale for change
Clarification and correction.
Section to be changed
Section 7.3.6 Pharmacokinetic methods
Section 7.4 Handling of missing data
Description of change
Deletion: (001-MCS-36-472, current version)

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Rationale for change
Administrative, text already states to follow 
relevant sponsor procedure which is more 
appropriate since procedure documents may 
change names/numbers.
Section to be changed
Section 8.6 Trial Milestones
Description of change
Delete repeated text:
Early termination of the trial is defined as the 
premature termination of the trial due to any 
reason before the end of the trial as specified in 
this protocol.
Rationale for change
Administrative, sentence was written twice.
Section to be changed
9.1 Published references
Description of change

Addition of references:
R16-4089, R16-4467, R16-5709

Deletion of references:
R06-0986, R06-1414, R06-1642, R09-1569, 
R10-4313, R10-5908, R10-6238, R10-6249, 
R10-6250, R10-6251, R10-6252, R10-6253, 
R10-6445, R10-6447

Correction of reference:
R11-0801 (pages added)
Rationale for change
Administrative, to reflect new references, 
references not applicable any longer, or 
correction.
Section to be changed
9.2 Unpublished references
Description of change
U03-3218 Investigator’s brochure, BIBW 2992 
(Afatinib).
Version 16, 06 July 2015
Was changed to:
Version 17, 05 July 2016
Rationale for change
To reflect the most recent IB version
Section to be changed
11 Description of global amendments
Description of change

Each individual global amendment was given 
a sub-section.

The date of the 2nd amendment (CTP 
modification 2) of 28 Jan 2016
Was changed to:
03 Mar 2016
Rationale for change
Enabling easier overview of global amendments; 
correction of the actual date for CTP version 3

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11.4
GLOBAL AMENDMENT 4
Number of CTP modification
4
Date of CTP modification
03 January 2019
BI Trial number
1200.161
BI Investigational Product
BIBW 2992 (Afatinib)
Title of protocol
LUX-Head & Neck 3
A randomised, open-label, phase III study to 
evaluate the efficacy and safety of oral Afatinib 
(BIBW 2992) versus intravenous methotrexate in 
patients with recurrent and/or metastatic head and 
neck squamous cell carcinoma who have 
progressed after platinum-based therapy
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities in OPUs applied to 
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
Cover page
Description of change
TCM information update
Rationale for change
Administrative changes
Section to be changed
Flow Chart for Visit 27 and onwards (i.e. from week 25)
Description of change
13) “until one year after last patient randomized”
14)The patients that are still on treatment at one 
year after last patient randomized can continue 
drug administration from the trial, until disease 
progression or earlier if stop of treatment for other 
reasons is considered the best interest for the 
patient per investigator’s judgment. An interim 
database lock will occur at around one year after 
last patient randomized. After this interim lock, 
only AE, dose change, drug termination date and 

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cause of termination are required to be collected 
in RDC or BRAVE, and all the other trial 
procedures will be waived.
Rationale for change
Clarify the required procedure for the 
ongoing patients on Afatinib treatment after 
10 Feb 2019.
Section to be changed
3.3.4.1  Removal of individual patients
Description of change
After completion of the primary analyses (see 
Section 7.3) and one year after last patient was 
randomised, the sponsor may decide to complete 
the study. If allowed by local regulation, patients 
may switch to the randomised study medication 
via marketed product supply or other means. The 
cost of any ongoing supply of the treatment will 
be incurred by the sponsor until disease 
progression occurs (or earlier, if stop of treatment 
for other reason if this judged in the best interest 
for the patient). If a patient is removed from the 
study medication within the frame of this study at 
end of study, an end of treatment and follow-up 
visit will be performed to ensure all AEs are 
followed up and then the patient will be 
considered to have completed the trial.
Was changed to:
After completion of the primary analyses (see 
Section 7.3) and one year after last patient 
randomised, if there is still any patient on 
treatment, the sponsor may decide to conduct 
another interim DBL for all patients in OP and 
treatment. The patients who are off treatment and 
have completed FU1 will be considered to have 
complete the study and will not be further 
followed in observational period. 
The patients that are still on treatment at one year 
after last patient randomized can continue drug 
administration from the trial until disease 
progression or earlier if stop of treatment for 
other reasons is considered the best interest for 
the patient per investigator’s judgment.
Rationale for change
The patients that are still on treatment at one year 
after last patient randomized need to be kept in 

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the trial for treatment until discontinuation. 
Section to be changed
3.3.4.2 Discontinuation of the trial by the sponsor
Description of change
4.Primary analysis has been performed (see 
Section 7.3.1) and one year after last patient 
randomised has passed (see Section 3.3.4.1).
Was changed to:
4. All the patients have discontinued study 
treatment by site or other cause by sponsor.
Rationale for change
Clarify the cause of trial discontinuation.
Section to be changed
6.2.3 End of treatment and follow-up period
Description of change
Added:
The patients that are still on treatment at one year 
after last patient randomized can continue drug 
administration from the trial, until disease 
progression or earlier if stop of treatment for other 
reasons is considered the best interest for the 
patient per investigator’s judgment. An interim 
database lock will occur at around one year after 
last patient randomized. After this interim lock, 
only AE, dose change, drug termination date and 
cause of termination are required to be collected 
in RDC or BRAVE, and all the other trial 
procedures will be waived.
Rationale for change
Clarify the required data to be collected for these 
patients.
Section to be changed
7.3.1 Planned Analysis
Description of change
The final analysis will be performed at study 
completion.
Was changed to:
Updated analysis if needed will be performed at 
interim DBL (if any) after primary analyses and at 
study completion.
Rationale for change
Due to the change of trial discontinuation date, 
the previously planned final analysis need to be 
updated.

 
 
 
 
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LUX-Head & Neck 3
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07 Jan 2019 09:44 CET
Approval-Team Member Medicine
07 Jan 2019 11:49 CET
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07 Jan 2019 12:43 CET
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