Clinical trial NCT01121393
Conditions: Carcinoma, Non-Small-Cell Lung Adenocarcinoma
Sponsor: Boehringer Ingelheim
Start date: 2010-04-19; Completion date: 2017-11-26
Enrollment: 364 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To investigate the efficacy and safety of BIBW 2992 compared to standard first-line chemotherapy in patients with stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR activating mutation

Detailed description:

Arms: arm 1: Patients receive a tablet of BIBW 2992 daily until progression or unacceptable toxicity arm 2: Patients receive Gemcitabine and Cisplatin, maximum is 6 courses
Interventions: intervention 1: Gemcitabine+Cisplatin intervention 2: BIBW 2992
Intervention descriptions: intervention 1: Gemcitabine d1,8, Cisplatin d1, 21 days as a course, up to 6 courses. intervention 2: starting dose is 40 mg, in the event of no or minimal drug-related adverse events after one course, the dose will be increased to 50mg. in the event of certain drug related Adverse Event (AE), dose reduction will be increments of 10 mg, with the lowest dose being 20mg.

Protocol documents:
Prot_000.pdf: 
 
 
Clinical Trial Protocol 
 
Doc. No.: U10-3034-01 
 
 
BI Trial No.: 
 
1200.34 
 
Investigational 
Product(s): 
BIBW 2992 
Title: 
LUX-Lung 6: A randomized, open-label, phase III study of BIBW 2992 
versus chemotherapy as first-line treatment for patients with Stage IIIB 
or IV adenocarcinoma of the lung harbouring an EGFR activating 
mutation 
Clinical Phase: 
Phase III 
Trial Clinical 
Monitor: 
Phone:
 Fax:
 
 
Co-ordinating 
Investigator: 
Phone:
Fax:
Status, Version, and 
Date of Protocol: 
Final, 22 Jan 2010 
Planned Dates of 
Trial: 
March 2010 – March 2012 
 
 
Page 1 of 
 
Proprietary confidential information.  
© 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 
 
105


CLINICAL TRIAL PROTOCOL SYNOPSIS 
Name of company: 
Tabulated 
Trial Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: 
Not applicable 
Name of active ingredient: 
 
BIBW 2992 
 
Protocol date 
Trial number 
Planned trial period 
Mar 2010 – Mar 2012 
22 Jan 2010 
1200.34 
Title of trial: 
LUX-Lung 6: A randomized, open-label, phase III study of BIBW 2992 versus 
chemotherapy as first-line treatment for patients with Stage IIIB or IV 
adenocarcinoma of the lung harbouring an EGFR activating mutation 
Co-ordinating 
Investigator: 
 
Trial site(s) : 
Multi-centre trial in Asia (China, India and Korea） 
Clinical phase: 
 Phase III 
Objectives: 
 To investigate the efficacy and safety of BIBW 2992 compared to standard first-line 
chemotherapy in patients with stage IIIB or IV adenocarcinoma of the lung 
harbouring an EGFR activating mutation. 
Methodology: 
 Open-label, randomized study 
No. of patients:  
 
 
total: 
1366 screened 
330 randomized 
 
each treatment: 
Arm A (BIBW 2992): 220 patients 
Arm B (Chemotherapy- Gemcitabine /Cisplatin) : 110 patients 
Diagnosis and main 
criteria for inclusion: 
Patients with stage IIIB or IV adenocarcinoma of the lung who have an activating 
mutation of EGFR 
Not eligible for standard curative-intent treatment with surgery or chemo-
radiotherapy. 
No prior systemic treatment for locally advanced, recurrent or metastatic NSCLC. 
Test product(s) : 
Arm A: BIBW 2992 
 
dose: 
Starting dose 40 mg / day 
 
mode of admin. : Oral, once daily continuous 
Reference therapy: 
Arm B: Chemotherapy 
 
dose: 
Gemcitabine 1000 mg/m2 on day 1 and day 8, Cisplatin 75 mg / m2 on day 1 
six courses should be given 
 
mode of admin. : i.v 
 
Final,  22 Jan 2010 
BI Trial No.: 
 
Trial Protocol 
Page 
 
 
 
 
 
 
Boehringer Ingelheim
1200.34
2


Name of company: 
Tabulated 
Trial Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: 
Not applicable 
Name of active ingredient: 
 
BIBW 2992 
 
Protocol date 
Trial number 
Planned trial period 
Mar 2010 – Mar 2012 
22 Jan 2010 
1200.34 
Duration of treatment: Arm A: continuous treatment in the absence of disease progression or adverse events.
Arm B: 6 treatment courses (3 weeks per treatment course) 
Criteria for efficacy:  
• 
Progression-free survival (PFS)  
• 
Complete response (CR), partial response (PR), stable disease (SD),
progressive disease(PD) according to RECIST 1.1 
• 
Overall survival (OS) 
Criteria for safety: 
Adverse events according to Common Terminology Criteria for Adverse Events (CTC 
AE Version 3). 
Statistical methods: 
The primary objective of the statistical analysis is to determine whether BIBW 2992 
prolongs progression-free survival (PFS) in comparison to chemotherapy. A log-rank 
test will be used to test for the effect of BIBW 2992. 
Unequal treatment after progression is expected to obscure the effect of BIBW 2992 
on survival. Survival will be assessed as a secondary endpoint. The analyses will 
describe the overall pattern of time to death, together with the extent and influence of 
post-progression treatment. 
 
Final,  22 Jan 2010 
BI Trial No.: 
 
Trial Protocol 
Page 
 
 
 
 
 
 
Boehringer Ingelheim
1200.34
3


FLOW CHART: ARM A (BIBW 2992) 
 
Screening* 
Treatment Courses 
1 - 2*** 
Treatment Course 
3 and subsequent 
courses 
End of 
Treatment 
Follow-up 
Observation 
period 
Visit abbreviation 
SV1 
SV2** 
CxV1a 
CxV2a 
CxV1a 
EOT 
FUxb 
OP 
Days 
Up to 6 
weeks 
before 
treatment 
Up to 28 
days 
before 
treatment 
Day 1 
(± 2 
days) 
Day 8 
(± 2 
days) 
Day 1 
(± 2 days) 
0-14 days after 
permanent 
discontinuation 
of BIBW 2992 
****
Every 21 days 
after EOT visit 
(± 7 days)***** 
Every 60 days 
after last 
follow-up visit  
(± 15 days) 
Informed Consent 1 
X (1) 
 
 
 
 
 
 
 
Informed Consent 2 
 
X (2) 
 
 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
Review of In-/Exclusion criteria 
 
X 
 
 
 
 
 
 
Randomization 
 
X (3) 
 
 
 
 
 
 
Complete physical examination (4) 
 
X 
 
 
 
X 
 
 
Limited physical examination (4) 
 
 
X 
 
X 
 
X 
 
Vital Signs  
 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
 
X 
X 
X 
X 
X 
X 
 
HRQOL and caregiver support assessment  
 
 
X 
 
X 
X 
X 
 
12 Lead Digital ECG (5) 
 
X 
 
X (5) 
X (5) 
X (5) 
 
 
ECHO or MUGA (6) 
 
X 
 
 
X (6) 
X (6) 
 
 
Safety lab (7) 
 
X 
X 
 
X 
X 
X 
 
Pregnancy test 
 
X 
 
 
 
 
 
 
Tumour biopsy for EGFR mutation analysis (8) 
X 
 
 
 
 
 
X (8) 
 
Blood sample for EGFR mutation analysis (9) 
 
 
X (9) 
 
 
 
X (9) 
 
Blood sample for DNA banking (10) 
 
 
X (10) 
 
 
 
 
 
Blood sample for pharmacokinetic analysis (11) 
 
 
X (11) 
X (11) 
X (11) 
 
 
 
Tumour assessment (12) 
 
X 
See schedule below (12) 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
 
Compliance Check 
 
 
X 
X 
X 
X 
 
 
Adverse events and healthcare usage 
 
X 
X 
X 
X 
X 
X 
 
Dispense Trial drugs 
 
 
X 
 
X 
 
 
 
BIBW 2992 treatment 
 
 
Continuous 
 
 
 
Termination of trial medication 
 
 
 
 
 
X 
 
 
Trial Completion 
 
 
 
 
 
 
X 
 
Collection of vital status information (13) 
 
 
 
 
 
 
 
X 
 
 
Final,  22 Jan 2010 
BI Trial No.: 
 
Trial Protocol 
Page 
 
 
 
 
 
 
Boehringer Ingelheim
1200.34
4


*  
The screening visits are identical for all patients but have been included on both flow charts for clarity. 
**  
EGFR mutation analysis will be performed at Screening visit 1. Only patients who test positive for an EGFR activating mutation should proceed to Screening visit 2. Procedures which are 
performed as part of routine clinical care prior to receiving the EGFR mutation test result do not need to be repeated at Screening visit 2 if they are within the allowed time window (within 
28 days prior to treatment). 
***  All courses are 3 weeks in duration (21 days). Patients may continue on treatment for unlimited courses, until the criteria for stopping medication are met (see Section 6.3.1). 
****  If the decision to permanently discontinue BIBW 2992 is taken during a scheduled visit, the EOT visit should be performed instead of the scheduled visit. 
***** All patients should have a follow-up visit 21 days after the EOT visit. Patients who have not progressed and not started further treatment should have further follow-up visits every 21 days 
until progression or start of further treatment. 
a 
x is the number of the treatment course 
b 
x is the number of the follow-up visit 
 
1 
Written informed consent must be obtained before any protocol specific screening assessments are performed. Informed Consent 1 must include consent to collection of demographic data 
and consent to obtaining a biopsy and testing of biopsy material for EGFR mutation status.  
2 
Informed Consent 2 will be obtained for patients who have positive EGFR mutation status and must include consent to all study procedures including a blood sample for analysis of EGFR 
mutation status. The only exception is that consent to collection of a blood sample for DNA banking is optional. 
3 
Treatment must commence as soon as possible after randomization, but within 2 days at the latest. 
4 
Includes height (at screening only) and weight. 
5 
A 12-lead resting digital electrocardiogram (ECG) will be performed at Screening, on Day 8 of Course 1, and then on Day 1 of every third course (Day 1 of Course 4, 7, 10 etc.), and at EOT 
(if not performed in the previous 8 weeks). 
6 
ECHO or MUGA will be performed at Screening, on Day 1 of Course 4 and then at every third course (Course 7, 10, 13, 16 etc.), and at EOT (if not performed in the previous 8 weeks). 
7 
Includes haematology, serum biochemistry, and urinalysis. Creatinine clearance must be measured at screening for all patients. 
8  
Tumour biopsy to be collected at screening visit 1 for analysis of EGFR mutation status. If a tumour biopsy is performed as part of routine clinical practice prior to trial participation and 
material is available for analysis, the biopsy does not need to be repeated. Tumour biopsy at follow-up (at the time of PD) is desirable but optional. 
9 
A single blood sample for EGFR mutation testing is mandatory at start of treatment and should be taken on Day 1 of Course 1. A single blood sample at follow-up for EGFR mutation testing 
is desirable but optional. 
10 
The blood sample for DNA banking is optional. Separate consent must be obtained. The sample may be taken any time after randomization, but preferably on Course1Day1. 
11 
Pharmacokinetic sampling will take place at C2V1, C2V2 and C3V1. For detailed PK sampling time schedule, refer to Section 5.5.  
12 
Tumour assessments should include CT scans of the chest and abdomen and, if clinically indicated, imaging of any other known or suspected sites of disease (e.g. pelvis, brain) using an 
appropriate method (CT scan or MRI).  The same radiographic procedure must be used throughout the study. In case of suspected (but not confirmed) bone metastasis at screening, tumour 
assessment at screening should include a bone scan. If bone lesions are already known or confirmed at screening, correlative imaging (X-ray or CT scan) should be performed. Correlative 
imaging should then be repeated at each tumour assessment (see Section 5.1.3 for more detail). Assessment will be performed at the following time points until progression or start of further 
treatment for disease;  
 
 
 
 
 
Screening visit 2 
 
 
 
 
 
During week 6 (35-42 days after randomization) 
 
 
 
 
 
During week 12 (77-84 days after randomization) 
 
 
 
 
 
During week 18 (119-126 days after randomization) 
 
 
 
 
 
During week 24 (161-168 days after randomization) 
 
 
 
 
 
During week 30 (203-210 days after randomization) 
 
 
 
 
 
Every 6 weeks thereafter until progression/ start of further treatment. After week 48, assessments will be performed every 12 weeks. 
 
In the event of early discontinuation or an interruption/delay to treatment the tumour assessment schedule should not be changed. 
13 
Collection of information on progression, further treatment and death. Information should be collected from the patient notes or by telephone contact with the patient. A formal study visit is 
not required. 
 
Final,  22 Jan 2010 
BI Trial No.: 
 
Trial Protocol 
Page 
 
 
 
 
 
 
Boehringer Ingelheim
1200.34
5


FLOW CHART: ARM B (GEMCITABINE/ CISPLATIN) 
 
Screening* 
Treatment Courses ***  
End of Treatment 
Follow-up 
Observation 
period 
Visit abbreviation 
SV1 
SV2** 
C1-2V1a 
C3-6V1a  
C1-6V2a 
EOT 
FUxb 
OP 
Days 
Up to 6 
weeks 
before 
treatment
Up to 28 
days 
before 
treatment 
Day 1 
(± 2 
days) 
Day 1 
(± 2 
days) 
Day 8 
(± 2 days) 
21 days after Course 6 
Day 1 (± 7 days) 
or  
If patient does not 
complete 6 courses, 0-14 
days after decision to end 
treatment 
Every 21 
days after 
EOT visit 
(± 7 days) 
**** 
Every 60 
days after 
last follow-up 
visit  
(± 15 days) 
Informed Consent 1 
X (1) 
 
 
 
 
 
 
 
Informed Consent 2 
 
X (2) 
 
 
 
 
 
 
Demographics 
X 
X 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
Review of In-/Exclusion criteria 
 
X 
 
 
 
 
 
 
Randomization 
 
X (3) 
 
 
 
 
 
 
Complete physical examination (4) 
 
X 
 
 
 
X 
 
 
Limited physical examination (4) 
 
 
X 
X 
 
 
X 
 
Vital Signs  
 
X 
X 
X 
X 
X 
X 
 
ECOG performance status 
 
X 
X 
X 
X 
X 
X 
 
HRQOL and caregiver support assessment 
 
 
X 
X 
 
X 
X 
 
12 Lead Digital ECG (5) 
 
X 
X (5) 
 
ECHO or MUGA (6) 
 
X 
X (6) 
 
Safety lab (7) 
 
X 
X 
X 
X 
X 
X 
 
Pregnancy test 
 
X 
 
 
 
 
 
 
Tumour biopsy for EGFR mutation analysis (8) 
X 
 
 
 
 
 
X (8) 
 
Blood sample for EGFR mutation analysis (9) 
 
 
X (9) 
 
 
 
X (9) 
 
Blood sample for DNA banking (10) 
 
 
X (10) 
 
 
 
 
 
Tumour assessment (11) 
 
X 
See schedule below (11) 
 
Concomitant medications 
 
X 
X 
X 
X 
X 
X 
 
Adverse events and healthcare usage 
 
X 
X 
X 
X 
X 
X 
 
Dispense Trial drugs 
 
 
X 
X 
 
 
 
 
Chemotherapy 
 
 
X(13) 
X(13) 
X(13) 
 
 
 
Termination of trial medication 
 
 
 
 
 
X 
 
 
Trial Completion 
 
 
 
 
 
 
X 
 
Collection of vital status information (12) 
 
 
 
 
 
 
 
X 
 
Final,  22 Jan 2010 
BI Trial No.: 
 
Trial Protocol 
Page 
 
 
 
 
 
 
Boehringer Ingelheim
1200.34
6


 
*  
The screening visits are identical for all patients but have been included on both flow charts for clarity. 
**  
EGFR mutation analysis will be performed at Screening visit 1. Only patients who test positive for an EGFR activating mutation should proceed to Screening visit 2. Procedures which are 
performed as part of routine clinical care prior to receiving the EGFR mutation test result do not need to be repeated at Screening visit 2 if they are within the allowed time window (within 
28 days prior to treatment). 
***  Courses 1-6 are each 3 weeks (21 days). 
**** All patients should have a follow-up visit 21 days after the EOT visit. Patients who have not progressed and not started further treatment should have further follow-up visits every 21 days 
until progression or start of further treatment. 
 
a 
C1-2, Course 1 and course 2, C1-6 Course 1 to course 6  
b 
x is the number of the follow-up visit 
 
1 
Written informed consent must be obtained before any protocol specific screening assessments are performed. Informed Consent 1 must include consent to collection of demographic data 
and consent to obtaining a biopsy and testing of biopsy material for EGFR mutation status.  
2 
Informed Consent 2 will be obtained for patients who have positive EGFR mutation status and must include consent to all study procedures including a blood sample for analysis of EGFR 
mutation status. The only exception is that consent to collection of a blood sample for DNA banking is optional. 
3 
Treatment must commence as soon as possible after randomization, but within 2 days at the latest. 
4 
Includes height (at screening only) and weight. 
5 
A 12-lead resting digital electrocardiogram (ECG) will be performed at Screening and then at any other time point if clinically indicated. 
6 
ECHO or MUGA will be performed at Screening and then at any other time point if clinically indicated. 
7 
Includes haematology, serum biochemistry, and urinalysis. Creatinine clearance must be measured at screening for all patients. 
8  
Tumour biopsy to be collected at screening visit 1 for analysis of EGFR mutation status. If a tumour biopsy is performed as part of routine clinical practice prior to trial participation and 
material is available for analysis, the biopsy does not need to be repeated. Tumour biopsy at follow-up (at the time of PD) is desirable but optional. 
9 
A single blood sample for EGFR mutation testing is mandatory at start of treatment and should be taken on Day 1 of Course 1. A single blood sample at follow-up for EGFR mutation testing 
is desirable but optional. 
10 
The blood sample for DNA banking is optional. Separate consent must be obtained. The sample may be taken any time after randomization, but preferably on Course1 Day1. 
11 
Tumour assessments should include CT scans of the chest and abdomen and, if clinically indicated, imaging of any other known or suspected sites of disease (e.g. pelvis, brain) using an 
appropriate method (CT scan or MRI).  The same radiographic procedure must be used throughout the study. In case of suspected (but not confirmed) bone metastasis at screening, tumour 
assessment at screening should include a bone scan. If bone lesions are already known or confirmed at screening, correlative imaging (X-ray or CT scan) should be performed. Correlative 
imaging should then be repeated at each tumour assessment (see Section 5.1.3 for more detail). Assessment will be performed at the following time points until progression or start of further 
treatment for disease; 
 
 
 
 
 
Screening visit 2 
 
 
 
 
 
During week 6 (35-42 days after randomization) 
 
 
 
 
 
During week 12 (77-84 days after randomization) 
 
 
 
 
 
During week 18 (119-126 days after randomization) 
 
 
 
 
 
During week 24 (161-168 days after randomization) 
 
 
 
 
 
During week 30 (203-210 days after randomization) 
 
 
 
 
 
Every 6 weeks thereafter until progression/ start of further treatment. After week 48, assessments will be performed every 12 weeks. 
12 
Collection of information on progression, further treatment and death. Information should be collected from the patient notes or by telephone contact with the patient. A formal study visit is 
not required 
13.  Day 1, Gemcitabine 1000 mg/m2 and Cisplatin 75 mg / m2; Day 8, Gemcitabine 1000 mg/m2 
 
 
Final,  22 Jan 2010 
BI Trial No.: 
 
Trial Protocol 
Page 
 
 
 
 
 
 
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7


TABLE OF CONTENTS  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TITLE PAGE
1
..............................................................................................
CLINICAL TRIAL PROTOCOL SYNOPSIS
2
........................................
FLOW CHART: ARM A (BIBW 2992)
4
...................................................
FLOW CHART: ARM B (GEMCITABINE/ CISPLATIN)
6
...................
TABLE OF CONTENTS
8
...........................................................................
ABBREVIATIONS
13
.....................................................................................
1. INTRODUCTION
16
..................................................................................
1.1 MEDICAL BACKGROUND
16
..............................................................................
1.2 DRUG PROFILE
19
.................................................................................................
1.3 RATIONALE FOR PERFORMING THE TRIAL
23
..........................................
1.4 BENEFIT - RISK ASSESSMENT
24
.....................................................................
2. TRIAL OBJECTIVES
25
...........................................................................
2.1 GENERAL AIM - OBJECTIVES
25
......................................................................
2.2 PRIMARY ENDPOINT
25
......................................................................................
2.3 SECONDARY ENDPOINTS
25
..............................................................................
3. DESCRIPTION OF DESIGN AND TRIAL POPULATION
26
.............
3.1 OVERALL TRIAL DESIGN AND PLAN - DESCRIPTION
26
.........................
3.2 DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
27
.......................................................................................
3.3 SELECTION OF TRIAL POPULATION
27
........................................................
3.3.1 Inclusion criteria
27
..........................................................................................
3.3.2 Exclusion criteria
28
..........................................................................................
4. TREATMENTS
30
......................................................................................
4.1 TREATMENTS TO BE ADMINISTERED
30
......................................................
4.1.1 Identity of investigational product
30
..............................................................
4.1.1.1  Identity of comparator treatment
30
...........................................................
4.1.2 Method of assigning patients to treatment groups
31
....................................
4.1.3 Selection of doses in the trial
32
.......................................................................
4.1.4 Selection and timing of doses for each patient
32
...........................................
4.1.4.1 BIBW 2992 (Arm A)
32
..............................................................................
4.1.4.2 Chemotherapy (Arm B)
35
..........................................................................
4.1.5 Blinding
35
.........................................................................................................
4.1.6 Packaging, labelling, and re-supply
35
............................................................
4.1.6.1 BIBW 2992
35
.............................................................................................
4.1.6.2 Chemotherapy
36
.........................................................................................
4.1.7 Storage conditions
37
........................................................................................
 
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4.2 CONCOMITANT THERAPY
37
............................................................................
4.2.1 Rescue medication and additional treatments
38
...........................................
4.2.2 Restrictions
38
...................................................................................................
4.2.2.1 Restrictions for patients randomized to arm A (BIBW 2992)
38
................
4.2.2.2 Restrictions for patients randomized to arm B 
(Gemcitabine/Cisplatin chemotherapy)
38
..................................................
4.3 TREATMENT COMPLIANCE
39
.........................................................................
4.3.1 BIBW 2992 (Arm A)
39
....................................................................................
4.3.2 Gemcitabine/Cisplatin Chemotherapy (Arm B)
39
........................................
4.4 MANAGEMENT OF ADVERSE EVENTS
39
......................................................
4.4.1 Management of diarrhoea following treatment with BIBW 2992 
(Arm A)
39
.........................................................................................................
4.4.2 Management of nausea and vomiting following treatment with 
BIBW 2992 (Arm A)
40
....................................................................................
4.4.3 Management of rash following treatment with BIBW 2992 (Arm 
A)
41
....................................................................................................................
5. OBSERVATIONS
43
...................................................................................
5.1 EFFICACY - CLINICAL PHARMACOLOGY OR 
PHARMACODYNAMICS
43
..................................................................................
5.1.1 Primary Endpoint
43
........................................................................................
5.1.2 Secondary Endpoints
43
...................................................................................
5.1.3 Tumour Assessment
43
.....................................................................................
5.1.4 Central imaging
44
............................................................................................
5.1.5 Health-Related Quality Of Life
45
...................................................................
5.2 SAFETY
46
................................................................................................................
5.2.1 Adverse Events
46
.............................................................................................
5.2.2 Worsening of pre-existing conditions
48
.........................................................
5.2.3 Assessment of Healthcare Resource use
49
.....................................................
5.2.4 Laboratory investigations
49
............................................................................
5.2.5 Physical examination, performance score
50
..................................................
5.2.6 ECG
50
...............................................................................................................
5.2.7 Left ventricular function
50
.............................................................................
5.2.8 Vital signs
51
......................................................................................................
5.2.9 Data and Safety Monitoring Committee (DMC)
51
.......................................
5.3 OTHER
51
.................................................................................................................
5.3.1 Demographics and history
51
...........................................................................
5.3.2 Concomitant therapies and diagnoses
52
........................................................
5.4 APPROPRIATENESS OF MEASUREMENTS
52
...............................................
 
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5.5 DRUG CONCENTRATION MEASUREMENTS - 
PHARMACOKINETICS
52
....................................................................................
5.5.1 Methods and timing of sample collection
52
...................................................
5.5.2 Analytical determinations
53
............................................................................
5.6 BIOMARKER - PHARMACODYNAMIC SAMPLING
53
................................
5.6.1 Methods and timing of sample collection
53
...................................................
5.6.2 Analytical determinations
55
............................................................................
5.6.2.1 Methods and timing of sample collection
55
..............................................
5.6.2.2 Analytical determinations
55
.......................................................................
5.7 PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
56
.......
5.8 DATA QUALITY ASSURANCE
56
.......................................................................
6. INVESTIGATIONAL PLAN
57
................................................................
6.1 VISIT SCHEDULE
57
..............................................................................................
6.1.1 Screening and randomization
57
.....................................................................
6.1.2 Treatment
57
......................................................................................................
6.1.3 End of Treatment visit
57
.................................................................................
6.1.4 Follow-up
57
.......................................................................................................
6.1.5 Observation period
58
.......................................................................................
6.1.6 Treatment after the End of Study
58
...............................................................
6.2 TRIAL PROCEDURES AT EACH VISIT
59
.......................................................
6.2.1 Screening and run-in in phases
59
...................................................................
6.2.2 Treatment phases
61
.........................................................................................
6.2.2.1 Treatment Arm A (BIBW 2992)
61
............................................................
6.2.2.2 Treatment Arm B (Gemcitabine/Cisplatin)
63
............................................
6.2.3 End of trial and follow-up
64
...........................................................................
6.2.4   Follow-up (all patients)
65
..............................................................................
6.2.5   Observation period
66
.....................................................................................
6.3 REMOVAL OF PATIENTS FROM THERAPY OR ASSESSMENT
66
...........
6.3.1 Removal of patients from study treatment
66
................................................
6.3.2 Removal of patients from trial
67
....................................................................
6.3.3 Replacement of patients
67
...............................................................................
7. STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
68
.......................................................................................
7.1 STATISTICAL DESIGN - MODEL
68
..................................................................
7.2 NULL AND ALTERNATIVE HYPOTHESES
68
................................................
7.3 PLANNED ANALYSES
68
......................................................................................
7.3.1 Primary analyses
68
..........................................................................................
7.3.2 Secondary analyses
69
.......................................................................................
 
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7.3.2.1 Key Secondary analyses
69
.........................................................................
7.3.2.1.1 Best RECIST assessment
69
....................................................................
7.3.2.1.2 Overall survival (OS)
70
..........................................................................
7.3.2.2 Other secondary analyses
70
.......................................................................
7.3.2.2.1 Sensitivity and exploratory analyses for PFS
71
......................................
7.3.2.2.2 Tumour shrinkage
71
................................................................................
7.3.2.2.3 Body weight and ECOG performance status
71
.......................................
7.3.2.2.4 Health-Related Quality of Life (HRQOL)
71
...........................................
7.3.3 Safety analyses
72
..............................................................................................
7.3.4 Interim analyses
74
............................................................................................
7.3.5 Pharmacokinetic methods
74
...........................................................................
7.4 HANDLING OF MISSING DATA
74
....................................................................
7.5 RANDOMISATION
76
............................................................................................
7.6 DETERMINATION OF SAMPLE SIZE
76
..........................................................
8. ADMINISTRATIVE MATTERS
77
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8.1 ETHICS
77
................................................................................................................
8.1.1 Independent Ethics Committee or Institutional Review Board
77
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8.1.2 Patient Information and Informed Consent
77
..............................................
8.2 RECORDS
78
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8.2.1 Drug accountability
78
......................................................................................
8.2.2 Emergency code break
78
.................................................................................
8.2.3 Case Report Forms (CRFs)
79
.........................................................................
8.2.4 Source documents
79
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8.2.5 Direct access to source data - documents
80
...................................................
8.3 QUALITY ASSURANCE AUDIT
80
......................................................................
8.4 PROCEDURES
80
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8.4.1 Adverse events
80
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8.4.2 Emergency procedures
82
................................................................................
8.4.3 Contraception and Pregnancy
82
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8.5 RULES FOR AMENDING PROTOCOL
83
.........................................................
8.6 DISCONTINUATION OF THE TRIAL BY THE SPONSOR
84
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8.7 STATEMENT OF CONFIDENTIALITY
84
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8.8 PUBLICATION POLICY
84
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9. REFERENCES
85
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9.1 PUBLISHED REFERENCES
85
.............................................................................
9.2 UNPUBLISHED REFERENCES
91
.......................................................................
10. APPENDICES
93
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10.1 APPENDIX 1   OVERVIEW OF STUDY VISITS
93
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10.2 APPENDIX 2   RECOMMENDED SUPPORTIVE CARE AND 
DOSE MODIFICATION SCHEME FOR GEMCITABINE / 
CISPLATIN CHEMOTHERAPY
94
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10.3 APPENDIX 3   QUESTIONNAIRES
96
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10.4 APPENDIX 4   RECIST 1.1 CRITERIA
102
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ABBREVIATIONS 
AE 
Adverse Event 
ALT 
Alanine Amino Transferase 
ANC 
Absolute Neutrophil Count 
ANCOVA 
Analysis of Covariance 
ASE 
American Society of Echocardiography 
AST 
Aspartate Amino Transferase 
ATP 
Adenosine Triphosphate 
AUC 
Area under the plasma concentration time curve of the analyte 
in plasma 
β-HCG 
Beta-Human Chorionic Gonadotropin 
BI 
Boehringer Ingelheim 
CA 
Competent (Regulatory) Authority 
Cmax 
Maximum measured concentration of the analyte in plasma 
CML 
Clinical Monitor Local 
CPK 
Creatine Phosphokinase 
CR 
Complete Response 
CRA 
Clinical Research Associate 
CRF/eCRF 
Case Report Form / electronic Case Report Form 
CT 
Computed Tomography 
CTC 
Common Terminology Criteria 
CTC AE 
Common Terminology Criteria for Adverse Events 
CTMF   
Clinical Trial Master File 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
CYP3A4 
Cytochrome P450 3A4 
DCF 
Data Clarification Form 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
DOC 
Documentation of Change 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
EC/IEC 
(Independent) Ethics Committee 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EGF 
Epidermal Growth Factor 
EGFR 
Epidermal Growth Factor Receptor 
EORTC 
European Organisation for Research and Treatment of Cancer 
EOT 
End of Treatment 
erbB 
Epidermal Growth Factor family of receptors 
(erB1/EGFR/HER1, erB2/HER2, erB3/HER3, erB4/HER4) 
FAS 
Full Analysis Set 
FU 
Follow-up Visit 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
 
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gMean 
Geometric Mean 
HER 
Human Epidermal Growth Factor Receptor 
HERG 
Human à ether go-go Gene 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
HRQOL 
Health-related Quality of Life 
HRU 
Healthcare Resource Usage 
ICH 
International Conference on Harmonisation 
IND 
Investigational New Drug 
INR 
International Normalised Ratio 
IRB 
Institutional review board 
ISF 
Investigator Site File 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
K-RAS 
v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LD 
Longest Diameter 
LVEF 
Left Ventricular Ejection Fraction 
MASCC 
Multinational Association of Supportive Care in cancer 
mg 
Milligram 
min 
Minute 
ml 
Millilitre 
MRI 
Magnetic Resonance Imaging 
MUGA 
Multiple Gated Acquisition Scan 
MTS 
3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl) 
-2-(4-sulfophenyl) -2H-tetrazolium 
No. 
Number 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
OPU 
Operative Unit (of BI) 
OP 
Observation Period 
OS 
Overall Survival 
PCR 
Polymerase Chain Reaction 
PD 
Progressive Disease 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetic 
PPS 
Per Protocol Set 
PR 
Partial Response 
PT 
Prothrombin Time 
PTT 
Partial Thromboplastin Time 
QLQ 
Quality of Life Questionnaire 
RBC 
Red Blood Cell 
RECIST 
Response Evaluation Criteria in Solid Tumours 
SAE 
Serious Adverse Event 
SD 
Stable Disease 
SFDA 
State Food and Drug Administration 
SOC 
System Organ Class 
 
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SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
SPF 
Sun Protection Factor 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Terminal half-life of the analyte in plasma 
TDMAP 
Trial Data Management and Analysis Plan 
TGF 
Transforming Growth Factor 
TK 
Tyrosine Kinase 
TKI 
Tyrosine Kinase Inhibitor 
tmax 
Time from (last) dosing to the maximum measured 
concentration of the analyte in plasma 
TNM 
Tumour, (lymph) Node, Metastasis 
ULN 
Upper Limit of Normal 
US-NCI 
United States National Cancer Institute 
VEGF 
Vascular endothelial growth factor 
WBC 
White Blood Cell 
 
 
 
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1. 
INTRODUCTION 
1.1 
MEDICAL BACKGROUND 
Non-small cell lung cancer (NSCLC) is the leading cause of cancer death globally with 
estimated one million new cases diagnosed and 880,000 deaths each year. The prognosis for 
advanced Stage disease has not changed significantly in the past 20 years. With an overall 5- 
year survival rate of only 15%, the treatment of this disease remains a major clinical 
challenge (R05-0876). 
 
In patients with advanced NSCLC (Stage IIIB pleural effusion or Stage IV metastatic 
disease) systemic chemotherapy is considered the first line treatment of choice, prolonging 
the median survival and palliating tumour-related symptoms (R05-0876). In an Eastern 
Cooperative Oncology Group (ECOG) trial, platinum-based doublets achieved an objective 
response in approximately 20% of advanced NSCLC patients and prolonged median survival 
to 7.9 months with a one-year survival rate of 33% and a two-year survival rate of 11% (R04-
1314). Currently, several different platinum-based doublet combinations are in use worldwide 
as historically there has been no globally recognised superior regimen.  
 
While systemic chemotherapy has demonstrated modest activity in advanced NSCLC, novel 
targeted therapies based on specific molecular and biological characteristics of lung cancer 
have emerged as a new treatment paradigm. The targets most extensively studied include the 
epidermal growth factor receptors (EGFR) or the Subclass I of the superfamily of 
transmembrane tyrosine kinase receptors (R06-1302, R07-1049, R07-1135). The Epidermal 
Growth Factor Receptor was the first member to be cloned and is the most biologically 
relevant receptor for NSCLC. The erbB signaling system now comprises four closely related 
tyrosine kinase receptors: human epidermal growth factor receptor 1, HER 1 (erbB1/EGFR), 
HER2 (erbB2), HER3 (erbB3), and HER4 (erbB4) (R06-1301, R06-1302). Growth factors, 
such as epidermal growth factor (EGF) and transforming growth factor-α (TGF-α), bind to 
EGFR and trigger the dimerisation of two EGFR molecules or the heterodimerisation with 
other closely related receptors, such as HER2. Autophosphorylation and transphosphorylation 
of the EGFR through its tyrosine kinase domain leads to the recruitment of downstream 
effector molecules and the activation of multiple intracellular signal transduction pathways. 
Activation of these signalling cascades is essential for controlling malignant cell growth and 
metastasis (R06-1262, R06-1301, R06-1302). 
 
Aberrant activation of EGFR is frequently observed in a variety of malignant tumours and 
can be caused by different molecular mechanisms including mutations, receptor over-
expression, ligand-dependent receptor dimerisation, and ligand-independent activation. Over-
expression of EGFR is detected in 40% to 80% of NSCLC and this has led to the 
development of specific small molecule EGFR antagonists (R06-1301, R06-1393, R06- 
1394). First-generation EGFR small molecule tyrosine kinase inhibitors (TKI) act as ATP 
analogues, competing reversibly for the tyrosine kinase (TK) catalytic site, and include 
gefitinib (Iressa®) and erlotinib (Tarceva®). 
 
Despite the high levels of EGFR over-expression in tumours in the majority of patients with 
NSCLC, recent clinical experiences with specific EGFR-tyrosine kinase inhibitors have 
 
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demonstrated tumour regression in only 10% to 15% of unselected NSCLC patients (R05- 
0867, R06-1301, R06-1306). Further analysis has demonstrated that an objective tumour 
response to TKI therapy is more likely to occur in Asian females with adenocarcinomas 
(often with bronchoalveolar differentiation) and with a history of modest or no cigarette 
smoking (R06-1259, R06-1306, R06-1395, R07-1049). 
 
Further investigations in patients who respond to TKI therapy have indicated that the 
sensitivity to therapy may correlate with the presence of EGFR activating mutations. 
Sequence analysis of tissue samples from NSCLC patients responsive to TKI therapy 
revealed approximately 30 different somatic mutations in the tyrosine kinase domain of 
EGFR (R06-1262, R06-1393). The frequency of EGFR somatic mutations in the general 
NSCLC population was found to be approximately 10% in patients from the US, Europe or 
Australia and up to 30% in patients from Japan and Taiwan (R06-1262, R06-1306, R06- 
1393). 
 
Specific mutations sensitising EGFR to TKI therapy are either short, in-frame nucleotide 
deletions, in-frame duplications/insertions or single-nucleotide substitutions clustered around 
the region of the ATP binding-pocket of the receptor tyrosine kinase domain (R04-4507, 
R06-1311, R07-1134, R07-1135). The two most common mutations, accounting for more 
than 90% of known sensitising EGFR mutations in NSCLC specimens result in an in-frame 
deletion, including the amino acids at codons 746 to 750 (E746 to A750) in Exon 19 and a 
point mutation resulting in an amino acid substitution at codon 858 (L858R) in Exon 21 
(R04-4507, R06-1311, R06-1393, R07-1134, R07-1135). Structural analysis has revealed that 
these mutations lead to a conformational change within the kinase domain, narrowing of the 
ATP binding cleft and result in enhanced ligand-dependent receptor activation (R06-1264). In 
addition, these mutations result in stabilisation of both ATP and competitive small molecule 
inhibitors within the binding pocket. 
 
Retrospective analyses of studies have indicated that patients with activating Exon 19 and 
Exon 21 EGFR mutations have a higher response rate and a prolonged survival following 
treatment with single-agent TKIs compared to patients with wild-type EGFR (R06-1306, 
R06-1311, R06-1406, R08-4128). Several prospective phase II studies have investigated 
further the use of TKIs in patients harbouring EGFR mutations (R06-1310, R06-1458, R06- 
1459, R08-4048, R08-4078, R08-4049). The median PFS observed in these studies ranged 
from 8.9 months to 12 months, with response rates of between 55% and 90%. Overall 
survival of up to 24 months has been observed in patients with EGFR mutations receiving 
customised treatment (R08-4049). The largest cumulative series to date is a combined 
analysis from seven trials of first-line gefitinib monotherapy in patients with EGFR mutations 
(R08-4050). This analysis included 148 patients and demonstrated a PFS of 9.7 months and a 
response rate of 76.4%. 
 
The IPASS trial is a phase III randomized trial of gefitinib versus carboplatin/paclitaxel 
chemotherapy as first-line treatment for Asian patients selected based on demographic 
features associated with a higher frequency of mutations (adenocarcinoma, never or light 
exsmokers) (R08-4132). Recently presented data from this trial indicated that the median 
progression-free survival (PFS) was equivalent in the two treatment arms (5.7 months with 
 
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gefitinib versus 5.8 months with carboplatin/ paclitaxel) (R09-4437). A subgroup of the 
overall population was tested for EGFR mutation status and an analysis was performed on 
this subgroup. Amongst the patients tested, the rate of mutation observed was 60%. Patients 
who tested positive for EGFR mutation had a significantly higher response rate when treated 
with gefitinib (71.2%) compared to treatment with carboplatin/ paclitaxel (47.3%). Patients 
who tested negative for EGFR mutation had a significantly higher response rate when treated 
with carboplatin/ paclitaxel (23.5%) compared to treatment with gefitinib (1.1%). Similarly 
when compared to chemotherapy, PFS was significantly longer in the presence of EGFR 
mutations (HR=0.48) and significantly shorter in the absence of EGFR mutations (HR=2.85) 
in the gefitinib arm. These results strongly suggest that the use of single agent TKIs for first-
line therapy may only be of value in patients with EGFR mutations but that in this group of 
patients, treatment with single-agent TKIs may be more beneficial than chemotherapy. 
 
The efficacy of EGFR TKIs in NSCLC with activating EGFR mutations depends on the type 
of mutation. Patients with one of the two most common mutations, Exon 19 deletions and 
L858R, have the highest response rates (84.2%) whereas patients with other, less common, 
mutations have lower response rates of less than 20% (R08-4109). 
 
In trial 1200.34, patients with adenocarcinoma of the lung harbouring an EGFR mutation will 
be randomized to receive either Gemcitabine/Cisplatin chemotherapy or the irreversible 
EGFR small molecule inhibitor BIBW 2992. 
 
BIBW 2992 is a member of the second generation of TKIs which bind irreversibly to EGFR 
and HER2 and are thought to have potential benefit over first generation TKIs such as 
erlotinib and gefitinib. One of the reasons for the potential benefit is that BIBW 2992 may 
have activity against mutations which are resistant to the first generation TKIs (U03-3218). 
Additionally the irreversible binding may confer more prolonged activity further delaying 
tumour progression when compared to reversible TKIs. 
 
Despite initially promising responses, most patients treated with currently available 
EGFRTKI therapies will eventually develop disease progression. Molecular analyses of 
relapsed NSCLC samples from this group of patients have demonstrated an EGFR mutation 
rendering the tumour cells resistant to EGFR-TKI therapy (R06-1263, R06-1264, R06-1265, 
R06-1266, R06-1393). This specific mutation in Exon 20 causes a single base pair change 
leading to a threonine to methionine amino acid alteration in position 790 (T790M). This 
specific threonine residue at position 790 serves as the ‘gatekeeper’ deep in the catalytic 
ATP-binding site of the kinase domain. The bulkier methionine side chain confers drug 
resistance to the tumour cells by sterically hindering the access of TKIs such as erlotinib or 
gefitinib to the ATP binding site (R06-1264). 
 
Studies of tumour biopsies taken at diagnosis have shown that the T790M is rarely detected 
prior to treatment with EGFR TKIs (R06-1405). However, a recent study of EGFR mutations 
in circulating tumour cells detected the T790M mutation in 38% of patients prior to 
commencing treatment (R08-4065). The authors also observed that the T790M mutation was 
present at a relatively low frequency, suggesting that it is present in only a sub-clone of cells 
and may not be detected by conventional techniques. Following treatment with TKIs, the 
 
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T790M mutation is detectable in approximately 50% of NSCLC with acquired resistance to 
erlotinib and gefitinib (R06-1264). 
 
One of the proposed strategies to prevent or overcome the acquired resistance to TKI therapy 
in malignant tumours is the use of small molecule inhibitors with higher binding affinity, i.e., 
irreversible kinase inhibitors (R06-1263, R06-1389, R06-1390, R06-1391, R07-1135, R07- 
1162). Recently published experimental data strongly support this strategy (R06-1307). 
Bronchioloalveolar NCI-H1650 NSCLC cells in vitro rapidly developed resistance to 
gefitinib but not to the irreversible EGFR inhibitors HKI-357, HKI-272, and EKB-569. 
Moreover, stable over-expression of T790M mutant EGFR conferred high-level biochemical 
resistance to the EGFR-TKIs gefitinib and erlotinib in Ba/F3 murine hematopoietic 
progenitor cells that remain sensitive to the irreversible EGFR small molecule inhibitor CL-
367,785 (R06-1390). BIBW 2992 also belongs to this class of irreversible kinase inhibitors 
and has recently shown in vitro activity against NIH-3T3 cell lines expressing the T790M 
mutation (P08-06904). BIBW 2992 also demonstrated activity in xenograft and transgenic 
lung cancer models expressing the T790M mutation. In the same experiment these xenografts 
were resistant to lapatinib and gefitinib (P08-06904). 
 
These preclinical data support the hypothesis that BIBW 2992 may be more efficacious in the 
treatment of tumours harbouring EGFR mutations than the currently available TKIs. 
 
1.2 
DRUG PROFILE 
BIBW 2992 is a highly selective and potent low molecular weight, irreversible inhibitor of 
the erbB-family of tyrosine kinase receptors EGFR (erbB1 / HER1) and HER 2 (erbB2). All 
references in this protocol concerning BIBW 2992 refer to the oral formulation (U03-3218). 
 
The potency of BIBW 2992 was determined in enzymatic assays using recombinant human 
wild-type EGFR (IC50 0.5 nM) and HER2 (IC50 14 nm) (U03-3218). A panel of 
recombinant human kinases tested in parallel was not inhibited, demonstrating the high target 
specificity of BIBW 2992 (U03-3218). Molecular modeling revealed that BIBW 2992 binds 
covalently and with high affinity to Cys773 within the catalytic cleft of the ATP-binding 
pocket of the EGF receptor. It has been reported that this specific molecular interaction 
results in irreversible inhibition of the EGFR tyrosine kinase domain (R02-2292). 
Experimental data from in vitro washout studies confirmed the irreversible binding of BIBW 
2992 to its molecular target. In constitutively EGFR-overexpressing A431 human epidermoid 
cancer cells, BIBW 2992 inhibition of EGFR-signaling lasted for up to 7 hours after removal 
of the compound from the cell cultures (U03-3218). In contrast, A431 cells exposed to 
reversible EGFR TKIs regained full receptor function almost immediately after inhibitor 
washout. 
 
The specific activity of BIBW 2992 was determined in two independent in vitro assay 
systems: i) EGF-induced EGFR autophosphorylation using immunoprecipitation and Western 
blot and ii) clonogenic, anchorage-independent cell growth in a soft-agar assay system (P07- 
02467). The antiproliferative effects observed with BIBW 2992 compare favourably to 
activity data published for gefitinib in the same NSCLC cell models (R06-1388). In addition, 
BIBW 2992 suppressed EGFR phosphorylation and clonogenic growth in the gefitinib-
 
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resistant NCI-H1975 model, suggesting that tumour cells harboring the T790M EGFR TKI 
resistance mutation remain sensitive to this irreversible EGFR small molecule inhibitor (R06-
1391). 
 
The in vivo activity of BIBW 2992 against EGFR was investigated in an A431 subcutaneous 
xenograft model (U03-3218). Daily oral treatment with BIBW 2992 at doses of 20 mg/kg 
resulted in an almost complete inhibition of tumour growth over a period of 25 days. Similar 
anti-tumour activity was observed in NCI-N87 tumour bearing mice treated with BIBW 2992 
at similar concentrations. In these in vivo studies, BIBW 2992 plasma concentrations of 80- 
285 nM corresponding to an AUC0-24 of 589-3198 nM*h were required for anti-tumour 
activity. All BIBW 2992 doses shown to be effective in mouse xenograft models were well 
tolerated. 
 
Pharmacology and toxicology profile 
 
The absolute bioavailability of BIBW 2992 after oral ingestion is 45% in rats with a median 
tmax reached after 4 hours and a terminal half-life (t1/2) of 4.5 hours. In rats the exposure was 
dose proportional and no gender-related effects or compound accumulation was observed. 
BIBW 2992 is primarily excreted via the faeces. No relevant inhibition of cytochrome P450 
isoenzymes was found. In vitro BIBW 2992 is however a CYP3A4 substrate (U05-1723-01). 
Since this is not considered a dominant metabolic pathway, in vitro drug-drug interactions 
with CYP3A4 inducers or inhibitors are not expected (U03-3218). In vivo BIBW 2992 was 
metabolised only to a minor extent and the metabolism was governed by adduct formation to 
proteins or nucleophilic small molecules. It was found that metabolism is of subordinate role 
for BIBW 2992 and that enzyme-catalyzed metabolic reactions play a negligible role for the 
metabolism of BIBW 2992 in vivo. Only approx. 2 % of the dose were metabolised by FMO3 
in vivo. The CYP3A4-dependent N-demethylation was even too low to be quantitatively 
detected in human volunteers (U07-1737, U06-2055- 01, U07-1296-01). Therefore, intrinsic 
(e.g. genetic predisposition) or extrinsic (e.g. by comedications) effects on the activity of 
FMO3 or CYP3A4 in vivo are expected to be of little, if any, relevance for the 
pharmacokinetics of BIBW 2992. The human ADME data confirmed the results of the 
preclinical [14C] ADME studies and all metabolites of the human  [14C] ADME study were 
observed in the rat or the minipig (See U04-1028 and U06-1093, respectively). 
 
In acute toxicology studies, oral administration of single doses in rats and mice indicated a 
low acute toxic potential of BIBW 2992. Changes in renal and hepatic function occurred only 
at doses that were 10-30 fold above the levels required for antitumour activity. BIBW 2992 
had effects on gastrointestinal function that were dose-dependent and in high doses, leading 
to profound inhibition. No acute toxic effects on the central nervous system were detected. In 
oral repeated dose studies for up to 26 weeks in rats and minipigs, the main target organs 
were the gastrointestinal tract (rats and minipigs), kidneys (rat), and the skin (rats). In the 
gastrointestinal tract, increasing systemic exposure was associated with dose-dependent 
atrophy of the epithelium and concomitant focal erosions/ulcerations in the stomach of rats 
and minipigs. In rat kidneys papillary necrosis and dilated tubules were found. Cutaneous 
alterations, i.e., epithelial atrophy were observed in rats. However, BIBW 2992 is not 
irritating to intact skin in albino rabbits and the effects observed in rats are most likely related 
 
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to the specific pharmacodynamic mechanism of EGFR-inhibition (U03-3218). A variety of 
organs including the aerodigestive tract and reproductive organs were affected by epithelial 
atrophy. These atrophic changes were not severe and fully reversed during a 2-week recovery 
period. Minor cardiovascular effects (increased blood pressure and heart rate) and a dose-
dependent decrease of QT time in the electrocardiogram (ECG) occurred in BIBW 2992-
treated minipigs. These data do not indicate a risk for QT-prolongation related arrhythmia. 
BIBW 2992 had no pro-arrhythmic potential. BIBW 2992 demonstrated mutagenic potential 
in bacteria but had no genotoxic potential in vivo even at highly toxic/lethal doses in animals. 
Because of its specific pharmacodynamic mechanism of action, BIBW 2992 is potentially 
embryo/ foetotoxic and/or teratogenic. 
 
BIBW 2992 Phase I and Phase II trial program 
 
The most up to date trial and safety information can be found in the current version of the 
Investigator Brochure (U03-3218). 
 
BIBW 2992 showed moderately fast absorption with median tmax values between 1 h to 6 h 
after administration. The gMean terminal half-life (t1/2) of BIBW 2992 mainly ranged 
between 13 h to 57 h. In general, the maximum blood concentration (Cmax) and the integral of 
the concentration time curve (AUC) of BIBW 2992 increased in a dose-proportional way 
(U03-3218). 
 
The maximum tolerated dose (MTD) of BIBW 2992 was identified as 50 mg once daily in 
phase I continuous dosing monotherapy trials. The 50mg dose is currently used in the phase 
IIb/III trial 1200.23 in NSCLC patients progressing on erlotinib or gefitinib, as maximum 
EGFR inhibition is required in this last-line population enriched for the presence of resistance 
mutations. For a more sensitive population with EGFR activating mutation, a starting dose of 
40mg is expected to be sufficient. In phase I clinical trials of BIBW 2992, durable responses 
(>20 months) were seen at daily doses of 40mg and less. 
 
In this trial, a starting dose of 40 mg will be used in order to optimize the efficacy/toxicity 
balance in the very sensitive population of first-line patients with EGFR activating mutations. 
Variability is expected in the incidence and severity of adverse events and to ensure 
maximum EGFR inhibition, dose escalation to 50mg will be allowed after the first course of 
treatment (21 days) in patients with minimal treatment-related adverse events. An interim 
analysis based on response rate is planned to allow an early assessment of the efficacy of the 
starting dose of 40mg (see Section 7.3.4). 
 
The Adverse Events (AEs) observed to date in Phase I and Phase II trials are consistent with 
those reported for other EGFR tyrosine kinase inhibitors (dose dependent diarrhoea and skin 
related adverse events including rash and acne). Other AEs were in the expected range for 
patients with advanced cancer disease (U03-3218). In the BIBW 2992 Phase I monotherapy 
trials, the most frequent drug-related adverse events were associated with gastrointestinal 
disorders (diarrhoea, nausea, vomiting, stomatitis), skin and subcutaneous tissue disorders 
(rash, dry skin, pruritus, acneiform rash, and acne), general disorders and administration site 
 
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conditions (fatigue, mucosal inflammation), respiratory disorders (epistaxis, typically grade 
1), and metabolism and nutritional disorders (anorexia, dehydration). 
 
Diarrhoea is the single most often reported gastrointestinal AE. An increased incidence of 
diarrhoea grade 3 (22.4%) has been observed in phase II monotherapy trials (starting dose of 
50 mg qd). Prompt and proactive management of diarrhoea together with timely treatment 
pause and dose reduction is crucial to reduce the severity of diarrhoea and its potential 
complications such as dehydration leading to serum electrolyte changes (hyponatraemia, 
hypokalaemia and hypomagnesaemia) and/or renal impairment.  
 
Nausea and vomiting are the other commonly reported gastrointestinal adverse events and 
can be generally managed successfully with the use of antiemetics.  
 
Skin related adverse events present in a number of forms, i.e., rash (including erythematous, 
maculo-papular, papular, etc.), acne, dermatitis acneiform, dry skin, skin reaction and 
pruritis. Folliculitis as well as nail changes (including paronychia) are other reported 
manifestations of skin-related adverse events with BIBW 2992. Early and adequate 
management of skin-related adverse events can reduce the frequency and the severity of them 
(R07-4077). 
 
Further AEs included oral discomfort (stomatitis, mouth ulceration, oral pain, dry mouth) soft 
tissue disorder) and mucosal inflammation. Conjunctivitis and rhinorrhoea as a result of 
inflammation in the mucosal membranes have been reported. Mucosal and skin dryness can 
lead to epistaxis, which has always been observed at CTCAE Grade 1. Anorexia, fatigue and 
asthenia are also frequently observed. 
 
Of 22 evaluable patients with NSCLC from Phase I trials, there have been four partial 
responses (PRs) (3 confirmed and 1 unconfirmed PR) ranging in duration from 5 months to 
24 months. All 4 patients were non-smoking Caucasian with adenocarcinoma of the lung. In 
two of these three patients with confirmed PR, EGFR sequencing has shown Exon 19 inframe 
deletions. These preliminary clinical efficacy data suggest that BIBW 2992 may be 
efficacious in patients with recurrent NSCLC harbouring sensitising EGFR mutations. 
 
The efficacy and safety of BIBW 2992 in NSCLC is being evaluated in a phase II trial. In this 
trial, patients with Stage IIIB/IV lung adenocarcinoma with EGFR mutation in exons 18-21 
and failure of one line of systemic chemotherapy are treated with BIBW 2992 at a dose of 
50mg once daily until disease progression. Preliminary results of 67 patients  treated in the 
2nd line setting have shown tumour size reductions in the majority of patients with disease 
control rate of 97%  and overall response rate of 66%. After amending and allowing first line 
patients into the trial preliminary data show an overall response rate of 63% and a disease 
control rate of 97% of patients in a total of 38 first line patients  Diarrhoea (83.3%) and skin-
related adverse events (87.4%) have been the main side effects but have been manageable 
with appropriate dose interruption/reduction (P08-07355).  
 
A global, randomized, placebo controlled, double blind phase IIB/III trial (LUX-Lung 1) is 
currently ongoing and is assessing the efficacy of BIBW 2992 plus best supportive care 
 
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(BSC) when compared to placebo plus BSC in non-small cell lung cancer patients failing 
erlotinib or gefitinib. Based on the planned interim analysis of safety and efficacy described 
in the protocol, the independent DMC has allowed for continuation of recruitment in the trial. 
 
1.3 
RATIONALE FOR PERFORMING THE TRIAL 
The introduction of the EGFR-TKIs gefitinib and erlotinib has changed the clinical 
management of patients with advanced NSCLC (R06-1394, R06-1307, R07-1049, R07-
1134). For the first time, a significant clinical benefit may be achieved by a treatment that 
controls NSCLC progression with acceptable levels of side effects through a defined and 
specific, targeted molecular mechanism (R06-1394). 
 
Patients with adenocarcinoma who have an EGFR mutation have a particularly significant 
benefit from treatment with TKIs (R08-5155). In these patients the objective response rates 
achieved with TKI therapy are superior to those obtained with chemotherapy. BIBW 2992 is 
a second generation irreversible EGFR-TKI (R07-1135, R07-1162) which may have 
improved potency when compared to erlotinib and gefitinib. BIBW 2992 may also prevent 
the emergence of the T790M resistance mutation which is commonly seen in patients 
relapsing after gefinitib or erlotinib. The preliminary results of a second-line study performed 
in EGFR mutation positive patients show a disease control rate of 87.5% with BIBW 2992 
(P08-07355). These promising data support the conduct of a phase III trial with BIBW 2992 
in patients with EGFR mutations. 
 
In this trial eligible patients will be randomized (2:1) into two treatment arms to receive 
either (Arm A) BIBW 2992 or (Arm B) Gemcitabine/Cisplatin chemotherapy. 
 
In the comparator arm of this trial, bevacizumab in addition to chemotherapy will not be 
included. Two recently reported randomized Phase III studies in the first line treatment of 
NSCLC, indicated that the addition of bevacizumab to standard paclitaxel and carboplatin 
(E4599) or gemcitabine and cisplatin chemotherapy (B017704) increased the progression free 
survival from 4.8 to 6.4 months (R07-1161) and 6.1 to 6.7 months (R08-0542) respectively. 
But in the AVAIL trial no significant difference in overall survival was observed. Based on 
this data, and the restrictions on its use, bevacizumab is currently not widely used worldwide 
as standard first-line treatment for NSCLC and will not be included in the comparator arm of 
this trial.  
 
Efficacy will be assessed by measuring progression-free survival according to RECIST 1.1 
criteria (R09-0262), while safety will be analysed using the Common Terminology Criteria 
for Adverse Events (CTCAE) Version 3.0 (R04-0474). In addition to evaluating treatment 
efficacy and safety, the study will also assess health-related quality of life and 
pharmacokinetics of BIBW 2992. 
 
 
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1.4 
BENEFIT - RISK ASSESSMENT 
The outcome for patients diagnosed with advanced NSCLC is poor, with an overall 5-year 
survival rate of only 15%. In recent years tyrosine kinase inhibitors have been developed to 
target the molecular pathways involved in tumour growth. There is now evidence that these 
agents are effective in NSCLC patients and particularly in the subgroup of patients whose 
tumours harbour mutations in the EGFR gene (R08-5155). 
 
The currently available preclinical data indicate that BIBW 2992 is potentially superior to 
reversible EGFR TKIs (gefitinib, erlotinib) (P08-06904). The preliminary clinical data from 
trial 1200.22 supports this (P08-07355). The results of first-line treatment with EGFR TKIs 
compare favourably with historical controls. However, only prospective and controlled 
clinical trials can establish these treatments as a new standard. The objective of this trial is to 
assess whether a targeted treatment for a targeted population can be identified, providing 
maximum benefit to the enriched population, whilst sparing those patients who are not likely 
to benefit. 
 
Based on the toxicology findings and the experiences from the phase I and II studies, a 
continuous oral daily dose of 40mg BIBW 2992, together with proactive management of 
common side effects and the proposed dose reduction scheme, will be well tolerated. The 
most common side effects are expected to be primarily gastrointestinal (including diarrhoea, 
nausea, vomiting and anorexia) as well as fatigue and rash. As an oral drug BIBW 2992 will 
be a much more convenient treatment for patients when compared to chemotherapy and the 
side effect profile is expected to be in favour of BIBW 2992. Although skin and 
gastrointestinal adverse events are common with BIBW 2992, they are rarely serious and 
almost always reversible, whereas chemotherapy is associated with potentially life-
threatening side effects as a result of bone marrow suppression as well as potential 
irreversible side effects. 
 
Regular and frequent assessment of clinical benefit (including early imaging with first 
radiological tumour assessment after 6 weeks of treatment) throughout Study 1200.34 will 
ensure that any patient not deriving clinical benefit will be withdrawn from the trial 
treatment. Furthermore an independent Data Safety Monitoring Board will oversee the study 
and will advise on the further conduct of the trial based on the ongoing assessment of efficacy 
and safety data. 
 
Considering the poor outcome in this group of patients and the need for the development of 
specific treatments with less side effects, it is expected that the benefits of first-line therapy 
with BIBW 2992 will outweigh the risks. 
 
 
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2. 
TRIAL OBJECTIVES 
2.1 
GENERAL AIM - OBJECTIVES 
This randomized, open label phase III trial will be performed in patients with 
adenocarcinoma of the lung with tumours harbouring an EGFR activating mutation. The 
objectives of the trial are to compare the efficacy of single agent BIBW 2992 (Arm A) with 
Gemcitabine/Cisplatin chemotherapy (Arm B) as first line treatment for this group of 
patients. 
 
2.2 
PRIMARY ENDPOINT 
The primary endpoint will be progression free survival in all randomized patients, as 
determined by RECIST 1.1 (R09- 0262). 
 
2.3 
SECONDARY ENDPOINTS 
The secondary endpoints of this trial are: 
• Complete response (CR), partial response (PR), stable disease (SD), progressive 
disease (PD) according to RECIST 1.1  (R09-0262) 
• Overall survival (OS) 
• Deterioration of body weight and ECOG performance status 
• Health-related quality of life (HRQOL) 
• Pharmacokinetics of BIBW 2992 
• Safety of BIBW 2992 as indicated by intensity and incidence of adverse events, 
graded according to US NCI CTCAE Version 3.0 (R04-0474) 
 
 
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3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION 
3.1 
OVERALL TRIAL DESIGN AND PLAN - DESCRIPTION 
This multi-centre, open-label, randomized phase III trial is designed to compare the efficacy 
of single agent BIBW 2992 with Gemcitabine/Cisplatin chemotherapy for the first-line 
treatment of patients with Stage IIIB (with pleural effusion) or IV adenocarcinoma of the 
lung harbouring an EGFR activating mutation. The primary endpoint of the trial will be 
progression free survival in all randomized patients.  
 
The trial will be performed by investigators specialised in the treatment of lung cancer in 
Asia countries (China, India and Korea). It is estimated that approximately 1366 patients will 
be screened for the trial in order to find 330 eligible patients.  
 
All patients will be required to provide a tumour biopsy sample at screening for EGFR 
mutation testing, which will be performed by a central laboratory. 
 
Eligible patients will be randomized (2:1) to receive either single agent BIBW 2992 (Arm A) 
or chemotherapy with Gemcitabine/Cisplatin (Arm B). 
 
In Arm A (BIBW 2992) 220 patients will receive continuous daily treatment with BIBW 
2992 until progression, unacceptable adverse events or other reason necessitating withdrawal 
(see Section 6.3.1). The treatment will be administered as courses of 21 days. The starting 
dose of BIBW 2992 will be 40 mg once daily. In the event of no or minimal drug-related 
adverse events after one course of treatment, the dose will be increased to 50 mg (see Section 
4.1.4.1 for details). As detailed in Section 4.1.4.1.1, dose reduction will occur in the event of 
certain drug-related adverse events. Dose reduction will be in increments of 10 mg, with the 
lowest dose being 20mg. Patients receiving 20 mg will be withdrawn from treatment if a 
drug-related grade 3 adverse event occurs. Regardless of the dose taken, a patient will be 
withdrawn from treatment if certain drug related events persist for more than 14 days despite 
stopping treatment (see Section 4.1.4.1.1), and then followed up as described in Section 6.1.4. 
 
A limited pharmacokinetic sampling approach will be carried out for patients in arm A 
(BIBW 2992) - only trough PK samples will be taken (refer to Section 5.5). 
 
In arm B (chemotherapy) 110 patients will receive Gemcitabine (1000 mg /m2) on day 1 and 
day 8, Cisplatin (75 mg /m2) on day 1 of each course. Patients will receive 6 courses of 3 
weeks of treatment unless unacceptable side effects prevent this. All patients who receive at 
least one dose of treatment will be followed every 3 weeks after ending treatment until 
progression or other reason necessitating withdrawal (see Section 6.3.1). Dose reduction will 
occur in the event of certain adverse events (see Section 4.1.4.2). 
 
Appendix 1 provides an overview of the trial design. 
 
All patients will visit the investigator at regular intervals for assessment of safety parameters 
and adverse events as outlined in the flow chart. Assessments of response will be made at 6 
weeks, 12 weeks and every 6 weeks thereafter until progression or withdrawal for another 
 
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reason. After week 48, assessment of response will be performed every 12 weeks until 
progression of withdrawal for another reason. Tumour response and progression will be 
assessed using RECIST 1.1 (R09-0262) and assessment at the investigator site will be 
sufficient for decisions on continuation of treatment. An independent analysis of response 
will also be performed by a Central Imaging Unit (see Section 5.1.4) but this will not be used 
to make treatment decisions. 
 
BIBW 2992, Gemcitabine and Cisplatin will be provided to the study sites by Boehringer 
Ingelheim and will be stored according to the specified conditions (see Section 4.1.7). 
 
All trial relevant documentation will be stored in the clinical trial master file (CTMF) at 
Boehringer Ingelheim. In addition each site will have an Investigator Site File (ISF) 
containing all trial documents relevant for the site. 
 
The coordinating investigators are investigators participating in the trial who have experience 
of this type of trial and investigations. The coordinating investigators have been designated 
by Boehringer Ingelheim and will sign the clinical trial report. 
 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S) 
The primary objective of this trial is to compare the efficacy of BIBW 2992 to chemotherapy 
in patients with adenocarcinoma of the lung harbouring an EGFR activating mutation. 
Patients will be randomized to receive either BIBW 2992 or chemotherapy with 
Gemcitabine/Cisplatin. Due to the inherent differences between the two treatment arms, the 
trial will be open-label. 
 
The primary endpoint of the trial is progression-free survival and therefore the patients will 
be followed until progression. 
 
3.3 
SELECTION OF TRIAL POPULATION 
A log of all patients who have signed the informed consent form will be maintained in the 
ISF at the investigational site. The trial will be conducted in multiple centres in Asia (China, 
India and Korea). It is estimated that approximately 1366 patients will be screened in order to 
recruit 330 eligible patients. 
 
Additional centres may be opened in the event of slower than expected recruitment and 
underperforming centres may be closed. Recruitment rates will vary between centres but it is 
expected that 36 patients per month will be randomized into the trial over a period of 9-10 
months recruitment. 
3.3.1 
Inclusion criteria 
Patients are eligible for inclusion (enrolment) if they fulfill the following criteria: 
 
 
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1. Pathologically confirmed diagnosis of Stage IIIB (with cytologically proven pleural 
effusion or pericardial effusion) or Stage IV adenocarcinoma of the lung. Patients 
with mixed histology are eligible if adenocarcinoma is the predominant histology. 
 
2. EGFR mutation detected by central laboratory analysis of tumour biopsy material. 
3. Measurable disease according to RECIST 1.1 (R09-0262). 
 
4. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1 (R01-0787). 
 
5. Age ≥ 18 years. 
 
6. Life expectancy of at least three (3) months. 
 
7. Written informed consent that is consistent with ICH-GCP guidelines. 
  
3.3.2 
Exclusion criteria 
Patients with any of the following conditions will be excluded:  
 
1. Prior chemotherapy for relapsed and/or metastatic NSCLC. Neoadjuvant/adjuvant 
chemotherapy is permitted if at least 12 months has elapsed between the end of 
chemotherapy and randomization. 
 
2. Prior treatment with EGFR targeting small molecules or antibodies. 
 
3. Radiotherapy or surgery (other than biopsy) within 4 weeks prior to randomization. 
 
4. Active brain metastases (defined as stable for <4 weeks and/or symptomatic and/or 
requiring treatment with anticonvulsants or steroids and/or leptomeningeal disease). 
 
5. Any other current malignancy or malignancy diagnosed within the past five (5) years 
(other than non-melanomatous skin cancer and in situ cervical cancer). 
 
6. Known pre-existing interstitial lung disease. 
 
7. Significant or recent acute gastrointestinal disorders with diarrhoea as a major 
symptom e.g. Crohn's disease, malabsorption or CTC grade ≥2 diarrhoea of any 
aetiology. 
 
8. History or presence of clinically relevant cardiovascular abnormalities such as 
uncontrolled hypertension, congestive heart failure NYHA classification of 3, 
unstable angina or poorly controlled arrhythmia. Myocardial infarction within 6 
months prior to randomization. 
 
9. Cardiac left ventricular function with resting ejection fraction of less than 50%.  
 
10. Any other concomitant serious illness or organ system dysfunction which in the 
 
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opinion of the investigator would either compromise patient safety or interfere with 
the evaluation of the safety of the test drug. 
 
11. Absolute neutrophil count (ANC) < 1500 / mm3. 
 
12. Platelet count < 100,000 / mm3. 
 
13. Creatinine clearance < 60 ml / min or serum creatinine > 1.5 times upper limit of 
normal. 
 
14. Bilirubin > 1.5 times upper limit of normal. 
 
15. Aspartate amino transferase (AST) or alanine amino transferase (ALT) > 3 times the 
upper limit of normal (ULN) (if related to liver metastases > 5 times ULN). 
 
16. Women of childbearing potential, or men who are able to father a child, unwilling to 
use a medically acceptable method of contraception during the trial. 
 
17. Pregnancy or breast-feeding. 
 
18. Patients unable to comply with the protocol. 
 
19. Active hepatitis B infection, active hepatitis C infection or known HIV carrier. 
 
20. Known or suspected active drug or alcohol abuse. 
 
21. Requirement for treatment with any of the prohibited concomitant medications listed 
in Section 4.2.2.2. 
 
22. Any contraindications for therapy with gemcitabine / cisplatin. 
 
23. Known hypersensitivity to BIBW 2992 or the excipients of any of the trial drugs. 
 
24. Use of any investigational drug within 4 weeks of randomization. 
 
 
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4. 
TREATMENTS 
4.1 
TREATMENTS TO BE ADMINISTERED 
Patients will be randomized to receive either BIBW 2992 or Gemcitabine/Cisplatin 
chemotherapy. 
 
4.1.1 
Identity of investigational product 
Substance:  
 
 
 
BIBW 2992 
 
Pharmaceutical form:  
Film-coated tablets 
 
Source:  
 
 
 
Boehringer Ingelheim Pharma GmbH & Co. KG 
 
Unit strength:  
50mg, 40mg, 30mg and 20mg film-coated tablets (the dose of 
BIBW 2992 in the film-coated tablets is related to the free base 
equivalent of BIBW 2992) 
 
Daily Dose:  
Starting dose 40mg 
 
Duration of use:  
Continuous daily dosing until progression, unacceptable adverse 
events or other reason necessitating withdrawal. For administrative 
purposes treatment is divided into courses which are each 3 weeks 
(21 days) in duration. 
 
Route of administration:  Oral (swallowed) 
 
Posology:  
 
 
 
Once daily.  
 
4.1.1.1  Identity of comparator treatment 
Chemotherapy: Gemcitabine/Cisplatin 
 
Source:  
Boehringer Ingelheim will provide commercially available 
gemcitabine/cisplatin. 
 
Unit strength:  
Gemcitabine, vial containing 200 mg white, lyophilized powder of 
gemcitabine for reconstitution 
 
                                          Gemcitabine, vial containing 1000 mg white, lyophilized powder of 
gemcitabine for reconstitution 
 
 
Cisplatin, vial containing 50ml solution of cisplatin [1mg/ml]  
 
 
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Daily Dose:  
Gemcitabine 1000 mg /m2 infusion over 30 min followed by 
Cisplatin 75 mg/ m2 infusion on day 1 of each course; Gemcitabine 
1000 mg /m2 infusion over 30 min on day 8. 
 
Duration of use:  
Each course is 21 days in duration. Patients may receive a 
maximum of 6 courses. 
 
Route of administration:  
Intravenous  
 
Gemcitabine reconstitution: The recommended diluent for reconstitution of gemcitabine is 
0.9% sodium chloride. Add 5 mL of 0.9% sodium chloride to the 
200-mg vial. The total volume upon reconstitution will be 5.26 mL. 
The appropriate amount of drug may be administered as prepared 
or further diluted with 0.9% sodium chloride to concentrations as 
low as 0.1 mg/mL. Reconstituted gemcitabine is a clear, colorless 
to light straw-colored solution. Reconstituted solution and infusion 
solution should be used immediately. Do not refrigerate solutions. 
Discard any unused medicine. 
 
Cisplatin reconstitution:  Cisplatin should be reconstituted with 0.9% sodium chloride. From 
a microbiological point of view the product should be used 
immediately. Only use clear reconstituted solutions. Do not 
refrigerate or freeze. Discard any unused medicine. 
Administration sets, cannulae and syringes containing aluminium 
must not be used with the product.  
 
Additional information:  Drugs should be administered according to the summary of product 
characteristics. The recommendations for supportive care should be 
followed (see Appendix 2). 
 
4.1.2 
Method of assigning patients to treatment groups 
Patients will be randomized 2:1 to either BIBW 2992 (Arm A) or chemotherapy with 
Gemcitabine/Cisplatin (Arm B). The randomization will be stratified according to the type of 
mutation present. Details of stratification can be found in Section 7.5.  
 
Randomization will be carried out centrally using an Interactive Voice/Web Response 
System (IVRS/IWRS). The company that provides the IVRS/IWRS system will receive the 
randomization list from Boehringer Ingelheim Clinical Trial Support Group or a CRO 
appointed by the sponsor. The BI standard validated random number generating system will 
be used to generate the randomization schedules which will be verified by an independent 
statistician who is not involved in the study. The access to the randomization code will be 
supervised by the Clinical Trial Support Group and persons directly involved in the conduct 
and analysis of the trial will have no access to the randomization schedule. 
 
 
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4.1.3 
Selection of doses in the trial 
Arm A:  
The starting dose for BIBW 2992 continuous dosing is 40 mg. 
 
Arm B:  
Standard chemotherapy with;  
Gemcitabine 1000 mg/m2 followed by Cisplatin 75 mg/ m2  
 
These doses have been chosen according to the published information for these drugs. 
 
4.1.4 
Selection and timing of doses for each patient 
4.1.4.1 BIBW 2992 (Arm A) 
For administrative purposes treatment will be divided into treatment courses, which are each 
3 weeks (21 days) in duration. Patients will take a single oral dose of 40mg BIBW 2992 each 
day for the first course (21 days). 
 
If the patient experiences ≥ Grade 1 diarrhoea, skin-related adverse events or mucositis or 
any drug-related event ≥ Grade 2 during the first course, the dose of BIBW 2992 should be 
continued at 40mg (unless dose reduction is necessary - see Section 4.1.4.1.1). 
 
If none of the above events are experienced during the first course of treatment, the dose for 
Course 2 should be increased to 50 mg. The patient should remain on 50 mg for subsequent 
treatment courses, unless dose reduction is necessary (see Section 4.1.4.1.1). Any exceptions 
to this will be decided by the Boehringer Ingelheim clinical monitor in agreement with the 
investigator. 
  
Dose escalation is prohibited in any situation other than that described above. 
 
The medication should be taken at the same time each day (± 2 hours) at least one hour 
before food intake and at least three hours after food intake. The tablet should be swallowed 
with a glass of water. BIBW 2992 tablets are film-coated and therefore should not be chewed 
or crushed, but may be administered via G-tube after dispersing the BIBW 2992 tablets 
according to the following procedure: Place the tablet into a glass containing 50 mL isotonic 
sodium chloride solution. Stir until the tablet is broken up into very fine particles (about 15 
minutes). Drink the suspension immediately or administer via a gastric tube. Rinse the glass 
with another 50 ml of isotonic sodium chloride solution and drink or administer the 
supplementary solution via the gastric-tube again (to pick up any drug remaining in the 
glass/gastric-tube). 
 
Pharmacokinetic sampling will be performed on Day 1 and Day 8 of Course 2 and on Day 1 
of Course 3. On these days patients should not take the trial medication and should not eat for 
at least three hours prior to their visit to the study site. If a patient needs to eat within 3 hours 
of a scheduled visit, tablets should be taken as usual and the time of food intake noted on the 
CRF. 
 
 
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4.1.4.1.1 
Dose reduction scheme for BIBW 2992 
 
In the event of treatment-related toxicities, the treatment with BIBW 2992 should be handled 
according to the schedule in Table 4.1.4.1.1:1 
 
 
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Table 4.1.4.1.1:1 Dose reduction scheme 
 
AE type and grade 
Action Dose 
Dose reduction 
scheme
Events related to study drug; 
• Any drug related AE CTCAE 
Grade ≥3. 
• CTCAE Grade ≥2 diarrhoea 
persisting for 2 or more 
consecutive days (48 hours) 
despite adequate anti-diarrhoeal 
medication/ hydration. 
• CTCAE Grade ≥2 nausea and/or 
vomiting persisting for 7 or more 
consecutive days despite 
antiemetic treatment/ hydration. 
• CTCAE Grade ≥2 worsening of 
renal function as measured by 
serum creatinine, newly developed 
proteinuria, or newly developed 
decrease in glomerular filtration 
rate of more than 50% from 
baseline. 
Pause treatment with BIBW 
2992 until patient has 
recovered to CTCAE Grade ≤ 
1 or baseline1. 
 
Resume treatment at reduced 
dose according to schedule 
opposite. If patient has not 
recovered to CTCAE Grade ≤ 
1 or baseline1 within 14 days 
study treatment should be 
permanently discontinued2 
If patient was 
receiving 50mg, 
resume treatment at 
a dose of 40mg. 
 
If patient was 
receiving 40mg, 
resume treatment at 
a dose of 30mg. 
 
If patient was 
receiving 30mg, 
resume treatment at 
a dose of 20mg. 
 
If patient was 
receiving 20mg, 
discontinue BIBW 
2992. 
 
1 Baseline is defined as the CTCAE grade at the start of treatment 
2 In the event that the patient is deriving obvious clinical benefit in the opinion of the investigator, but has not recovered 
within 14 days, the further treatment of the patient will be decided by the BI clinical monitor in agreement with the 
investigator 
 
Dose reduction should always follow a treatment pause. In the event of a treatment pause, 
subsequent visits/courses should not be delayed. 
 
Patients will discontinue treatment if they experience deterioration in left ventricular cardiac 
function (LVEF) to CTCAE Grade ≥3. 
 
In the event of a prolonged (≥7 consecutive days) Grade 2 drug-related event not listed in 
Table 4.1.4.1.1:1, which is poorly tolerated by the patient, the investigator may choose to 
pause the medication for up to 14 days to allow the patient to recover followed by a dose 
reduction according to the schedule in Table 4.1.4.1.1:1. 
 
In the event of any unrelated adverse events or unrelated serious adverse events, the 
investigator may choose to pause the medication for up to 7 days to allow the patient to 
recover, but no dose reduction should occur. If the investigator chooses to pause the 
 
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medication for more than 7 days and believes that the patient would derive clinical benefit 
from continuing medication, the decision to continue medication will be made by the BI 
clinical monitor in agreement with the investigator. 
 
4.1.4.2 Chemotherapy (Arm B) 
Gemcitabine/Cisplatin chemotherapy will be administered at the investigator site and will be 
prepared and administered in accordance with the current summary of product characteristics 
(SPC). Up to six 3 week (21 day) courses of chemotherapy will be administered. 
 
Haematology should be checked prior to commencing each course and treatment should be 
delayed if platelet count is <100,000 cells/ mm3 or ANC is < 1500 cells/ mm3. 
 
The patient must be given supportive care (such as anti-emetics, hydration and vitamin 
supplements) during chemotherapy in accordance with the current summary of product 
characteristics and institutional guidelines. A summary of the current SPC is provided in 
Appendix 2. 
 
In the event of treatment related adverse events, the treatment with chemotherapy will be 
delayed and/or the dose will be reduced in accordance with the guidance in the current 
summary of product characteristics (SPC). A summary of the current SPC is provided in 
Appendix 2. 
 
In the event of a delay due to adverse events, subsequent courses and assessments should also 
be delayed, with the exception of the tumour assessment which should be performed 
according to the original schedule. 
 
In the event of adverse events or serious adverse events which are not related to treatment, 
the investigator may choose to delay the medication for up to 7 days to allow the patient to 
recover, but no dose reduction should occur. If the investigator chooses to delay the 
medication for more than 7 days and believes that the patient would derive clinical benefit 
from continuing medication, the decision to continue medication will be made by the BI 
clinical monitor in agreement with the investigator. 
 
4.1.5 
Blinding 
Not applicable.  
 
4.1.6 
Packaging, labelling, and re-supply 
4.1.6.1 BIBW 2992 
BIBW 2992 will be supplied as film-coated tablets. Available dosage strengths will be 20mg, 
30mg, 40mg and 50mg. Tablets will be supplied in HDPE, child-resistant, tamper-evident 
bottles. 
 
 
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Bottles will be labelled according to local regulations and will include the following as a 
minimum; 
• Study number (1200.34) 
• Product name (BIBW 2992) 
• Contents of the bottle (30 tablets) 
• Tablet 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 
 
Examples of the labels will be filed in the investigator site file (ISF). 
 
Medication numbers will be unique to each bottle and will be used for tracking purposes 
only. The medication numbers will not be linked to randomization numbers. 
 
A new bottle of medication will be dispensed on day 1 of each course, regardless of the 
number of tablets remaining in the bottle from the previous course. The patient will initially 
receive one bottle of 40mg tablets and in the event that dose increase or reduction is 
necessary the patient will return to the clinic and new medication will be dispensed. 
. 
4.1.6.2 Chemotherapy 
Gemcitabine will be supplied as vials containing 200 mg or 1000mg  of gemcitabine. Cisplatin 
will be supplied as a 50-ml vial containing 1mg/ml solution of cisplatin. 
 
Vials will be labeled according to local regulations and will include the following as a 
minimum; 
• Study number (1200.34) 
• Product name 
• Contents of the vial 
 
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• Dose 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 
•  
Examples of the labels will be filed in the investigator site file (ISF). 
 
Medication numbers will be unique to each vial and will be used for tracking purposes only. 
The medication numbers will not be linked to randomization numbers. 
 
4.1.7 
Storage conditions 
BIBW 2992 must be stored in the original packaging in order to protect from light. Film-
coated tablets are humidity sensitive and therefore bottles must be kept tightly closed. Tablets 
will be stored at the study site in a limited access area and must not be stored above 25ºC. 
 
Gemcitabine and Cisplatin will be stored in accordance with the instructions on the label. 
 
4.2 
CONCOMITANT THERAPY 
Pre-treatment hydration with 1 - 2 litres of fluid infused for 8 - 12 hours prior to Cisplatin 
will initiate diuresis. Adequate subsequent hydration should maintain diuresis during the 24 
hours following administration. Additional pre-medications immediately after randomization 
are listed in Appendix 2. 
 
During study participation symptomatic treatment of tumour-associated symptoms is allowed. 
Concomitant medications or therapy to provide adequate care, including bisphosphonates, 
may be given as clinically necessary. Localised radiation therapy to alleviate symptoms such 
as bone 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) utilised for 
response determination. 
 
 
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Treatment with certain agents which may interfere with trial medication is prohibited (see 
Section 4.2.2). 
 
All concomitant (non-oncological) medications which are taken between informed consent 
and the last follow-up visit should be recorded in the electronic case report form (CRF), 
including anaesthetic agents, vitamins, homeopathic remedies and nutritional supplements. If 
a patient requires parenteral nutrition it is not necessary to specify the detail on the CRF; it 
will be sufficient to indicate “parenteral nutrition”. 
 
4.2.1 
Rescue medication and additional treatments 
Rescue medications to reverse the actions of BIBW 2992, Gemcitabine and Cisplatin are not 
available. Side effects of these treatments should be treated symptomatically. 
 
The current version of the investigator brochure lists the AEs expected with BIBW 2992 
(U03-3218). Suggested treatments for diarrhoea, nausea, vomiting, rash/acne and stomatitis 
are described in Section 4.4 below.  
 
G-CSF use is permitted but not mandated for patients who experience CTCAE Grade 3 or 4 
neutropenia or who develop neutropenic fever between cycles of Gemcitabine/Cisplatin 
chemotherapy. The following doses and schedules are recommended; G-CSF (Filgastrim, 5μ
g/kg/day) SC beginning 24 hours after the completion of Gemcitabine and continued daily 
until the neutrophil count is >10,000/µL in two successive analysis or G-CSF (Pentagastrim, 
6 mg) SC once per chemotherapy cycle at least 24 hours after completion of Gemcitabine. 
 
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. Study 
drug should be interrupted pending investigation of these symptoms. If interstitial lung 
disease is diagnosed, study drug should be permanently discontinued and appropriate 
treatment instituted as necessary 
 
4.2.2 
Restrictions 
4.2.2.1 Restrictions for patients randomized to arm A (BIBW 2992) 
Patients randomized to treatment with BIBW 2992 should not receive any additional 
experimental anti-cancer treatment, chemotherapy, immunotherapy, hormone treatment (with 
the exception of megestrol acetate) or radiotherapy (except palliative short-course 
radiotherapy to non-target lesions) between informed consent and the end of treatment visit. 
 
4.2.2.2 Restrictions for patients randomized to arm B (Gemcitabine/Cisplatin chemotherapy) 
Patients randomized to treatment with Gemcitabine/Cisplatin chemotherapy should not 
receive any additional experimental anti-cancer treatment, chemotherapy, immunotherapy, 
hormone treatment (with the exception of megestrol acetate), maintenance therapy for 
 
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NSCLC or radiotherapy (except palliative short-course radiotherapy to non-target lesions) 
between informed consent and the end of treatment visit. 
 
Patients should not receive any of the prohibited medications as listed in the current summary 
of product characteristics (SPC) for the Gemcitabine /Cisplatin chemotherapy regimen. 
 
4.3 
TREATMENT COMPLIANCE 
Study medications will be given in accordance with the protocol and under the instruction of 
the site investigator. 
 
4.3.1 
BIBW 2992 (Arm A) 
Patients randomized to BIBW 2992 should take the first dose of treatment at the trial site and 
subsequent doses will be taken at home. A compliance check should be performed on day 8 
of course 1 to ensure that the medication is being taken correctly. Subsequently, at the end of 
each course of treatment the patient should bring all remaining medication to the site and a 
compliance check should be performed. Discrepancies between the number of tablets 
remaining and the calculated number of tablets that the patient should have taken should be 
documented and explained. At the end of each course any remaining medication should be 
collected. If the patient is eligible for a further course of treatment a new bottle should be 
dispensed. 
 
Patients experiencing emesis should not take a replacement dose. BIBW 2992 should not be 
taken more than once a day under any circumstances. 
 
4.3.2 
Gemcitabine/Cisplatin Chemotherapy (Arm B) 
Chemotherapy will be administered at the trial site under the supervision of the investigator. 
 
In the event that the patient does not receive the full dose of chemotherapy this should be 
documented and a reason given. 
. 
4.4 
MANAGEMENT OF ADVERSE EVENTS 
4.4.1 Management of diarrhoea following treatment with BIBW 2992 (Arm A) 
Close monitoring and proactive management of diarrhoea is essential for successful treatment 
of patients with BIBW 2992. Early and appropriate intervention can prevent the development 
of more severe diarrhoea. In most cases, loperamide controls diarrhoea caused by BIBW 
2992. Loperamide should be available at the start of therapy and kept with the patient at all 
times; it is therefore advisable that patients be given a prescription at the time of initiating 
treatment with BIBW 2992. 
 
The recommendations for management are as follows: 
 
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• 
If any diarrhoea is experienced (CTCAE Grade 1), two 2 mg loperamide tablets 
should be taken immediately, followed by one 2 mg tablet with every loose bowel 
movement, up to a maximum daily dose of 10 tablets (20 mg). 
• 
In the event of diarrhoea patients should be advised to avoid lactose-containing 
products or any foods known to aggravate diarrhoea. 
• 
Oral hydration is essential regardless of severity; appropriate rehydration (1.5 
l/m2/day plus equivalent of actual fluid loss) and electrolyte replacement has to be 
ensured in the event of CTCAE Grade 2 and Grade 3 adverse events. 
• 
For CTCAE Grade 3 diarrhoea or CTCAE Grade 2 diarrhoea lasting ≥ 2 days (48 
hours) despite adequate antidiarrhoeal treatment, BIBW 2992 must be paused until 
recovery to CTCAE ≤ Grade 1. Upon recovery, BIBW 2992 should be resumed at a 
reduced dose according to the dose reduction scheme outlined in Section 4.1.4.1.1. 
 
The occurrence of diarrhoea and the outcome of treatment will be recorded in the AE section 
of the CRF. Antidiarrhoeal treatments should be documented in the concomitant medication 
section of the CRF. 
 
If despite optimal supportive care and a treatment pause, diarrhoea does not resolve to CTC 
Grade ≤1 within 14 days, the patient must not receive any further BIBW 2992 treatment and 
the end of treatment (EOT) visit should be performed. 
 
4.4.2 Management of nausea and vomiting following treatment with BIBW 2992 (Arm 
A) 
Nausea and vomiting may significantly affect patients’ adherence to the treatment and their 
quality of life. In order to reduce the occurrence and the intensity of emesis, the patients 
should be treated according to the recommendation given in Table 4.4.2:1. 
 
Table 4.4.2:1 Management of nausea and vomiting 
CTCAE Grade 
Antiemetic treatment 
Nausea = grade 0 
and 
Vomiting = grade 0  
No antiemetic prophylactic treatment 
Nausea = grade 1 
and 
Vomiting = grade 0 
No antiemetic treatment 
 
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Nausea = grade 2 
and 
Vomiting = grade 0 
 
Nausea = grade 0, 1 or 2 
and 
Vomiting = grade 1 or 2 
Antiemetic treatment1
 
Pause BIBW 2992 treatment if grade 2 vomiting or 
grade 2 nausea persist for 7 or more consecutive 
days despite optimal supportive care. Resume 
treatment when CTCAE grade ≤ 1. 
Vomiting ≥ grade 3 
or  
Nausea ≥ grade 3 
Antiemetic treatment1 
 
Pause BIBW 2992 treatment until return to CTCAE 
grade ≤ 1 or baseline2. 
 
1  Antiemetic treatment should follow the recommendations given in the Consensus Statement of the Antiemetic 
Subcommittee of the Multinational Association of Supportive Care in cancer (MASCC): Prevention of chemotherapy- 
and radiotherapy-induced emesis: Results of the Perugia Consensus Conference (R06-0986). 
2  Baseline is defined as the CTCAE grade at the start of treatment. 
 
After a treatment pause the dose of BIBW 2992 should be reduced according to the dose 
reduction scheme in Table 4.1.4.1.1:1. 
 
The occurrence of nausea and/or vomiting and the outcome of treatment will be recorded in 
the AE section of the CRF. Antiemetic treatments should be documented in the concomitant 
medication section of the CRF with the start and end of treatment dates and daily dose. 
 
In case of nausea and/or vomiting ≥ CTCAE grade 2, appropriate hydration (1.5 L/m2/day 
plus hydration deficit) must be ensured. 
 
4.4.3 Management of rash following treatment with BIBW 2992 (Arm A) 
A proactive and early approach to management of rash is crucial. Rash can be managed by a 
variety of treatment options to relieve symptoms and reduce the rash. 
 
The recommendations for management are as follows: 
• General/Prevention: strict sun protection; use of a sunscreen of Sun Protection Factor 
15 (SPF 15) or higher, preferably containing zinc oxide; use of a thick, alcohol-free 
emollient cream; avoid harsh detergents, avoid using a solarium. 
• CTCAE Grade 1 rash: mild rash may not need treatment. However, if treatment is 
considered necessary, topical hydrocortisone (1% or 2.5%) cream and/or clindamycin 
1% gel can be used. 
• CTCAE Grade 2 rash: relief from major symptoms caused by CTCAE Grade 2 skin-
related adverse events should be achieved by a combination of local and systemic 
therapies including: 
1) Systemic antibiotics (doxycycline or minocycline etc.). 
2) Topical treatment (hydrocortisone 2.5% cream, clindamycin 1% gel, pimecrolimus 
1% cream). 
 
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And / or 
1) Antihistamines (diphenhydramine, etc.) 
2) Oral prednisone (short term i.e., <14 days treatment) may be added at investigator’s 
discretion. 
Systemic and topical treatment should be initiated at the start of CTCAE Grade 2 rash 
and continue until improvement or resolution to CTCAE Grade ≤1. If grade 2 rash 
persists for ≥ 7 days despite treatment and is poorly tolerated by the patient, the 
investigator may choose to pause treatment for up to 14 days followed by a reduction in 
the dose of BIBW 2992 according to the dose reduction scheme in Table 4.1.4.1.1:1. 
• CTCAE Grade 3 (or greater) rash: may be treated in a manner similar to CTCAE 
Grade 2 rash. In the event of CTCAE Grade ≥3 rash, treatment with BIBW 2992 should 
be paused until recovery to CTCAE Grade ≤1. Treatment should be resumed at a reduced 
dose (see Section 4.1.4.1). If CTCAE Grade ≥3 rash does not resolve to CTCAE Grade 
≤1 within 14 days of stopping BIBW 2992 treatment and despite optimal supportive care, 
the patient should not receive any further treatment with BIBW 2992 and the End of 
Treatment visit should be performed. 
 
 
 
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5. 
OBSERVATIONS 
5.1 
EFFICACY - CLINICAL PHARMACOLOGY OR PHARMACODYNAMICS 
5.1.1 Primary Endpoint 
The primary endpoint is progression free survival (PFS) in all randomized patients, defined as 
time from the date of randomization to the date of progression or to the date of death, 
whichever occurs first. 
 
5.1.2 Secondary Endpoints 
Secondary endpoints are; 
• Complete response (CR), partial response (PR), stable disease (SD), progressive disease 
(PD) according to RECIST 1.1  (R09-0262) 
• Overall survival (OS) defined as the number of days from the date of randomization to the 
date of death. 
• Time to deterioration of body weight (defined as the first occurrence of a decrease from 
baseline of more than 10 %) and time to deterioration of ECOG performance status.  
• Health-related quality of life (HRQOL). 
• Pharmacokinetics of BIBW 2992 (see Section 5.5) 
• Safety of BIBW 2992 as indicated by intensity and incidence of adverse events, graded 
according to US NCI CTCAE Version 3.0 (R04-0474). 
 
5.1.3 Tumour Assessment 
Response will be evaluated according to RECIST 1.1 (R09-0262). Complete Response (CR), 
Partial Response (PR), Stable Disease (SD) or Progressive Disease (PD) will be assessed by 
the investigator and also by a central imaging unit (see Section 5.1.4). 
 
Every effort should be made 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 prematurely. 
 
One to five target lesions (not exceeding two lesions per organ) should be identified at 
screening by Computed Tomography (CT). Skin lesions should be measured and 
photographic documentation should be performed. Individual lesions detected at screening 
will be numbered and recorded in the CRF. These lesions should be followed up with the 
same method(s) used at screening and the same numbering should be applied. The size of the 
target lesions will be recorded in millimetres. The examinations should be performed at 
screening, after 6 weeks, after 12 weeks and every 6 weeks thereafter. After week 48, 
assessments should be performed every 12 weeks. If a patient develops an allergy to contrast 
media, MRI scans can be substituted for CT scans. 
 
 
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Tumour assessment does not need to be performed at the screening visit if there are valid 
results available from assessments which were performed as part of routine clinical practice 
within the allowed time window (within 28 days prior to start of treatment). 
 
Target lesions should be selected based on their size (those with the longest diameter) 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 will be followed during 
the patients’ participation and will be taken into consideration when determining the patients’ 
response. 
 
Full details of RECIST 1.1 assessment can be found in Appendix 4. 
 
A bone scan should be performed at baseline in cases of clinical suspicion of previously 
unknown bone metastasis (e.g. bone or joint pain associated with relevant increases of 
calcium and alkaline phosphatase). If the patient has known bone metastases or if bone 
metastases are detected at screening, correlative imaging (X-ray or CT scan) should be done 
of the respective lesion(s) at baseline and subsequently correlative imaging of known bone 
lesions should be performed at every imaging time-point. During study treatment, bone scans 
should be performed when medically indicated e.g. in case of suspected new bone metastases. 
 
In the event of a delay, interruption or discontinuation of treatment, tumour assessment 
should continue to follow the original schedule. The schedule should be followed until 
progression is observed or until the patient commences further treatment for disease, 
whichever occurs first. 
 
5.1.4 Central imaging 
All image data will be sent to a central imaging unit to obtain an independent blinded 
confirmation of tumour response assessment based on a uniform interpretation of 
radiographic image data for all patients enrolled in the trial. Upon receipt, the central imaging 
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 
blinded (with regard to patient, treatment, and visit) radiologists. In the case of disagreement 
on the radiological assessment at any time-point between the two primary reviewers, a third 
adjudicating radiologist will select one of the primary reviewer’s interpretations for all time-
points. The data will also be reviewed by an oncologist who will provide a final assessment 
for each patient. 
 
The review of the image data will be performed by independent radiologists, who are not 
affiliated with the study. All procedures will be done according to the specifications provided 
in the investigator site file. The purpose of the blinded reading is to independently assess 
patient response to therapy and disease progression. 
 
 
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Modifications of the conventional RECIST 1.1 lesion measurement criteria will be introduced 
into the measurement process in an attempt to reduce variability in the measurements for the 
independent central imaging review. 
 
Eligibility and treatment decisions will be based on the assessment of disease by the 
investigator. Central imaging will not be used for this purpose and the results of the central 
imaging review will not be communicated to the investigator. 
 
5.1.5 Health-Related Quality Of Life 
Health-Related Quality Of life (HRQOL) will be measured with the following 
multidimensional questionnaires included in Appendix 3. 
 
• 
EQ-5D health status self-assessment questionnaire (R96-2382) 
 
• EORTC QLQ-C30, European Organisation for Research and Treatment of Cancer 
(EORTC) Quality of Life Questionnaire (QLQ-C30) (R99-1213, R07-2064) 
 
• EORTC Lung cancer specific supplementary module (EORTC QLQ-LC13) (R07-2060, 
R07-2065) 
 
All three questionnaires will be completed at the time points specified in the Flow Chart. 
Questionnaires should be completed by patients prior to seeing the clinician, prior to clinical 
assessment, prior to any treatment at the clinic, and before provision of any new information 
about their disease status so that the responses are not influenced (biased). The questionnaires 
generally take about 5-10 minutes to complete. Once completed, the questionnaires should be 
handed to the study co-ordinator or nurse. The data will then be transferred into the CRF by 
the sponsor. The questionnaires represent source documents (please refer to Section 8.2.4).  
Validated translations exist for all questionnaires for all countries participating in the study 
and patients will receive the questionnaires in their native language. 
 
Any unsolicited information provided by the patient on the questionnaire and any safety 
related data obtained from the patient’s responses to the standard questions on the 
questionnaires will be immediately reported to the investigator. Adverse event information 
from the questionnaire will be appropriately reported in the CRF. 
 
If local regulations require the completed questionnaires to be confidential (i.e. not seen by 
the site staff) appropriate arrangements will be made to ensure confidentiality. 
 
The patient perspective is considered a supportive contribution to inform physicians on the 
clinical utility of BIBW 2992 compared to standard chemotherapy in the NSCLC population 
under investigation. In addition, the EQ-5D, HRQOL assessment will inform a later health 
economic (cost-effectiveness) analysis. 
 
EQ-5D 
 
 
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The EQ-5D is a disease generic instrument that has been widely used and has been found to 
capture HRQOL changes in NSCLC (R07-2129, R07-2130). The EQ-5D comprises the 
following two questionnaires: 
 
1. The EQ-5D comprises 5 dimensions of health (mobility, self-care, usual activities, 
pain/discomfort, anxiety/depression). Each dimension comprises three levels (no 
problems, some/moderate problems, extreme problems). 
 
2. The EQ VAS records the respondents self-rated health status on a vertical graduated (0- 
100) visual analogue scale. 
 
For the EQ-5D the respondent is asked to indicate his/her health state by placing a cross in 
the box against the most appropriate statement in each of the 5 dimensions. Additional 
instructions are provided in the ISF. 
 
QLQ-C30 and LC-13 
 
The QLQ-C30 is comprised of 30 questions. The QLQ-C30 incorporates both multi-items 
scales and single-item measures. These include one global health status/HRQOL scale, five 
functional scales, three symptoms scales and six single items to assess dyspnea, insomnia, 
appetite loss, constipation, diarrhoea and financial difficulties. Each of the multi-item scales 
includes a different set of items- no item occurs in more than one scale (R07-2064). The 
QLQ-LC13 module comprises 13 questions. The module is designed for use in patients 
receiving treatment with chemotherapy and / or radiotherapy. The QLQ-LC13 incorporates 
one multi-item scale to assess dyspnoea, and a series of single items assessing pain, 
coughing, sore mouth, dysphagia, peripheral neuropathy, alopecia, and haemoptysis (R07- 
2064). 
 
5.2 
SAFETY 
5.2.1 Adverse Events 
During the screening phase of the trial, the patient’s condition will be assessed (e.g., 
documentation of history / concomitant diagnoses and diseases), and subsequently all 
relevant changes from baseline will be noted. 
 
The definition of adverse events (AEs) and serious adverse events (SAEs) can be found in 
Section 8.4.1. A list of expected adverse events with BIBW 2992 can be found in the 
investigator brochure (U03-3218). 
 
Patients will be required to report spontaneously any adverse events (AEs) as well as the 
dates of onset and end of these events. Specific questions will be asked wherever required or 
useful to more precisely describe an AE and to allow a grading according to CTCAE, Version 
3 (R04-0474). 
 
 
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A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the date of onset, end date and CTCAE grading of the 
event as well as any treatment or action required for the event and its outcome. 
 
Regular and continuing assessment of safety will be performed at least once per course 
during the first 6 courses and every 3 weeks thereafter. Dose reduction schemes are provided 
in Section 4.1.4.1.1 and Section 4.1.4.2 for patients who experience specified adverse events 
and who, at the discretion of the investigator, could derive benefit from continuing treatment 
on the protocol. 
 
Adverse events with an onset during therapy with trial medication or within 28 days after 
discontinuation of drug intake are considered as “on-treatment”. Adverse events which are 
not yet recovered at the End of Treatment visit will be followed up until recovery or in case 
of persistence sufficient characterisation of the toxic effects has been achieved and the 
investigator and Boehringer Ingelheim agree not to pursue them further. Adverse events that 
occur between Follow-up 1 (21 days after End of Treatment) and the final follow-up visit 
(see Section 6.1.4 for definition) will only be reported if they are considered related to trial 
medication or procedures by the investigator. 
 
Adverse events occurring after the final follow-up visit (during the observation period) will 
be reported only if considered serious (SAEs) and related to trial medication. Data regarding 
deaths which are not related to trial medication will be collected for the purposes of assessing 
the overall survival endpoint but these deaths will not be reported as SAEs. 
 
A summary of the requirements is given in Table 5.2.1:1. 
 
Table 5.2.1:1 AE/SAE reporting requirements 
 
Time period 
Reporting requirements 
Screening to Follow-up 1 (21 days after End 
of Treatment (EOT)) 
Report all AEs and SAEs regardless of 
relatedness. This includes all deaths. 
Follow-up 1 to Final Follow-up (see Section 
6.1.4 for definition of final follow-up) 
Report AEs and SAEs which are considered 
related to study treatment or procedures. 
 
Death should not be reported as an SAE 
unless considered related to study treatment 
or procedures (because death is an endpoint  
and will be followed-up separately) 
Observation Period 
Report only SAEs which are considered 
related to study treatment or procedures. 
 
Death should not be reported as an SAE 
unless considered related to study treatment 
or procedures (because death is an endpoint 
and will be followed-up separately). 
 
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Definitions and requirements for documentation and reporting of AEs and serious adverse 
events (SAEs) during a trial in the CRF are provided in Section 8.4.1. 
 
Patients may be hospitalised for administrative reasons during the trial. These and other 
hospitalisations planned at the beginning of the trial need not be reported as SAEs if they 
have been documented at the screening visit and have been performed as planned. 
 
Changes observed in safety tests including blood pressure, pulse rate, electrocardiogram 
(ECG) and laboratory tests will be recorded as AEs and graded according to CTCAE, if they 
are not associated with an already reported AE, symptom or diagnosis, and meet at least one 
of the following criteria: 
 
• 
Action is required and taken with the investigational drug, i.e., dose reduction or 
treatment discontinuation 
 
• 
Treatment is required (i.e., a concomitant medication is added or changed). 
 
5.2.2 Worsening of pre-existing conditions 
Expected fluctuations or expected deterioration of the underlying disease will not be recorded 
as an AE. If progressive disease occurs and is associated with symptoms or meets one of the 
seriousness criteria (see Section 8.4.1), the signs and symptoms of progressive disease will be 
reported as an adverse event or a serious AE (if applicable). 
 
The only exception to the above is in the event of a death which is attributed to progressive 
disease but where the signs and symptoms are not available. In this situation it is acceptable 
to report the progressive disease as the serious AE. 
 
A pre-existing condition present at baseline, which remains unchanged during the trial, does 
not need to be recorded as adverse event. However, any worsening of any pre-existing 
baseline condition should be reported as an adverse event. Examples of worsening of a 
preexisting condition that should be recorded as an AE are given below; 
 
• 
Worsening of condition meets the criteria for an SAE 
 
• 
Action is taken with the investigational drug (i.e. dose is reduced or treatment is 
discontinued) 
 
• 
Treatment is required (concomitant medication is added or changed) 
 
• 
The investigator believes a patient has shown a clear deterioration from baseline 
symptoms 
 
 
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5.2.3 Assessment of Healthcare Resource use 
If patients are hospitalised due to adverse events, the reason for hospitalisation, the duration 
of hospital stay, emergency room admission and time in the intensive care unit will be 
documented in the CRF. Adverse event related outpatient visits and interventions will also be 
documented in the CRF. 
 
Information on caregiver support (home care), hospital and outpatient visits (other than 
scheduled visits) collected in the CRF will inform on healthcare resource use required to treat 
the trial indication and adverse events observed during the trial. The data collected will be 
used for a later health economic (cost-effectiveness) analysis. 
 
5.2.4 Laboratory investigations 
Blood 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. Safety laboratory examinations 
include haematology and biochemistry. In case of neutropenia, blood will be examined as 
clinically indicated at the discretion of the investigator until recovery. 
 
For patients randomized to Gemcitabine/Cisplatin chemotherapy (Arm B) the decision to 
continue treatment will be based on assessment of laboratory parameters. Therefore the 
results of these assessments should be available and assessed on the day of treatment prior to 
commencing treatment. 
 
Safety laboratory assessment may be performed according to local practice but must include 
at least the following parameters: 
 
Haematology            Red blood cell count (RBC), neutrophils, haemoglobin, hematocrit, 
white blood cell count (WBC) and differential, platelets. 
 
Biochemistry  
Glucose, sodium, potassium, calcium, creatinine, aspartate amino 
transferase (AST), alanine amino transferase (ALT), alkaline 
phosphatase (ALP), lactate dehydrogenase (LDH), bilirubin, urea 
(BUN), total protein, uric acid, creatine phosphokinase (CPK). In case 
of pathological CPK further evaluation (e.g., by Troponin assays) 
should be performed and the findings documented in the CRF. 
Glomerular Filtration Rate (GFR) will be estimated by the Cockgroft-
Gault Formula utilizing serum creatinine values. 
 
Urinalysis  
pH, glucose, erythrocytes, leukocytes, protein, nitrite will be analysed 
by dipstick. In case of abnormal findings, further evaluation (g/24 hrs 
urine sampling) should be performed and the findings documented in 
the CRF. 
 
Pregnancy test  
β-HCG testing in urine will be performed in women of childbearing 
potential at screening (SV2). 
 
 
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At screening, creatinine clearance for study eligibility may be measured or may be calculated 
using the Cockroft-Gault Formula. 
 
5.2.5 Physical examination, performance score 
A physical examination will be performed at screening and at the time points specified in the 
Flow Chart. 
 
A full physical exam serves as a clinical tumour assessment and should include a 
cardiopulmonary examination, examination of the regional lymph nodes, examination of the 
abdomen and an assessment of the mental and neurological status. Additional symptoms 
which have not been reported during a previous examination should be clarified. Wherever 
possible the same investigator should perform this examination. 
 
A limited physical examination should include a cardiopulmonary examination, a clinical 
tumour assessment, an examination of the regional lymph nodes and an examination of the 
abdomen. 
 
Measurement of height (in cm) and body weight (in kg) and the evaluation of the ECOG 
performance score will be performed at the time points specified in the Flow Chart. 
 
5.2.6 ECG 
A 12-lead resting ECG will be performed at the time points specified in the Flow Chart. 
ECGs will be performed using a digital ECG machine and the data will be sent to a central 
assessment centre for evaluation. 
 
The investigator should also review the ECG data at the time of the visit and this will be used 
to make decisions on eligibility for the study and treatment. However, the investigator should 
also review the results of the central review when received. 
 
5.2.7 Left ventricular function 
Left Ventricular Ejection Fraction (LVEF) as measured by echocardiography or MUGA scan 
will be assessed at time points specified in the Flow Chart. The same method of measurement 
must be used throughout the study. 
 
Echocardiography (ECHO) 
 
Echocardiography will be performed to assess the LVEF according to the standard guidelines 
of the American Society of Echocardiography (ASE). http://asecho.org/Guidelines.php (R06- 
1414). 
 
MUGA Scan 
 
 
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The Multiple Gated Acquisition scan (MUGA) is recommended as a non-invasive method for 
the assessment of diseases of the heart muscle. It is used for the monitoring of the ejection 
fraction of the cardiac ventricles, especially the left ventricular ejection fraction (LVEF). 
 
5.2.8 Vital signs 
Vital signs (blood pressure, pulse and respiratory rate after 2 minutes supine rest) and 
temperature will be recorded at the screening visit and at the time points specified in the Flow 
Chart. 
 
5.2.9 Data and Safety Monitoring Committee (DMC) 
A Data and Safety Monitoring Committee (DMC) will be set up for this study in order to 
ensure its ongoing safety. The DMC will include three members, including an independent 
statistician and two independent oncologists. Safety review meetings will be held according 
to the DMC charter; approximately every 6 months (depending on the rate of enrolment). 
 
Inclusion of patients in the study 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. 
 
5.3 
OTHER 
5.3.1 Demographics and history 
Demographics (sex, birth date, race), alcohol history, and histological subtype will be 
collected during the screening 1 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 smoked per day x number of years 
smoked)/ 20 (R08-4072) 
 
• 
Date of last cigarette 
 
History of NSCLC will be obtained during screening 2 and reported in the CRF: 
 
• 
The date of first histological diagnosis 
 
• 
The primary tumour site 
 
• 
The number and location of metastatic sites (bone, brain, liver, pleural effusion, other)  
 
 
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• 
Tumour Stage according to the TNM-classification at diagnosis 
 
• 
Previous surgery and radiotherapy for NSCLC 
 
• 
Previously administered neoadjuvant/adjuvant chemotherapy including start and end 
dates and the outcome 
 
5.3.2 Concomitant therapies and diagnoses 
Concomitant diagnoses and/or therapies present during study participation (between informed 
consent and the follow-up visit) will be recorded in the CRF.. 
 
5.4 
APPROPRIATENESS OF MEASUREMENTS 
RECIST 1.1 (R09-0262), which will be used for evaluation of tumour response, is well 
established and scientifically accepted. The US NCI CTCAE criteria (R04-0474) are used in 
the assessment of adverse events in cancer patients. 
 
5.5 
DRUG CONCENTRATION MEASUREMENTS - PHARMACOKINETICS 
5.5.1 
Methods and timing of sample collection 
For patients randomized to arm A (BIBW 2992) blood sampling will be performed to 
estimate the BIBW 2992 trough (pre-dose) plasma concentrations at steady state. Samples 
will be taken at the time-points specified in the table below and at each sampling time, 4 ml 
of venous blood will be collected. 
 
Table 5.5.1:1 Time schedule for pharmacokinetic (PK) sampling 
 
Course 
Visit 
Visit 
name 
Time of 
sampling 
Allowed 
time 
window
CRF 
Time/ 
PTM 
Sample 
No. 
Course 2 
Day 1 
C2V1 
Just before 
drug 
administration 
None 
-0:05 
1 
Day 8 
C2V2 
Just before 
drug 
administration 
None 
-0:05 
2 
Course 3 
Day 1 
C3V1 
Just before 
drug 
administration
None 
-0:05 
3 
 
 
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Date and time of pharmacokinetic blood sampling should be recorded in the eCRF. In 
addition, the dose, date and time of BIBW 2992 administration and time of food intake before 
and after medication for the four (4) days prior to pharmacokinetic sampling should be 
recorded in the eCRF. 
Correct and complete documentation of drug administration and blood sampling is mandatory 
to obtain data of adequate quality for the pharmacokinetic analysis. 
 
The PK sample should not be taken if the patient has not taken any BIBW 2992 tablets during 
the 4 days prior to the visit (due to dose interruption). 
 
Detailed instructions for the collection and shipping of these samples will be provided in the 
ISF. 
 
 
5.5.2 
Analytical determinations 
BIBW 2992 drug concentrations will be determined by a validated by a high performance 
liquid chromatography-mass spectrometry (HPLC-MS/MS) assay. The procedure and 
specification of the analytical method are available at the determination site (Department of 
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim Pharma GmbH and Co. KG, 
Biberach, Germany). 
 
5.6 
BIOMARKER - PHARMACODYNAMIC SAMPLING 
5.6.1 
Methods and timing of sample collection 
The presence of an EGFR mutation, detected by central laboratory analysis, is mandatory for 
study enrolment. The results of local analysis of EGFR mutation status will not be accepted 
for study enrolment. 
 
EGFR mutation analysis will be performed at Screening visit 1. Tumour material will be 
submitted to the central laboratory as at least five (5), but preferably seven (7), 10 µm 
unstained sections mounted on non-charged microscopic slides as described in the Laboratory 
Manual and in the Investigator Site File (ISF). If an equivalent quantity of material is 
available as sections of different thickness, this is acceptable (e.g. 6 x 7.5 µm, 8 x 5 µm). It is 
recommended that the sections should contain at least 20% tumour pathology. 
 
Tumour tissue should be paraffin-embedded material obtained from initial diagnostic surgery 
for NSCLC. If a tumour biopsy is performed as part of routine clinical practice prior to trial 
participation and material is available for analysis, the biopsy does not need to be repeated. If 
tissue is available from more than one occasion, the latest obtained tissue should be used 
wherever possible. The site of biopsy (primary tumour or metastatic site) will be recorded in 
the eCRF. 
 
 
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DNA extraction, amplification and quantification using real-time PCR will be performed as 
described in detail in the Laboratory Manual in the ISF. Mutation genotyping of the most 
common activating EGFR mutations will be conducted using an established quantitative real-
time PCR protocol together with fluorescence detection (Therascreen: EGFR29, DxS 
Limited). In addition, a central pathology review will be performed, including assessment of 
percentage of tumour involvement, but this will not be reported to investigators. 
 
The following somatic EGFR mutations are detected; 
 
• 19 deletions in exon 19 
 
• L858R 
 
• 3 insertions in exon 20 
 
• L861Q 
 
• G719S, G719A and G719C 
 
• T790M 
 
• S768I 
 
Samples testing positive for one of these mutations will be reported as 'Positive' and the 
patient will be eligible for Screening Visit 2. The stratification category and the type of 
mutation will be specified in the report to the investigator. If a mutation is not detected, the 
result will be reported as 'Negative' and the patient will be recorded as a Screen Failure. In 
the event that the EGFR mutation test is inconclusive the investigator is allowed to send 
further material for testing if desired. 
 
In addition, a blood sample will be collected on Course 1 day 1 for EGFR mutation analysis. 
This sample is compulsory but the results will not be reported to investigators 
 
During follow-up (after progression) a further blood sample and tissue sample for EGFR 
mutation analysis may be taken but are optional. The sample requirements are the same as 
those at screening. 
 
Material submitted for EGFR mutation analysis may be used for the validation of alternative 
methods for detection of EGFR mutations, which may include detection of additional 
mutations. The results of these analyses will not be reported to investigators. If local 
regulations allow, any excess material will be shipped and stored at Boehringer Ingelheim, 
Germany until any required validation has taken place or until it is decided that there is no 
requirement for validation. Samples will be destroyed at the latest 5 years after the last patient 
study visit. 
 
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If both L858R and a deletion in exon 19 are detected in the same sample, the patient will be 
allocated to the ‘L858R’ stratificatkion category. In any other case where more than one 
mutation is detected, the patient will be allocated to the ‘other mutation’ stratification 
category. 
 
5.6.2 
Analytical determinations 
Pharmacogenetics investigates genetic variations in patients to explain and to predict their 
individual response to drugs. 
 
To allow pharmacogenetic analyses, patients will be asked for one extra blood sample after 
randomization. Donation of this blood sample for pharmacogenetics is voluntary and not a 
prerequisite for participation in the study. The sample will only be taken and processed or 
stored after separate informed consent is given in accordance with local ethical and 
regulatory requirements. 
 
The blood sample for pharmacogenetic analysis will be anonymised. The anonymisation 
procedure will guarantee the legally required level of data protection for the donor. Once the 
anonymisation has been carried out, there will be no legal way to trace back to the identity of 
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, safety and pharmacokinetics. The sample (or the DNA derived from it) 
will be stored at Boehringer Ingelheim for 15 years after the end of the clinical trial or until 
there is no more material available for tests. 
 
The pharmacogenetic sampling will not be performed in countries where local regulations 
prohibit the shipment of biological materials to Germany. 
 
5.6.2.1 Methods and timing of sample collection 
If consent is given, the sample for pharmacogenetic testing may be taken at any time after 
randomization, but preferably on Day 1 of Course 1. A maximum of 8.5 mL blood will be 
collected in a PaxGene DNA blood sampling tube. The Paxgene Blood DNA tubes can be 
stored and shipped at room temperature within 14 days. If a longer storage and shipment 
period for Paxgene Blood DNA tubes is necessary, the blood samples have to be stored at a 
temperature of -20 centigrade or below. Once frozen, thawing of the samples should be 
avoided. Detailed instructions for pharmacogenetic sampling, handling and shipment of 
samples are provided in the ISF 
 
5.6.2.2 Analytical determinations 
Genomic DNA will be extracted from blood samples according to standard molecular 
genetics methods and analysed by TaqMan®or other standard genotyping technologies. 
 
 
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5.7 
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP 
Correlation between drug concentration and response may be made if adequate appropriate 
data are available. In addition, exploratory correlation will also be made between drug 
concentration and AEs. Correlation between drug concentration and response may be made if 
adequate appropriate data are available. 
 
5.8 
DATA QUALITY ASSURANCE 
The trial will be conducted in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki (see Section 8), local law and according to the principles of GCP and 
the company standard operating procedures (SOPs). Each investigator will receive an ISF 
with all information relevant for the performance of the trial. 
 
Investigators will be visited at regular intervals for on-site monitoring by a Boehringer 
Ingelheim employee or a clinical research associate (CRA) authorised by BI. An audit may 
be performed if required or if Boehringer Ingelheim decides to perform an audit. 
 
Data quality review meetings will be performed at regular intervals to evaluate the quality of 
the data collected. 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. 
 
 
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6. 
INVESTIGATIONAL PLAN 
6.1 
VISIT SCHEDULE 
6.1.1 
Screening and randomization 
The screening process is divided into two visits, Screening Visit 1 and Screening Visit 2. At 
Screening Visit 1, biopsy material will be analysed by a central laboratory for EGFR 
mutation status. Patients who test positive for an EGFR mutation will proceed to Screening 
Visit 2, when full assessments will take place. 
 
All Screening Visit 2 procedures must be performed in the 28 days prior to the first 
administration of study medication. 
 
Patients who meet the eligibility criteria will be randomized and treatment must commence 
within 2 days after randomization. 
 
6.1.2 
Treatment 
Patients randomized to arm A (BIBW 2992) will receive continuous daily treatment until the 
criteria for stopping medication are met (see Section 6.3.1). For administrative purposes 
treatment is divided into courses, which are each 3 weeks (21 days) in duration. 
 
Patients randomized to arm B (Gemcitabine/Cisplatin chemotherapy) will receive up to 6 
courses of treatment, each 21 days in length. Treatment may be discontinued prior to 6 
courses if the criteria for stopping medication are met (see Section 6.3.1). 
 
During the treatment phase visits should be performed as scheduled wherever possible, but 
within 2 days of the scheduled date. 
 
6.1.3 
End of Treatment visit 
All patients should be evaluated at the end of treatment (EOT). 
 
In arm A (BIBW 2992) the EOT visit should be performed within 14 days of permanent 
discontinuation of BIBW 2992. If the decision to discontinue BIBW 2992 is taken during a 
scheduled visit, the EOT visit should be performed instead of the scheduled visit. 
 
In arm B (Gemcitabine/Cisplatin chemotherapy) the EOT visit should be performed 21 days 
(± 7 days) after course 6 day 1. If the patient does not complete 6 courses of treatment, the 
visit should be performed within 14 days of the decision to end treatment. 
 
6.1.4 
Follow-up 
All patients should have the first follow-up visit (FU1) 21 days (± 7 days) after the EOT visit. 
This visit should be performed regardless of whether the patient has commenced further 
treatment. If the patient has already started another treatment at the first follow-up, the visit 
 
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should still be performed and the new treatment should be recorded as concomitant 
medication. 
 
Patients who have not progressed and not started further treatment at the first follow-up visit 
should have further follow-up visits every 21 days (± 7 days) until progression or start of 
further treatment. 
 
Patients will be considered to have completed the study at the follow-up visit where 
progression is first documented or where further treatment has begun. This follow-up visit 
will be termed the 'final follow-up visit'. 
 
6.1.5 
Observation period 
After completion of the study patients will enter an observation period. During the 
observation period no study visits will be performed, but data regarding progression, further 
treatment (including best response and reason for stopping treatment) and death will be 
collected every 60 days (± 15 days) until death. Information will be collected from the patient 
notes or by telephone contact with the patient. 
 
The observation period will end after all patients have died or 5 years after the last follow up 
visit, whichever occurs first. 
 
6.1.6 
Treatment after the End of Study 
Following progression, patients should receive adequate further treatment to prevent a 
treatment bias between the two arms. 
 
It is recommended that patients who progress after receiving BIBW 2992 in the clinical trial 
are subsequently treated with standard platinum-based combination chemotherapy if eligible. 
Licensed single-agent chemotherapy can be considered if patients are unable to tolerate 
combination chemotherapy. 
 
It is recommended that patients who progress after receiving first-line chemotherapy in the 
clinical trial should receive standard second line treatment with single agent chemotherapy 
and/or a licensed EGFR TKI, as long as they are clinically eligible.  
 
Second-line therapy should only be started following an objective and confirmed progression. 
 
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6.2 
TRIAL PROCEDURES AT EACH VISIT 
6.2.1 
Screening and run-in in phases 
Screening Visit 1 
Screening Visit 1 should be performed within 6 weeks of the first administration of study 
medication 
Informed Consent 1 
Written informed consent must be obtained 
before any study-specific screening 
assessments are performed. Informed 
Consent 1 must include consent to collection 
of demographic data and consent to obtaining 
a biopsy and testing of biopsy material for 
EGFR mutation status 
Demographics 
Sex, birth date, race, alcohol history and 
smoking history 
Tumour biopsy for EGFR 
mutation analysis 
Tumour biopsy will be collected for analysis 
of EGFR mutation status. If a tumour biopsy 
is performed as part of routine clinical 
practice prior to trial participation and 
material is available for analysis, the biopsy 
does not need to be repeated. 
 
Material should be submitted to the central 
laboratory for analysis as described in 
Section 5.6.1. 
 
 
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Screening Visit 2 
This visit should only be performed by patients who have tested positive for an EGFR 
mutation. All screening visit 2 procedures should be performed within 28 days of the first 
administration of study medication. 
Informed 
Consent 2 
Informed Consent 2 will be obtained for patients who have positive EGFR 
mutation status and must include consent to all study procedures 
including a blood sample for analysis of EGFR mutation status. The only 
exception is that consent to collection of a blood sample for DNA banking 
is optional. 
Demographics 
Sex, birth date, race, alcohol history and smoking history will be taken for 
patients who had a tumour biospy performed as routine clinical practice 
and did not participate Screening Visit 1 
Medical history 
Oncological and relevant non-oncological history including details of any 
previous treatment for NSCLC (see Section 5.3.1) 
Patient 
eligibility 
Assessment of eligibility according to inclusion and exclusion criteria 
should be performed.. 
Randomization 
If the patient meets the eligibility criteria, randomization should be 
performed. Treatment should commence within 2 days after 
randomization. If the patient is randomized to chemotherapy, pre-
medication should commence immediately after randomization (see 
Appendix 2). 
Physical 
examination 
Cardiopulmonary examination, examination of the regional lymph nodes, 
examination of the abdomen and an assessment of the mental and 
neurological status. Measurement of height and weight. 
Vital signs 
Blood pressure, pulse rate, respiratory rate and temperature 
ECOG 
ECOG performance status will be assessed and documented 
ECG 
12-lead resting ECG will be performed. 
ECHO/MUGA 
Cardiac left ventricular function assessment by either ECHO or MUGA 
Safety lab 
Haematology, Biochemistry, Urinalysis and Creatinine Clearance (see 
Section 5.2.4 for minimum assessments). 
Pregnancy test 
β-HCG testing in urine will be performed in women of childbearing 
potential 
Tumour 
assessment 
CT scans of the chest and abdomen and, if clinically indicated, imaging of 
any other known or suspected sites of disease (e.g. pelvis, brain) using an 
appropriate method (CT scan or MRI). The assessment does not need to 
be repeated if there are valid results available from assessments which 
were performed as part of routine clinical practice within the allowed 
time. In case of suspected (but not confirmed) bone metastasis at 
screening, tumour assessment at screening should include a bone scan. If 
bone lesions are already known or confirmed at screening, correlative 
imaging (X-ray or CT scan) should be performed. 
Con meds 
Document indication, start and stop date of each concomitant medication 
Adverse events 
Document details of any new AEs and obtain any new information about 
AEs ongoing at the last visit. 
 
 
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6.2.2 
Treatment phases 
6.2.2.1 Treatment Arm A (BIBW 2992) 
Arm A (BIBW 2992) Day 1 of each course (± 2 days) 
C1V1, C2V1, C3V1, C4V1, C5V1 etc. 
N.B. In the event of progression or decision to end treatment, please complete the EOT 
visit instead. 
HRQOL 
Ask patient to complete HRQOL questionnaires prior to any 
other assessments or discussions 
Caregiver support 
Collect information on any meal delivery, caregiver support 
(home care) and healthcare professional support 
Physical examination 
Cardiopulmonary examination, an examination of the 
regional lymph nodes and an examination of the abdomen. 
Measurement of weight. 
Vital signs 
Blood pressure, pulse rate, respiratory rate and temperature 
ECOG performance status 
ECOG performance status will be assessed and documented 
ECG 
12-lead resting ECG will be performed on day 1 of every 
third course (C4V1, C7V1, C10V1 etc.). 
ECHO/MUGA 
Cardiac left ventricular function assessment by either ECHO 
or MUGA will be performed on day 1 of every third course 
(C4V1, C7V1, C10V1 etc.) 
Safety lab 
Haematology, Biochemistry and Urinalysis (see Section 
5.2.4 
for minimum assessments). 
Serum sample for EGFR 
mutation analysis 
A serum sample will be collected on Day 1 of Course 1 for 
analysis of EGFR mutation status. 
Blood sample for 
pharmacokinetic analysis 
Pharmacokinetic sampling will be performed on Day 1 of 
Course 2 and Day 1 of Course 3 (see Section 5.5 for 
sampling schedule). 
Blood sample for 
pharmacogenetic analysis 
If consent is given, a blood sample for pharmacogenetic 
analysis is taken at any time after randomization, but 
preferably on Day 1 of Course 1. 
Tumour assessment 
Ensure that tumour assessments are scheduled at the time-
points specified in the flow chart. 
Concomitant medications 
Document indication, start and stop date of each medication 
Compliance Check 
Check number of tablets remaining and check that trial 
medication taken correctly (not applicable at C1V1). 
Adverse events 
Document details of any new AEs and obtain any new 
information about AEs ongoing at the last visit. In particular 
the presence of diarrhoea, skin related AEs and mucositis 
has to be assessed and appropriately managed 
Healthcare usage 
Collect information on any unscheduled outpatient visits 
and hospitalisations. 
Dispense trial drugs 
Dispense sufficient medication for the next course of 
treatment. 
 
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Arm A (BIBW 2992) Day 8 of course 1 and course 2 (± 2 days) 
C1V2, C2V2 
N.B. In the event of progression or decision to end treatment, please complete the EOT 
visit instead. 
Vital signs 
Blood pressure, pulse rate, respiratory rate and temperature 
ECOG performance status 
ECOG performance status will be assessed and documented 
ECG 
12-lead resting ECG will be performed on day 8 of course 1 
(C1V2). 
Blood sample for 
pharmacokinetic analysis 
Pharmacokinetic sampling will be performed on Day 8 of 
Course 2 (see Section 5.5 for sampling schedule). 
Tumour assessment 
Ensure that tumour assessments are scheduled at the time-
points specified in the flow chart. 
Concomitant medications 
Document indication, start and stop date of each medication 
Compliance Check 
Check number of tablets remaining and check that trial 
medication taken correctly. 
Adverse events 
Document details of any new AEs and obtain any new 
information about AEs ongoing at the last visit. In particular 
the presence of diarrhoea, skin related AEs and mucositis 
has to be assessed and appropriately managed 
Healthcare usage 
Collect information on any unscheduled outpatient visits 
and hospitalisations. 
 
 
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6.2.2.2 Treatment Arm B (Gemcitabine/Cisplatin) 
Arm B (Gemcitabine/Cisplatin Day 1 of each course (± 2 days) 
C1V1, C2V1, C3V1, C4V1, C5V1, C6V1 
N.B. In the event of progression or decision to end treatment, please complete the EOT 
visit instead. 
HRQOL 
Ask patient to complete HRQOL questionnaires prior to any 
other assessments or discussions 
Caregiver support 
Collect information on any meal delivery, caregiver support 
(home care) and healthcare professional support 
Physical examination 
Cardiopulmonary examination, an examination of the 
regional lymph nodes and an examination of the abdomen. 
Measurement of weight. 
Vital signs 
Blood pressure, pulse rate, respiratory rate and temperature 
ECOG performance status 
ECOG performance status will be assessed and documented 
ECG 
12-lead resting ECG will be performed if clinically 
indicated. 
ECHO/MUGA 
Cardiac left ventricular function assessment by either ECHO 
or MUGA will be performed if clinically indicated 
Safety lab 
Haematology, Biochemistry and Urinalysis (see Section 
5.2.4 for minimum assessments). Results must be available 
prior to commencing treatment. 
Serum sample for EGFR 
mutation analysis 
A serum sample will be collected on Day 1 of Course 1 for 
analysis of EGFR mutation status. 
Blood sample for 
pharmacokinetic analysis 
Pharmacokinetic sampling will be performed on Day 1 of 
Course 2 and Day 1 of Course 3 (see Section 5.5 for 
sampling schedule). 
Blood sample for 
pharmacogenetic analysis 
If consent is given, a blood sample for pharmacogenetic 
analysis is taken at any time after randomization, but 
preferably on Day 1 of Course 1. 
Tumour assessment 
Ensure that tumour assessments are scheduled at the time-
points specified in the flow chart. 
Concomitant medications 
Document indication, start and stop date of each medication 
Adverse events 
Document details of any new AEs and obtain any new 
information about AEs ongoing at the last visit.  
Healthcare usage 
Collect information on any unscheduled outpatient visits 
and hospitalisations. 
Dispense trial drugs and 
administer treatment 
Dispense and administer chemotherapy. Gemcitabine 1000 
mg/m2 and Cisplatin 75 mg / m2 
 
. 
 
 
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Arm B (Gemcitabine/Cisplatin) Day 8 of each course (± 2 days) 
C1V2, C2V2 
N.B. In the event of progression or decision to end treatment, please complete the EOT 
visit instead. 
Vital signs 
Blood pressure, pulse rate, respiratory rate and temperature 
ECOG performance status 
ECOG performance status will be assessed and documented 
ECG 
12-lead resting ECG will be performed on day 8 of course 1 
(C1V2). 
Safety lab 
Haematology, Biochemistry and Urinalysis (see Section 
5.2.4 for minimum assessments). Results must be available 
prior to commencing treatment. 
Tumour assessment 
Ensure that tumour assessments are scheduled at the time-
points specified in the flow chart. 
Concomitant medications 
Document indication, start and stop date of each medication 
Adverse events 
Document details of any new AEs and obtain any new 
information about AEs ongoing at the last visit.  
Healthcare usage 
Collect information on any unscheduled outpatient visits 
and hospitalisations. 
Administer trial drugs 
Gemcitabine 1000 mg/m2 
 
6.2.3 
End of trial and follow-up 
End of treatment 
EOT 
Complete this visit at the following time-point; 
• 0-14 days after permanent discontinuation of BIBW 2992 
• 21 days after Course 6 day 1 of chemotherapy (± 7 days) 
• If patient does not complete 6 courses of chemotherapy, perform visit 0-14 days after 
decision to end treatment 
HRQOL 
Ask patient to complete HRQOL questionnaires prior to any other 
assessments or discussions. 
Caregiver 
support 
Collect information on any meal delivery, caregiver support (home 
care) and healthcare professional support 
Physical 
examination 
Cardiopulmonary examination, examination of the regional lymph 
nodes, examination of the abdomen and an assessment of the mental 
and neurological status. Measurement of weight. 
Vital signs 
Blood pressure, pulse rate, respiratory rate and temperature 
ECOG 
ECOG performance status will be assessed and documented 
ECG 
Arm A (BIBW 2992); A12-lead resting ECG will be performed if not 
performed in the previous 8 weeks. 
Arm B (Gemcitabine/Cisplatin); A12-lead resting ECG will be 
performed if clinically indicated. 
ECHO/MUGA 
Arm A (BIBW 2992); Cardiac left ventricular function assessment by 
 
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either ECHO or MUGA will be performed if not performed in the 
previous 8 weeks. 
Arm B (Gemcitabine/Cisplatin); Cardiac left ventricular function 
assessment by either ECHO or MUGA will be performed if clinically 
indicated. 
Safety lab 
Haematology, Biochemistry, Urinalysis (see Section 5.2.4 for 
minimum assessments). 
Tumour 
assessment 
Ensure that tumour assessments are scheduled at the time-points 
specified in the flow chart. 
Con meds 
Document indication, start and stop date of each concomitant 
medication 
Compliance 
Check 
Arm A (BIBW 2992) only: Check number of tablets remaining and 
check that trial medication taken correctly. 
Adverse events 
Document details of any new AEs and obtain any new information 
about AEs ongoing at the last visit. 
Healthcare 
usage 
Collect information on any unscheduled outpatient visits and 
hospitalisations. 
 
6.2.4   Follow-up (all patients) 
Follow-up 
Every 21 days after EOT visit 
FU1 is performed 21 days (± 7 days) after EOT visit and is mandatory, even if new 
treatment has commenced. 
If patient has not progressed at FU1, perform further follow-up visits every 21 days (± 7 
days) until progression or start of further treatment (FU2, FU3, FU4 etc.). 
HRQOL 
Ask patient to complete HRQOL questionnaires prior to any other 
assessments or discussions. 
Caregiver support Collect information on any meal delivery, caregiver support (home 
care) and healthcare professional support 
Physical 
examination 
Cardiopulmonary examination, examination of the regional lymph 
nodes, examination of the abdomen. Measurement of weight. 
Vital signs 
Blood pressure, pulse rate, respiratory rate and temperature 
ECOG 
ECOG performance status will be assessed and documented 
Safety lab 
Haematology, Biochemistry, Urinalysis (see Section 5.2.4 for 
minimum assessments). 
Tumour 
assessment 
Ensure that tumour assessments are scheduled at the time-points 
specified in the flow chart. 
Serum sample for 
EGFR mutation 
analysis 
An optional serum sample for analysis of EGFR mutation status may 
be collected at Follow-up 1 
Tumour biopsy 
for EGFR 
mutation analysis 
An optional tumour biopsy for analysis of EGFR mutation status may 
be collected during the Follow-up phase. 
Con meds 
Document indication, start and stop date of each concomitant 
medication 
 
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Adverse events 
Document details of any new AEs and obtain any new information 
about AEs ongoing at the last visit. 
Healthcare usage 
Collect information on any unscheduled outpatient visits and 
hospitalisations. 
Study completion Study completion occurs at the follow-up visit where progression or 
start of further treatment is first documented. 
 
6.2.5   Observation period 
Observation period 
Collect data every 60 days (± 15 days) after last follow-up visit. A formal study visit is 
not required; data should be collected from patient notes or by telephone. 
Progression 
Collect date of progression. 
Further treatment 
Collect details of any further treatment for NSCLC, 
including best response and reason for stopping treatment. 
Death 
Collect date and cause of death. 
 
6.3 
REMOVAL OF PATIENTS FROM THERAPY OR ASSESSMENT 
6.3.1 
Removal of patients from study treatment 
A patient will be withdrawn from further study treatment in the following circumstances: 
 
• The patient withdraws consent to further treatment. For safety reasons it is recommended 
that the patient is encouraged to return for at least one follow-up visit. Wherever possible 
patients should be encouraged to return for regular follow-up visits until progression or 
start of further treatment. 
 
• Documented disease progression (see Section 5.1.3). 
 
• The patient is no longer able to participate in the treatment phase (e.g. surgery, 
concomitant diagnoses, concomitant therapies or administrative reasons). In these cases 
the investigator should record the reason for a patients’ removal in the CRF. 
 
• Significant deviation from the protocol or eligibility criteria. The decision to continue or 
withdraw treatment will be made by the Boehringer Ingelheim (BI) clinical monitor in 
agreement with the investigator. 
 
• Requirement to stop treatment due to adverse events as described in Sections 4.1.4.1.1 
and 4.1.4.2. 
 
If during the treatment phase the patient no longer meets the inclusion/exclusion criteria this 
is not automatically a reason for withdrawal but the investigator should consider the ongoing 
 
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safety of the patient and withdraw the patient from further treatment if the safety of the 
patient is at risk. 
 
The EOT visit should be performed after permanent discontinuation of treatment. In arm A 
(BIBW 2992) the visit should be performed 0-14 days after permanent discontinuation of 
BIBW 2992. In arm B (chemotherapy) the visit should be performed 21 days (± 7 days) after 
Course 6 Day 1 (for patients completing 6 courses) or 0-14 days after the decision to end 
treatment (for patients not completing 6 courses). For safety reasons all patients should be 
encouraged to return to the clinic 21 days after the EOT visit for the first follow-up visit. 
 
6.3.2 
Removal of patients from trial 
A patient will be withdrawn from the trial in the following circumstances: 
 
• Requirement for further treatment of NSCLC after the first follow-up visit (21 days after 
EOT) 
 
• Patient withdraws consent to all further study procedures and elects to discontinue 
participation in the trial. 
 
• Termination of the study by the sponsor 
 
The reason for discontinuation must be recorded and if consent is given, patients should be 
followed up in the observation period until the date of death (Section 6.2.5). 
 
Every effort should be made to follow-up patients in case an adverse event is ongoing at the 
time of withdrawal. 
 
6.3.3 
Replacement of patients 
Patients who prematurely discontinue the study treatment or trial will not be replaced. 
 
 
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7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
7.1 
STATISTICAL DESIGN - MODEL 
This is a randomised, open-label, active-controlled multi-center trial in Asia. The primary 
objective of the statistical analysis is to determine whether BIBW 2992 prolongs progression-
free survival (PFS) in comparison to chemotherapy. 
 
7.2 
NULL AND ALTERNATIVE HYPOTHESES 
The alternative hypothesis of the primary analysis is that the progression-free survival time is 
longer for patients treated with BIBW 2992 than for those who receive chemotherapy.  That 
is 
 
HA: SBIBW(t) > SChemo(t), for t>0 
The null hypothesis tested by this trial is: 
 
H0: SBIBW(t) ≤ SChemo(t), for t>0 
where S(t) is the probability that a patient passes time t without dying or experiencing disease 
progression. The subscripts represent the two treatment groups.  The null hypothesis will be 
tested at the one-sided 0.025 level. 
If the difference between the treatment groups for the primary efficacy endpoint is 
statistically significant then formal statistical testing will be performed on the key secondary 
endpoints. In order to protect the overall type I error rate a closed testing procedure will be 
employed, whereby each key secondary endpoint will only be formally analysed if the 
previous endpoint was found to be statistically significant. The key secondary endpoints will 
be analysed according to the order they are presented in Section 7.3.2 below. 
 
7.3 
PLANNED ANALYSES 
The primary analyses will include all randomized patients. 
 
7.3.1 
Primary analyses 
The primary endpoint of this study is progression-free survival, defined as the time from the 
date of randomisation to the date of disease progression, or to the date of death if a patient 
died earlier. The analysis will be based upon the evaluation of tumour imaging as reviewed 
by an independent central unit, blinded to treatment assignments. 
The primary analysis of PFS will be conducted when at least 217 patients have progressed or 
died.  This is expected to take approximately 19-20 months, assuming 330 patients are 
randomised over a period of 9-10 months. 
 
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A stratified log-rank test will be used to test for the effect of BIBW 2992. The test will be 
stratified by EGFR mutation (L858R vs. del 19 vs. other).  
A Cox proportional-hazards model will be used to derive the hazard ratio and 95 % 
confidence interval between the two randomised regimens.  Kaplan-Meier estimates and 95% 
CI will be calculated at the time of each planned imaging assessment. 
Disease progression will be evaluated according to the RECIST 1.1 criteria (R09-0262), with 
adaptations as described in the imaging charter. 
For patients with known date of progression (or death): 
• PFS [days] = earlier of date of progression or death – date of randomisation + 1. 
 
Patients with unknown disease progression status or date, or who are treated with new 
anticancer therapy will be handled as described in Section 7.4 
 
7.3.2 
Secondary analyses 
7.3.2.1 Key Secondary analyses 
The following key secondary analyses will be performed according to the statistical testing 
strategy detailed in Section 7.2 
7.3.2.1.1 Best RECIST assessment 
Each patient will be assigned to one of the following RECIST 1.1 categories based on 
independent central review, irrespective of protocol violations or missing data:  
• CR (complete response) 
• PR (partial response) 
• SD (stable disease) 
• PD (progressive disease) 
• Not evaluable (not assessable, insufficient data) 
 
Objective response is defined as CR and PR. Time to objective response is the time from 
randomisation to the date of first documented CR or PR. The duration of objective response 
is the time from first documented CR or PR to the time of progression or death. Disease 
control is defined as CR, PR, and/or SD.  
Logistic regression will be used to test for a difference between regimens for objective 
response and for disease control. The statistical model will include the same stratification 
factor used for the analysis of PFS.  Nominal significance levels will be reported. 
 
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Objective response will be tabulated both overall and within EGFR mutation categories.  
Descriptive statistics will be calculated for the duration of objective response and duration of 
disease control. 
7.3.2.1.2 Overall survival (OS)  
The treatment regimens will be compared in terms of time to death, but unequal treatment 
after progression is expected to obscure any effect of BIBW 2992 relative to chemotherapy.  
Similarly to PFS, the stratified log-rank test will be used to test OS.   
OS will be analyzed twice. The first analysis will be performed at the time of the primary 
PFS analysis.  A second analysis will be performed somewhat later with the aim of providing 
as much information as possible on OS.  With 330 patients randomised over a period of 9-10 
months and a median time to death of 20 months (HR= 1.0), approximately 219 deaths would 
be expected within 36 months. 
To preserve the overall 0.025, one-sided alpha-level, a Haybittle-Peto stopping boundary will 
be used (p-value <0.0001) for the analysis of OS performed at the time of the primary PFS 
analysis. 
In addition to the formal treatment comparison, the analyses will describe the overall pattern 
of time to death, together with the extent and influence of post-progression treatment.  
The following analyses will examine the pattern of time to death for consistency with the PFS 
results, while accounting for the extent and influence of post-progression intervention: 
• 
test for a difference between treatment regimens at six, nine, and twelve months, 
• 
describe the cumulative proportion of deaths at each scheduled tumour assessment time 
point 
• 
tabulate the specific anti-cancer treatments after progression 
• 
describe the effect of additional anti-cancer treatment, by separating patients into the 
following sub-groups 
 
those not eligible for additional treatment 
o 
patients who did not progress 
o 
patients who died within one month of progression 
 
those eligible for additional treatment 
o 
did not take additional treatment 
o 
did take additional treatment  
7.3.2.2 Other secondary analyses 
The following other secondary analyses will be performed. 
 
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7.3.2.2.1 Sensitivity and exploratory analyses for PFS  
The timing of imaging assessments will be described.  In order to account for the possible 
effect of mistimed or delayed imaging assessments, a sensitivity analyses will assign the 
midpoint to PFS failures within time intervals that will be formed around the planned times 
of imaging assessments. 
An additional analysis will assign all patients who progress in the chemotherapy arm to the 
later assessment of progression (investigator or independent central unit review) and all 
patients who progress in the BIBW 2992 arm to the earliest assessment of progression. 
An exploratory analysis will stratify the log-rank test by each of the EGFR mutations for 
which there are sufficient randomized patients. 
Descriptive methods (e.g. Forest plot) and Cox proportional-hazards will be used to examine 
the effects of other baseline disease characteristics and demographic factors, including the 
stratification factor (EGFR mutation category), baseline sum of target lesions, geographical 
region, ECOG, gender, and age. 
7.3.2.2.2 Tumour shrinkage  
The two treatment groups will be compared in terms of the minimum sum of target lesion 
diameters recorded for each patient after randomisation, as measured by central imaging.  
The analysis will compare the treatments using analysis of covariance (ANCOVA) for 
minimum sum of diameters, using baseline sum of diameters as a covariate.  The 
randomization stratum will be included as a classification factor. 
7.3.2.2.3 Body weight and ECOG performance status 
Analyses will compare the treatment groups in terms of time to deterioration of: 
• body weight, defined as the first occurrence of a decrease from baseline of more than 
10 %, and 
• ECOG performance status, defined as the first instance of an increase in ECOG 
category. 
 
Patients who die before deteriorating will be analysed as having deteriorated at the time of 
death. Disease progression without deterioration will be censored at the time of the last 
measurement of weight or ECOG performance status. 
Time to deterioration will be analysed similarly to PFS i.e. by stratified log-rank test. 
7.3.2.2.4 Health-Related Quality of Life (HRQOL)  
The relevant HRQOL endpoints are the time to deterioration for the following three symptom 
scales/items measured on the QLQ-C30 or QLQ-LC13 questionnaire (R99-1213, R07-2060):  
 
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• cough (Question 1 on the QLQ-LC13),  
• dyspnoea (composite of Questions 3-5 on the QLQ-LC13),  
• pain (composite of Questions 9 and 19 on the 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) (R07-2064). 
Time to deterioration for the cough, dyspnoea, pain and symptom scales/items will be defined 
as the time to a 10-point increase from the baseline score (R07-2064, R99-1223, R07-2061).  
Patients who die before deteriorating will be analysed as having deteriorated at the time of 
death. Disease progression without scale deterioration will be censored at the time of the last 
scale measurement. Patients with no HRQOL assessments will be censored at day of 
randomisation. If a HRQOL assessment is missed, but followed by another assessment and 
deterioration occurs during that period, the time to deterioration will be defined as the 
midpoint between the two observed assessments. In addition, the three alternative measures 
of pain (Questions 10-12* in QLQ-LC13) will be examined descriptively for consistency 
with the composite of questions 9 and 19 from the QLQ-C30, as will dyspnoea (Question 8) 
from the EORTC QLQ-C30 be compared with the dyspnoea composite (Questions 3-5* on 
the QLQ-LC13). 
Time to deterioration will be analysed similarly to PFS i.e. log-rank test stratified by the 
stratification factor used at randomisation will be used to test for the effect of BIBW 2992.  
The individual items of the symptom scales will be examined for consistency with the 
composites.  
In addition, a comprehensive analysis of all subscales/items (where a single item is scored, 
R07-2064) will estimate the hazard ratio for time to deterioration with 95% confidence. The 
results of these analyses will be displayed using a Forest plot to summarise the impact of 
therapy over the entire profile of the EORTC QLQ-C30 and LC13 measures. 
Additional analysis will describe the distribution of patients that are improved, stable, or 
worsened for each of the QLQ-C30 and QLQ-LC13 summary scales and items (where a 
single item is scored, R07-2061). 
* Note that questions on the QLQ-LC13 are numbered consecutively following the QLQ-C30 
as shown in Appendix 4. Consequently, Question 1 is numbered as Question 31 and 
Questions 3-5 as Questions 33-35 
 
7.3.3 
Safety analyses 
All randomised and treated patients will be included in the analysis of safety. 
 
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The primary analysis of adverse events will be based upon events that start on or after first 
administration of trial medication and within 28 days after the last administration trial 
medication.  An additional analysis will compare the treatment regimens over a period of 
time equivalent to six courses of chemotherapy. 
Adverse events as well as laboratory parameters will be graded according to CTCAE, 
Version 3.0 (R04-0474).  Key safety measures will include: 
• events leading to dose reduction 
• events leading to permanent treatment discontinuation 
• the overall incidence and intensity of adverse events, as well as relatedness of adverse 
events to treatment 
• causes of death 
• gastrointestinal events (diarrhoea, vomiting, nausea) 
• cutaneous reactions 
• oral irritation 
• decreased renal function 
• elevated liver function tests, 
• haematological abnormalities (anaemia, thrombocytopenia, neutropenia) 
• CTCAE Grade 2 with increase by at least one CTCAE grade from baseline, for selected 
laboratory tests:  
• (high values) INR, PTT, creatinine, AST, ALT, bilirubin, alkaline phosphatase, 
proteinuria (dipstick or [g/24 hrs]) 
• (low values) haemoglobin, neutrophils, platelets, total WBC 
• descriptive statistics for change from baseline for all laboratory tests   
 
Additional, more in-depth analyses will be performed as needed.  These analyses will 
examine the influence of extent of exposure and time to event onset. 
Key adverse event tables will be reproduced to examine the effect of BIBW 2992 among 
special populations e.g. elderly, females. 
 
 
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7.3.4 
Interim analyses 
A Data and Safety Monitoring Committee (DMC) will review the safety data approximately 
every six months. In order to completely assess the risk-benefit advantage of BIBW 2992, the 
committee may see the need during such regular meetings to examine survival and PFS. 
However, the significance level for the primary analysis of PFS will not be adjusted for the 
interim looks by the DMC.  This is because the trial will not be stopped for superiority of 
BIBW 2992 vs. chemotherapy in terms of PFS prior to the primary analysis, which is 
scheduled to occur after 217 PFS failures. 
 
7.3.5 
Pharmacokinetic methods 
BIBW 2992 plasma concentrations will be summarized by time point by descriptive statistics 
and, if feasible, graphically inspected. A pharmacokinetic correlation plot analysis will be 
performed on BIBW 2992 plasma concentrations.  
Objectives of this analysis will be: 
• describe the trough BIBW 2992 plasma concentrations at steady state in the target 
patient population 
• to estimate the inter-individual and intra-individual variability of BIBW 2992 trough 
plasma concentrations  
• to estimate the influence of covariates such as age, gender or weight on the variability 
of the BIBW 2992 trough plasma concentrations using correlation plot analysis 
7.4 
HANDLING OF MISSING DATA 
The central imaging unit will work with the clinical sites towards a standard implementation 
of the RECIST 1.1 criteria. An imaging charter will detail all procedures, including quality 
control and the criteria needed to handle missing assessments.  
Patients will continue to be followed for both progression and death after discontinuation of 
study treatment. 
Table 7.4: 1 describes how patients will be classified for the analysis of PFS. Sensitivity 
analyses will examine the effect of using alternative rules. 
 
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Table 7.4: 1 
 
Endpoint determination for PFS 
Situation 
Outcome  
(event or censored) 
Date of PFS or censoring 
No baseline tumour assessment 
censored 
Date of randomisation 
Progressed according to central review 
(no missed radiological assessments) 
event 
Date of PD determined by central 
review 
Non-PD from central review1, death 
before next scheduled assessment 
event 
Date of death  
Non-PD from central review1,  
one missed assessment, death or 
progression after date of missed 
assessment, but before a second 
scheduled assessment 
event 
Date of PD or death 
Non-PD from central review1,  
more than one consecutive missed 
assessment,  
death or progression after date of  
second missed assessment 
censored 
Date of last imaging before missed 
assessment 
New anti-cancer medication before 
progression or death 
censored 
Date of last imaging before new 
anti-cancer medication 
Death  before the scheduled date of 
first imaging 
event 
Date of death 
No imaging performed post-baseline, 
patient dies between first and second 
scheduled assessments 
event 
Date of  death 
No imaging performed post-baseline,  
Patient dies after second scheduled 
assessment 
censored 
Day of randomisation 
No imaging performed post-baseline, 
vital status is unknown or patient is 
known to be alive 
censored 
Day of randomisation 
Alive and not progressed according to 
central review (no missed radiological 
assessments) 
censored 
Date of last imaging 
1 This is from the last assessment at which non-PD ( SD or better) was assessed. 
Table 7.4: 2 describes how patients will be classified for the analysis of death. Patients will 
be censored at the date of last contact if the investigator is no longer able to contact a patient 
or caregiver, and vital status cannot otherwise be determined, provided that no other 
information indicates that the patient was near death at that point. 
 
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Table 7.4: 2 
 
Endpoint determination for overall survival 
Situation 
Outcome (event or 
censored) 
Date of death or censoring 
 
Patients died and the date of death is 
known 
event 
Date of death 
Patients died and date of death is 
unknown 
censored 
Date of last contact when 
the patient is known to be 
alive 
Patient alive 
censored 
Date of last contact  
Unknown 
censored 
Date of last contact when 
the patient is known to be 
alive 
 
Patients who are randomised, but never receive randomised treatment will be censored on the 
day of randomisation (Tables 7.4: 1 and 7.4: 2). 
 
7.5 
RANDOMISATION 
Two patients will be randomized to BIBW 2992 for each patient randomized to 
chemotherapy. The randomization will be stratified by EGFR mutation (L858R vs. del 19 vs. 
other).  
 
Randomization will be performed by IVRS/IWRS. Boehringer Ingelheim Pharma GmbH & 
Co. KG, Clinical Trial Support Group or a CRO appointed by the Sponsor will provide the 
randomization lists using a validated randomization number generating system. Access to the 
randomization codes will be controlled and documented. 
 
7.6 
DETERMINATION OF SAMPLE SIZE 
Table 7.6: 1 indicates that 217 PFS failures would be expected to provide 90% power for the 
log-rank test, presuming a hazard ratio of 0.64 for BIBW 2992 relative to chemotherapy.  In a 
previous trial of gefitinib vs. chemotherapy the upper limit of the 95% confidence limit of the 
hazard ratio was observed to be 0.64  (R08-5155).  
Table 7.6: 1 
 
Number of PFS events required for 90% power 
 
90% power
0.025, one-sided
  
 
BIBW median 
11 months 
Control median
7 months
  
57% increase 
(0.64 hazard ratio)
  
 
# PFS failures 
217 failures
# patients with mutations 
330 patients
 
Calculations performed using EAST-5 software using the log-rank test, excluding interim analysis 
 
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8. 
ADMINISTRATIVE MATTERS 
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, version as of October 1996, in accordance with the ICH Harmonised 
Tripartite Guideline for Good Clinical Practice (GCP) and relevant BI Standard Operating 
Procedures (SOPs). Standard medical care (prophylactic, diagnostic and therapeutic 
procedures) remains in the responsibility of the treating physician of the patient. 
 
The terms and conditions of the insurance cover are made available to the investigator and 
the patients via documentation in the ISF (Investigator Site File). 
 
8.1 
ETHICS 
8.1.1 
Independent Ethics Committee or Institutional Review Board 
The trial will not be initiated before the protocol and informed consent and patient 
information form have been reviewed and received approval / favourable opinion from the 
local Institutional Review Board (IRB) / Independent Ethics Committee (IEC) and approval 
by / notification to the Competent Authority (CA) / regulatory authority as required according 
to national regulations. 
 
Should a Clinical Trial Protocol (CTP) amendment be made that needs IRB / IEC approval 
and authority notification/approval, the changes in the CTP will not be instituted until the 
amendment and revised informed consent (if appropriate) have been reviewed and received 
approval / favourable opinion from the local IRB / IEC and the CA / regulatory authority has 
been notified / provided approval (as required according to local regulations). A CTP 
amendment intended to eliminate an apparent immediate hazard to patients may be 
implemented immediately providing that the regulatory authority and IRB / IEC are notified 
as soon as possible and an approval is requested. CTP amendments exclusively for logistical 
or administrative changes may be implemented with notification to the IRB / IEC and CA 
only. 
 
The constitution of the IRB / IEC must meet the requirements of ICH GCP and of the 
participating country. A list of the IRB / IEC members who attended the meeting when the 
CTP / CTP amendment was discussed, including names and qualifications, needs to be 
provided by the IRB / IEC to the investigator or sponsor (according to local practice). The 
investigator or sponsor (according to local practice) must provide to the regulatory authorities 
the name and address of the IRB / IEC along with a statement from the IRB / IEC that it is 
organised according to GCP and the applicable laws and regulations. The IRB / IEC must 
perform all duties outlined by the requirements of ICH GCP and of the participating country. 
 
8.1.2 
Patient Information and Informed Consent 
Prior to patient participation in the trial, a signed and dated written informed consent must be 
obtained from each patient (or the patient’s legally accepted representative) according to ICH 
GCP and to the regulatory and legal requirements of the participating country. Each signature 
 
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must be personally dated by each signatory and the informed consent and any additional 
patient-information form retained by the investigator as part of the trial records. A signed 
copy of the informed consent and any additional patient information must be given to each 
patient or the patient’s legally accepted representative. 
 
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient. 
 
The patient must be informed that his / her medical records may be examined by authorized 
monitors (Clinical Monitor Local (CML)/Clinical Research associate (CRA)) or Clinical 
Quality Assurance auditors appointed by Boehringer Ingelheim, by appropriate IRB / IEC 
members, and by inspectors from regulatory authorities. 
 
Should a CTP amendment become necessary, the patient consent form and patient 
information form may need to be revised to reflect the changes to the CTP. It is the 
responsibility of the investigator or sponsor (according to local practice) to ensure that an 
amended consent form is reviewed and has received approval / favourable opinion from the 
IRB / IEC and the CA / regulatory authority has provided approval / has been notified (as 
required according to local regulations), and that it is signed by all patients subsequently 
entered in the trial and those currently in the trial, if affected by the amendment. 
 
8.2 
RECORDS 
8.2.1 
Drug accountability 
Drug supplies must be kept in a secure, limited access storage area under the storage 
conditions defined by the sponsor. Where necessary, a temperature log must be maintained to 
make certain that the drug supplies are stored at the correct temperature. 
 
The investigator and/or pharmacist must maintain records of the product’s delivery to the trial 
site, the inventory at the site, the use by each patient, and the return to the sponsor or 
alternative disposition of unused product(s). These records will include dates, quantities, 
batch/serial numbers, expiry (‘use by’) dates, and the unique code numbers assigned to the 
investigational product(s) and trial patients. The investigator / pharmacist will maintain 
records that document adequately that the patients were provided the doses specified by the 
CTP and reconcile all investigational product(s) received from the sponsor. At the time of 
return to the sponsor the investigator / pharmacist 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. 
 
8.2.2 
Emergency code break 
Not applicable. 
 
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8.2.3 
Case Report Forms (CRFs) 
All the clinical data will be captured via electronic data capture (EDC) using the Oracle 
Clinical Remote Data Capture system, a web-based tool. The investigator site staff will enter 
and edit the data via a secure network, with secure access features (username, password and 
secure identification or username and password – an electronic password system). A 
complete electronic audit trail will be maintained. The investigator will approve the data 
using an electronic signature (Ref: 21 CFR Part 11), and this approval is used to confirm the 
accuracy of the data recorded. 
 
Electronic CRFs (eCRFs) will be used for all patients. The investigator’s data will be 
accessible from the investigator’s site throughout the trial. Relevant medical history prior to 
enrolment will be documented at the baseline visit. Thereafter during the trial, narrative 
statements relative to the patient’s progress during the trial will be maintained. The electronic 
CRFs must be kept current to reflect patient status at each phase during the course of the trial. 
The patients must not be identified on the electronic CRF by name. Appropriate coded 
identification (i.e. Patient Number) must be used. The investigator must make a separate 
confidential record of these details (patient identification code list) to permit identification of 
all patients enrolled in a clinical trial in case follow-up is required. While a trial is ongoing 
and until the access to the database has been terminated, there will be no Documentation of 
Changes (DOCs). All changes will be requested from the investigator through the EDC 
system. If a change is necessary once the investigator has no further access to the database, a 
DOC will be sent to the investigator for confirmation of the change. The investigator’s 
signature or seal is requested to show he/she agrees with the change that was made. The 
original DOC is kept by the investigator. 
 
Copies of the electronic CRF together with all data changes made will be supplied to the 
investigator at the end of the trial. The investigator will be responsible for retaining all 
records pertaining to the trial as specified in the appropriate contract. 
 
8.2.4 
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRFs or entered in the CRFs that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the trial; also current medical records must be available. 
For eCRFs all data must be derived from source documents, including the following: 
• 
Patients identification (gender, date of birth) 
• Patients 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) 
 
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• 
Medication history 
• 
Adverse events (onset date (mandatory), and end date (if available)) 
• 
Serious adverse events (onset date (mandatory), and end date (if available)) 
• 
Concomitant therapy (start date, changes) 
• 
Originals or copies of laboratory results (in validated electronic format, if available) 
• 
Conclusion of Patient’s Participation in the trial 
 
8.2.5 
Direct access to source data - documents 
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. sFDA). The Clinical Research 
Associate (CRA) or on-site monitor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.2.4. 
 
Data collected during the Observation Period will be checked for completeness and 
plausibility but will not require source data verification. 
 
8.3 
QUALITY ASSURANCE AUDIT 
A quality assurance audit of this trial may be conducted by the sponsor or sponsor’s 
designees. 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. 
 
8.4 
PROCEDURES 
8.4.1 
Adverse events 
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. 
 
All adverse events occurring during the course of the clinical trial (i.e., from signing the 
informed consent to the final follow-up visit) will be collected, documented and reported to 
the sponsor by the investigator according to the specific definitions and instructions detailed 
in the ‘Adverse Event Reporting’ section of the Investigator Site File. 
 
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalization, is a congenital anomaly / birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
 
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judgment which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions. 
 
All adverse events, serious and non-serious, will be fully documented on the appropriate 
CRFs. For each adverse event, the investigator will provide the onset, end, CTCAE grade 
(R04-0474), 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 the 'Adverse Event Reporting' Section of the Investigator Site 
File. 
 
There are no events defined as 'significant' for this study. All events will be categorised as 
either Adverse Event (AE) or Serious Adverse Event (SAE). 
 
The basis for judging the causal relationship between the investigational product and the AE 
is described below. 
 
Causal relationship 
 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms. 
 
z 
Yes: There is a reasonable causal relationship between the investigational drug 
administered and the AE. 
 
z 
No: There is no reasonable causal relationship between the investigational drug 
administered and the AE. 
 
The investigator has the obligation to report all AEs/ SAEs occurring between informed 
consent and follow-up visit 1, regardless of causality. From follow-up 1 to final follow-up the 
investigator should report all AEs/SAEs which are related to the study treatment or 
procedures. During the observation period, only SAEs considered related to the study 
treatment should be reported. Deaths occurring after follow-up 1 do not need to be reported 
as SAEs unless considered related to study treatment or procedures. 
 
SAEs are to be reported to the sponsor using the BI Serious Adverse Event Report Form 
including a documented causal relationship assessment and providing as much detail 
regarding the SAE as possible. When follow-up information becomes available, all remaining 
fields on the SAE form are to be completed or updated. 
 
Any serious AE, whether or not considered related to the investigational product, and 
whether or not the investigational product has been administered, must be reported 
immediately by telephone / fax to the sponsor. Expedited reporting of serious adverse events, 
e.g. suspected unexpected serious adverse reactions (SUSARs), will be done according to 
 
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local regulatory requirements. Further details regarding this reporting procedure are provided 
in the ISF. 
 
Following every such telephone / fax report, the Clinical Monitor must provide a written 
report of the serious AE and any sequelae to Corporate Drug Safety according to the 
appropriate Corporate SOP(s). These narratives, which confirm the information collected by 
telephone, may give additional information not available at the time of the initial report. 
 
8.4.2 
Emergency procedures 
Not applicable. 
 
8.4.3 
Contraception and Pregnancy 
Female patients who are not of childbearing potential due to being postmenopausal (2 years 
without menses) or surgical sterilisation (oophorectomy, hysterectomy and/or tubal ligation) 
do not need to use contraception. 
 
All other female patients are considered to have childbearing potential and should use 
adequate contraception throughout the study (from screening until end of study participation 
or 28 days after last dose of trial medication, whichever is later). 
 
Acceptable methods of contraception for females include hormonal contraception and double 
barrier method. Double barrier method of contraception is defined as two barrier methods 
used simultaneously each time the patient has intercourse. Accepted barrier methods include 
diaphragm, female condom, cervical cap, male condom and IUD (the diaphragm and cervical 
cap must be used in conjunction with spermicidal jelly/cream). If hormonal contraceptives 
are used, at least one barrier method should also be used. Partner vasectomy, natural 'rhythm' 
and spermicidal jelly/cream are not acceptable as methods of contraception.  
 
Male patients should use adequate contraception throughout the study (e.g. condom and 
spermicidal jelly). 
 
Female patients must have a negative pregnancy test (β-HCG test in urine or serum) prior to 
commencing study treatment. 
If a patient is found to be pregnant during study participation, this should be handled as 
follows;
 
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Table 8.4.3: 1 Pregnancy reporting 
Timing of pregnancy 
Action 
Prior to commencing 
study medication 
Patient should be withdrawn from the study immediately. 
No reporting necessary 
During study 
treatment 
Treatment must be stopped immediately and the pregnancy should 
be reported to the sponsor immediately using the pregnancy form. 
If the investigator wishes to give any further treatment with study 
medication, this must be discussed and agreed with the BI clinical 
monitor. 
The pregnancy should be followed up to final outcome and the 
outcome, including any premature termination should be reported 
to the sponsor on the pregnancy form. 
In addition, any event leading to the termination of pregnancy (i.e. 
spontaneous, accidental, or induced abortion; as well as 
miscarriage, intrauterine foetal demise/death) must be reported as 
an SAE. 
During follow-up 
(after finishing 
treatment but before 
end of study 
participation). 
The pregnancy should be reported to the sponsor immediately 
using the pregnancy form. 
The pregnancy should be followed up to final outcome and the 
outcome, including any premature termination should be reported 
to the sponsor on the pregnancy form. 
In addition, any event leading to the termination of pregnancy (i.e. 
spontaneous, accidental, or induced abortion; as well as 
miscarriage, intrauterine foetal demise/death) must be reported as 
an SAE. 
Within 28 days of last 
dose of study 
medication (even if no 
longer participating in 
study 
 
8.5 
RULES FOR AMENDING PROTOCOL 
All CTP amendments must be documented, dated and signed by all signatories (or their 
successors) of the original protocol. This also applies to any local amendment that may 
become necessary. Amendments (excluding those exclusively for administrative or logistical 
changes) need to be submitted to the IRB / IEC for review/approval and to the competent 
authority (CA) / regulatory authority for approval / notification according to local regulations. 
Local Amendments will only be submitted in the countries / centres concerned. 
 
 
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8.6 
DISCONTINUATION OF THE TRIAL BY THE SPONSOR 
Boehringer Ingelheim reserves the right to discontinue the trial at any time for the following 
reasons: 
 
1. Failure to meet expected enrolment goals overall or at a particular trial site, 
 
2. Emergence of any efficacy/safety information that could significantly affect continuation 
of the trial, 
 
3. Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing the 
appropriate conduct of the trial. 
 
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason). 
 
8.7 
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers. 
 
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities. 
 
8.8 
PUBLICATION POLICY 
Boehringer Ingelheim is as much as possible dedicated to support process of free exchange of 
relevant scientific information. Any publication of the result of this trial must be consistent 
with the Boehringer Ingelheim publication policy. 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. 
 
 
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9. 
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42nd Ann Mtg of the American Society of Clinical Oncology (ASCO), Atlanta, 
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lung cancers sensitive to epidermal growth factor receptor kinase inhibitors. 3rd 
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EGFR-Targeted Agents, Cambridge, 23-24 Sep 2005. Clin Cancer Res 
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[R06-1306]  Jaene PA, Johnson BE. Effect of epidermal growth factor receptor tyrosine 
kinase domain mutation on the outcome of patients with non-small cell lung 
cancer treated with epidermal growth factor receptor tyrosine kinase inhibitors. 
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gefitinib and erlotinib. Clin Cancer Res 2006;12(13):3908- 3914. 
 
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mutations predict treatment outcome of stage IIIB/IV patients with 
 
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chemotherapy-naive non-small-cell lung cancer receiving first-line gefitinib 
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clinically selected patients (pts) with advanced non-small-cell lung cancer 
(NSCLC) (IPASS). 33rd Ann Cong of the European Society for Medical 
Oncology (ESMO), Stockholm, 12 - 16 Sep 2008 Ann Oncol 2008;19(Suppl 
8):VIII1 Abstr LBA2 
 
[R09-0262]  Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D et al., New 
response evaluation criteria in solid tumours: revised RECIST guideline 
(version 1.1). Eur J Cancer 2009;45:228-247 
 
[R09-4437]     Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, et al. Gefitinib or 
carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 
361(10):947-957 
 
9.2 
UNPUBLISHED REFERENCES 
[U03-3218]  
 and 
. Investigator’s brochure. BIBW 2992 
MA2. Version 94 May 2009, 21 April 2009. 
 
[U04-1028]        Metabolism of BIBW 2992 MA2 in rats and covalent binding of BIBW 2992 
MA2 to blood constituents [Report/Study No. A224/02TE (B2211)]. 
Nonclinical report submitted to IND 67,969 on March 17, 2005 (Serial 
Number 0026). 
 
[U05-1723-01]  
Investigation of the human cytochrome P450 
enzymes involved in the metabolism of [14C]BIBW 2992 MA2, 07 July 
2005  
 
[U06-1093]       
Absorption, distribution and metabolism of 
BIBW2992 MA2 in minipigs. A239, 05TE, A129/05RB, B2705. 13 
February 2006. 
 
[U06-2055-01]   A Phase I open label dose escalation study of once-daily oral treatment with 
BIBW 2992 for 14 days in patients with advanced solid tumors (Study 
 
Final,  22 Jan 2010 
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1200.1). Clinical trial report submitted to IND 67,969 December 14, 2006 
(Serial Number 0097). 
 
 
[U07-1296-01]   Metabolism of BIBW 2992 MA2 in human. Clinical report submitted to 
IND 67,969 on August 14, 2007 (Serial Number 0172). 
 
[U07-1737]        Metabolism of [14C] BIBW 2992 MA2 in healthy volunteers. Clinical report 
submitted to IND 67,969 on November 28, 2007 (Serial Number 0194) 
 
Final,  22 Jan 2010 
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10. 
APPENDICES 
10.1 
APPENDIX 1   OVERVIEW OF STUDY VISITS
Progressi
on or start 
of further 
treatment 
Patient has 
already 
progressed 
or started 
further 
treatment 
Eligibility 
check 
Screening 
Randomisation 
Arm A (BIBW 2992) 
Continuous daily treatment 
until progression or other 
criteria for stopping 
medication. 
Treatment is divided into 21-
day courses for 
administrative purposes. 
Arm B 
(Gemcitabine/Cisplatin 
chemotherapy) 
Patients may receive up to 6 
courses of chemotherapy. 
Each course is 21 days in 
length. 
End of 
Treatment 
(EOT) Visit 
Performed 0-14 
days after 
permanent 
discontinuation 
of BIBW 2992 
OR  
21 days (± 7 
days) after 
Course 6 Day 1 
of 
chemotherapy 
OR 
If patient does 
not complete 6 
courses of 
chemotherapy, 
0-14 days after 
decision to end 
treatment 
Follow-up 1 
Performed 21 
days after the 
EOT visit. 
Mandatory for all 
patients, even if 
further treatment 
has commenced. 
Follow up 
visits 
Every 21 days 
until 
progression or 
start of further 
treatment. 
No 
progressi
on and no 
further 
treatment
End of Study 
participation. 
Observation 
Period.
Screening 
Screening 
Week 6 
(day 35-42) 
Week 12 
(day77-84)
Week 18 
(day119-126)
Week 24 
(day161-168) 
Week 30 
(day 203-210)
Every 6 weeks 
thereafter until week 48
Every 12 weeks 
after week 48 
Tumour Assessment (CT/MRI and bone scans/ conventional imaging if required) 
Perform at the times specified above until progression is observed. In the event of early discontinuation or an interruption/delay to treatment, 
the tumour assessment schedule should not be changed..
 
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10.2 
APPENDIX 2   RECOMMENDED SUPPORTIVE CARE AND 
DOSE MODIFICATION SCHEME FOR GEMCITABINE / 
CISPLATIN CHEMOTHERAPY 
The guidance below is taken from the summary of product characteristics (SPC). 
The guidance given in the latest published SPC should always take precedence 
over the guidance given below. 
 
Supportive Care 
 
Pre-medication should commence after a patient is randomised to receive 
chemotherapy. The recommended supportive care for Gemcitabine / Cisplatin 
chemotherapy is as follows; 
 
• 
Pre-treatment hydration with 1 - 2 litres of fluid infused for 8 - 12 hours prior 
to Cisplatin will initiate diuresis. Adequate subsequent hydration should 
maintain diuresis during the 24 hours following administration. 
• 
Antiemetic treatment should follow the recommendations given in the 
Consensus Statement of the Antiemetic Subcommittee of the Multinational 
Association of Supportive Care in cancer (MASCC): Prevention of 
chemotherapy- and radiotherapyinduced emesis: Results of the Perugia 
Consensus Conference (R06-0986). 
 
Dose Modification Scheme 
 
Dosage adjustments for hematologic toxicity may be required for gemcitabine and 
for cisplatin. Gemcitabine dosage adjustment for hematological toxicity is based on 
the granulocyte and platelet counts taken on the day of therapy. Patients receiving 
gemcitabine should be monitored prior to each dose with a complete blood count 
(CBC), including differential and platelet counts. If marrow suppression is 
detected, therapy should be modified or suspended according to the guidelines in 
Table 10.2:1. 
 
In general, for severe (Grade 3 or 4) non-hematological toxicity, except alopecia 
and nausea/vomiting, therapy with gemcitabine plus cisplatin should be held or 
decreased by 50% depending on the judgment of the treating physician. During 
combination therapy with cisplatin, serum creatinine, serum potassium, serum 
calcium, and serum magnesium should be carefully monitored (Grade 3/4 serum 
creatinine toxicity for gemcitabine plus cisplatin was 5% versus 2% for cisplatin 
alone). 
 
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Table 10.2:1 Dosage Reduction Guidelines for Gemcitabine in combination with 
Cisplatin  
 
Absolute granulocyte count  
(x 10
6/L)  
 
Platelet count  
(x 10
6
/L)  
% of full dose  
≥1000  
and  
≥100,000  
100 
500-999  
or  
50,000-99,999  
75  
<500  
or  
<50,000  
Hold  
 
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10.3 
APPENDIX 3   QUESTIONNAIRES 
 
 
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10.4 
APPENDIX 4   RECIST 1.1 CRITERIA  
The criteria below are based on RECIST 1.1 (R09-0262). 
 
Measurability of the disease 
 
Measurable lesions 
 
Lesions that can be accurately measured in at least one dimension with longest 
diameter ≥ 10 mm (by CT scan, MRI, caliper measurement) or ≥ 20 mm (by chest 
X-ray). 
 
Measurable disease 
 
Measurable disease requires the presence of at least one measurable lesion. If the 
measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
 
Non-measurable disease 
 
Non-measurable lesions are all other lesions, including small lesions (longest 
diameter <10 mm with CT scan, MRI or caliper measurement or <20 mm with 
chest X-ray or pathological lymph nodes with shortest axis ≥10 and <15 mm) as 
well as truly non-measurable lesions. Lesions considered truly unmeasurable 
include leptomeningeal disease, ascites, pleural or pericardial effusion, 
inflammatory breast disease, lymphangitic involvement of skin or lung, abdominal 
masses/ abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
 
New lesions in irradiated fields 
 
Previously irradiated lesions should not be used as indicator lesions. However, new 
lesions occurring in previously irradiated fields can be used to assess the 
antitumour response. 
 
Methods of measurement 
 
All measurements must be recorded in metric notation, using a ruler or calipers. 
All baseline evaluations must be performed as close as possible to the treatment 
start and never more than 4 weeks before the beginning of the treatment. If a lesion 
is considered too small to measure, a default measurement of 5mm should be 
applied. If the lesion is not visible, a default measurement of 0mm should be 
applied. 
 
The same method of assessment and the same technique must be used to 
characterise each identified and reported lesion at baseline and during follow-up. 
Clinical lesions will only be considered measurable when they are superficial (e.g., 
skin nodules, palpable lymph nodes). In the case of skin lesions, documentation by 
colour photography including a ruler to estimate the size of the lesion is obligatory. 
 
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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 (longest diameter = LD) and numbered at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repetitive measurements (either by 
imaging techniques or clinically). Lymph nodes must be ≥15mm in order to be 
considered as target lesions. 
 
A sum of the longest diameter (LD) for all target lesions will be calculated and 
reported as the baseline sum LD. The baseline sum LD will be used as reference to 
further characterize the objective tumour response of the measurable dimension of 
the disease (see Table 10.4:1). 
 
Table 10.4:1 Evaluation of target lesions 
Complete Response 
(CR) 
Disappearance of all target lesions. 
Partial Response (PR)  
At least a 30% decrease in the sum of LD of target 
lesions taking as reference the baseline sum LD. 
Progression (PD) 
At least a 20% increase in the sum of LD of target 
lesions taking as reference the smallest sum LD 
recorded since the treatment started, together with an 
absolute increase in the sum of LD of at least 5mm. OR  
The appearance of one or more new lesions. 
Stable Disease (SD)  
 
Neither sufficient shrinkage to qualify for PR, taking as 
reference the baseline sum LD, nor sufficient increase to 
qualify for PD taking as reference the smallest sum LD 
since the treatment started. 
 
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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 10.4:2). 
 
Table 10.4:2  Evaluation of non-target lesions and new lesions 
Complete 
Response (CR) 
Disappearance of all non-target lesions and normalisation of 
tumour marker level. 
Non-CR/ Non-PD  
Persistence of one or more non-target lesions or/and 
maintenance of tumour marker level above normal limits. 
Progression (PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. 
 
Although a clear progression of non-target lesions only is 
exceptional, in such circumstances, the opinion of the 
treating physician should prevail and the progression status 
should be confirmed later by the review panel (or study 
chair). 
 
In some circumstances it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of complete response depends upon this 
determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) before confirming the complete response status. 
 
Confirmation 
 
In the case of SD, follow-up measurements must have met SD criteria at least once 
after study entry at a minimum interval of six weeks.  
 
Evaluation of Best Response to Study Treatment 
 
The best response to study treatment (Table 10.4:3) is the best response recorded 
from the start of treatment until disease progression or start of further anti-cancer 
treatment (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). In general, the patient’s best response 
assignment will depend on the achievement of both measurements and 
confirmation criteria (Table 10.4:3). 
 
Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration”. Every effort should be made to document 
the objective progression even after discontinuation of treatment. 
 
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Table 10.4:3  Algorithm for evaluation of overall best response* 
 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non- PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not 
evaluated 
No 
PR 
SD 
Non-PD or not 
evaluated 
No 
SD 
Not evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
* In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a 
minimum 
 
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TITLE PAGE 
 
ABCD 
Clinical Trial Protocol Amendment 
Doc. No.: U10-3034-01-AM1 
 
Amendment 
Number: 
1 
 
 
Date: 
Final, 14 May 2010 
□ 
To be implemented only after 
documented approval of the IRB / 
IEC / Competent Authorities 
 
BI Trial No.: 
 
1200.34 
x 
To be implemented immediately 
in order to eliminate hazard – 
IRB / IEC / Competent Authority 
to be notified of change with 
request for approval 
Investigational 
Product(s): 
BIBW 2992 
 
□ 
Can be implemented without IRB 
/ IEC / Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only 
Title: 
LUX-Lung 6: A randomized, open-label, phase III study of BIBW 2992 
versus chemotherapy as first-line treatment for patients with Stage IIIB or IV 
adenocarcinoma of the lung harbouring an EGFR activating mutation 
Rationale for 
Amendment: 
Since BIBW 2992 is a P-gp substrate, BI performed a phase I trial 1200.79 in healthy 
volunteers to assess the effects of the potent P-gp inhibitor ritonavir on the 
pharmacokinetics (PK) of BIBW 2992.   
The initial results of the study show that, although the median tmax and terminal half-
life of BIBW 2992 were not affected, the rate and extent of absorption of BIBW 2992 
was increased by co-treatment with ritonavir. These results also indicate that an effect 
of potent P-gp inducers on the PK characteristics of BIBW 2992 cannot be excluded. 
To ensure continued subject safety, the following amendment have been made 
in the protocol: 
1. Change of exclusion criteria to clarify section listing restricted 
medications (Change 1) 
2. Change of restricted medications to be given together with BIBW 2992 
(Change 2) 
 
Page 1 of 4 
Proprietary confidential information.  
© 2010 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 


Boehringer Ingelheim 
Final, 14 May 2010 
BI Trial No.: 1200.34           Protocol amendment 1 
Page 2 of 4 
 
Change 1: 
Change of an exclusion criterion in section 3.3.2 Exclusion criteria 
21. Requirement for treatment with any of the prohibited concomitant medications listed in 
section 4.2.2.2  
was change to 
21. Requirement for treatment with any of the prohibited concomitant medications listed in 
section 4.2.2 
Reason For Change 1: 
During the consent process it is not known what medication the patient will be randomised to 
so it is necessary to have the exclusion criteria cover both arms of treatment. 
Change 2: 
Addition of explanatory paragraph (s) on restrictions regarding BIBW 
2992 treatment to section 4.2.2   
4.2.2 Restrictions 
4.2.2.1 Restrictions for patients randomised to arm A (BIBW 2992) 
Patients randomised to treatment with BIBW 2992 should not receive any additional 
experimental anti-cancer treatment, chemotherapy, immunotherapy, hormone treatment (with 
the exception of megestrol acetate) or radiotherapy (except palliative short-course 
radiotherapy to non-target lesions) between informed consent and the end of treatment visit. 
4.2.2.2 Restrictions for patients randomised to arm B (Gemcitabine/ Cisplatin 
chemotherapy) 
 
Patients randomised to treatment with Gemcitabine/ Cisplatin chemotherapy should not 
receive any additional experimental anti-cancer treatment, chemotherapy, immunotherapy, 
hormone treatment (with the exception of megestrol acetate), maintenance therapy for 
NSCLC or radiotherapy (except palliative short-course radiotherapy to non-target lesions) 
between informed consent and the end of treatment visit. 
Patients should not receive any of the prohibited medications as listed in the current summary 
of product characteristics (SPC) for the Gemcitabine/ Cisplatin chemotherapy regimen. 
was change to 
4.2.2 Restrictions 
All patients randomised should not receive any additional experimental anti-cancer treatment, 
chemotherapy, immunotherapy, hormone treatment (with the exception of megestrol acetate) 
or radiotherapy (except palliative short-course radiotherapy to non-target lesions) between 
informed consent and the end of treatment visit. 


Boehringer Ingelheim 
Final, 14 May 2010 
BI Trial No.: 1200.34           Protocol amendment 1 
Page 3 of 4 
 
In addition patients randomised to treatment with Gemcitabine/ Cisplatin chemotherapy 
should not receive any maintenance therapy for NSCLC or receive any of the prohibited 
medications as listed in the current summary of product characteristics (SPC) for the 
Gemcitabine/ Cisplatin chemotherapy regimen. 
BIBW 2992 is a substrate of P-gp and its plasma concentrations can be affected by the use of 
P-gp inhibitors (data on file) and it is also likely that P-gp inducers could also influence 
BIBW 2992 plasma concentrations. The use of potent P-gp inhibitors (including Cyclosporin, 
Erythromycin, Ketoconazole, Itraconazole, Quinidine, Phenobarbital salt with Quinidine, 
Ritonavir, Valspodar, Verapamil) and potent P-gp inducers (including St John's wort, 
rifampicin) must be avoided during treatment with BIBW 2992. Any exemptions to this must 
be discussed with the BI clinical monitor. 
In any patient ongoing in the trial receiving BIBW 2992 and a concomitant potent P-gp 
inhibitor or inducer at the time of amendment 1 being implemented, the decision for 
continuation of either drug will be based on the individual circumstances of the patient upon 
discussion with the responsible BI clinical monitor. 
Reason For Change 2: 
The restriction was added based on the results of a phase 1 trial 1200.79 performed in healthy 
volunteers. Since BIBW 2992 is a P-gp substrate, BI performed this trial to assess the effects 
of the potent P-gp inhibitor ritonavir on the pharmacokinetics (PK) of BIBW 2992. 
In this open-label, randomised, two-way crossover study the relative exposure after a single 
oral dose of BIBW 2992 (20 mg), co-administered with multiple oral doses of ritonavir (200 
mg bid for 3 days), was compared to the exposure after a single oral dose of BIBW 2992 (20 
mg) alone in healthy male volunteers. The study was designed to determine the maximum 
effect of P-gp inhibition on the PK of BIBW 2992. 
The initial results of the study show that, although the median tmax and terminal half-life of 
BIBW 2992 were not affected, the rate and extent of absorption of BIBW 2992 was increased 
by co-treatment with ritonavir. The exposure to BIBW 2992, when taken in combination with 
ritonavir (AUC0-∞, AUC0-tz and Cmax), increased by 50.0%, 47.6%, and 38.5%, respectively 
(Data on file). 
These results also indicate that an effect of potent P-gp inducers on the PK characteristics of 
BIBW 2992 cannot be excluded. 
The data in trial 1200.79 were obtained at a dose of 20 mg BIBW 2992. It is currently unclear 
whether the results can be extrapolated to higher doses of BIBW 2992 currently used in phase 
II/III trials. However, considering the dose dependence of adverse events and for safety 
reasons caution has to be exercised in combining BIBW 2992 with potent P-gp inhibitors and 
inducers. 
In addition guidance for management of patients who already receive BIBW 2992 in 
combination with Pgp-inhibitors and Pgp-inducers was provided, as in these patients careful 


Boehringer Ingelheim 
Final, 14 May 2010 
BI Trial No.: 1200.34           Protocol amendment 1 
Page 4 of 4 
 
risk-benefit assessment of the individual case may need to be performed upon discussion with 
the responsible BI clinical monitor. 
This is reflected by the modification of an exclusion criterion to all ongoing trials (Change 1), 
and the addition of restrictions for concomitant medications to be given together with BIBW 
2992 ( Change 2). 


TITLE PAGE 
 
ABCD 
Clinical Trial Protocol Amendment 
Doc. No.: U10-3034-01-AM2 
 
Amendment 
Number: 
2 
 
 
Date: 
9 May 2011 
x 
To be implemented only after 
documented approval of the IRB / 
IEC / Competent Authorities 
BI Trial No.: 
1200.34 
□ 
To be implemented immediately 
in order to eliminate hazard – 
IRB / IEC / Competent Authority 
to be notified of change with 
request for approval 
Investigational 
Product: 
BIBW 2992 
 
 
□ 
Can be implemented without IRB 
/ IEC / Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only 
Title: 
LUX-Lung6; A randomised, open-label, phase III study of BIBW 2992 
versus chemotherapy as first-line treatment for patients with stage IIIB or IV 
adenocarcinoma of the lung harbouring an EGFR activating mutation 
Rationale for 
Amendment: 
1.Changes and clarifications to adverse event reporting 
2. Multiple administrative changes and clarifications 
3. Change of Trial Clinical Monitor’s information 
4. Changes to statistical analyses 
5. Changes to collection of demographic data 
 
Page 1 of  30 
Proprietary confidential information.  
© 2011 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 


Boehringer Ingelheim 
          Final, 9 May 2011 
BI Trial No.: 1200.34                               Protocol amendment 2                                     Page 2 of 30 
Change 1: 
 
Change of TCM’s information 
 
Phone: 
, Fax: 
 
  
Was changed to: 
Phone: 
, Fax: 
 
 
Reason For Change 1: Office address moved 
 
Change 2: 
Flow Chart: Arm A (BIBW 2992)  
“x” in flowchart for Demographics was moved from SV1 to SV2  
Reason for change 2: Clarification that demographic information will not be collected prior to 
signature of informed consent for screening visit 2. 
 
Change 3:  
Flow Chart: Arm A (BIBW 2992)  
Footnote 1: Written informed consent must be obtained before any protocol specific screening 
assessments are performed. Informed Consent 1 must include consent to collection of 
demographic data and consent to obtaining a biopsy and testing of biopsy material for EGFR 
mutation status.  
 
Was changed to: 
Footnote 1: Written informed consent must be obtained before any protocol specific screening 
assessments are performed. Informed Consent 1 must include consent to obtaining a biopsy 
and testing of biopsy material for EGFR mutation status.  
 


Boehringer Ingelheim 
          Final, 9 May 2011 
BI Trial No.: 1200.34                               Protocol amendment 2                                     Page 3 of 30 
Reason for change3: Informed consent that has been signed by patients at SV1 does not 
specify that demographic information will be collected. 
 
Change 4:  
Flow Chart: Arm A (BIBW 2992)  
Footnote 7: Includes haematology, serum biochemistry and urinalysis. Creatinie clearance 
must be measured at screening for all patients. 
Was changed to: 
Footnote 7: Includes haematology, serum biochemistry and urinalysis.  Creatinie clearance 
must be measured at screening for all patients. In case of course 1 day 1, assessments do not 
need to be repeated if the visit is within 2 days of the screening visit 2 assessments. 
Reason for change 4: To clarify about assessments that should be performed during the trial. 
 
Change 5:  
Flow Chart: Arm A (BIBW 2992)  
Was added: 
Footnote 14: Adverse events and healthcare usage: Adverse events should be assessed from 
signature of informed consent until 21 days after end of treatment visit (see table 5.2.1:1). 
Health care usage is only assessed from course 1 day 1 to end of treatment and is not assessed 
in screening period. 
Reason for change 5: To clarify about assessments that should be performed during the trial. 
 
Change 6: 
Flow Chart: Arm B (Gemcitabine/Cisplatin)                          
“x” in flowchart for Demographics was moved from SV1 to SV2  
Reason for change 6: Clarification that demographic information will not be collected prior to 
signature of informed consent for screening visit 2. 
 
Change 7: 


Boehringer Ingelheim 
          Final, 9 May 2011 
BI Trial No.: 1200.34                               Protocol amendment 2                                     Page 4 of 30 
Flow Chart: Arm B (Gemcitabine/Cisplatin) 
Footnote 1: Written informed consent must be obtained before any protocol specific screening 
assessments are performed. Informed Consent 1 must include consent to collection of 
demographic data and consent to obtaining a biopsy and testing of biopsy material for EGFR 
mutation status.  
 
Was changed to: 
Footnote 1: Written informed consent must be obtained before any protocol specific screening 
assessments are performed. Informed Consent 1 must include consent to obtaining a biopsy 
and testing of biopsy material for EGFR mutation status.  
 
Reason for change 7: Informed consent that has been signed by patients at SV1 does not 
specify that demographic information will be collected. 
 
Change 8:  
Flow Chart: Arm B (Gemcitabine/Cisplatin) 
Footnote 7: Includes haematology, serum biochemistry and urinalysis. Creatinie clearance 
must be measured at screening for all patients. 
Was changed to: 
Footnote 7: Includes haematology, serum biochemistry and urinalysis. Creatinie clearance 
must be measured at screening for all patients. In case of course 1 day 1, assessments do not 
need to be repeated if the visit is within 2 days of the screening visit 2 assessments. 
Reason for change 8: To clarify about assessments that should be performed during the trial. 
 


Boehringer Ingelheim 
          Final, 9 May 2011 
BI Trial No.: 1200.34                               Protocol amendment 2                                     Page 5 of 30 
Change 9:  
Flow Chart: Arm B (Gemcitabine/Cisplatin))  
Was added: 
Footnote 14: Adverse events and healthcare usage: Adverse events should be assessed from 
signature of informed consent until 21 days after end of treatment visit (see table 5.2.1:1). 
Health care usage is only assessed from course 1 day 1 to end of treatment and is not assessed 
in screening period. 
Reason for change 9: To clarify about assessments that should be performed during the trial. 
 
Change 10: 
4.1.4.1 Selection and timing of doses for each patient: BIBW 2992 (Arm A) 
 
The medication should be taken at the same time each day (± 2 hours) at least one hour before 
food intake and at least three hours after food intake.  
Was changed to: 
The medication should be taken at approximately the same time each day at least one hour 
before food intake and at least three hours after food intake.  
Reason for change 10: In light of the long half-life of afatinib (gMean terminal half-life 37,2 
hrs), the strict window for drug intake can be removed to accomodate individual patients’ 
daily schedule preference. 
 
 
Change 11: 
 
4.1.6.1 Packaging, labelling and re-supply: BIBW 2992 
 
Was added: 
 
The patient may take their daily tablet in the morning before coming to the clinic and in this 
case it is acceptable that the tablet comes from the bottle dispensed at the previous course.  
 
Reason for change 11:  To clarify that doses may be taken from bottle not for that course in 
case of tablet needing to be taken before the patient comes into clinic for day 1 assessments. 
 
 
 
 


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BI Trial No.: 1200.34                               Protocol amendment 2                                     Page 6 of 30 
  
Change 12: 
4.2 Concomitant Therapy 
 
All concomitant (non-oncological) medications which are taken between informed consent 
and the last follow-up visit should be recorded in the electronic case report form (eCRF), 
including anaesthetic agents, vitamins, and homeopathic remedies and nutritional 
supplements. If a patient requires parenteral nutrition it is not necessary to specify the detail 
on the eCRF; it will be sufficient to indicate 'parenteral nutrition'. 
Was changed to: 
 
All concomitant (non-oncological) medications which are taken between informed consent at 
screening visit 2 and the last follow-up visit should be recorded in the electronic case report 
form (eCRF), including anaesthetic agents, vitamins, and homeopathic remedies and 
nutritional supplements. If a patient requires parenteral nutrition it is not necessary to specify 
the detail on the eCRF; it will be sufficient to indicate 'parenteral nutrition'. 
Reason for change 12: Clarification on when concomitant medications should start to be 
collected. 
 
 
 
Change 13: 
4.2.1 Rescue medication and additional treatments 
G-CSF use is permitted but not mandated for patients who experience CTCAE Grade 3 or 4 
neutropenia or who develop neutropenic fever between cycles of Gemcitabine/Cisplatin 
chemotherapy. The following doses and schedules are recommended; G-CSF (Filgastrim, 5 
µg/kg/day) SC beginning 24 hours after the completion of Gemcitabine and continued daily 
until the neutrophil count is >10,000/µL in two successive analysis or G-CSF (Pentagastrim, 6 
mg) SC once per chemotherapy cycle at least 24 hours after completion of Gemcitabine. 
Was changed to:  
 
G-CSF use is permitted but not mandated for patients who experience CTCAE Grade 3 or 4 
neutropenia or who develop neutropenic fever between cycles of Gemcitabine/Cisplatin 
chemotherapy. The following doses and schedules are recommended; G-CSF (Filgastrim, 5 
µg/kg/day) SC beginning 24 hours after the completion of Gemcitabine and continued daily 
until the neutrophil count is >10,000/µL in two successive analysis or G-CSF (PegFilgastrim, 
6 mg) SC once per chemotherapy cycle at least 24 hours after completion of Gemcitabine. 
 
Reason for change 13: The incorrect name for PegFilgastrim was used in original protocol. 
 
 


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          Final, 9 May 2011 
BI Trial No.: 1200.34                               Protocol amendment 2                                     Page 7 of 30 
Change 14:  
 
5.1.5 Health-Related Quality of Life 
Any unsolicited information provided by the patient on the questionnaire and any safety 
related data obtained from the patient’s responses to the standard questions on the 
questionnaires will be immediately reported to the investigator. Adverse event information 
from the questionnaire will be appropriately reported in the eCRF. 
 
Was changed to:  
Any unsolicited information provided by the patient on the questionnaire and any safety 
related data obtained from the patient’s responses to the standard questions on the 
questionnaires will be immediately reported to the investigator and as such the medical 
records will be the primary source for adverse event information. 
 
Reason for change 14: To clarify how data in the quality of life questionnaires should be 
handled in terms of adverse event reporting. 
 
Change 15:  
 
5.2.1 Adverse Events 
During the screening phase of the trial, the patient’s condition will be assessed (e.g., 
documentation of history / concomitant diagnoses and diseases), and subsequently all relevant 
changes from baseline will be noted. 
Was changed to:  
During the first screening phase of the trial (screening visit 1 to screening visit 2) no medical 
history will be collected. No adverse event data will be collected (unless related to the 
patient’s participation in the trial).  
During the second screening phase of the trial (after informed consent is signed for screening 
visit 2), the patient’s condition will be assessed (e.g., documentation of history / concomitant 
diagnoses and diseases), and subsequently all relevant changes from baseline will be noted.  
 
Reason for change 15: To clarify adverse event reporting in the screening period of the trial. 
 
 
 
 
 
 
 
 
 
 
 


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          Final, 9 May 2011 
BI Trial No.: 1200.34                               Protocol amendment 2                                     Page 8 of 30 
Change 16: 
Table 5.2.1: 1 
AE/SAE reporting requirements 
Time period 
Reporting requirements 
Screening to Follow-up 1 (21 days after End 
of Treatment (EOT)) 
Report all AEs and SAEs regardless of 
relatedness. This includes all deaths. 
 
 
Was changed to: 
Table 5.2.1: 1 
AE/SAE reporting requirements 
Time period 
Reporting requirements 
Screening Visit 1 to Screening Visit 2 
Report only AEs or SAEs related to the 
patients participation in the trial.  
Screening Visit 2 to Follow-up 1 (21 days 
after End of Treatment (EOT)) 
Report all AEs and SAEs regardless of 
relatedness. This includes all deaths.  
 
 
Reason for change 16: To clarify adverse event reporting in the screening period of the trial. 
 
Change 17: 
5.2.4 Laboratory investigations 
Was added: 
 
At course 1 day 1, safety laboratory assessments (haematology, biochemistry and urinalysis) 
do not need to be repeated if visit date is within 2 days from screening visit 2 assessments) 
 
Reason for change 17: Clarification that assessments do not need to be repeated. 
 
 
Change 18: 
 
5.3.1 Demographics and history 


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BI Trial No.: 1200.34                               Protocol amendment 2                                     Page 9 of 30 
Demographics (sex, birth date, and race), alcohol history, and histological subtype will be 
collected during the screening 1 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 smoked per day x number of years 
smoked)/ 20 (R08-4072) 
• 
Date of last cigarette 
History of NSCLC will be obtained during screening 2 and reported in the eCRF: 
• 
The date of first histological diagnosis 
• 
The primary tumour site 
• 
The number and location of metastatic sites (bone, brain, liver, pleural effusion, other) 
• 
Tumour Stage according to the TNM-classification at diagnosis 
• 
Previous surgery and radiotherapy for NSCLC 
• 
Previously administered neoadjuvant/adjuvant chemotherapy including start and end 
dates and the outcome 
 
Was changed to: 
 
Consent date and histological subtype will be collected during the screening 1 visit. 
Demographics, history of NSCLC as well as alcohol and smoking history will be obtained 
during screening 2 and reported in the eCRF: 
• 
Demographics (sex, birth date, race, ethnicity) 
• 
The date of first histological diagnosis 
• 
The primary tumour site 
• 
The number and location of metastatic sites (bone, brain, liver, pleural effusion, other) 
• 
Tumour Stage according to the TNM-classification at diagnosis 
• 
Previous surgery and radiotherapy for NSCLC 
• 
Previously administered neoadjuvant/adjuvant chemotherapy including start and end 
dates and the outcome 


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          Final, 9 May 2011 
BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 10 of 30 
• 
Alcohol history, 
• 
Smoking history, to be documented as follows; 
• 
Smoking status; never smoker (<100 cigarettes/lifetime), current-smoker or former 
smoker 
• 
Number of pack years = (number of cigarettes smoked per day x number of years 
smoked)/ 20 (R08-4072) 
• 
Date of last cigarette 
 
Reason for change 18: Informed consent signed at screening visit 1 does not clearly document 
the collection of demographic information and therefore this will only be collected for patients 
who have signed the informed consent at screening visit 2. 
 
 
Change 19: 
5.3.2     Concomitant therapies and diagnoses 
Concomitant diagnoses and/or therapies present during study participation (between informed 
consent and the follow-up visit) will be recorded in the eCRF. 
Was changed to: 
 
Concomitant diagnoses and/or therapies present during study participation (between informed 
consent at screening visit 2 and the follow-up visit) will be recorded in the eCRF. 
 
Reason for change 19: To clarify the collection of information during the screening phase of 
the trial. 
 
 
Change 20: 
 
6.1.5 Observation Period 
 
After completion of the study patients will enter an observation period. During the 
observation period no study visits will be performed, but data regarding progression, further 
treatment (including best response and reason for stopping treatment) and death will be 
collected every 60 days (± 15 days) until death. Information will be collected from the patient 
notes or by telephone contact with the patient. 
The observation period will end after all patients have died or five years after the last follow-
up visit, whichever occurs first. 
 


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BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 11 of 30 
Was changed to:  
 
 
After completion of the study patients will enter an observation period. During the 
observation period no study visits will be performed, but data regarding progression, further 
treatment (including best response and reason for stopping treatment) and death will be 
collected every 60 days (± 15 days) until death. Information will be collected from the patient 
notes or by telephone contact with the patient. 
The observation period will end after all patients have died or five years after the last follow-
up visit, whichever occurs first. However, the observation period may end earlier depending 
upon the timing of analyses requested by regulatory authorities. 
 
Reason for change 20: To give the option of ending the study earlier if the timing of requested 
analyses by regulatory authorities have been met. 
 
 
 
Change 21: 
 
6.2.1 Screening and run-in in phases 
 
Screening Visit 1 
Screening Visit 1 should be performed within 6 weeks of the first administration of study 
medication 
Informed Consent 1 
Written informed consent must be obtained before any 
study-specific screening assessments are performed. 
Informed Consent 1 must include consent to collection of 
demographic data and consent to obtaining a biopsy and 
testing of biopsy material for EGFR mutation status.  
Demographics 
Sex, birth date, race, alcohol history and smoking history. 
Tumour biopsy for EGFR 
mutation analysis 
Tumour biopsy will be collected for analysis of EGFR 
mutation status. If a tumour biopsy is performed as part of 
routine clinical practice prior to trial participation and 
material is available for analysis, the biopsy does not need to 
be repeated. 
Material should be submitted to the central laboratory for 
analysis as described in section 5.6.1. 
 
 
 


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          Final, 9 May 2011 
BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 12 of 30 
 
 
Was changed to: 
 
Screening Visit 1 
Screening Visit 1 should be performed within 6 weeks of the first administration of study 
medication 
Informed Consent 1 
Written informed consent must be obtained before any study-
specific screening assessments are performed. Informed 
Consent 1 must include consent to obtaining a biopsy and 
testing of biopsy material for EGFR mutation status as well 
as provision of histological classification.  
Tumour biopsy for EGFR 
mutation analysis 
Tumour biopsy will be collected for analysis of EGFR 
mutation status. If a tumour biopsy is performed as part of 
routine clinical practice prior to trial participation and 
material is available for analysis, the biopsy does not need to 
be repeated. 
Material should be submitted to the central laboratory for 
analysis as described in section 5.6.1. 
 
 
Reason for change 21: To clarify the collection of information during the screening phase of 
the trial. Demographic information will not be collected for patients only signing consent at 
screening visit 1 
 
 
Change 22: 
 
6.2.1 Screening and run-in phase 


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BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 13 of 30 
Screening Visit 2 
This visit should only be performed by patients who have tested positive for an EGFR 
mutation. All screening visit 2 procedures should be performed within 28 days of the first 
administration of study medication. 
Informed 
consent 2 
Informed Consent 2 will be obtained for patients who have positive EGFR 
mutation status and must include consent to all study procedures including 
a blood sample for analysis of EGFR mutation status. The only exception is 
that consent to collection of a blood sample for DNA banking is optional. 
 Demographics 
Sex, birth date, race, alcohol history and smoking history will be taken for 
patients who had a tumour biospy performed as routine clinical practice 
and did not participate Screening Visit 1 
Medical history 
Oncological and relevant non-oncological history including details of any 
previous treatment for NSCLC (see section 5.3.1). 
Patient 
eligibility 
Assessment of eligibility according to inclusion and exclusion criteria 
should be performed. 
Randomisation 
If the patient meets the eligibility criteria, randomisation should be 
performed. Treatment should commence within 2 days after randomisation. 
If the patient is randomised to chemotherapy, pre-medication should 
commence immediately after randomisation (see appendix 2). 
Physical 
examination 
Cardiopulmonary examination, examination of the regional lymph nodes, 
examination of the abdomen and an assessment of the mental and 
neurological status. Measurement of height and weight. 
Vital signs 
Blood pressure, pulse rate, respiratory rate and temperature. 
ECOG  
ECOG performance status will be assessed and documented. 
ECG 
12-lead resting ECG will be performed. 
ECHO/MUGA 
Cardiac left ventricular function assessment by either ECHO or MUGA. 
Safety lab 
Haematology, Biochemistry, Urinalysis and Creatinine Clearance (see 
section 5.2.4 for minimum assessments). 
Pregnancy test 
Β-HCG testing in urine or serum will be performed in women of 
childbearing potential. 
Tumour 
assessment 
CT scans of the chest and abdomen and, if clinically indicated, imaging of 
any other known or suspected sites of disease (e.g. pelvis, brain) using an 
appropriate method (CT scan or MRI). The assessment does not need to be 
repeated if there are valid results available from assessments which were 


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          Final, 9 May 2011 
BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 14 of 30 
performed as part of routine clinical practice within the allowed time. 
In case of suspected (but not confirmed) bone metastasis at screening, 
tumour assessment at screening should include a bone scan. If bone lesions 
are already known or confirmed at screening, correlative imaging (X-ray or 
CT scan) should be performed. 
Con meds 
Document indication, start and stop date of each concomitant medication. 
Adverse events 
Document details of any new AEs and obtain any new information about 
AEs ongoing at the last visit. 
 
Was changed to: 


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BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 15 of 30 
Screening Visit 2 
This visit should only be performed by patients who have tested positive for an EGFR 
mutation. All screening visit 2 procedures should be performed within 28 days of the first 
administration of study medication. 
Informed 
consent 2 
Informed Consent 2 will be obtained for patients who have positive EGFR 
mutation status and must include consent to all study procedures including 
a blood sample for analysis of EGFR mutation status. The only exception is 
that consent to collection of a blood sample for DNA banking is optional. 
Demographics 
Sex, birth date, race, alcohol history and smoking history. 
Medical history 
Oncological and relevant non-oncological history including details of any 
previous treatment for NSCLC (see section 5.3.1). 
Patient 
eligibility 
Assessment of eligibility according to inclusion and exclusion criteria 
should be performed. 
Randomisation 
If the patient meets the eligibility criteria, randomisation should be 
performed. Treatment should commence within 2 days after randomisation. 
If the patient is randomised to chemotherapy, pre-medication should 
commence immediately after randomisation (see appendix 2). 
Physical 
examination 
Cardiopulmonary examination, examination of the regional lymph nodes, 
examination of the abdomen and an assessment of the mental and 
neurological status. Measurement of height and weight. 
Vital signs 
Blood pressure, pulse rate, respiratory rate and temperature. 
ECOG  
ECOG performance status will be assessed and documented. 
ECG 
12-lead resting ECG will be performed. 
ECHO/MUGA 
Cardiac left ventricular function assessment by either ECHO or MUGA. 
Safety lab 
Haematology, Biochemistry, Urinalysis and Creatinine Clearance (see 
section 5.2.4 for minimum assessments). 
Pregnancy test 
Β-HCG testing in urine or serum will be performed in women of 
childbearing potential. 
Tumour 
assessment 
CT scans of the chest and abdomen and, if clinically indicated, imaging of 
any other known or suspected sites of disease (e.g. pelvis, brain) using an 
appropriate method (CT scan or MRI). The assessment does not need to be 
repeated if there are valid results available from assessments which were 
performed as part of routine clinical practice within the allowed time. 


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BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 16 of 30 
In case of suspected (but not confirmed) bone metastasis at screening, 
tumour assessment at screening should include a bone scan. If bone lesions 
are already known or confirmed at screening, correlative imaging (X-ray or 
CT scan) should be performed. 
Con meds 
Document indication, start and stop date of each concomitant medication. 
Adverse events 
Document details of any new AEs and obtain any new information about 
AEs ongoing at the last visit. 
 
Reason for change 22: Demographic information to be collected at screening visit 2 once the 
informed consent for screening visit 2 is signed.  
 
 
Change 23: 
 
6.2.2.1 Treatment Phase: Treatment Arm A (BIBW 2992) 
 
Safety lab: Haematology, Biochemistry, and Urinalysis, (see section 5.2.4 for minimum 
assessments) 
 
Was changed to: 
 
Safety lab: Haematology, Biochemistry, and Urinalysis, (see section 5.2.4 for minimum 
assessments) (Note: For course 1 day 1 the assessments do not need to be repeated if within 2 
days of screening visit 2 assessments) 
 
Reason for change 23: To clarify that repeated tests do not need to be done if course 1 day 1 is 
within 2 days of laboratory assessments for screening visit 2. 
 
Change 24: 
 
6.2.2.2 Treatment Arm B (Gemcitabine/Cisplatin)  


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Arm B (Gemcitabine/Cisplatin) Day 8 of each course (± 2 days) 
C1V2, C2V2 
N.B. In the event of progression or decision to end treatment, please complete the EOT visit 
instead. 
Vital signs 
Blood pressure, pulse rate, respiratory rate and temperature. 
ECOG performance 
status 
ECOG performance status will be assessed and documented. 
ECG 
12-lead resting ECG will be performed on day 8 of course 1(C1V1). 
Safety lab 
Haematology, biochemistry and Urinalysis (see Section 5.2.4 for 
minimum assessements). Results must be available pior to 
commencing treatment 
Tumour assessment 
Ensure that tumour assessments are scheduled at the timepoints 
specified in the flow chart. 
Concomitant 
medications 
Document indication, start and stop date of each medication. 
Adverse events 
Document details of any new AEs and obtain any new information 
about AEs ongoing at the last visit. 
 
Healthcare usage 
Collect information on any unscheduled outpatient visits and 
hospitalisations. 
Administer trial drugs 
Gemcitabine 1000mg/m2 
 
 
 
 
 
 
 
 


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Was changed to: 
6.2.2.2 Treatment Arm B (Gemcitabine/Cisplatin)  
Arm B (Gemcitabine/Cisplatin) Day 8 of each course (± 2 days)C1V2, C2V2, C3V2, 
C4V2, C5V2, C6V2 
N.B. In the event of progression or decision to end treatment, please complete the EOT visit 
instead. 
Vital signs 
Blood pressure, pulse rate, respiratory rate and temperature. 
ECOG performance 
status 
ECOG performance status will be assessed and documented. 
ECG 
12-lead resting ECG will be performed if clinically indicated. 
Safety lab 
Haematology, biochemistry and Urinalysis (see Section 5.2.4 for 
minimum assessements). Results must be available pior to 
commencing treatment 
Tumour assessment 
Ensure that tumour assessments are scheduled at the timepoints 
specified in the flow chart. 
Concomitant 
medications 
Document indication, start and stop date of each medication. 
Adverse events 
Document details of any new AEs and obtain any new information 
about AEs ongoing at the last visit. 
 
Healthcare usage 
Collect information on any unscheduled outpatient visits and 
hospitalisations. 
Administer trial drugs Gemcitabine 1000mg/m2 
 
Reason for change 24: Table for day 8 assessments corrected to state that day 8 visit needs to 
be done for all 6 cyles. ECG will be performed if clinically indicated for Arm B.  
 
Change 25 
7.3.2.2.4 Health-Related Quality of Life (HRQOL) 


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The relevant HRQOL endpoints are the time to deterioration for the following three symptom 
scales/items measured on the QLQ-C30 or QLQ-LC13 questionnaire (R99-1213, R07-2060): 
 
• cough (Question 1 on the QLQ-LC13), 
• dyspnoea (composite of Questions 3-5 on the QLQ-LC13), 
• pain (composite of Questions 9 and 19 on the 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) (R07-2064). 
 
Time to deterioration for the cough, dyspnoea, pain and symptom scales/items will be defined 
as the time to a 10-point increase from the baseline score (R07-2064, R99-1223, R07-2061). 
Patients who die before deteriorating will be analysed as having deteriorated at the time of 
death. Disease progression without scale deterioration will be censored at the time of the last 
scale measurement. Patients with no HRQOL assessments will be censored at day of 
randomisation. If a HRQOL assessment is missed, but followed by another assessment and 
deterioration occurs during that period, the time to deterioration will be defined as the 
midpoint between the two observed assessments. In addition, the three alternative measures of 
pain (Questions 10-12* in QLQ-LC13) will be examined descriptively for consistency with 
the composite of questions 9 and 19 from the QLQ-C30, as will dyspnoea (Question 8) from 
the EORTC QLQ-C30 be compared with the dyspnoea composite (Questions 3-5* on the 
QLQ-LC13). 
 
Time to deterioration will be analysed similarly to PFS i.e. log-rank test stratified by the 
stratification factors used at randomisation will be used to test for the effect of BIBW 2992. 
The individual items of the symptom scales will be examined for consistency with the 
composites. 
 
In addition, a comprehensive analysis of all subscales/items (where a single item is scored, 
R07-2064) will estimate the hazard ratio for time to deterioration with 95% confidence. The 
results of these analyses will be displayed using a Forest plot to summarise the impact of 
therapy over the entire profile of the EORTC QLQ-C30 and LC13 measures. 
 
Additional analysis will describe the distribution of patients that are improved, stable, or 
worsened for each of the QLQ-C30 and QLQ-LC13 summary scales and items (where a 
single item is scored, R07-2061). 
 
 * Note that questions on the QLQ-LC13 are numbered consecutively following the QLQ-C30 
as shown in Appendix 4. Consequently, Question 1 is numbered as Question 31 and Questions 
3-5 as Questions 33-35. 
 
Was changed to:  


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BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 20 of 30 
7.3.2.2.4 Health-Related Quality of Life (HRQOL) 
 
The analyses will focus on cough, dyspnea, and pain measured on the EORTC QLQ-C30 and 
QLQ-LC13 questionnaires (R99-1213, R07-2060). 
 
For each of summary scales and items measuring cough, dyspnea, and pain, the treatments 
will be compared in terms of: 
• the distribution of patients that are improved, stable, or worsened 
Improvement is defined as scores that improve by at least 10 points at any time during 
the study. If a patient does not improve, worsening is defined as a 10 point worsening 
in EORTC scores at any time.  Otherwise, a patient would be considered stable if they 
neither improve nor worsen.  
 
• time to deterioration  
 
Time to deterioration will be defined as the time to a 10-point increase from the 
baseline score (R07-2064, R99-1223, R07-2061). 
 
Patients who die before deteriorating will be analysed as having deteriorated at the 
time of death. Disease progression without scale deterioration will be censored at the 
time of the last scale measurement. Patients with no HRQOL assessments will be 
censored at day of randomisation. If a HRQOL assessment is missed, but followed by 
another assessment and deterioration occurs during that period, the time to 
deterioration will be defined as the midpoint between the two observed assessments.  
 
Time to deterioration will be analysed similarly to PFS i.e. log-rank test stratified by 
the stratification factors used at randomisation will be used to test for the effect of 
BIBW 2992. 
 
• change in cough, dyspnea and pain scores over time  
 
The change in cough, dyspnea and pain will be assessed using a mixed-effects growth 
curve model with the average profile over time for each endpoint described by a 
piecewise linear model adjusted for baseline EGFR mutation category and ethnicity  
(R10-4359). 
                                                                             
The results of the time to deterioration analyses and the longitudinal analysis will be displayed 
using Forest plots. 
 
These analyses will be repeated in subgroups defined by: 
• baseline  ECOG:  0 vs. 1 
• presence of symptoms at baseline:  no vs. yes 
 
In addition, similar analyses will be summarized for all QLQ-C30 and QLQ-LC13 
subscales/items (where a single item is scored, R07-2064). 


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BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 21 of 30 
 
Finally, the usage of cough, dyspnea and pain medication will be described.  
 
Reason for change 25:  
The focus of the analysis of HRQOL was broadened to include all summary scales and items 
measuring cough, dyspnea, and pain measured on the EORTC QLQ-C30 and QLQ-LC13 
questionnaires.  This change was made to more comprehensively characterize the treatment 
effects on the signs and symptoms of NSCLC. 
 
 
Change 26: 
8.4.1 Adverse Events 
All adverse events occurring during the course of the clinical trial (i.e., from signing the 
informed consent to the final follow-up visit) will be collected, documented and reported to 
the sponsor by the investigator according to the specific definitions and instructions detailed 
in the ‘Adverse Event Reporting’ section of the Investigator Site File. 
Was changed to: 
All adverse events occurring during the course of the clinical trial (i.e., from signing the 
informed consent at screening visit 2 to the final follow-up visit) will be collected, 
documented and reported to the sponsor by the investigator according to the specific 
definitions and instructions detailed in the ‘Adverse Event Reporting’ section of the 
Investigator Site File. In addition only trial related adverse events will be collected between 
screening visit 1 and screening visit 2. 
Reason for change 26: To clarify collection of safety data during the screening phase of the 
trial. 
Change 27: 
Was added: 
8.9  
COMPLETION OF TRIAL 
The trial will be considered complete when the last patient completes the last follow-up visit. 
Reason for change 27: To clarify the defination of completion of trial. 
 
 
 


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Change 28: Appendix 4: RECIST 1.1 Criteria 
The criteria below are based on RECIST 1.1 (R09-0262). 
Measurability of the disease 
Measurable lesions 
Lesions that can be accurately measured in at least one dimension with longest diameter ≥ 10 
mm (by CT scan, MRI, caliper measurement) or ≥ 20 mm (by chest X-ray).  
Measurable disease 
Measurable disease requires the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology. 
Non-measurable disease 
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 
mm with CT scan, MRI or caliper measurement or <20 mm with chest X-ray or pathological 
lymph nodes with shortest axis ≥10 and <15 mm) as well as truly non-measurable lesions. 
Lesions considered truly unmeasurable include leptomeningeal disease, ascites, pleural or 
pericardial effusion, 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. 
New lesions in irradiated fields 
Previously irradiated lesions should not be used as indicator lesions. However, new lesions 
occurring in previously irradiated fields can be used to assess the antitumour response. 
Methods of measurement 
All measurements must be recorded in metric notation, using a ruler or calipers. All baseline 
evaluations must be performed as close as possible to the treatment start and never more than 
4 weeks before the beginning of the treatment. If a lesion is considered too small to measure, a 
default measurement of 5mm should be applied. If the lesion is not visible, a default 
measurement of 0mm should be applied. 
The same method of assessment and the same technique must be used to characterise each 
identified and reported lesion at baseline and during follow-up. 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). In the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is obligatory. 


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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 (longest diameter = LD) and numbered at baseline. Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their suitability 
for accurate repetitive measurements (either by imaging techniques or clinically). Lymph 
nodes must be ≥15mm in order to be considered as target lesions.  
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as the 
baseline sum LD. The baseline sum LD will be used as reference to further characterise the 
objective tumour response of the measurable dimension of the disease (see Table 10.4:1). 


Boehringer Ingelheim 
          Final, 9 May 2011 
BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 24 of 30 
Table 10.4: 1 
Evaluation of target lesions 
Complete Response 
(CR) 
Disappearance of all target lesions. 
Partial Response 
(PR) 
At least a 30% decrease in the sum of LD of target lesions taking as 
reference the baseline sum LD. 
Progression (PD) 
At least a 20% increase in the sum of LD of target lesions taking as 
reference the smallest sum LD recorded since the treatment started, 
together with an absolute increase in the sum of LD of at least 5mm. 
OR 
The appearance of one or more new lesions. 
Stable Disease (SD) Neither sufficient shrinkage to qualify for PR, taking as reference 
the baseline sum LD, nor sufficient increase to qualify for PD taking 
as reference the smallest sum LD since the treatment started. 
 
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. Measurements are not required and these lesions should be followed 
as “present” or “absent” (see Table 10.4:2). 
Table 10.4: 2 
Evaluations of non-target lesions and new lesions 
Complete Response 
(CR) 
Disappearance of all non-target lesions and normalisation of 
tumour marker level. 
Non-CR/ Non-PD 
Persistence of one or more non-target lesions or/and maintenance 
of tumour marker level above normal limits. 
Progression (PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. 
 
Although a clear progression of non-target lesions only is 
exceptional, in such circumstances, the opinion of the treating 
physician should prevail and the progression status should be 
confirmed later by the review panel (or study chair). 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 


Boehringer Ingelheim 
          Final, 9 May 2011 
BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 25 of 30 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
Confirmation 
In the case of SD, follow-up measurements must have met SD criteria at least once after study 
entry at a minimum interval of six weeks. 
Evaluation of Best Response to Study Treatment 
The best response to study treatment (Table 10.4:3) is the best response recorded from the 
start of treatment until disease progression or start of further anti-cancer treatment (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). In general, the patient’s best response assignment will depend on the achievement of 
both measurements and confirmation criteria (Table 10.4:3). 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 
 


Boehringer Ingelheim 
          Final, 9 May 2011 
BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 26 of 30 
Table 10.4: 3 
Algorithms for evaluation of overall best response* 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not 
evaluated 
No 
PR 
SD 
Non-PD or not 
evaluated 
No 
SD 
Not evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
* In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a minimum 
interval of six (6) weeks. 
 
Was changed to: 
(please note that due to size of this section all changes are italicised to clearly show 
differences) 
The criteria below are based on RECIST 1.1 (R09-0262). 
Measurability of the disease 
Measurable lesions 
Lesions that can be accurately measured in at least one dimension with longest diameter ≥ 10 
mm (by CT scan, MRI, caliper measurement) or ≥ 20 mm (by chest X-ray). Lymph nodes 
must be ≥15mm in short axis when assessed by CT scan 
Measurable disease 
Measurable disease requires the presence of at least one measurable lesion.  
Non-measurable disease 


Boehringer Ingelheim 
          Final, 9 May 2011 
BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 27 of 30 
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 
mm with CT scan, MRI or caliper measurement or <20 mm with chest X-ray or pathological 
lymph nodes with shortest axis ≥10 and <15 mm) as well as truly non-measurable lesions. 
Lesions considered truly unmeasurable include leptomeningeal disease, ascites, pleural or 
pericardial effusion, 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. 
New lesions in irradiated fields 
Previously irradiated lesions should not be used as indicator lesions. However, new lesions 
occurring in previously irradiated fields can be used to assess the antitumour response. 
Methods of measurement 
All measurements must be recorded in metric notation, using a ruler or calipers. All baseline 
evaluations must be performed as close as possible to the treatment start and never more than 
4 weeks before the beginning of the treatment. If a lesion is considered too small to measure, a 
default measurement of 5mm should be applied. If the lesion is not visible, a default 
measurement of 0mm should be applied. 
The same method of assessment and the same technique must be used to characterise each 
identified and reported lesion at baseline and during follow-up. 
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). In the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is obligatory. 
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 5 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to the chest, abdomen and 
pelvis. 
Ultrasound, endoscopy and laparoscopy should not be used to measure tumour lesions or 
evaluate tumour response. However, these techniques can be useful to supplement information 
from other techniques. 
Tumour markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, they must normalise for a patient to be considered in complete clinical 
response. 
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 


Boehringer Ingelheim 
          Final, 9 May 2011 
BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 28 of 30 
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs should be identified as target lesions and will be 
recorded, measured (longest diameter = LD for all lesions except lymph node and shortest 
diameter = ShD for lymph nodes) and numbered at baseline. Target lesions should be selected 
on the basis of their size (lesions with the longest diameter) and their suitability for accurate 
repetitive measurements (either by imaging techniques or clinically). Lymph nodes must be 
≥15mm in order to be considered as target lesions.  
A sum of the diameters (SoD) for all target lesions will be calculated and reported as the 
baseline SoD. The baseline SoD will be used as reference to further characterise the objective 
tumour response of the measurable dimension of the disease (see Table 10.4:1). 
Table 10.4: 1 
Evaluation of target lesions 
Complete Response 
(CR) 
Disappearance of all target lesions. 
Partial Response 
(PR) 
At least a 30% decrease in the SoD of target lesions taking as 
reference the baseline SD. 
Progression (PD) 
At least a 20% increase in the SoD of target lesions taking as 
reference the smallest SoD recorded since the treatment started, 
together with an absolute increase in the SoD of at least 5mm. 
OR 
The appearance of one or more new lesions. 
Stable Disease (SD) Neither sufficient shrinkage to qualify for PR, taking as reference 
the baseline SoD, nor sufficient increase to qualify for PD taking as 
reference the smallest SoD since the treatment started. 
 
All other lesions (or sites of disease) should be identified as non-target lesions and should also 
be recorded at baseline. Measurements are not required and these lesions should be followed 
as “present” or “absent” (see Table 10.4:2). 


Boehringer Ingelheim 
          Final, 9 May 2011 
BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 29 of 30 
Table 10.4: 2 
Evaluations of non-target lesions and new lesions 
Complete Response 
(CR) 
Disappearance of all non-target lesions and normalisation of 
tumour marker level. 
Non-CR/ Non-PD 
Persistence of one or more non-target lesions or/and maintenance 
of tumour marker level above normal limits. 
Progression (PD) 
Appearance of one or more new lesions and/or unequivocal 
progression of existing non-target lesions. 
 
Although a clear progression of non-target lesions only is 
exceptional, in such circumstances, the opinion of the treating 
physician should prevail and the progression status should be 
confirmed later by the review panel (or study chair). 
 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status. 
Confirmation 
In the case of SD, follow-up measurements must have met SD criteria at least once after study 
entry at a minimum interval of 35 days. 
Evaluation of Best Response to Study Treatment 
The best response to study treatment (Table 10.4:3) is the best response recorded from the 
start of treatment until disease progression or start of further anti-cancer treatment (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). In general, the patient’s best response assignment will depend on the achievement of 
both measurements and confirmation criteria (Table 10.4:3). 
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment. 
 
 
 


Boehringer Ingelheim 
          Final, 9 May 2011 
BI Trial No.: 1200.34                              Protocol amendment 2                                     Page 30 of 30 
Table 10.4: 3 
Algorithms for evaluation of overall best response* 
Target lesions 
Non-target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/ Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not 
evaluated 
No 
PR 
SD 
Non-PD or not 
evaluated 
No 
SD 
Not evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
* In the case of SD, follow-up measurements must have met the SD criteria at least once after study entry at a minimum 
interval of thirty five (35) days. 
 
Reason for change 28: To update protocol appendix to match RECIST 1.1 criteria and ensure 
consistency with the imaging charter for central analysis of the images. 
 
Change 29: 
APPENDIX 5: COCKROFT-GAULT FORMULA 
Was added: 
 
  
 
  
Reason for change 29: To document the formula in protocol to calculate creatinine clearance. 
 
GFR (ml/min) = 
(140-Age) X Mass (in kilograms) X [0.85 if Female] 
72 X Serum Creatinine (in mg/dL) 


TITLE PAGE 
ABCD 
Clinical Trial Protocol Amendment 
Doc. No.: U10-3034-01-AM3 
Amendment 
Number: 
 
3 
 
Date: 
9 Aug 2011 
□ 
To be implemented only after 
documented approval of the IRB / 
IEC / Competent Authorities 
BI Trial No.: 
1200.34 
□ 
To be implemented immediately 
in order to eliminate hazard – IRB 
/ IEC / Competent Authority to be 
notified of change with request 
for approval 
Investigational 
Product(s): 
Afatinib (BIBW2992) 
 
■ 
Can be implemented without IRB 
/ IEC / Competent Authority 
approval as changes involve 
logistical or administrative 
aspects only 
Title: 
LUX-Lung 6: A randomized, open-label, phase III study of BIBW 2992 
versus chemotherapy as first-line treatment for patients with Stage IIIB 
or IV adenocarcinoma of the lung harbouring an EGFR activating mutation 
Rationale for 
Amendment: 
The protocol stipulates that this trial is a multinational study and we are including 
patients from 3 countries; China, Thailand and South Korea.  Since patients in 
Thailand and South Korea are enrolling toward the end of the study and to ensure 
an adequate representation of patients from Thailand and South Korea, we are 
amending the protocol to allow for a slight increase in the total number of 
randomized patients in the trial to approximately 360 patients rather than 330 
patients. 
 
 
 
Page 1 of 3 
Proprietary confidential information.  
© 2011 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 


Boehringer Ingelheim 
9 Aug 2011 
BI Trial No.: 1200.34 
Protocol amendment 3 
Page 2 of 3 
 
Change 1: 
The total number of randomized patients in the trial changes to approximately 
363 patients rather than 330 patients. 
Page 2  
No. of Patients: 
Total:  
           330 randomized  
Was changed to: 
Total:  
           Approximately 360 randomized  
 
And  
Page 26 
3.1 OVERALL TRIAL DESIGN AND PLAN-DESCRIPTION 
It is estimated that approximately 1366 patients will be screened for the trial in order to find 
330 eligible patients. 
 
Was changed to: 
It is estimated that approximately 1366 patients will be screened for the trial in order to find 
approximately 360 eligible patients. 
 
And  
Page 27 
 3.3 SELECTION OF TRIAL POPULATION 
It is estimated that approximately 1366 patients will be screened in order to find 330 eligible 
patients. 
 
 
Was changed to: 
It is estimated that approximately 1366 patients will be screened in order to find 
approximately 360 eligible patients. 
 
 
Reason For Change 1: 
 


Boehringer Ingelheim 
9 Aug 2011 
BI Trial No.: 1200.34 
Protocol amendment 3 
Page 3 of 3 
The protocol stipulates that this trial is a multinational study and we are including patients 
from 3 countries; China, Thailand and South Korea.  Since patients in Thailand and South 
Korea are enrolling toward the end of the study and to ensure an adequate representation of 
patients from Thailand, and South Korea, we are amending the protocol to allow for a slight 
increase in the total number of randomized patients in the trial to approximately 363 patients 
rather than 330 patients 


TITLE PAGE
ABCD
Clinical Trial Protocol Amendment
Doc. No.: U10-3034-01-AM4
Amendment 
Number:
4
Date:
16 Oct 2013
■
To be implemented only after 
documented approval of the IRB / 
IEC / Competent Authorities
BI Trial No.:
1200.34
□
To be implemented immediately 
in order to eliminate hazard – IRB 
/ IEC / Competent Authority to be 
notified of change with request 
for approval
Investigational 
Product:
BIBW2992
□
Can be implemented without IRB 
/ IEC / Competent Authority
approval as changes involve 
logistical or administrative 
aspects only
Title:
LUX-Lung6; A randomised, open-label, phase III study of BIBW 2992 
versus chemotherapy as first-line treatment for patients with stage IIIB or 
IV adenocarcinoma of the lung harbouring an EGFR activating mutation
Rationale for 
Amendment:
1.
Reschedule the trial procedures to reduce or omit unnecessary ECG,
ECHO/MUGA measurements, and clinic visit for on-going patients, 
since the available data of afatinib does not show any cardiotoxicity 
risk. 
2.
Define a timepoint for the termination of independent image review 
as the primary PFS analysis has already been performed.  
3.
Redefine the trial completion timeline to allow a flexible completion 
time point in the future based on regulatory authority requirements.
4.
Stop collecting follow-up biopsy sample and blood sample of EGFR 
mutation as the data is unlikely to be of additional value.
5.
Stop the collection of HRQOL data as sufficient long term data has 
already been collected.
6.
Update the latest information of afatinib from the IB and implement 
newly introduced procedures and SOPs according to the company 
procedural changes:
•
concomitant use of PgP inhibitors and inducers.
•
DILI related content and appendix.
•
management of keratitis.
•
adverse events considered “always serious”.
7.
Other administrative changes.
Page 1 of 38
Proprietary confidential information. 
2014 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


Boehringer Ingelheim
Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 2 of 38
TABLE OF CONTENTS
        Title Page .......................................................................................................................................1
TABLE OF CONTENT................................................................................................................2
Change 1:
Change of Trial Clinical Monitor........................................................................6
Reason for Change 1.................................................................................................................................6
Change 2:
Coordinator Investigator’s name.........................................................................6
Reason for Change 2.................................................................................................................................6
Change 3:
Synopsis: Trial site(s)............................................................................................6
Reason for Change 3.................................................................................................................................7
Change 4:
Flow Chart: Arm A (BIBW2992) ........................................................................7
Reason for Change 4.................................................................................................................................7
Change 5:
Flow Chart: Arm A (BIBW2992) ........................................................................7
Reason for Change 5.................................................................................................................................7
Change 6:
Flow Chart: Arm A (BIBW2992) ........................................................................8
Reason for Change 6.................................................................................................................................8
Change 7:
Flow Chart: Arm A (BIBW2992) ........................................................................8
Reason for Change 7.................................................................................................................................8
Change 8:
Flow Chart: Arm A (BIBW2992) ........................................................................8
Reason for Change 8.................................................................................................................................8
Change 9:
Flow Chart: Arm A (BIBW2992) ........................................................................9
Reason for Change 9.................................................................................................................................9
Change 10:
Flow Chart: Arm A (BIBW2992) ........................................................................9
Reason for Change 10...............................................................................................................................9
Change 11:
Flow Chart: Arm B (GEMCITABINE/CISPLATIN) .......................................9
Reason for Change 11...............................................................................................................................9
Change 12:
ABBREVIATIONS.............................................................................................10
Reason For Change 12............................................................................................................................10
Change 13:
Section 1.1 Pharmacology and toxicology profile.............................................10
Reason for Change 13.............................................................................................................................10
Change 14:
Section 1.4 BENEFIT - RISK ASSESSMENT .................................................10
Reason for Change 14.............................................................................................................................10
Change 15:
Section 3.1 OVERALL TRIAL DESIGN AND PLAN-DESCRIPTION.......11
Reason for Change 15.............................................................................................................................11
Change 16:
Section 3.1 OVERALL TRIAL DESIGN AND PLAN-DESCRIPTION.......11
Reason for Change 16.............................................................................................................................12


Boehringer Ingelheim
Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 3 of 38
Change 17:
Section 3.3 SELECTION OF TRIAL POPULATION ....................................12
Reason for Change 17.............................................................................................................................12
Change 18:
Section 3.3.1 Inclusion criteria...........................................................................12
Reason for Change 18.............................................................................................................................12
Change 19: Section 4.1.1    Identity of investigational product...............................................12
Reason for Change 19.............................................................................................................................13
Change 20:
Section 4.1.4.1    Selection and timing of doses for each patient .....................13
Reason for Change 20.............................................................................................................................13
Change 21:
Section 4.1.4.1 BIBW 2992 (Arm A)..................................................................13
Reason for Change 21.............................................................................................................................14
Change 22:
Section 4.1.6.1   Packaging, labelling and re-supply BIBW 2992 ...................14
Reason for change 22..............................................................................................................................14
Change 23:
Section 4.2.1 Rescue medication and additional treatments ...........................14
Reason for Change 23.............................................................................................................................14
Change 24:
Section 4.2.2 Restrictions....................................................................................15
Reason For Change 24............................................................................................................................16
Change 25: 
Section 4.3.1   TREATMENT COMPLIANCE BIBW 2992 (Arm A)............16
Reason for change 25..............................................................................................................................16
Change 26:
Section 4.4 MANAGEMENT OF ADVERSE EVENTS..................................16
Reason for Change 26.............................................................................................................................23
Change 27:
Section 5.1.3 Tumor assessment.........................................................................23
Reason for Change 27.............................................................................................................................23
Change 28:
Section 5.1.4 Central imaging ............................................................................24
Reason for Change 28.............................................................................................................................24
Change 29:
Section 5.1.5 Health-Related Quality Of Life ...................................................24
Reason for Change 29.............................................................................................................................24
Change 30:
Section 5.2.1 Adverse Events..............................................................................24
Reason for change 30..............................................................................................................................25
Change 31:
Section 5.2.6 ECG................................................................................................25
Reason for Change 31.............................................................................................................................25
Change 32:
Section 5.2.7 Left ventricular function..............................................................25
Reason for Change 32.............................................................................................................................25
Change 33:
Section 5.6.1 Methods and timing of sample collection ...................................26
Reason for Change 33.............................................................................................................................26
Change 34:
Section 5.6.1 Methods and timing of sample collection ...................................26
Reason for Change 34.............................................................................................................................26


Boehringer Ingelheim
Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 4 of 38
Change 35:
Section 6.1.2 Treatment......................................................................................26
Reason for Change 35.............................................................................................................................27
Change 36:
Section 6.1.4 Follow-up.......................................................................................27
Reason for Change 36.............................................................................................................................27
Change 37:
Section 6.1.5 Observation period.......................................................................27
Reason for Change 37.............................................................................................................................28
Change 38:
Section 6.2.1 EGFR mutation analysis..............................................................28
Reason for Change 38.............................................................................................................................28
Change 39:
Section 6.2.2.1 Treatment Arm A (BIBW2992)................................................28
Reason for Change 39.............................................................................................................................29
Change 40:
Section 6.2.3 End of trial and follow-up............................................................29
Reason for Change 40.............................................................................................................................30
Change 41:
Section 6.2.4   Follow-up (all patients)...............................................................30
Reason for change 41..............................................................................................................................30
Change 42:
Section 6.2.4 Follow-up (all patients).................................................................30
Reason for Change 42.............................................................................................................................31
Change 43:
Section 6.2.5 Observation period.......................................................................31
Reason for Change 43.............................................................................................................................31
Change 44:
Section 6.3.2 Removal of patients from trial.....................................................31
Reason for change 44..............................................................................................................................31
Change 45:
Section 7.3.2.1.2 Overall survival (OS)..............................................................32
Reason for Change 45.............................................................................................................................32
Change 46:
Section 8.4.1 Adverse events...............................................................................32
Reason for Change 46.............................................................................................................................32
Change 47:
Section 8.4.1 Adverse events...............................................................................32
Reason for Change 47.............................................................................................................................33
Change 48:
Section 8.9 COMPLETION OF TRIAL ...........................................................33
Reason for Change 48.............................................................................................................................34
Change 49:
APPENDIX 1.......................................................................................................34
Reason for change 49..............................................................................................................................34
Change 50:
APPENDIX 1.......................................................................................................34
Reason for change 50..............................................................................................................................35
Change 51:
APPENDIX 1.......................................................................................................35
Reason for change 51..............................................................................................................................35
Change 52:
Addition of new appendix...................................................................................35
Reason for Change 52.............................................................................................................................37


Boehringer Ingelheim
Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 5 of 38
Change 53:
Additon of new appendix....................................................................................37
Reason For Change 53............................................................................................................................38


Boehringer Ingelheim
Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 6 of 38
Change 1:
Change of Trial Clinical Monitor
Phone:
, Fax:
Was changed to:
Phone:
, Fax:
Reason for Change 1
change of trial clinical monitor
Change 2:
Coordinator Investigator’s name 
Was changed to:
Reason for Change 2
correct the format of the coordinator investigator’s name
Change 3:
Synopsis: Trial site(s)
Multi-centre trial in Asia (China, India and Korea）
Was changed to:
Multi-centre trial in Asia (China, Thailand and Korea）


Boehringer Ingelheim
Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 7 of 38
Reason for Change 3
Thailand replace India attended this trial
Change 4:
Flow Chart: Arm A (BIBW2992)
*** All courses are 3 weeks in duration (21 days). Patients may continue on treatment for 
unlimited courses, until the criteria for stopping medication are met (see Section 6.3.1).
***** All patients should have a follow-up visit 21 days after the EOT visit. Patients who 
have not progressed and not started further treatment should have further follow-up 
visits every 21 days until progression or start of further treatment.
Was changed to:
*** All courses are 3 weeks in duration (21 days). Following the second (primary) analysis 
of overall survival (see Section 7.3.2.1.2), the clinic visit of an on-treatment patient will 
be extended from every 3 weeks to every 9 weeks. Patients may continue on treatment 
for unlimited courses, until the criteria for stopping medication are met (see Section 
6.3.1).
***** All patients should have a follow-up visit 21 days after the EOT visit. Patients who 
have not progressed and not started further treatment should have further follow-up 
visits every 21 days until progression or start of further treatment, following the second 
(primary) analysis of overall survival (see Section 7.3.2.1.2), patients who have not 
progressed and not started further treatment should have further follow-up visits every 9 
weeks until progression or start of further treatment.
****** Following the second (primary) analysis of overall survival (see section 7.3.2.1.2), 
the collection of observation period data may be reduced in frequency as appropriate, as 
communicated by the Trial Clinical Monitor.
Reason for Change 4
To reduce the monitoring frequency to avoid the unnecessary clinical monitoring to patients 
with long time stable disease and good medication tolerance.
Change 5:
Flow Chart: Arm A (BIBW2992)
Was added to footnote5:
Following the second (primary) analysis of overall survival (see Section 7.3.2.1.2), ECG 
assessment will be performed as clinically indicated.
Reason for Change 5
ECG data has been collected and centrally assessed for at least 18 months for all randomised 
patients. Clinical trial data shows afatinib does not have an effect on QTc interval or other 


Boehringer Ingelheim
Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 8 of 38
ECG parameters, and therefore routine monitoring is no longer indicated. This is further 
supported by results from dedicated QTc trial. Patients who have been previously identified 
with abnormal findings will continue ECG assessment if investigator judges that it is 
clinically indicated. 
Change 6:
Flow Chart: Arm A (BIBW2992)
Was added to footnote 6:
Following the second (primary) analysis of overall survival (see Section 7.3.2.1.2), ECHO or 
MUGA will be performed only as clinically indicated.
Reason for Change 6
Available clinical trial data shows afatinib does not have an effect on LVEF, and therefore 
routine monitoring is no longer indicated.
Change 7:
Flow Chart: Arm A (BIBW2992)
Was added to footnote 8:
After approval of amendment 4, no further follow-up biopsy samples will be collected.
Reason for Change 7
Available data already collected has indicated that the collection of further samples is 
unlikely to be of additional value.
Change 8:
Flow Chart: Arm A (BIBW2992)
Was added to Footnote 9:
After approval of amendment 4, no further follow-up blood samples for EGFR mutation 
testing will be collected.
Reason for Change 8
Available data already collected has indicated that the collection of further samples is 
unlikely to be of additional value.


Boehringer Ingelheim
Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 9 of 38
Change 9:
Flow Chart: Arm A (BIBW2992)
Was added to footnote 12:
Following the second (primary) analysis of overall survival (see section 7.3.2.1.2), 
assessment will be performed every 18 weeks.
Reason for Change 9
Following the second (primary) analysis of overall survival, patients will have been on 
treatment for over 2 years and such frequent tumour assessment is no longer required now 
that the primary endpoint of PFS has been assessed.
Change 10:
Flow Chart: Arm A (BIBW2992)
Was added to footnote 15:
The assessment and collection of HRQOL data will be ceased after the second (primary) 
analysis of overall survival (see section 7.3.2.1.2).
Reason for Change 10
Sufficient long term HRQOL data will have been collected by the second (primary) analysis 
of OS; it is expected that there will only be 10-20 patients still being treated in the afatinib 
arm.
Change 11:
Flow Chart: Arm B (GEMCITABINE/CISPLATIN)
A new footnote will be added as follows:
***** added next to OP
***** Following the second (primary) analysis of overall survival (see section 7.3.2.1.2), the 
collection of observation period data may be reduced in frequency or stopped as appropriate, 
as decided and communicated by the Trial Clinical Monitor.
Reason for Change 11
To allow flexibility in collection of vital status data after the second (primary) analysis of 
overall survival.


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Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 10 of 38
Change 12:
ABBREVIATIONS
Was added:
DILI        Drug induced liver injury
MDR1     MultiDrug-Resistance Protein 1
Reason For Change 12
Addition of new abbreviations introduced by other changes
Change 13:
Section 1.1 Pharmacology and toxicology profile
Was added after paragraph 2:
Afatinib is a substrate of the P-gp transporter. Concomitant administration of the potent P-gp
inhibitor ritonavir did not relevantly change the exposure to 40 mg afatinib when taken
simultaneously with or 6 h after afatinib but increased the bioavailability of afatinib (single
dose of 20 mg) by 48% and 39% for AUC0-∞and Cmax when given 1 h before afatinib,
respectively. Pretreatment with the potent P-gp inducer rifampicin decreased the plasma
exposure of 40 mg afatinib by 34 % afatinib (AUC0-∞) and 22 % (Cmax), respectively.
Caution should be exercised when combining afatinib with potent P-gp modulators.
Reason for Change 13
Addition of latest clinical data on the concomitant use of PgP inhibitors and inducers
Change 14:
Section 1.4 BENEFIT - RISK ASSESSMENT
Was added after paragraph 4:
Although rare, a potential for drug-induced liver injury is under constant surveillance by
sponsors and regulators. Therefore, this study requires timely detection, evaluation, and
follow up of laboratory alterations of selected liver laboratory parameters to ensure patients’
safety.
Reason for Change 14
To be compliant to the new corporate standard for monitoring and assessment of drug –
induced liver injury.


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Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 11 of 38
Change 15:
Section 3.1 OVERALL TRIAL DESIGN AND PLAN-DESCRIPTION
The trial will be performed by investigators specialised in the treatment of lung cancer in 
Asia countries (China, India and Korea). It is estimated that approximately 1366 patients will 
be screened for the trial in order to find approximately 360 eligible patients.
Was changed to:
The trial will be performed by investigators specialised in the treatment of lung cancer in 
Asia countries (China, Thailand and Korea). It is estimated that approximately 1366 patients 
will be screened for the trial in order to find approximately 360 eligible patients.
Reason for Change 15
India was replaced by Thailand for patient recruitment. 
Change 16:
Section 3.1 OVERALL TRIAL DESIGN AND PLAN-DESCRIPTION
All patients will visit the investigator at regular intervals for assessment of safety parameters 
and adverse events as outlined in the flow chart. Assessments of response will be made at 6 
weeks, 12 weeks and every 6 weeks thereafter until progression or withdrawal for another 
reason. After week 48, assessment of response will be performed every 12 weeks until 
progression of withdrawal for another reason. Tumour response and progression will be
assessed using RECIST 1.1 (R09-0262) and assessment at the investigator site will be 
sufficient for decisions on continuation of treatment. An independent analysis of response 
will also be performed by a Central Imaging Unit (see Section 5.1.4) but this will not be used 
to make treatment decisions.
Was changed to:
All patients will visit the investigator at regular intervals for assessment of safety parameters 
and adverse events as outlined in the flow chart. Assessments of response will be made at 6 
weeks, 12 weeks and every 6 weeks thereafter until progression or withdrawal for another 
reason. After week 48, assessment of response will be performed every 12 weeks until 
progression or withdrawal for another reason. Following the second (primary) analysis of 
overall survival (see section 7.3.2.1.2), assessment will be performed every 18 weeks.
Tumour response and progression will be assessed using RECIST 1.1 (R09-0262) and 
assessment at the investigator site will be sufficient for decisions on continuation of 
treatment. An independent analysis of response will also be performed by a Central Imaging 
Unit (see Section 5.1.4) but this will not be used to make treatment decisions. After the 
second (primary) analysis of overall survival (see Section 7.3.2.1.2) images will no longer be 
sent to the central imaging unit for independent review.


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Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 12 of 38
Reason for Change 16
To change frequency of visits. Following the second (primary) analysis of overall survival, 
patients will have been on treatment for over 2 years and such frequent monitoring is no 
longer required. There is also no longer the requirement for central analysis of imaging as 
primary endpoint of PFS has been assessed.
Change 17:
Section 3.3 SELECTION OF TRIAL POPULATION
A log of all patients who have signed the informed consent form will be maintained in the 
ISF at the investigational site. The trial will be conducted in multiple centres in Asia (China, 
India and Korea). It is estimated that approximately 1366 patients will be screened in order to 
recruit approximately 360 eligible patients.
Was changed to:
A log of all patients who have signed the informed consent form will be maintained in the 
ISF at the investigational site. The trial will be conducted in multiple centres in Asia (China, 
Thailand and Korea). It is estimated that approximately 1366 patients will be screened in 
order to recruit approximately 360 eligible patients.
Reason for Change 17
India was replaced by Thailand for patient recruitment.
Change 18:
Section 3.3.1 Inclusion criteria
Patients are eligible for inclusion (enrolment) if they fulfill the following criteria
Was changed to:
Patients are eligible for inclusion (enrollment) if they fulfill the following criteria
Reason for Change 18
Typo is corrected.
Change 19: Section 4.1.1    Identity of investigational product
Substance (INN): BIBW 2992


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Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 13 of 38
Was added in section: Duration of use:  
Following the second (primary) analysis of overall survival (see Section 7.3.2.1.2), treatment 
will be divided into courses which are 9 weeks (63 days) in duration.
Reason for Change 19
Change in visit frequency.
Change 20:
Section 4.1.4.1    Selection and timing of doses for each patient
BIBW 2992 (ARM A)
For administrative purposes treatment will be divided into treatment courses, which are each 
3 weeks (21 days) in duration. Patients will take a single oral dose of 40mg BIBW 2992 each 
day for the first course (21 days).
Was changed to:
For administrative purposes treatment will be divided into treatment courses, which are each 
3 weeks (21 days) in duration. Following the second (primary) analysis of overall survival 
(see Section 7.3.2.1.2), treatment will be divided into courses which are 9 weeks (63 days) in 
duration. Patients will take a single oral dose of 40mg BIBW 2992 each day for the first 
course (21 days).
Reason for Change 20
Change in visit frequency
Change 21:
Section 4.1.4.1 BIBW 2992 (Arm A)
The medication should be taken at approximately the same time each day at least one hour 
before food intake and at least three hours after food intake. The tablet should be swallowed 
with a glass of water. BIBW 2992 tablets are film-coated and therefore should not be chewed 
or crushed, but may be administered via G-tube after dispersing the BIBW 2992 tablets 
according to the following procedure: Place the tablet into a glass containing 50 mL isotonic 
sodium chloride solution. Stir until the tablet is broken up into very fine particles (about 15 
minutes). Drink the suspension immediately or administer via a gastric tube. Rinse the glass 
with another 50 ml of isotonic sodium chloride solution and drink or administer the 
supplementary solution via the gastric-tube again (to pick up any drug remaining in the 
glass/gastric-tube).
Was changed to:


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Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 14 of 38
The medication should be taken at approximately the same time each day at least one hour 
before food intake and at least three hours after food intake. 
If dosing of whole tablets is not possible, afatinib tablets can also be dispersed in 
approximately 100 ml of non-carbonated drinking water. No other liquids should be used. 
The tablet should be dropped in the water, without crushing it, and occasionally stirred for up 
to 15 min until the tablet is broken up into very small particles. The dispersion should be 
drunk immediately. The glass should be rinsed with approximately 100 ml of water which 
should also be drunk. The dispersion can also be administered through a naso-gastric tube.
Reason for Change 21
To be compliant to new corporate standard description on administration of afatinib for 
patients unable to take whole tablets.
Change 22:
Section 4.1.6.1   Packaging, labelling and re-supply BIBW 2992
Was added at end of section:
After the second (primary) analysis of overall survival, patients may switch BIBW2992 from 
trial supplies to marketed product, an expanded-access program, named patient use program, 
or compassionate use protocol. This may mean a change in packaging and labelling. 
Reason for change 22
To ensure an on-going supply of BIBW2992 to patients who have not yet met the criteria for 
ceasing study treatment and to allow completion of the trial.
Change 23:
Section 4.2.1 Rescue medication and additional treatments
Was added after paragraph 4: 
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.
Reason for Change 23
Added additional guidance for management of keratitis according to the IB update.


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Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 15 of 38
Change 24: Section 4.2.2 Restrictions
BIBW 2992 is a substrate of P-gp and its plasma concentrations can be affected by the use of
P-gp inhibitors (data on file) and it is also likely that P-gp inducers could also influence
BIBW 2992 plasma concentrations. The use of potent P-gp inhibitors (including Cyclosporin,
Erythromycin, Ketoconazole, Itraconazole, Quinidine, Phenobarbital salt with Quinidine,
Ritonavir, Valspodar, Verapamil) and potent P-gp inducers (including St John's wort,
rifampicin) must be avoided during treatment with BIBW 2992. Any exemptions to this must
be discussed with the BI clinical monitor.
In any patient ongoing in the trial receiving BIBW 2992 and a concomitant potent P-gp
inhibitor or inducer at the time of amendment 1 being implemented, the decision for
continuation of either drug will be based on the individual circumstances of the patient upon
discussion with the responsible BI clinical monitor.
Was changed to:
Afatinib is a substrate of the P-gp transporter. Caution should be exercised when combining 
afatinib with P-gp modulators. For a list of potent P-gp inhibitors and inducers see Appendix
7
Patients who are not of childbearing potential due to being postmenopausal (1 year without 
menstruations and at least 2 years without menstruation following chemotherapy) (R11-1406) 
or surgical sterilisation (oophorectomy, hysterectomy and/or tubal ligation) do not need to 
use contraception to be eligible for the trial.
All other patients are considered to have childbearing potential and must use adequate 
contraception throughout the trial (from screening until end of trial participation or 28 days 
after last dose of trial medication, whichever is later).
Acceptable methods of contraception include surgical sterilisation and double barrier method, 
and must be in accordance with local regulations where applicable. Double barrier method of 
contraception is defined as two barrier methods used simultaneously each time the patient has 
intercourse. Accepted barrier methods include diaphragm, female condom, cervical cap, male 
condom and intrauterine device (UID) (the diaphragm and cervical cap must be used in 
conjunction with spermicidal jelly/cream). Those using hormonal contraceptives, or with 
partners using hormonal contraceptives, must also be using an additional approved method of 
contraception (as described above).  Partner vasectomy, natural "rhythm" and spermicidal 
jelly/cream are not acceptable methods of contraception.
Women who become pregnant while participating in the study must discontinue study 
medication immediately.  The pregnancy must be reported following procedures detailed in 
section 5.2.2.3


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 16 of 38
Reason For Change 24
Update to incorporate latest guidance on the use of concomitant medications.
Change 25:
Section 4.3.1   TREATMENT COMPLIANCE BIBW 2992 (Arm A)
…. At the end of each course remaining medication should be collected. If the patient is 
eligible for a further course of treatment a new bottle should be dispensed.
Was changed to:
…. At the end of each course remaining medication should be collected. If the patient is 
eligible for a further course of treatment a new bottle/new bottles should be dispensed.
Reason for change 25
As courses will change to 9 weekly after the second (primary) analysis of overall survival, 3 
bottles of medication will need to be dispensed to patient.
Change 26:
Section 4.4 MANAGEMENT OF ADVERSE EVENTS
4.4.1
Management of diarrhoea following treatment with BIBW 2992 (Arm A)
Close monitoring and proactive management of diarrhoea is essential for successful treatment 
of patients with BIBW 2992. Early and appropriate intervention can prevent the development 
of more severe diarrhoea. In most cases, loperamide controls diarrhoea caused by BIBW 
2992. Loperamide should be available at the start of therapy and kept with the patient at all 
times; it is therefore advisable that patients be given a prescription at the time of initiating 
treatment with BIBW 2992.
The recommendations for management are as follows:
•
If any diarrhoea is experienced (CTCAE Grade 1), two 2 mg loperamide tablets 
should be taken immediately, followed by one 2 mg tablet with every loose bowel 
movement, up to a maximum daily dose of 10 tablets (20 mg).
•
In the event of diarrhoea patients should be advised to avoid lactose-containing 
products or any foods known to aggravate diarrhoea.
•
Oral hydration is essential regardless of severity; appropriate rehydration (1.5 
l/m2/day plus equivalent of actual fluid loss) and electrolyte replacement has to be 
ensured in the event of CTCAE Grade 2 and Grade 3 adverse events.
•
For CTCAE Grade 3 diarrhoea or CTCAE Grade 2 diarrhoea lasting ≥ 2 days (48 
hours) despite adequate antidiarrhoeal treatment, BIBW 2992 must be paused until 
recovery to CTCAE ≤ Grade 1. Upon recovery, BIBW 2992 should be resumed at a 


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Final, 16 Oct 2013
BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 17 of 38
reduced dose according to the dose reduction scheme outlined in Section 4.1.4.1.1.
The occurrence of diarrhoea and the outcome of treatment will be recorded in the AE section 
of the CRF. Antidiarrhoeal treatments should be documented in the concomitant medication 
section of the CRF.
If despite optimal supportive care and a treatment pause, diarrhoea does not resolve to CTC 
Grade ≤1 within 14 days, the patient must not receive any further BIBW 2992 treatment and 
the end of treatment (EOT) visit should be performed.
4.4.2
Management of nausea and vomiting following treatment with BIBW 2992 (Arm 
A)
Nausea and vomiting may significantly affect patients’ adherence to the treatment and their 
quality of life. In order to reduce the occurrence and the intensity of emesis, the patients 
should be treated according to the recommendation given in Table 4.4.2:1.
Table 4.4.2:1 Management of nausea and vomiting
CTCAE Grade
Antiemetic treatment
Nausea = grade 0
and
Vomiting = grade 0
No antiemetic prophylactic treatment
Nausea = grade 1
and
Vomiting = grade 0
No antiemetic treatment
Nausea = grade 2
and
Vomiting = grade 0
Nausea = grade 0, 1 or 2
and
Vomiting = grade 1 or 2
Antiemetic treatment1
Pause BIBW 2992 treatment if grade 2 vomiting or 
grade 2 nausea persist for 7 or more consecutive 
days despite optimal supportive care. Resume 
treatment when CTCAE grade ≤ 1.
Vomiting ≥ grade 3
or 
Nausea ≥ grade 3
Antiemetic treatment1
Pause BIBW 2992 treatment until return to CTCAE 
grade ≤ 1 or baseline2.
1 
Antiemetic treatment should follow the recommendations given in the Consensus Statement of the Antiemetic 
Subcommittee of the Multinational Association of Supportive Care in cancer (MASCC): Prevention of chemotherapy-
and radiotherapy-induced emesis: Results of the Perugia Consensus Conference (R06-0986).
2 
Baseline is defined as the CTCAE grade at the start of treatment.
After a treatment pause the dose of BIBW 2992 should be reduced according to the dose 
reduction scheme in Table 4.1.4.1.1:1.


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 18 of 38
The occurrence of nausea and/or vomiting and the outcome of treatment will be recorded in 
the AE section of the CRF. Antiemetic treatments should be documented in the concomitant 
medication section of the CRF with the start and end of treatment dates and daily dose.
In case of nausea and/or vomiting ≥ CTCAE grade 2, appropriate hydration (1.5 L/m2/day 
plus hydration deficit) must be ensured.
4.4.3
Management of rash following treatment with BIBW 2992 (Arm A)
A proactive and early approach to management of rash is crucial. Rash can be managed by a 
variety of treatment options to relieve symptoms and reduce the rash.
The recommendations for management are as follows:
•
General/Prevention: strict sun protection; use of a sunscreen of Sun Protection Factor 
15 (SPF 15) or higher, preferably containing zinc oxide; use of a thick, alcohol-free 
emollient cream; avoid harsh detergents, avoid using a solarium.
•
CTCAE Grade 1 rash: mild rash may not need treatment. However, if treatment is 
considered necessary, topical hydrocortisone (1% or 2.5%) cream and/or clindamycin 
1% gel can be used.
•
CTCAE Grade 2 rash: relief from major symptoms caused by CTCAE Grade 2 skin-
related adverse events should be achieved by a combination of local and systemic 
therapies including:
1) Systemic antibiotics (doxycycline or minocycline etc.).
2) Topical treatment (hydrocortisone 2.5% cream, clindamycin 1% gel, pimecrolimus 
1% cream).
And / or
1) Antihistamines (diphenhydramine, etc.)
2) Oral prednisone (short term i.e., <14 days treatment) may be added at investigator’s 
discretion.
Systemic and topical treatment should be initiated at the start of CTCAE Grade 2 rash 
and continue until improvement or resolution to CTCAE Grade ≤1. If grade 2 rash 
persists for ≥ 7 days despite treatment and is poorly tolerated by the patient, the 
investigator may choose to pause treatment for up to 14 days followed by a reduction in 
the dose of BIBW 2992 according to the dose reduction scheme in Table 4.1.4.1.1:1.
•
CTCAE Grade 3 (or greater) rash: may be treated in a manner similar to CTCAE 
Grade 2 rash. In the event of CTCAE Grade ≥3 rash, treatment with BIBW 2992 should 
be paused until recovery to CTCAE Grade ≤1. Treatment should be resumed at a reduced 
dose (see Section 4.1.4.1). If CTCAE Grade ≥3 rash does not resolve to CTCAE Grade 
≤1 within 14 days of stopping BIBW 2992 treatment and despite optimal supportive care, 
the patient should not receive any further treatment with BIBW 2992 and the End of 
Treatment visit should be performed.
Was changed to:


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 19 of 38
Dermatologic adverse events and diarrhoea are the most common side-effects associated with 
treatment with afatinib. Treatment of these side-effects should be proactive and should be 
started as early as possible after onset of symptoms.
4.4.1 Management of diarrhoea and hydration status following treatment with afatinib
Diarrhoea occurs at a high frequency and generally begins within 2 weeks of exposure to 
afatinib. Although usually mild to moderate, diarrhoea may lead to dehydration and compel 
treatment modification or discontinuation, so early management is essential (Table 4.4.1: 1). 
At the time of initiation of treatment with afatinib patients should be given a supply of 
loperamide to keep with them at all times or access to loperamide should be confirmed; and 
patients should be counselled on the appropriate use. 
Patients must be advised to drink an adequate amount of fluids to make up for the fluid lost 
through diarrhoea. 
Table 4.4.1: 1 Grade specific treatment recommendations for afatinib related diarrhoea 
Severity 
(CTCAE Grading)
Description 
Intervention 
concerning afatinib
treatment
Specific intervention
Mild (Grade 1)
Increase of < 4 stools per 
day over baseline; mild 
increase in ostomy output 
compared with baseline
Continue same dose
Stop laxatives and advise 
patient to drink at least 8-10 
glasses of water of clear fluids 
per day;
4 mg (2 tablets) of loperamide 
to be taken immediately, 
followed by 2 mg (1 tablet) 
after each loose stool until 
bowel movements cease for 12 
hours
Moderate (Grade 2)
Increase of 4-6 stools per 
day over baseline; i.v. 
fluids indicated < 24 
hours; moderate increase 
in ostomy output 
compared with baseline; 
not interfering with ADL
Continue same dose 
unless Grade 2 
diarrhoea continues for
≥2 days (48 hours) in 
which case treatment 
must be interrupted 
until recovered to ≤
Grade 1 followed by 
dose reduction
Continue loperamide; 
assess for dehydration and 
electrolyte imbalance;
consider IV fluids and 
electrolyte replacement 
Severe (Grade 3) 
Increase of ≥7 stools per 
day over baseline; 
incontinence; IV fluids > 
24 hours; hospitalization; 
severe increase in ostomy 
output compared with 
baseline; interfering with 
ADL
Dose interruption until 
recovered to ≤Grade 1 
followed by dose 
reduction*
See Grade 2; plus:
an infectious process should be 
ruled out with stool cultures; 
aggressive iv fluid replacement 
≥ 24 hours; hospitalization to 
monitor progress;
consider prophylactic 
antibiotics if patient is also 
neutropenic; 
Life threatening 
Life-threatening 
consequences (e.g. 
Dose interruption until 
recovered to ≤Grade 1 
See Grade 3


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 20 of 38
(Grade 4)
haemodynamic collapse) 
followed by dose 
reduction*
* If despite optimal supportive care and a treatment interruption, diarrhoea does not resolve to CTC AE Grade ≤ 
1 within 14 days, treatment with afatinib must be permanently discontinued. In the event that the 
patient is deriving obvious clinical benefit according to the investigator’s judgement, further treatment 
with afatinib will be decided in agreement between the sponsor and the investigator.
4.4.2 Management recommendations for dermatological AEs following treatment with 
afatinib
Dermatologic AEs of afatinib include rash, acne, dermatitis acneiform, and dry skin. General 
recommendations for prophylaxis are summarized in Table 4.4.2: 1 and grade-specific 
treatment recommendations are summarized in Table 4.4.2: 2. For dose adjustment of afatinib 
refer to Table 4.1.4.1.1:1.  
Specific interventions should be reassessed at least after 2 weeks or at any worsening of 
symptoms, in which case the specific intervention should be adjusted and, depending on own 
clinical experience, early involvement of a dermatologist should be considered. (Adapted 
from R11-0826)
Table 4.4.2: 1  General recommendations for prophylaxis while receiving afatinib
Personal hygiene
Use of gentle soaps and shampoos for the body, e.g. pH5 neutral bath and 
shower formulations and tepid water.
Use of very mild shampoos for hair wash.
Only clean and smooth towels are recommended because of potential risk of 
infection. The skin should be patted dry after a shower, whereas rubbing the skin 
dry should be avoided.
Fine cotton clothes should be worn instead of synthetic material.
Shaving has to be done very carefully.
Manicure, i.e. cutting of nails, should be done straight across until the nails no 
longer extend over the fingers or toes. Cuticles are not allowed to be trimmed 
because this procedure increases the risk of nail bed infections
Sun protection
Sunscreen should be applied daily to exposed skin areas regardless of season. 
Hypoallergenic sunscreen with a high SPF (at least SPF30, PAPA free, 
UVA/UVB protection), preferably broad spectrum containing zinc oxide or 
titanium dioxide are recommended
Patients should be encouraged to consequently stay out of the sun.
Protective clothing for sun protection and wearing a hat should be recommended.
Moisturizer treatment
It is important to moisturize the skin as soon as anti-EGFR therapy is started.
Hypoallergenic moisturizing creams, ointments and emollients should be used 
once daily to smooth the skin and to prevent and alleviate skin dryness. 
Note: avoid greasy creams (e.g. petrolatum, soft paraffin, mineral oil based) and 
topical acne medications
Prevention of paronychia 
Patients should keep their hands dry and out of water if ever possible.
They should avoid friction and pressure on the nail fold as well as picking or 
manipulating the nail.
Topical application of petrolatum is recommended around the nails due to its 
lubricant and smoothing effect on the skin.
Table 4.4.2: 2 Grade specific treatment recommendations of skin reactions to afatinib


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 21 of 38
Severity 
(CTCAE Grading)
Description
Specific intervention
ACNEIFORM RASH
Mild (Grade 1)
Macular or papular eruptions or 
erythema without associated 
symptoms
Consider topical antibiotics, e.g. 
clindamycin 2% or topical erythromycin 1% 
cream of metronidazole 0.75% or topical 
nadifloxacin 1%;
Isolated scattered lesion: cream preferred
Multiple scattered areas: lotion preferred
Moderate (Grade 2)
Macular or papular eruptions with 
pruritus or other associated 
symptoms; localized desquamation 
or other lesions covering <50% of 
BSA 
Topical treatment as for Grade 1 
plus short term topical steroids, e.g. 
prednicarbate cream 0.02% plus
an oral antibiotic (for at least 2 weeks) e.g. 
Doxycycline 100mg b.i.d. or Minocycline 
hydrochloride 100mg b.i.d
Severe (Grade 3)
Severe, generalized erythroderma or 
macular, popular or vesicular 
eruption; desquamation covering ≥ 
50% of BSA; associated with pain, 
disfigurement, ulceration or 
desquamation
Topical and systemic treatment as for   
Grade 2.
Consider referral to dermatologist
Consider systemic steroids
Life threatening 
(Grade 4)
Generalized exfoliative, ulcerative, 
or bullous dermatitis
See Grade 3
Systemic steroids are recommended
EARLY AND LATE XEROTIC SKIN REACTIONS - PRURITUS
Mild (Grade 1)
Mild or localized
Topical polidocanol cream.
Consider oral antihistamines, e.g. 
diphenhydramine, dimethindene, cetirizine, 
levocetirizine, desloratidine, fexofenadine 
or clemastine)
Moderate (Grade 2)
Intense or widespread
See Grade 1 plus oral antihistamines;
Consider topical steroids, e.g. topical 
hydrocortisone
Severe (Grade 3)
Intense or widespread and interfering 
with activities of daily living (ADL)
See Grade 2.
XEROSIS (DRY SKIN)
Mild (Grade 1)
Asymptomatic
Soap-free shower gel and/or bath oil.
Avoid alcoholic solutions and soaps.
Urea- or glycerin-based moisturizer.
In inflammatory lesions consider topical 
steroids (e.g. hydrocortisone cream)
Moderate (Grade 2)
Symptomatic, not interfering with 
ADL
See Grade 1.
In inflammatory lesions consider topical 
steroids (e.g. hydrocortisone cream)
Severe (Grade 3)
Symptomatic,
interfering with ADL
See Grade 2.
Topical steroids of higher potency (e.g. 
prednicarbate, mometasone furoate)
Consider oral antibiotics
FISSURES


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 22 of 38
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.
1 If Grade 2 rash persists for ≥7 days despite treatment and is poorly tolerated by the patient, the investigator 
may choose to pause treatment up to 14 days followed by a reduction in the dose of afatinib according to the 
dose reduction scheme in Table 4.1.4.1.1:1
4.4.3
Management of mucositis/stomatitis
General and grade specific recommendations are described in Table 4.4.3:1. For dose 
adjustment refer to Section 4.1.4.1.1 and for restrictions on concomitant therapies refer to 
Sections 4.2.2 and 10.7.
Treatment is supportive and aimed at symptom control. These may include atraumatic 
cleansing and rinsing with non-alcoholic solutions such as normal saline, diluted salt and 
baking soda solution (e.g. one-half teaspoonful of salt and one teaspoon of baking soda in one 
quart of water every four hours); avoidance of agents containing iodine, thyme derivatives 
and prolonged use of hydrogen peroxide; dietary modification 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 4.4.3:1 include: topical analgesics –
viscous lidocaine 2%; mucosal coating agents - topical kaolin/pectin; oral antacids, 
maltodextrin, sucralfate; topical antifungals – nystatin suspension. (Adapted from P11-
09424)
Table 4.4.3: 1
Grade specific treatment recommendations of study-drug related 
mucositis/stomatitis 
Severity 
(CTCAE grading)
Description 
Treatment recommendations
Intervention concerning 
afatinib treatment/ dose 
modification
Mild (Grade 1)
Minimal 
symptoms; 
normal diet 
Oral rinses with agents such as non-
alcoholic mouth wash,  normal saline, 
diluted salt and baking soda solution .
No change .
Moderate (Grade 
2)
Symptomatic, but 
can eat and 
swallow 
modified diet
Addition of topical analgesic mouth 
treatments, topical corticosteroids, 
antiviral therapy if herpetic infection 
confirmed, antifungal therapy 
preferably topical on a case by case 
basis.
Maintain dose if tolerable; 
Hold dose if intolerable 
until recovery to grade ≤1, 
then restart at the same 
dose.


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Severe (Grade 3) 
Symptomatic and 
unable to 
adequately 
aliment or 
hydrate orally
Same as for Grade 2; institute 
additional symptomatic therapy (topical 
or systemic) as clinically indicated .
Hold dose until recovery to 
grade ≤1 or baseline, then 
restart at the reduced dose 
according to Section 4.1.4.
Life threatening 
(Grade 4)
Symptoms 
associated with 
life-threatening 
consequences 
Same as for Grade 2; institute 
additional symptomatic therapy (topical 
or systemic) as clinically indicated .
Hold dose until recovery to 
grade ≤1 or baseline, then 
restart at the reduced dose 
according to Section 4.1.4
Reason for Change 26
Update to incorporate latest guidance on the management of adverse events.
Change 27:
Section 5.1.3 Tumor assessment
One to five target lesions (not exceeding two lesions per organ) should be identified at 
screening by Computed Tomography (CT). Skin lesions should be measured and 
photographic documentation should be performed. Individual lesions detected at screening 
will be numbered and recorded in the CRF. These lesions should be followed up with the 
same method(s) used at screening and the same numbering should be applied. The size of the 
target lesions will be recorded in millimetres. The examinations should be performed at 
screening, after 6 weeks, after 12 weeks and every 6 weeks thereafter. After week 48, 
assessments should be performed every 12 weeks. If a patient develops an allergy to contrast 
media, MRI scans can be substituted for CT scans.
Was changed to:
One to five target lesions (not exceeding two lesions per organ) should be identified at 
screening by Computed Tomography (CT). Skin lesions should be measured and 
photographic documentation should be performed. Individual lesions detected at screening 
will be numbered and recorded in the CRF. These lesions should be followed up with the 
same method(s) used at screening and the same numbering should be applied. The size of the 
target lesions will be recorded in millimetres. The examinations should be performed at 
screening, after 6 weeks, after 12 weeks and every 6 weeks thereafter. After week 48, 
assessments should be performed every 12 weeks. Following the second (primary) analysis of 
overall survival (see Section 7.3.2.1.2), the assessments should be performed every 18 weeks. 
If a patient develops an allergy to contrast media, MRI scans can be substituted for CT scans.
Reason for Change 27
To modify the tumor assessment frequency according to the modified clinical visit following 
the second (primary) analysis of overall survival.  


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 24 of 38
Change 28:
Section 5.1.4 Central imaging
Was added after paragraph 4:
After the second (primary) analysis of overall survival (see Section 7.3.2.1.2) images will no 
longer be sent to the central imaging unit for independent review.
Reason for Change 28
The primary PFS analysis of independent data has already been performed and will be re-
analysed at the time of the second (primary) analysis of overall survival. Additional 
independent review data after this time will be of little value.  Investigator tumour response 
assessments will continue to be performed.
Change 29:
Section 5.1.5 Health-Related Quality Of Life
Was added at last:
The assessment of Health-Related Quality Of life (HRQOL) will be stopped after the second 
(primary) analysis of overall survival (see section 7.3.2.1.2).
Reason for Change 29
Sufficient long term HRQOL data will have been collected by the second (primary) analysis 
of OS; it is expected that there will only be 10-20 patients still being treated in the afatinib 
arm.
Change 30:
Section 5.2.1 Adverse Events
Was added at paragraph 6
Regular and continuing assessment of safety will be performed at least once per course 
during the first six courses and every three weeks thereafter….
Was changed to:
Regular and continuing assessment of safety will be performed at least once per course 
during the first six courses and every three weeks thereafter until after the second (primary) 
analysis of overall survival. After the second (primary) analysis of overall survival (see 
section 7.3.2.1.2), safety will be assessed at least every nine weeks unless an unscheduled 
visit is required for safety reasons.


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 25 of 38
Reason for change 30
Updated frequency of visits.
Change 31:
Section 5.2.6 ECG
A 12-lead resting ECG will be performed at the time points specified in the Flow Chart. 
ECGs will be performed using a digital ECG machine and the data will be sent to a central 
assessment centre for evaluation.
Was changed to:
A 12-lead resting ECG will be performed at the time points specified in the Flow Chart. 
ECGs will be performed using a digital ECG machine and the data will be sent to a central 
assessment centre for evaluation. Central evaluation of ECG data will end after the second 
(primary) analysis of overall survival (see section 7.3.2.1.2).
Reason for Change 31
Available clinical trial data shows afatinib does not have an effect on QTc interval or other 
ECG parameters, and therefore routine monitoring is no longer indicated. Patients who have 
been previously identified with abnormal findings will continue ECG assessment if 
investigator confirms that it is clinically indicated.
Change 32:
Section 5.2.7 Left ventricular function
Was added in paragraph 1:
After the second (primary) analysis of overall survival, the LVEF measurement would be 
performed only as clinical indicated.
Reason for Change 32
Available clinical trial data shows afatinib does not have an effect on LVEF, and therefore 
routine monitoring is no longer indicated. Patients who have been previously identified with 
abnormal findings will continue LVEF assessment if investigator confirms that it is clinically 
indicated.


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Change 33:
Section 5.6.1 Methods and timing of sample collection
During follow-up (after progression) a further blood sample and tissue sample for EGFR 
mutation analysis may be taken but are optional. The sample requirements are the same as 
those at screening.
Was changed to:
During follow-up (after progression) a further blood sample and tissue sample for EGFR 
mutation analysis may be taken but is optional. The sample requirements are the same as 
those at screening. After approval of amendment 4, no further follow-up tissue or blood
samples will be collected.
Reason for Change 33
Available data already collected has indicated that the collection of further samples is 
unlikely to be of additional value.
Change 34:
Section 5.6.1 Methods and timing of sample collection
If both L858R and a deletion in exon 19 are detected in the same sample, the patient will be 
allocated to the ‘L858R’ stratificatkion category.
Was changed to:
If both L858R and a deletion in exon 19 are detected in the same sample, the patient will be 
allocated to the ‘L858R’ stratification category.
Reason for Change 34
Typo is corrected.
Change 35:
Section 6.1.2 Treatment
Patients randomized to arm A (BIBW 2992) will receive continuous daily treatment until the 
criteria for stopping medication are met (see Section 6.3.1). For administrative purposes 
treatment is divided into courses, which are each 3 weeks (21 days) in duration.
Was changed to:
Patients randomized to arm A (BIBW 2992) will receive continuous daily treatment until the 
criteria for stopping medication are met (see Section 6.3.1). For administrative purposes 
treatment is divided into courses, which are each 3 weeks (21 days) in duration. After the 
second analysis of overall survival (see section 7.3.2.1.2), clinic visit for mandated 
assessments will be prolonged to each 9 weeks (63 days).


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 27 of 38
Reason for Change 35
To align with modified flowchart.
Change 36:
Section 6.1.4 Follow-up
Patients who have not progressed and not started further treatment at the first follow-up visit 
should have further follow-up visits every 21 days (± 7 days) until progression or start of 
further treatment.
Was changed to:
Patients who have not progressed and not started further treatment at the first follow-up visit 
should have further follow-up visits every 21 days (± 7 days) until progression or start of 
further treatment. After the second (primary) analysis of overall survival, Patients who have 
not progressed and not started further treatment should have further follow-up visits every 9 
weeks (± 7 days) until progression or start of further treatment.
Reason for Change 36
To align with modified flowchart.
Change 37:
Section 6.1.5 Observation period
After completion of the study patients will enter an observation period. During the 
observation period no study visits will be performed, but data regarding progression, further 
treatment (including best response and reason for stopping treatment) and death will be 
collected every 60 days (± 15 days) until death. Information will be collected from the patient 
notes or by telephone contact with the patient.
Was changed to:
After completion of the study patients will enter an observation period. During the 
observation period no study visits will be performed, but data regarding progression, further 
treatment (including best response and reason for stopping treatment) and death will be 
collected every 60 days (± 15 days) until death. Information will be collected from the patient 
notes or by telephone contact with the patient. Following the second (primary) analysis of 
overall survival (see section 7.3.2.1.2), the collection of observation period data may be 
reduced in frequency or stopped as appropriate, as communicated by the Trial Clinical 
Monitor.


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 28 of 38
Reason for Change 37
To allow flexibility in collection of vital status data after the second (primary) analysis of 
overall survival.
Change 38:
Section 6.2.1 EGFR mutation analysis
During follow-up (after progression) a further blood sample and tissue sample for EGFR
mutation analysis may be taken but are optional. The sample requirements are the same as
those at screening.
Was changed to:
During follow-up (after progression) a further blood sample and tissue sample for EGFR
mutation analysis may be taken but are optional. The sample requirements are the same as
those at screening. After approval of amendment 4, no further follow-up tissue or blood
samples will be collected.
Reason for Change 38
Available data already collected has indicated that the collection of further samples is 
unlikely to be of additional value. Therefore, this change has been implemented to prevent 
ongoing patients from being exposed to unnecessary procedures.  
Change 39:
Section 6.2.2.1 Treatment Arm A (BIBW2992)
HRQOL
Ask patient to complete HRQOL questionnaires prior to any 
other assessments or discussions.
ECG
12-lead resting ECG will be performed on day 1 of every 
third course (C4V1, C7V1, C10V1 etc.).
ECHO/MUGA
Cardiac left ventricular function assessment by either ECHO 
or MUGA will be performed on day 1 of every third course
(C4V1, C7V1, C10V1 etc.). 
Was changed to:
HRQOL
Ask patient to complete HRQOL questionnaires prior to any 
other assessments or discussions. After the second (primary) 
analysis of overall survival, this is no longer required.
ECG
12-lead resting ECG will be performed on day 1 of every 
third course (C4V1, C7V1, C10V1 etc.). After the second 
(primary) analysis of overall survival, ECG assessment will 
be performed as clinically indicated.
ECHO/MUGA
Cardiac left ventricular function assessment by either ECHO 


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 29 of 38
or MUGA will be performed on day 1 of every third course
(C4V1, C7V1, C10V1 etc.). After the second (primary) 
analysis of overall survival, ECHO or MUGA will be 
performed only as clinically indicated.
Reason for Change 39
To align with modified flowchart.
Change 40:
Section 6.2.3 End of trial and follow-up
HRQOL
Ask patient to complete HRQOL questionnaires prior to any other 
assessments or discussions.
ECG
Arm A (BIBW 2992); A12-lead resting ECG will be performed if not 
performed in the previous 8 weeks.
Arm B (Gemcitabine/Cisplatin); A12-lead resting ECG will be 
performed if clinically indicated.
ECHO/MUGA
Arm A (BIBW 2992); Cardiac left ventricular function assessment by 
either ECHO or MUGA will be performed if not performed in the 
previous 8 weeks.
Arm B (Gemcitabine/Cisplatin); Cardiac left ventricular function 
assessment by either ECHO or MUGA will be performed if clinically 
indicated.
Was changed to:
HRQOL
Ask patient to complete HRQOL questionnaires prior to any other 
assessments or discussions. After the second (primary) analysis of 
overall survival, this is no longer required.
ECG
Arm A (BIBW 2992); A12-lead resting ECG will be performed if not 
performed in the previous 8 weeks. After the second (primary) 
analysis of overall survival, ECG assessment will be performed as 
clinically indicated.
Arm B (Gemcitabine/Cisplatin); A12-lead resting ECG will be 
performed if clinically indicated.
ECHO/MUGA
Arm A (BIBW 2992); Cardiac left ventricular function assessment by 
either ECHO or MUGA will be performed if not performed in the 
previous 8 weeks. After the second (primary) analysis of overall 
survival, ECHO or MUGA will be performed only as clinically 
indicated.
Arm B (Gemcitabine/Cisplatin); Cardiac left ventricular function 
assessment by either ECHO or MUGA will be performed if clinically 
indicated.


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 30 of 38
Reason for Change 40
To align with modified flowchart.
Change 41:
Section 6.2.4   Follow-up (all patients)
If patient has not progressed at FU1, perform further follow-up visits every 21 days (+/- 7 
days) until progression or start of further treatment (FU2, FU3, FU4 etc.)
Was changed to:
If patient has not progressed at FU1, perform further follow-up visits every 21 days (+/- 7 
days) until progression or start of further treatment (FU2, FU3, FU4 etc.)
After the second (primary) analysis of overall survival, if patient has not progressed at FU1, 
perform further follow-up visits every 9 weeks (63 days) +/- 7 days until progression or start 
of further treatment (FU2, FU3, FU4 etc.)
Reason for change 41
Change in frequency of visits.
Change 42:
Section 6.2.4 Follow-up (all patients)
HRQOL
Ask patient to complete HRQOL questionnaires prior to any other 
assessments or discussions.
ECOG
ECOG performance status will be assessed and documented. 
Serum sample for 
EGFR mutation 
analysis
An optional serum sample for analysis of EGFR mutation status may 
be collected at Follow-up 1
Tumour biopsy 
for EGFR 
mutation analysis
An optional tumour biopsy for analysis of EGFR mutation status may 
be collected during the Follow-up phase.
Was changed to:
HRQOL
Ask patient to complete HRQOL questionnaires prior to any other 
assessments or discussions. After the second (primary) analysis of 
overall survival, this is no longer required.
ECOG
ECOG performance status will be assessed and documented. After
the second (primary) analysis of overall survival, ECG will be 
performed only as clinically indicated.
Serum sample for 
EGFR mutation 
analysis
An optional serum sample for analysis of EGFR mutation status may 
be collected at Follow-up 1. After approval of amendment 4, no 
further serum samples will be collected.
Tumour biopsy 
An optional tumour biopsy for analysis of EGFR mutation status may 


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 31 of 38
for EGFR 
mutation analysis
be collected during the Follow-up phase. After approval of 
amendment 4, no further biopsy samples will be collected.
Reason for Change 42
To align with modified flowchart and omit unnecessary procedures.
Change 43:
Section 6.2.5 Observation period
Observation period
Collect data every 60 days (± 15 days) after last follow-up visit. A formal study visit is 
not required; data should be collected from patient notes or by telephone.
Was changed to:
Observation period
Collect data every 60 days (± 15 days) after last follow-up visit. A formal study visit is 
not required; data should be collected from patient notes or by telephone. Following the 
second analysis of overall survival (see section 7.3.2.1.2), the collection of observation 
period data may be reduced in frequency, as communicated by the Trial Clinical Monitor.
Reason for Change 43
To allow flexibility in collection of vital status data after the second analysis of overall 
survival.
Change 44:
Section 6.3.2 Removal of patients from trial
Was added at end of section:
The sponsor may remove patients from the study, after the second (primary) analysis of 
overall survival, if the patient has access to BIBW2992 through marketed product, an 
expanded-access program, named patient use program, or compassionate use protocol. If a 
patient is removed from the study as communicated by TCM, an end of treatment and follow 
up 1 visit will need to be performed to ensure all adverse events are followed up. No 
observational visits will be required.
The cost of any on-going supply of BIBW2992 will be incurred by the Sponsor.
Reason for change 44
To ensure an on-going supply of BIBW2992 to patients who have not yet met the criteria for 
ceasing study treatment and to allow completion of the trial


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Change 45:
Section 7.3.2.1.2 Overall survival (OS)
OS will be analyzed twice. The first analysis will be performed at the time of the primary 
PFS analysis.  A second analysis will be performed somewhat later with the aim of providing 
as much information as possible on OS.  With 330 patients randomised over a period of 9-10
months and a median time to death of 20 months (HR= 1.0), approximately 219 deaths would 
be expected within 36 months.
Was changed to:
OS will be analyzed twice. The first analysis will be performed at the time of the primary
PFS analysis.  A second (primary) analysis will be performed somewhat later with the aim of 
providing as much information as possible on OS.  With 360 patients randomised over a 
period of 9-10 months and a median time to death of 20 months (HR= 1.0), approximately 
237 deaths would be expected within 36 months.
Reason for Change 45
Section updated in line with increase in sample size implemented in the protocol amendment 
3.
Change 46:
Section 8.4.1 Adverse events
Was added after paragraph 3:
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non serious 
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the event. If the event description is correct, the item 
“serious” needs to be ticked and an SAE has to be reported in expedited fashion following the 
same procedure as above. The list of these adverse events can be found via the RDC-system.
Reason for Change 46
To be compliant to new corporate standard for events considered “always serious”.
Change 47:
Section 8.4.1 Adverse events
There are no events defined as 'significant' for this study. All events will be categorised as 
either Adverse Event (AE) or Serious Adverse Event (SAE).


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Was replaced with:
Protocol-specified significant events
Although rare, drug-induced liver injury is under constant surveillance by sponsors and
regulators and is considered a protocol-specified significant adverse event. 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 is
important for patient safety. The following are considered as Protocol-specified significant
events:
Hepatic injury defined by the following alterations of liver parameters:
o
For patients with normal liver function (ALT, AST and 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. 
Patients showing these lab abnormalities need to be followed up according to 
section 10.6 of this clinical trial protocol and the “DILI checklist” provided in the 
ISF.
o
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. Patients showing these lab abnormalities need to 
be followed up according to section 10.6 of this clinical trial protocol and the 
“DILI checklist” provided in the ISF.
Protocol-specified significant events are to be reported in an expedited manner similar to
Serious Adverse Events, even if they do not meet any of the seriousness criteria.
If the investigator determines any protocol-specific significant event is related to study drug,
the administration of the study drug must be managed according to section 4.1.4 of the
protocol.
Reason for Change 47
To be compliant to new corporate standard for monitoring and assessment of drug induced
liver injury.
Change 48:
Section 8.9 COMPLETION OF TRIAL
The trial will be considered complete when the last patient completes the last follow-up visit.
Was changed to:
The trial will be considered complete when the last patient completes the last follow-up visit. 
An earlier trial completion may occur if BIBW2992 is approved and available locally, 


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 34 of 38
whereby patients still taking trial medication will be switched to marketed product and 
complete the trial. Such a scenario will only take place if adequate trial data has been 
collected for analysis.  
After mandatory follow-up visits required for each patient’s trial completion, each patient 
will enter the observation period.  The observation period of the trial will end after all 
patients have died or five years after the last follow-up visit, whichever occurs first. 
However, the observation period may end earlier depending upon the timing of analyses 
requested by regulatory authorities or communicated by TCM.
Reason for Change 48
To be consistent with section 6.1.5, and allow trial termination when the trial drug is 
approved by local authority and trial data is adequate for analysis.
Change 49:
APPENDIX 1
Arm A (BIBW2992)
Continuous daily treatment until progression or other criteria for stopping medication. 
Treatment is divided into 21-day courses for administrative purposes.
Was changed to:
Continuous daily treatment until progression or other criteria for stopping medication.  
Treatment is divided into 21-day courses for administrative purposes. After the second 
(primary) analysis of overall survival, treatment is divided into 9 week (63 day) courses for 
administrative purposes.
Reason for change 49
Change in visit frequency.
Change 50:
APPENDIX 1
Follow up visits
Every 21 days until progression or start of further treatment.
Was changed to:
Every 21 days until progression or start of further treatment. After the second (primary) 
analysis of overall survival, every 9 weeks (63 days) until progression or start of further 
treatment.


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 35 of 38
Reason for change 50
Change in visit frequency.
Change 51:
APPENDIX 1
Was added:
* added next to “Every 12 weeks after week 48”
* After the second (primary) analysis of overall survival, imaging will be performed every 18 
weeks.
Reason for change 51
Change in frequency of imaging.
Change 52:
Addition of new appendix
10.6     APPENDIX 6 Clinical Evaluation of Liver Injury
10.6.1 Introduction
Alterations of liver laboratory parameters, as described in section 8.4.1 (Protocol-specified 
Significant Events), are to be further evaluated using the following procedures:
10.6.2 Procedures
Any elevation of ALT/AST and bilirubin qualifying as laboratory alert should be confirmed 
using the initial sample if possible. 
If the alert is confirmed on initial sample, or it is not possible to repeat testing using initial 
sample, the following must be completed;
1) Evaluate the patient within 48 hours and,
2) Perform the following laboratory tests:
1. Repeat of AST, ALT, bilirubin (with fractionation to total and direct)
2. Haptoglobin
3. Complete blood count and cell morphology
4. Reticulocyte count
5. CK
6. LDH
7. Alkaline Phosphatase


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 36 of 38
The results of these laboratory tests must be reported to BI as soon as possible. 
If the initial alert values (ie AST,ALT, and bilirubin) are confirmed on the second sample 
described as above, then an abdominal ultrasound or clinically appropriate alternate imaging 
(to rule out biliary tract, pancreatic or intrahepatic pathology, e.g. bile duct stones or 
neoplasm) must be completed within 48 hours. 
The findings from the hepatic imaging (including comparison to prior imaging if available) 
must be made available as soon as possible as part of the adverse event reporting process. In 
the event the etiology of the abnormal liver tests results is not identified based on the imaging 
(e.g. biliary tract, pancreatic or intrahepatic pathology), then the “DILI checklist” must be 
completed. Details of the “DILI checklist” are provided in the ISF. The following 
assessments need to be performed in order to complete the “DILI checklist”. Any resulting 
diagnoses will be reported via the eCRF:
o
obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF;
o
obtain history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets according to the “DILI checklist” provided in the ISF;
o
obtain a history of exposure to environmental chemical agents (consider home and 
work place exposure) according to the “DILI checklist” provided in the ISF;
o
complete the following laboratory tests as detailed in the DILI checklist provided in 
the ISF: 

Clinical chemistry 
alkaline phosphatase, cholinesterase (serum)*, albumin, PT or INR, CK,
CK-MB, coeruloplasmin*, α-1 antitrypsin*, transferrin*, amylase, lipase, 
fasting glucose, cholesterol, triglycerides

Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs,DNA), 
Hepatitis C (Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-
IgM, Anti-IgG), Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti-
HEV IgM positive), Anti-Smooth Muscle antibody (titer), Antinuclear
antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-
mitochondrial antibody, Epstein Barr Virus (VCA IgG, VCA IgM),
cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, IgM)*, varicella
(IgG, IgM)*, parvovirus (IgG, IgM)*

Hormones, tumormarker
Thyroid-stimulating hormone(TSH)*

Haematology
Thrombocytes, eosinophils
*If clinically indicated (e.g immunocompromised patients) 


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 37 of 38
Long term follow-up
o
Initiate close observation of subjects by repeat testing of ALT, AST, and bilirubin 
(with fractionation to total and direct) at least weekly until the laboratory ALT and or 
AST abnormalities stabilize or return to normal, then according to the protocol. 
Depending on further laboratory changes, additional parameters identified e.g. by 
reflex testing will be followed up based on medical judgement and Good Clinical 
Practices (GCP).
Report any resulting diagnoses via the eCRF.
Reason for Change 52
To be compliant to new corporate standard for monitoring and assessment of drug induced
liver injury.
Change 53:
Additon of new appendix
10.7     APPENDIX 7 List of potent inhibitors and inducers of PGP
List of potent inhibitors and inducers of P-glycoprotein (MDR1)
Inhibitors
Inducers
Amiodarone
Azithromycin
Captopril
Carvedilol
Clarithromycin
Conivaptan
Cyclosporine
Diltiazem
Dronedarone
Erythromycin
Felodipine
Itraconazole
Ketoconazole
Lopinavir
Nelfinavir
Ritonavir
Quinidine
Ranolazine
Saquinavir
Tacrolimus
Ticagrelor
Verapamil
Carbamazepine
Phenytoin
Rifampicin
St John’s Wort
Phenobarbital Salt
Tipranavir
Ritonavir


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BI Trial No.: 1200.34 Protocol amendment 4                                                                Page 38 of 38
As the information on potent inhibitors and inducers of P-glycoprotein may evolve, it is 
important for the investigator to assess such status on concomitant therapies and in case of 
questions contact BI clinical monitor.
Reason For Change 53
Addition of latest guidance on the concomitant use of P-gp inhibitors and inducers.

SAP_001.pdf: 
 
SIGNATURE INFORMATION 
 
Document: 
                               
                           
Document No.:                                                                                                                        
 
Title 
                             
 
 
 
 
 
 
                         
 
SIGNATURES  (ELECTRONICALLY OBTAINED)  
 
Meaning of Signature: 
Signed by: 
Date signed: (GMT) 
                                   
 
 
 
                             
                                                                            
                                   
 
 
 
                             
                                                                            
                                   
 
 
 
                             
                                                                            
                                   
 
 
 
                             
                                                                            
                                   
 
 
 
                               
                                                                            
                                  
 
 
 
                               
                                                                                                                     
                                   
 
 
 
                               
                                                                                                                       
1200-0034--tsap-revision-1
T12-1008-02
LUX-Lung 6; A randomised, open-label, phase III study of BIBW 2992
versus chemotherapy as first-line treatment for patients with stage IIIB or
IV adenocarcinoma of the lung harbouring an EGFR activating mutation
Author-Trial Clinical
Pharmacokineticist
12/5/2012 13:11:25
Author-Trial Clinical Monitor
12/5/2012 13:20:13
Approval-Project Statistician
12/5/2012 13:22:25
Author-Trial Medical Writer
12/5/2012 13:52:00
Author-Trial Statistician
12/5/2012 14:45:47


 
SIGNATURE INFORMATION (continued) 
Document 
                              
                          
Document No.:                                                                                                                        
 
Title 
                             
 
 
 
 
 
 
                         
SIGNATURES  (ELECTRONICALLY OBTAINED)  
(There are no entries on this page if there are up to seven signatures.) 
Meaning of Signature: 
Signed by: 
Date signed: (GMT) 
                                   
 
 
 
                               
                                                                                                                      
                                   
 
 
 
                               
                                                                                                                      
                                   
 
 
 
                               
                                                                                                                      
                                     
 
 
 
                                 
                                                                                                                      
                                     
 
 
                                 
                                                                                                                      
                                     
 
 
                               
                                                                                                                       
                                     
 
 
                                
                                                                                                                       
                                     
 
 
                                 
                                                                                                                     
 
1200-0034--tsap-revision-1
T12-1008-02
LUX-Lung 6; A randomised, open-label, phase III study of BIBW 2992
versus chemotherapy as first-line treatment for patients with stage IIIB or
IV adenocarcinoma of the lung harbouring an EGFR activating mutation


 
TITLE PAGE 
Trial Statistical Analysis Plan  
T12-1008-02 
BI Trial No.: 
1200.34 
Title: 
LUX-Lung 6; A randomised, open-label, phase III study of BIBW 
2992 versus chemotherapy as first-line treatment for patients with 
stage IIIB or IV adenocarcinoma of the lung harbouring an EGFR 
activating mutation 
Including protocol amendments 1 [U10-3034-01-AM1], 2 [U10-
3034-01-AM2] and 3 [U10-3034-01-AM3]. 
Investigational 
Product: 
BIBW 2992 
Responsible trial 
statistician: 
Tel:
Fax:
Date of statistical 
analysis plan: 
05 December 2012 Revised 
Version: 
Revised 
Page 1 of 32
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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. 
 
 
 


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1. 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................... 1 
1. 
TABLE OF CONTENTS ...................................................................... 2 
LIST OF TABLES .............................................................................................. 4 
2. 
LIST OF ABBREVIATIONS ............................................................... 5 
3. 
INTRODUCTION .................................................................................. 7 
4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ...... 8 
5. 
ENDPOINTS .......................................................................................... 9 
5.1 
PRIMARY ENDPOINT ...................................................................................... 9 
5.2 
SECONDARY ENDPOINTS .............................................................................. 9 
5.2.1 
Key secondary endpoints ................................................................................ 9 
5.2.2 
Other secondary endpoints ............................................................................. 9 
................................................................................. 9 
................................................................................. 9 
6. 
GENERAL ANALYSIS DEFINITIONS ........................................... 10 
6.1 
TREATMENTS .................................................................................................. 10 
6.2 
IMPORTANT PROTOCOL VIOLATIONS .................................................. 10 
6.3 
PATIENT SETS ANALYSED .......................................................................... 13 
.................................................................................................... 13 
6.5 
POOLING OF CENTRES ................................................................................ 14 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS ................................... 14 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS .................. 14 
7. 
PLANNED ANALYSIS ....................................................................... 16 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ........ 16 
7.2 
CONCOMITANT DISEASES AND MEDICATION .................................... 16 
7.3 
TREATMENT COMPLIANCE ....................................................................... 17 
7.4 
PRIMARY ENDPOINT .................................................................................... 17 
7.5 
SECONDARY ENDPOINTS ............................................................................ 20 
7.5.1 
Key secondary endpoints .............................................................................. 21 
7.5.1.1 
Best RECIST tumour assessment ............................................................... 21 
7.5.1.2 
Overall survival .......................................................................................... 22 
7.5.2 
Other secondary endpoints ........................................................................... 23 
7.5.2.1 
Tumour shrinkage ....................................................................................... 23 
7.5.2.2 
Body weight ................................................................................................ 23 
7.5.2.3 
ECOG performance status .......................................................................... 23 
7.5.2.4 
Health-related quality of life ....................................................................... 24 
................................................................................ 25 
7.7 
EXTENT OF EXPOSURE ................................................................................ 25 
7.8 
SAFETY ANALYSIS ......................................................................................... 26 
7.8.1 
Adverse events ............................................................................................... 26 
7.8.2 
Laboratory data ............................................................................................. 28 
7.8.3 
Vital signs ....................................................................................................... 28 
7.8.4 
ECG ................................................................................................................ 28 
7.8.5 
Others ............................................................................................................. 28 


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8. 
REFERENCES ..................................................................................... 30 
................................................................ 31 
10. 
HISTORY TABLE ............................................................................... 32 
 


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LIST OF TABLES 
 
Table 6.2: 1 
Important protocol violations .......................................................................... 10 
Table 7.4: 1 
Rules to determine events and censoring for PFS ........................................... 18 
Table 10: 1 
History table .................................................................................................... 32 
 
 


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2. 
LIST OF ABBREVIATIONS 
Term 
Definition / description 
AE 
Adverse event 
ANCOVA 
Analysis of Covariance 
AUC 
Area under the curve 
BRPM 
Blinded Report Planning Meeting 
CI 
Confidence interval 
CR 
Complete Response 
CTC 
Common Terminology Criteria 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
Epidermal Growth Factor Receptor 
EMA 
European Medicines Agency 
EORTC 
European Organisation for Research and Treatment of Cancer 
FAS 
Full analysis set 
GFR 
Glomerular filtration rate 
HRQOL 
Health-Related Quality of Life 
ICH 
International Conference on Harmonisation 
IPV 
Important Protocol Violation 
LOCF 
Last observation carried forward 
LVEF 
Left Ventricular Ejection Fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MQRM 
Medical Quality Review Meeting 
NE 
Not Evaluable 
NN 
Non-CR/Non-PD 
O*C 
Oracle Clinical 
OS 
Overall Survival 
PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
PPS 
Per protocol set 
PR 
Partial Response 


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Term 
Definition / description 
PT 
Preferred term 
Q1 
Lower quartile 
Q3 
Upper quartile 
QLQ 
Quality of Life Questionnaire 
RECIST 
Response Evaluation Criteria in Solid Tumours 
SA 
Statistical analysis 
StD 
Standard deviation 
SD 
Stable Disease 
SOC 
System Organ Class 
TOC 
Table of contents 
TSAP 
Trial statistical analysis plan 
 


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3. 
INTRODUCTION 
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data. 
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP), including Protocol Amendments. In particular, the TSAP is based on the 
planned analysis specification as written in CTP Section 7 “Statistical Methods and 
Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, 
randomization.” 
SAS® Version 9.2 will be used for all analyses. 


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4. 
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY 
The following changes to those statistical methods described in the CTP and its subsequent 
amendments were made: 
• The CTP describes that the effect of Afatinib on PFS compared with standard 
chemotherapy will be tested at the one-sided, 0.025 significance level.  This is identical to 
the effect of Afatinib being tested at the more commonly used two-sided, 0.05 (5%) 
significance level if the treatment effect is in favour of Afatinib.  In order to aid in the 
interpretation of this study two-sided p-values will therefore be presented throughout. 
• Further details to those given in the CTP have been provided for the timing of the 
statistical analyses; refer to Section 7 for further details. 
• An additional row (3d) was added to the Table 7.4: 1 to cover a scenario that had not been 
considered at the time of writing the CTP. 
• The CTP specifies that patients who are randomised but never receive randomised 
treatment will be censored on the day of randomisation, for both PFS and overall survival 
(OS) analyses.  In order to handle all randomised patients the same, irrespective of 
whether they received randomised treatment or not, the above censoring rule will not be 
considered.  Refer to Table 7.4: 1 for a complete list of censoring rules. 
• The CTP specifies that if a Health-Related Quality of Life (HRQOL) assessments is 
missed, but followed by another assessment which shows deterioration then the time to 
deterioration will be defined as the mid-point of the two available assessments 
immediately before and after the missed assessments.  As it was thought that this planned 
imputation was likely to be a rare occurrence as well as being unnecessarily complicated 
it will not be performed.  Refer to Section 7.5.2.4 for further details. 
• The time to deterioration in body weight and Eastern Cooperative Oncology Group 
(ECOG) performance status endpoints have been removed as descriptive summaries of 
changes from baseline will suffice.  Refer to Section 7.5.2 for further details. 
• The CTP states that adverse events will be compared over a period of time equivalent to 
six courses of chemotherapy, such a comparison was included due the expected 
difference in length of treatment exposure between the two treatment groups.  This 
analysis has been replaced by exposure adjusted adverse event incidence rate summaries 
which have the benefit of not excluding any treatment emergent adverse events from 
summary.  Refer to Section 7.8.1 for further details. 
• The list of laboratory parameters to be focussed upon detailed in the CTP was revised; 
refer to Section 7.8.2 for further details. 
 


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5. 
ENDPOINTS 
5.1 
PRIMARY ENDPOINT 
The primary efficacy endpoint will be progression free survival (PFS) calculated as the time 
from randomisation to the occurrence of disease progression or death, whichever occurs first.  
Disease progression will be evaluated according to Response Evaluation Criteria in Solid 
Tumours (RECIST) 1.1 criteria. 
5.2 
SECONDARY ENDPOINTS 
5.2.1 
Key secondary endpoints 
• Objective response to study treatment, defined as complete response (CR) or partial 
response (PR) as determined by RECIST 1.1. Time to objective response, defined as the 
time from randomisation to the first recorded objective response. Duration of objective 
response will be measured from the time of first objective response to the time of 
progression or death, whichever occurs first (or date of censoring for PFS). 
• Disease control, defined as a patient with an objective response or stable disease (SD). 
Duration of disease control will be measured from randomisation to the time of 
progression or death, whichever occurs first (or date of censoring for PFS). 
• Overall survival (OS) calculated as the time from randomisation to death. 
5.2.2 
Other secondary endpoints 
• Tumour shrinkage measured as the minimum sum of target lesion diameters recorded 
after randomisation. 
• Change from baseline in body weight. 
• Change from baseline in ECOG performance status. 
• HRQOL as measured by the European Organisation for Research and Treatment of 
Cancer (EORTC) core Quality of Life Questionnaires (QLQ-C30) and lung cancer 
specific questionnaire module (QLQ-LC13). 
 


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6. 
GENERAL ANALYSIS DEFINITIONS 
6.1 
TREATMENTS 
For reporting purposes, all randomised patients will be classified into either ‘Afatinib 40’ or 
‘Ge1000+Cis75’ as randomised.  For efficacy analyses patients will be analysed as 
randomised.  For safety analyses, treated patients will be analysed according to the initial 
treatment taken. 
The following study periods based on actual start and stop dates of study treatment 
administration are defined: 
• Pre-screening: for any data recorded prior to day of first signing informed consent. 
• Screening: day of first signing informed consent to day prior to starting study treatment. 
• On-treatment: day of first administration of study treatment to day of last administration 
of study treatment. 
• Post-treatment: day after last administration of study treatment to the 28th day after last 
administration of study treatment. 
• Post-study: 29th day after last administration of study treatment. 
For safety summaries data recorded up to 28 days after last administration of study treatment 
will be considered as on-treatment (i.e. the actual on-treatment and post-treatment periods 
defined above will be combined into one ‘on treatment’ analysing treatment). 
6.2 
IMPORTANT PROTOCOL VIOLATIONS 
No per protocol set (PPS) analysis will be performed for this study; however patients with 
potentially important protocol violations (IPVs) will be documented.  The following list of 
potentially IPVs will be used; note that this is a working list and may not be finalised until the 
final Blinded Report Planning Meeting (BRPM) prior to database lock. 
Table 6.2: 1 
Important protocol violations 
Category/ 
Code 
Description of Violation 
Comment/Example 
A 
 
Entrance criteria not met 
 
 
A1 
Diagnosis including disease 
staging and measurability not 
as per protocol. 
Refers to IN1 and IN3, also check 
oncological history and baseline tumour 
measurement details from investigator. 
 
A2.1 
Prior treatment for NSCLC 
does not meet entrance criteria 
Refers to EX1, EX2, EX3, and EX24 also 
check previous therapy details. 
 


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Table 6.2: 1 
Important protocol violations - continued 
Category/ 
Code 
Description of Violation 
Comment/Example 
 
A2.2 
Genotypic tumour 
characteristics do not meet 
entrance criteria 
Refer to IN2 also check tumour biopsy 
details. 
 
A2.3 
Baseline imaging taken outside 
of the protocol defined window 
Date of baseline imaging of target and 
non-target lesions must be no more than 
28 days from starting study treatment; 
and not after starting study treatment. 
 
A3 
Laboratory values do not meet 
entrance criteria 
Refers to EX11, EX12, EX13, EX14 and 
EX15, also check against screening 
laboratory values. 
 
A4 
Chronic diarrhoea or other pre-
existing event that might 
exacerbate expected Afatinib 
events 
Refers to EX7, EX10 and EX23 also 
check baseline conditions. 
 
A5 
Other deviation from entrance 
criteria 
Refers to IN4, 5 and 6 and EX4, 5, 6, 8, 
9, 16, 17, 18, 19, 20 and 22. Also check 
baseline demographics, oncological 
history, ECG, LVEF, pregnancy test, 
ECOG score and baseline conditions. 
B 
 
Informed consent 
 
 
B1 
Patient’s written informed 
consent not available 
Refers to IN7.  Date of written informed 
consent 1 and 2 must be available. 
 
 
B2 
Patient’s written informed 
consent too late 
Date of written informed consent must be 
on or before screening visit 1.  Date of 
written informed consent 2 must and on 
or before screening visit 2. 
 
B3 
Procedure performed prior to 
written informed consent 
Study procedure performed prior to 
patient giving informed consent. 
C 
 
Trial medication and 
randomisation 
 


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Table 6.2: 1 
Important protocol violations - continued 
Category/ 
Code 
Description of Violation 
Comment/Example 
 
C1 
Incorrect trial medication taken For Afatinib patients: starting dose of 
Afatinib treatment not 40mg.  Afatinib 
dose not paused, reduced or increased 
according to Section 4.1.4 of the CTP. 
For chemotherapy patients: 
chemotherapy dose calculated 
incorrectly, >6 courses given or <6 
courses without good reason. 
 
C2 
Randomisation not followed 
Patient not treated according to 
randomisation.  Patient randomised into 
incorrect stratum. 
 
C3 
Non-compliance 
Check medication compliance details for 
extreme non-compliance only. 
D 
 
Concomitant medication 
 
 
D2 
Prohibited medication use 
Review concomitant medications for 
prohibited medication use, refer to 
Section 4.2.2 of the CTP. 
E 
 
Missing primary endpoint 
data 
 
 
E4 
Non-evaluable by RECIST 
criteria during the entire trial 
Note individual non-evaluable timepoints 
will be described as part of a description 
of the accuracy of the PFS determination. 
G  
Trial specific 
 
 
G1 
Non-adherence to safety 
related withdrawal criteria 
Check for patients that are continuing 
when they should have been withdrawn 
from treatment/trial according to the 
criteria detailed in Section 6.3 of the 
CTP. 
 


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6.3 
PATIENT SETS ANALYSED 
• Randomised set: 
This patient set includes all patients randomised to receive treatment, whether treated 
or not.  This set of patients will be used for the primary evaluation of efficacy. 
• Treated set: 
This patient set includes all patients who were dispensed with and documented to 
have taken at least one dose of study medication.  This set of patients will be used for 
the evaluation of safety. 


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6.5 
POOLING OF CENTRES 
This section is not applicable because centre is not included in any of the statistical models; it 
is not included to avoid over-fitting the model. 
6.6 
HANDLING OF MISSING DATA AND OUTLIERS 
In general missing efficacy data will not be imputed and all reasonable efforts will be taken 
during the study to obtain such data.  Patients with unknown vital status, missing tumour 
imaging data and missing HRQOL assessments will be censored for time to event analyses; 
further details are provided in Section 7. 
Missing or incomplete adverse event (AE) dates are imputed according to BI standards 
['Handling of missing and incomplete AE dates' 001-MCG-156_RD-01 (1)]. 
Missing data and outliers of PK data are handled according to BI standards ['Non-
compartmental Pharmacokinetic/Pharmacodynamic Analyses of Clinical Studies' 001-MCS-
36-472 RD-01 (2)]. 
6.7 
BASELINE, TIME WINDOWS AND CALCULATED VISITS 
Baseline values will be the measurements taken most recently prior to first administration of 
the study drug. 
Study day will be calculated relative to the date of the first administration of study drug.  The 
day prior to first administration of study drug will be ‘Day -1’ and the day of first 
administration of study drug will be ‘Day 1’; therefore ‘Day 0’ will not exist. 
All data collected at a visit level will be presented according to the actual protocol visit it was 
measured at.  Visits will be labelled as Screening Visit 1 (SV1), Screening Visit 2 (SV2), 
Course 1 Visit 1 (C1 V1), C1 V2, C2 V1, C2 V2, C3 V1, C4 V1 … CX V1, End of 
Treatment (EOT), Follow-up 1 (FUP1) … FUP X and Observation Period 1 (OP1) … OP X.  
Data obtained at unplanned/additional visits will be listed and suitably labelled. 
For the presentation of tumour response data which will follow a calculated visit approach 
based on the protocol specified tumour imaging schedule.  Imaging will be performed at 6-
weekly intervals up until Week 48 and in 12-weekly intervals thereafter from the date of 
randomisation; images will be slotted to Week 6, 12, 18, … XX based on their relative day 
(from randomisation) and using a ± 3, ±6 week window as appropriate (images taken in the 


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first 3 weeks from randomisation will be slotted to Week 6).  If two or more images for a 
patient are assigned to one interval then the last assessment will be used to ensure progressive 
disease is not missed. 


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7. 
PLANNED ANALYSIS 
For end-of-text tables, the set of summary statistics is: N / Mean / StD / Min / Median / Max.  
For appendix tables, the set of summary statistics is: N / Mean / StD / Min / Q1 (lower 
quartile) / Median / Q3 (upper quartile) / Max. 
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed only if there are actually missing values. Percentages will be based 
on all patients in the respective patient set whether they have non-missing values or not. 
The primary analysis will take place when 217 patients have progressed or died, as assessed 
by independent review.  The time point of the data cut-off (extract of data from BI database) 
for sending the latest data packages (radiological scans and completed dossiers) for 
independent review will be determined by the progression and death data from the 
investigator assessments.  Based upon the discrepancy observed (on blinded data) between 
the number of events from the independent review (ongoing during the trial) and the 
investigator assessments the time point for observing 217 independent review events will be 
estimated.  All data up to and including this time point (including response data from patients 
who did not progress) will be sent for independent review.  The estimation of this time point 
is likely to lead to some deviation, though relatively small, from the planned 217 independent 
review events.  The trial will only be un-blinded after the independent review data has been 
received back, loaded into the database and considered final. 
A second analysis, primarily for assessing OS, will be performed when approximately 209 
have died. The timing of this analysis may be adjusted to coincide with future regulatory 
submissions or if an update is required at the time a decision is being made regarding 
regulatory approval.  All data collected after this will be reported in a revision to the CTR. 
7.1 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Descriptive statistics using standard summary tables for the randomised set of patients are 
planned for this section of the report. 
 
7.2 
CONCOMITANT DISEASES AND MEDICATION 
Descriptive statistics using standard summary tables for the randomised set of patients are 
planned for this section of the report. 


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7.3 
TREATMENT COMPLIANCE 
Descriptive statistics using standard summary tables for the treated set of patients are planned 
for this section of the report.  A summary of whether patients took their treatment according 
to the protocol and whether they missed any doses (Afatinib only) will be produced for each 
planned visit.  In addition a summary of overall percentage compliance (Afatinib only) will 
be produced using visit dates and the total number of doses missed during the study. 
7.4 
PRIMARY ENDPOINT 
The primary endpoint of this study is PFS, defined as the time (months) from the date of 
randomisation to the date of disease progression, or to the date of death if a patient died 
earlier.  The date of progression for the primary analyses will be determined by an 
independent central imaging review incorporating both radiologist and oncologist reviews, 
blinded to treatment assignments.  The primary endpoint analysis will be performed on the 
randomised set of patients. 
A stratified log-rank test (two-sided, 0.05 significance level) will be used to test the effect of 
Afatinib on PFS compared with standard chemotherapy.  The test will be stratified by EGFR 
mutation group (L858R, Del 19 or Other), according to the patient data entered in the CRF. 
A Cox proportional hazards model, stratified by EGFR mutation group will be used to 
estimate the hazard ratio and 95% confidence interval (CI) between the two treatment groups.  
Kaplan-Meier estimates and 95% CIs (using Greenwood’s standard error estimate) will be 
tabulated at 3-monthly time points and will include a comparison of the treatment groups 
using a z-test (approximation of the normal distribution).  Kaplan-Meier curves for the two 
treatment groups will also be produced. 
The assumption of proportional hazards within each EGFR mutation group and the 
homogeneity of the hazard ratio across the EGFR mutation groups will be checked 
descriptively. 
The rules to determine whether or not patients have had a PFS event (progression or death) 
along with the date of event or date of censoring (for those with no event) are specified in 
Table 7.4: 1.  These rules will be applied to the independent central review data prior to 
analysis.  A summary table of the reasons for censoring will be produced by treatment group.  
Event and censoring rates will also be presented at each planned imaging time point. 


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Table 7.4: 1 
Rules to determine events and censoring for PFS 
Rule # Situation 
Outcome  
(event or 
censored) 
Date of PFS event or 
censoring 
1 
No baseline tumour assessment (no 
death before second scheduled 
assessment) 
censored 
Date of randomisation 
2 
Progressed from central imaging (no 
missed radiologic assessments) 
event 
Date of PD 
3a 
Non-PD from central imaging1, death 
before next scheduled assessment 
event 
Date of death 
3b 
Non-PD from central imaging1, one 
missed assessment, death or 
progression after date of missed 
assessment, but before a second 
scheduled assessment 
event 
Date of PD or death 
3c 
Non-PD from central imaging1, more 
than one consecutive missed 
assessment, death or progression 
after date of second missed 
assessment 
censored 
Date of last imaging 
before missed assessment 
3d 
Non-PD from central imaging1, more 
than one consecutive missed 
assessment, non-PD according to 
imaging after missed assessments 
censored 
Date of last non-PD 
imaging 
4 
New anti-cancer medication before 
progression or death 
censored 
Date of last imaging 
before new anti-cancer 
medication 
5 
Death before the scheduled date of 
first imaging 
event 
Date of death 
6a 
No imaging performed post-baseline, 
patient dies between first and second 
scheduled assessments 
event 
Date of death 
6b 
No imaging performed post-baseline, 
patient dies after second scheduled 
assessment 
censored 
Date of randomisation 
6c 
No imaging performed post-baseline, 
vital status is unknown or patient 
known to be alive 
censored 
Date of randomisation 
7 
Alive and not progressed from 
central imaging (no missed 
assessments) 
censored 
Date of last imaging 
  1 - From the last assessment at which CR, PR or SD was assessed. 


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7.5 
SECONDARY ENDPOINTS 
Secondary endpoints are split into ‘key’ and ‘other’ endpoints.  If the difference between the 
treatment groups is statistically significant then formal statistical testing will be performed on 
the key secondary endpoints.  In order to protect the overall type I error rate a closed testing 


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procedure will be employed, whereby each key secondary endpoint will only be formally 
analysed if the previous endpoint was found to be statistically significant.  The key secondary 
endpoints will be analysed according to the order they are presented below. 
All analyses of secondary endpoints will be produced on the randomised set of patients. 
7.5.1 
Key secondary endpoints 
7.5.1.1 Best RECIST tumour assessment 
Each patient will be given a best overall response of CR, PR, SD, Non-CR/Non-PD (NN), PD 
or Not Evaluable (NE) based on the independent central imaging data, following the RECIST 
(1.1).  This will be based on all responses taken from the start of treatment until the start of 
any new anti-cancer therapy. 
Objective response 
An objective response is defined as a best overall response of CR or PR.  A logistic 
regression model, stratified by EGFR mutation group will be used to compare the objective 
response rate between the two treatment groups.  This analysis will be considered as the first 
key secondary endpoint analysis.  Objective response rates will be presented with exact 95% 
Clopper-Pearson CIs. 
For those patients with an objective response, time to response measured from the date of 
randomisation to the date of first response will be summarised by the planned imaging time 
points.  A descriptive summary of the duration of response (months), measured from the first 
date of response to progression or death will also be produced.  Kaplan-Meier curves for the 
two treatment groups will also be produced for the duration of response, where applicable 
patients will be censored as for the PFS primary analysis. 
 
 
 
 
  
 
 
The RECIST guidelines state that confirmation of response is not required for Phase III 
studies that have PFS as the primary endpoint; hence the above summaries will be produced 
without the requirement for confirmation.  However, for completeness all the above 
summaries and analyses will be repeated with the requirement for confirmation, these will be 
considered secondary in nature. 


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Disease control 
Disease control is defined as a best overall response of CR, PR, SD or NN.  A logistic 
regression model, stratified by EGFR mutation group will be used to compare the disease 
control rate between the two treatment groups.  This analysis will be considered as the second 
key secondary endpoint analysis.  Disease control rates will be presented with exact 95% 
Clopper-Pearson CIs. 
A descriptive summary of the duration of disease control (months), measured from the date 
of randomisation to progression or death will also be produced.  Kaplan-Meier curves for the 
two treatment groups will also be produced for the duration of disease control, where 
applicable patients will be censored as for the PFS primary analysis. 
 
 
  
 
 
As for the objective response summaries, analyses of disease control will be repeated with the 
requirement for confirmation, these will be considered secondary in nature. 
7.5.1.2 Overall survival 
OS (months), defined as the time from the date of randomisation to the date of death will be 
formally analysed twice and will be considered as the third and final key secondary endpoint.  
The first analysis will be performed at the time of the primary PFS analysis and the second at 
a time when more information is available on OS.  To preserve the overall 0.025, one-sided 
alpha level, a Haybittle-Peto stopping boundary will be used (p-value<0.0001) for the first 
analysis. 
Patients for whom there is no evidence of death at the time of analysis will be censored on the 
date that they were last known to have been alive. 
A stratified log-rank test will be used to test the effect of Afatinib on OS compared with 
standard chemotherapy.  The test will be stratified by EGFR mutation group.  A Cox 
proportional hazards model, stratified by EGFR mutation group will be used to estimate the 
hazard ratio and 95% confidence interval (CI) between the two treatment groups.  Kaplan-
Meier estimates and 95% CIs (using Greenwood’s standard error estimate) will be tabulated 
at 3-monthly time points and will include a comparison of the treatment groups using a z-test 
(approximation of the normal distribution).  Kaplan-Meier curves for the two treatment 
groups will also be produced. 
 
 


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7.5.2 
Other secondary endpoints 
7.5.2.1 Tumour shrinkage 
Tumour shrinkage for each patient, measured (via central imaging review) as the minimum 
sum of target lesion diameters after randomisation, will be compared for the two treatment 
groups.  An analysis of covariance (ANCOVA) for the minimum sum of diameters, with the 
baseline sum of diameters fitted as a covariate and EGFR mutation group fitted as a factor 
will be performed. 
In addition waterfall plots of the maximum percentage decrease from baseline will be 
presented for each treatment group. 
 
7.5.2.2 Body weight 
The lowest and last body weight recorded on treatment or during follow-up will be 
summarised along with the change in weight from baseline. 
7.5.2.3 ECOG performance status 
A shift table of the worst (highest) and last ECOG performance status category recorded on 
treatment or during follow-up by baseline category will be produced. 


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7.5.2.4 Health-related quality of life 
HRQOL questionnaires as measured by the EORTC QLQ-C30 and QLQ-LC13 at baseline, 
during treatment and follow-up will be included in the analysis.  All scoring of the symptom 
scales/items will follow the EORTC scoring algorithm. 
The analyses will focus on cough, dyspnoea and pain; specifically: 
• Cough: Q1 - How much did you cough? (QLQ-LC13) 
• Dyspnoea: Composite of: Q3 - Were you short of breath when you rested? Q4 - Were 
you short of breath when you walked? Q5 - Were you short of breath when you 
climbed stairs? (QLQ-LC13).  Individual item from QLQ-C30, Q8 - Were you short 
of breath? 
• Pain: Composite of: Q9 - Have you had pain? Q19 - Did pain interfere with your daily 
activities? (QLQ-C30).  Individual items from QLQ-LC13, Q10 - Have you had pain 
in your chest? Q11 - Have you had pain in your arm or shoulder? Q12 - Have you had 
pain in other parts of your body? 
For each of the summary scales and items measuring the above the treatment groups will be 
compared for the following: 
Distribution of patients improved, stable or worsened 
Improvement will be defined as a score that improves from baseline by at least 10 points (on 
the 0-100 point scale) at anytime during the study.  If a patient has not improved, worsening 
will be defined as a 10 point worsening at anytime during the study.  Otherwise, a patient will 
be considered as stable. 
The number and percentage of patients falling into each of these three categories will be 
summarised by treatment group.  A logistic regression model, stratified by EGFR mutation 
group will be used to compare the distribution of patients improving/not improving across the 
two treatment groups. 
Time to deterioration 
Time to deterioration (months) is defined as the time from randomisation to an increase 
(worsening) from the baseline score of at least 10 points on the 0-100 point scale.  Patients 
that die during the period of interest with no evidence of a deterioration will be considered to 
have deteriorated at the time of death. 
This time to event data will be analysed and summarised using the same methodology as for 
the primary efficacy endpoint, refer to Section 7.4.  The results of the analyses will be 
displayed using Forest plots. 
Patients with no deterioration (including those with disease progression) will be censored at 
the last available HRQOL assessment date; patients with no post-baseline assessments will be 
censored on the day of randomisation. 


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Change in scores over time 
Changes in scores over time will be assessed using longitudinal models; these will be mixed-
effects growth curve models with the average profile over time for each endpoint described 
by a piecewise linear model adjusted for the fixed effect of EGFR mutation group.  The 
models will allow the slope to change at 3, 6, 12 and 18 weeks.  Each model will also include 
the two random effects of intercept and slope (time from randomisation).  The area under the 
estimated growth curve (AUC) up to the median follow-up time will be calculated as a 
summary measure for each treatment group; this will be divided by the median follow-up 
time so that it can be interpreted as the mean HRQOL score up to the median follow-up time.  
The treatment effect will be estimated as the average difference between the treatment group 
means scores, together with a 95% confidence interval and associated p-value based on a t-
statistic with degrees of freedom calculated using the Kenward-Roger method.  The results of 
the analyses will be displayed using Forest plots. 
 
 
 
 
 
 
In addition, all single items and subscales (functional and symptom) from both questionnaires 
will be analysed in a similar fashion to summarise the impact of therapy over the entire 
profile of the measures, and to examine the consistency of component items with the 
composite measures. 
Note as higher scores represent a ‘better’ level of functioning; deterioration in scales/items 
related to functioning will be defined as a decrease from baseline score of at least 10 points. 
Finally, the usage of cough, dyspnoea and pain medication along with the incidence of cough 
and dyspnoea AEs will be described. 
7.7 
EXTENT OF EXPOSURE 
Total treatment time (days and number of courses) will be calculated for each patient; off-
drug periods due to non-compliance or toxicity prior to permanent discontinuation will be 
included as treatment time.  For Afatinib, 21 days will be considered a treatment course.  In 
addition the total treatment time will be summed over all patients and transformed to patient 
years.  Standard descriptive summaries, by treatment group, of these data will be provided for 
the treated set of patients. 
A Kaplan-Meier plot showing the number of patients at risk (exposed) during the study 
treatment period will also be produced. 


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Further summaries will also be produced for the Afatinib treatment group only: 
• Treatment time (days) broken down by each dose level (50 mg, 40 mg, 30 mg and 
20 mg). 
• Number and proportion of patients on each dose level over time. 
• Time to first dose reduction and duration (days) of off-drug periods prior to first dose 
reduction. 
• Kaplan-Meier plot of time from first dose of study medication to the first dose 
reduction 
 
7.8 
SAFETY ANALYSIS 
All safety analyses will be performed on the treated set. 
7.8.1 
Adverse events 
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of patients with AEs and not on the number of AEs. 
Furthermore, for analysis of AE attributes such as duration, severity and CTC grade multiple 
AE occurrence data on the CRF, will be collapsed into AE episodes provided that all of the 
following applies: 
• The same MedDRA lowest level term was reported for the occurrences. 
• The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence). 
• Treatment did not change between the onset of the occurrences or treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence 
For further details on summarization of AE data, please refer to the guideline 'Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries' [001-
MCG-156 (7)]. 
The main analysis of adverse events will be based on the concept of treatment emergent 
adverse events. That means that all adverse events occurring between first drug intake until 
28 days after last drug intake will be assigned to the randomised treatment. All AEs occurring 
outside of this period will be handled according to the treatment definition rules detailed in 
Section 6.1 and will only be listed unless stated otherwise. 
An overall summary of adverse events will be presented.  This summary will exclude the 
rows ‘Severe AEs’, ‘Significant AEs’ and ‘Other significant AEs’ but will include additional 
rows for ‘AEs leading to dose reduction’ and ‘AEs by highest Common Terminology Criteria 
(CTC)’ grade. 


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The frequency of patients with adverse events will be summarised by highest CTC grade 
(grades 3, 4, 5 and all grades to allow both treatment groups to fit on one page), treatment, 
primary system organ class (SOC) and preferred term (PT) for each of the following AE 
tables: 
• All AEs. 
• Drug related AEs. 
• AEs leading to dose reduction. 
• AEs leading to treatment discontinuation. 
• Drug related AEs leading to treatment discontinuation 
• Serious AEs. 
• Drug related serious AEs. 
• AEs leading to death. 
• AEs in Afatinib patients who dose escalate from 40 mg to 50 mg. 
All tables will be sorted by SOC according to the standard sort order specified by the 
European Medicines Agency (EMA); PTs will be sorted by frequency (within SOC). 
The above tables except for AEs leading to death will be repeated with the project defined 
grouping of AE terms (rash, stomatitis, ocular effects, lip effects, nail effects and fatigue).  
Details of the project defined groupings are defined in the technical TSAP.  In these tables 
the grouped AEs will replace the original PTs for all AEs that are included within the 
grouped term.  The grouped AE categories will then be tabulated along with all remaining 
MedDRA PTs, sorted by descending frequency.  A reference table presenting all of the 
project defined groupings and MedDRA PTs within each grouping will also be produced. 
 
 
 
Additional AE tables will be produced for AEs of special interest (diarrhoea, and the project 
defined groupings of rash, renal insufficiency, leukopenia and neuropathy), providing further 
details on highest CTC grade, action taken with study drug and time to first onset of AE. 
A supportive analysis of adverse events will be performed using treatment exposure adjusted 
incidence rate tables.  These will be produced for the project defined grouping of AE terms 
(rash, stomatitis, ocular effects, lip effects, nail effects and fatigue) in a similar manner to that 
described above.  The following tables will be produced for all AEs and for all AEs with a 
CTC grade ≥3: 
• All AEs. 
• Drug related AEs. 
• Serious AEs. 
Specifications for the calculation of incidence rates, rate ratios and CI for rate ratios are 
detailed in the technical TSAP (also refer to 8). 


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7.8.2 
Laboratory data 
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards ['Display and Analysis of Laboratory Data' 001-MCG-157 (9)].  CTC grades will 
be applied to laboratory parameters using the current BI oncology standard as detailed in the 
document ‘Conversion of laboratory parameters to CTCAE grades within BI’ (10). 
Descriptive statistics of all laboratory values by visit will be provided including changes from 
baseline.  Frequency tables of transitions relative to the reference range and of possible 
clinically significant abnormalities will be produced.  For those parameters that have CTC 
grading possible clinically significant abnormalities are defined as those laboratory values 
with a CTC grade ≥ 2 that have had an increase of ≥ 1 grade from baseline.  For those 
parameters for which no CTC grade has been defined standard BI project definitions will be 
used to decide on clinical significance.  Further frequency tables will show the transition of 
CTC grade from baseline to worst value and last value on treatment. 
Summaries will be produced of laboratory data recorded prior to treatment, on-treatment and 
28 days after last study drug intake. 
The focus of the laboratory data analysis will be on the following laboratory parameters: 
• Low values: haemoglobin, white blood cells, neutrophils, lymphocytes, platelets, 
potassium, sodium and glomerular filtration rate. 
• High values: creatinine, asparate aminotransferase, alanine aminotransferase, 
bilirubin, alkaline phosphatase and creatinine phosphokinase. 
7.8.3 
Vital signs 
Only descriptive statistics are planned for this section of the report. 
A summary table of left ventricular ejection fraction (LVEF) will be produced for the final 
and minimum on-treatment values along with the corresponding percentage change from 
baseline.  The number of patients with a significant LVEF event will also be presented; a 
significant event is defined as a decrease of ≥20% from baseline that is also below the lower 
limit of normal for the particular site (50% will be used if the lower limit of normal is 
missing). 
7.8.4 
ECG 
A descriptive summary of QTcF values will be produced by each scheduled visit along with 
the change from baseline.  All other ECG data will be listed. 
7.8.5 
Others 
The relationship between trough Afatinib concentration, categorised using the quartile values, 
will be explored for the following endpoints: 


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• Week 6 tumour shrinkage; measured as the absolute and percentage change in the 
sum of target lesion diameters from randomisation. 
• PFS and OS. 
Trough Afatinib concentrations will be taken as the values measured on Day 42 prior to study 
treatment intake; if this value is missing then the value taken on Day 29, or Day 21 if that is 
missing will be used. 


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8. 
REFERENCES 
1. 
001-MCG-156_RD-01, ‘Handling of missing and incomplete AE dates’, current 
version; IDEA for CON. 
2. 
001-MCS-36-472 RD-01, 'Non-compartmental Pharmacokinetic/Pharmacodynamic 
Analyses of Clinical Studies', current version; IDEA for CON) 
3. 
R10-4999, P Korhonen and J Palmgren 'Effect modification in a randomized trial 
under non-ignorable non-compliance: an application to the alpha-tocopherol beta-
carotene study', Applied Statistics (2002) 51, Part 1: 115-133 
4. 
R10-5000, P Korhonen, N Laird and J Palmgren 'Correcting for non-compliance in 
randomized trials: An application to the ATBC study', Statistics in Medicine (1999). 
18, 2879-2897 
5. 
R10-4487, J Robins and D Finkelstein 'Correcting for Noncompliance and Dependent 
Censoring in an AIDS Clinical Trial with Inverse Probability of Censoring Weighted 
(IPCW) Log-Rank Tests', Biometrics (Sept 2000), 56, 779-788 
6. 
R10-4484, J Robins 'Information recovery and bias adjustment in proportional 
hazards regression analyses of randomized trials using surrogate markers' 
Proceedings of the Biopharmaceutical Section, American Statistical Association 
(1993), 24-33 
7. 
001-MCG-156, ‘Handling and summarisation of adverse event data for clinical trial 
reports and integrated summaries’, current version; IDEA for CON. 
8. 
R07-1386, Rothman K and Greenland S. Modern Epidemiology, 2nd ed. 1998 
9. 
001-MCG-157, ‘Display and Analysis of Laboratory Data’, current version, IDEA for 
CON. 
10. 
BI Guidance document ‘Conversion of laboratory values to CTCAE grades within 
Boehringer Ingelheim’ 
 


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10. 
HISTORY TABLE 
Table 10: 1 
History table 
Version 
Date 
(DD-Mmm-YY) 
Author 
Sections 
changed 
Brief description of change 
Revised 
05-Dec-12 
4 
Removal of details regarding reduced 
assay set. 
Revised 
05-Dec-12 
6.2 
Revision of IPV category A2.3. 
Removal of IPV category E3. 
Revised 
05-Dec-12 
6.3 
Reduced assay set removed as not 
required for this study. 
Revised 
05-Dec-12 
Revised 
05-Dec-12 
7.4 
 
 
 
 
 
 
Revised 
05-Dec-12 
8 
Change to location and identification of 
reference 2.