Clinical trial NCT01271725
Conditions: Breast Neoplasms
Sponsor: Boehringer Ingelheim
Start date: 2011-05-24; Completion date: 2017-03-13
Enrollment: 74 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
The general aim of this study is to investigate the efficacy and safety of afatinib (BIBW 2992) alone and in combination with weekly paclitaxel or weekly vinorelbine (in patients who progress on afatinib monotherapy within this trial) as treatment in patients with HER2-overexpressing, metastatic breast cancer, who failed HER2-targeted treatment in the neoadjuvant or adjuvant setting

Detailed description:

Arms: arm 1: Patient to receive afatinib monotherapy at a dose of 40 mg/d until progression of their disease arm 2: Patients to additionally receive paclitaxel at a dose of 80 mg/m2 weekly on disease progression on afatinib monotherapy arm 3: Patients to additionally receive vinorelbine at a dose of 25 mg/m2 weekly on disease progression on afatinib monotherapy
Interventions: intervention 1: Vinorelbine 25 mg/m2 weekly intervention 2: Afatinib 40mg once daily (OD) intervention 3: Paclitaxel 80 mg/m2 weekly
Intervention descriptions: intervention 1: Patients to additionally receive vinorelbine at a dose of 25 mg/m2 weekly on disease progression on afatinib monotherapy intervention 2: Patient to receive afatinib monotherapy at a dose of 40 mg/d until progression of their disease intervention 3: Patients to additionally receive paclitaxel at a dose of 80 mg/m2 weekly on disease progression on afatinib monotherapy

Protocol documents:
Prot_001.pdf: 
 
SIGNATURE INFORMATION 
 
Document: 
                               
                           
Document No.:                                                                                                                        
 
Title 
                             
 
 
 
 
 
 
                         
 
SIGNATURES  (ELECTRONICALLY OBTAINED)  
 
Meaning of Signature: 
Signed by: 
Date signed: (GMT) 
                                   
 
 
 
                               
                                                                                        
                                   
 
 
 
                               
                                                                 
                                   
 
 
 
                               
                                                                                                 
                                   
 
 
 
                               
                                                                                        
                                   
 
 
 
                               
                                                                                        
                                  
 
 
 
                               
                                                                                                                     
                                   
 
 
 
                               
                                                                                                                       
1200-0098--protocol-revision-07
U10-2538-07
LUX-Breast 2. An open label, phase II trial of BIBW 2992 (afatinib) in
patients with metastatic HER2-overexpressing breast cancer failing
HER2-targeted treatment in the neoadjuvant and/or adjuvant treatment
setting
Author-Trial Clinical Monitor
7/1/2013 09:22:48
Approval-Team Member Medicine
7/1/2013 09:25:48
Author-Trial Statistician
7/1/2013 11:44:19
Approval-Therapeutic Area 
7/1/2013 12:47:26
Verify Paper Signature Completion
7/10/2013 10:07:16


 
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) 
                                   
 
 
 
                               
                                                                                                                      
                                   
 
 
 
                               
                                                                                                                      
                                   
 
 
 
                               
                                                                                                                      
                                     
 
 
 
                                 
                                                                                                                      
                                     
 
 
                                 
                                                                                                                      
                                     
 
 
                               
                                                                                                                       
                                     
 
 
                                
                                                                                                                       
                                     
 
 
                                 
                                                                                                                     
 
1200-0098--protocol-revision-07
U10-2538-07
LUX-Breast 2. An open label, phase II trial of BIBW 2992 (afatinib) in
patients with metastatic HER2-overexpressing breast cancer failing
HER2-targeted treatment in the neoadjuvant and/or adjuvant treatment
setting


TITLE PAGE 
 
 
 
Clinical Trial Protocol 
 
Doc. No.: U10-2538-07
EudraCT No.:  
BI Trial No.:  
2010-021945-29 
1200.98 
 
BI Investigational 
Product(s): 
BIBW 2992 (afatinib) 
Title: 
LUX-Breast 2; An open label, phase II trial of BIBW 2992 (afatinib) in 
patients with metastatic HER2-overexpressing breast cancer failing 
HER2-targeted treatment in the neoadjuvant and/or adjuvant treatment 
setting  
Clinical Phase: 
II  
Trial Clinical 
Monitor: 
 
 
Phone: 
 
Fax: 
 
Co-ordinating 
Investigator: 
  
  
 
 
 
 
 
 
  Phone: 
 
   Fax: 
 
Status, Version, and 
Date of Protocol: 
Final Protocol, Version 1.0, 5th October 2010 
Status, Version, and 
Date of Revised 
Protocol: 
Revised Protocol, Version 2.0, 22 December 2010  
Revised Protocol, Version 3.0, 27 April 2011 
Revised Protocol, Version 4.0, 29 July 2011 
Revised Protocol, Version 5.0, 6 December 2011 
Revised Protocol, Version 6.0, 6 November 2012 
Revised Protocol, Version 7.0, 27 June 2013 
 
Page 1 of 101 
Proprietary confidential information.  
© 2013 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. 
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission. 


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27 June2013 
BI Trial No.: 1200.98 
Revised Trial Protocol 
Page 2 of 101 
 
 
 
 
CO-ORDINATING 
INVESTIGATOR SIGNATURE  
 
 
 
 
Trial Title: LUX-Breast 2; An open label, phase II trial of BIBW 2992 (afatinib) in 
patients with metastatic HER2-overexpressing breast cancer failing HER2-targeted treatment  
in the neoadjuvant and/or adjuvant treatment setting 
 
 
 
Trial Number: 1200.98 
 
Revised Protocol based upon Global Protocol Amendment 6, 27 June 2013 
 
 
I herewith certify that I agree to adhere to the trial protocol 
and to all documents referenced in the trial protocol. 
 
 
 
 Name: 
      Signature:__________________________ 
Signed signature page is located in the electronic Clinical Trial Master File 
 
  
 
Affiliation: 
 
 
 
Date:  
___________________________ 
 


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27 June2013 
BI Trial No.: 1200.98 
Revised Trial Protocol 
Page 3 of 101 
 
 
LOCAL SIGNATURES 
(PRINCIPAL INVESTIGATOR OF SITE AND CLINICAL MONITOR LOCAL) 
Revised Protocol based upon Global Protocol Amendment 6, 27 June 2013 
Clinical Monitor Local: 
 
 
 
 
 
Date 
 
Name 
 
 
 
Full name 
 
 
Organisation/Department 
 
 
 
<Add other signatories if applicable.> 
 
 
 
 
I herewith certify that I agree to adhere to the trial protocol and to all documents 
referenced in the trial protocol. 
 
 
Principal Investigator (site): 
 
 
 
 
 
 
 
 
Date 
 
Name 
 
 
 
Full name 
 
 
 
Organisation/Department 
Signed signature page is located in the electronic Clinical Trial Master File 


Boehringer Ingelheim 
27 June2013 
BI Trial No.: 1200.98 
Revised Trial Protocol 
Page 4 of 101 
 
 
CLINICAL TRIAL PROTOCOL SYNOPSIS 
Name of company: 
Tabulated 
Trial Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: 
Afatinib 
Name of active ingredient: 
 
BIBW 2992 (afatinib) 
 
Protocol date: 
Trial number: 
 
Revision date: 
27 June 2013 
05 October 2010 
1200.98 
Title of trial: 
LUX-Breast 2; An open label, phase II trial of  BIBW 2992 (afatinib) in patients with 
metastatic HER2-overexpressing breast cancer failing HER2-targeted treatment in the 
neoadjuvant and/or adjuvant treatment setting 
Co-ordinating 
Investigator  
 
  
 Phone: 
 
 Fax: 
 
Trial site(s) : 
Multicentre trial, international  
Clinical phase: 
II  
Objectives: 
To investigate the efficacy and safety of  
• 
BIBW 2992  (afatinib) alone and of 
• 
BIBW 2992 (afatinib) in combination with weekly paclitaxel or vinorelbine 
upon progression on BIBW 2992 (afatinib) monotherapy  
in patients with HER2-overexpressing, metastatic breast cancer, who failed HER2-
targeted treatment in the adjuvant and/or neoadjuvant setting 
Methodology: 
Open-label, Phase II study  
No. of patients:  
 
 
total entered: 
120 patients will be entered. Approximately 150 patients will be enrolled 
With protocol amendment 6 the sponsor will stop enrolment into the trial (part 
A), pending approval by IRBs and IECs. 
At the time point of implementation approximately 80 patients are expected to 
have been entered 
Diagnosis : 
Metastatic HER2 over-expressing breast cancer after prior HER2 targeted treatment in 
the adjuvant and/or neoadjuvant setting 


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27 June2013 
BI Trial No.: 1200.98 
Revised Trial Protocol 
Page 5 of 101 
 
 
Name of company: 
Tabulated 
Trial Protocol 
 
Boehringer Ingelheim 
 
Name of finished product: 
Afatinib 
Name of active ingredient: 
 
BIBW 2992 (afatinib) 
 
Protocol date: 
Trial number: 
 
Revision date: 
27 June 2013 
05 October 2010 
1200.98 
Main criteria 
for inclusion: 
• 
patients with histologically confirmed HER2-overexpressing breast cancer  
• 
patients with metastatic disease (stage IV) 
• 
patients must have received prior HER2-targeted treatment, i.e. trastuzumab  
and/or lapatinib in the adjuvant or neoadjuvant setting 
• 
paclitaxel treatment can only be repeated after a treatment free interval for 
paclitaxel of at least 12 months 
• 
no prior vinorelbine treatment allowed (only for patients entered in part B  
in the Afatinib + Vinorelbine combination before the 3rd May 2013 as 
per protocol amendment 6) 
• 
patients with quickly progressing visceral disease will be excluded 
Test products : 
 
 
dose: 
BIBW 2992 (afatinib) dose 40 mg daily 
 
mode of admin. : Oral  
Combination product:  
 
dose: 
Paclitaxel 80 mg/m2 weekly upon treatment failure on BIBW 2992 (afatinib)  
monotherapy  
 
mode of admin. : Intravenous infusion over 60 min 
Combination product:  
         dose: 
Vinorelbine 25 mg/m2 weekly upon treatment failure on BIBW 2992 (afatinib) 
monotherapy  
No new patient entered in this treatment combination after 3 May 2013 
         mode of admin. : 
Intravenous infusion of about 10 minutes 
Duration of treatment: Continuous treatment in the absence of disease progression or undue adverse events 
Criteria for efficacy: 
Objective Response  (OR) consisting of  Complete Response (CR) and Partial 
Response (PR), Best Overall Response using the Response Evaluation Criteria in 
Solid Tumours (RECIST 1.1), Progression-Free Survival (PFS),
 
 
Criteria for safety:  
Incidence and severity of adverse events to Common Terminology Criteria for 
Adverse Events (CTC s, AE Version 3.0), cardiac left ventricular function, changes in 
vital signs and safety laboratory parameters 
Statistical methods: 
Exploratory data analysis, calculate objective tumour response rate with 95% 
Clopper-Pearson confidence interval, descriptive statistics. 
Futility analysis based on objective response in first 20 evaluable patients.  


Boehringer Ingelheim 
27 June 2013 
BI Trial No.: 1200.98 
Revised Trial Protocol 
Page 6 of 101 
 
 
FLOW CHART A (BIBW 2992 (AFATINIB) MONOTHERAPY)  
Follow this flow chart if patient 
continues on BIBW 2992 (afatinib) 
Monotherapy 
Screening 
Treatment 
Course 1 ** 
Treatment Course 2 
and subsequent 
courses** 
End of 
Treatment 
*** 
Follow-up 
**** 
Additional 
Follow- up visits 
***** 
Visit abbreviation 
SV* 
C1V1 
C1V2 
C2V1 to CnV1 
EOT 
FU 1 
FU Vn 
Days 
Up to 14 days 
before 
treatment 
Day 1 
Day 15
(± 2 
days) 
Day 1 
(± 2 days) 
0-14 days after 
permanent 
discontinuation of 
BIBW 2992  # 
28 days after 
EOT visit (± 7 
days) # 
Every 6 weeks 
after first FU Visit  
# 
Informed Consent 1 
X
 
Demographics 
X 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
Review of In-/Exclusion criteria 
(For Part A – Monotherapy part of study) 
X 
 
 
 
 
 
 
Complete physical examination 2 
X 
 
 
 
X 
 
 
Limited physical examination2 
 
X 
 
X 
 
X 
X 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
X 
 
X 
X 
X 
X 
12 Lead  ECG 3 
X 
 
X 
X3 
X3 
 
 
ECHO or MUGA scan 4 
X4 
 
 
X4 
X4 
 
 
Safety lab 5 
X 
X 
 
X 
X 
X 
X 
Pregnancy test 6 
X 
X 
 
X 
X 
 
 
Archived tissue sample available for 
central re-assessment of HER2-status. 
X 7 
 
 
 
 
 
 
Tumour assessment8 
X 
 
 
See schedule below 
X8 
 
 
 
 
 
 
 
 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
Compliance Check  BIBW 2992 (afatinib) 
 
 
X 
X 
X 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X9 
Dispense Trial drug 
 
X 
 
X 
 
 
 
BIBW 2992 (afatinib) treatment10 
 
Continuous 
 
 
 
Termination of active treatment 
 
 
 
 
X 
 
 
Trial Completion 
 
 
 
 
 
X 
X 


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Revised Trial Protocol 
Page 7 of 101 
 
 
Abbreviations for Visit types: SV = Screening Visit, C = Treatment course, V = Visit, EOT = End of Treatment Visit, FU = Follow-up Visit  
*  
 HER2-retesting on archived biopsies will be performed by a central laboratory. Inclusion into the trial will be based on documented HER2-status (see #7 
below) –No more patients will be screened after approval of amendment 6 
**  
All courses are 3 weeks in duration (21days). Patients may continue on treatment for unlimited courses, until the criteria for stopping medication are met 
***  
 If the decision to permanently discontinue BIBW 2992 (afatinib) monotherapy is taken during a scheduled visit, the EOT visit should be performed 
instead of the scheduled visit  
****  
Patients who discontinue BIBW 2992 (afatinib) monotherapy trial treatment permanently should have a follow-up visit 28 days after the EOT visit. See 
section 5.2.2.2 for AEs reporting during this period. 
 
*****  Patients who have not progressed and not started further treatment ( i.e. not started on combination treatment as described in Flowchart B, or other 
antitumour treatment outside of this trial) should have further follow-up visits every 6 weeks until progression or start of further treatment. 
#  
 The EOT, FU and all subsequent follow-up visits in Flow Chart A are only applicable to patients who are permanently withdrawn from the study during 
BIBW 2992 (afatinib) monotherapy.  
 
1. Written informed consent must be obtained before any protocol specific screening assessments are performed. Informed Consent must include consent 
to collection of demographic data and consent to obtaining and re-testing of archived biopsy material for HER2-status and blood samples for tumour 
markers. Inclusion will be allowed on documented HER2-positive status in patient’s files- All patients who signed the written informed consent 
before the approval of amendment 6 by  IRBs and IECs may continue in the trial- After approval of protocol amendment 6, no new informed 
consent must be signed as patient recruitment in part A will be stopped. 
2. Includes height (at screening only), respiratory rate, weight and body temperature. See section 5.2.5.1 for difference between a complete and limited 
physical examination  
3. A 12-lead resting electrocardiogram (ECG) will be performed at Screening, on Day 15 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). 
4. ECHO or MUGA will be performed at Screening, on Day 1 of Course 4 and then at every third course (Course 7, 10, 13 etc.), and at EOT (if not 
performed in the previous 8 weeks). Note: LVEF assessment does not need to be repeated at the Screening Visit if there are valid results available from 
assessments which were performed as part of routine clinical practice within 28 days prior to start of treatment and the patient has given consent to 
utilising these results. 
5. Includes haematology, serum biochemistry, coagulation and urinalysis (Baseline and EOT Visits only). See Section 5.2.3.  
6. Pregnancy test is only to be performed if patient is of child bearing potential (See Section 3.3.3 exclusion criterion # 19). Also refer to Sections 5.2.2.2 
Pregnancy and 3.3.4 Removal of patients from therapy or assessments 
7. Archived tumour biopsy material to be collected at Screening Visit. The following tests will be done by the central laboratory: HER2 IHC and reflex 
FISH testing, HrR (ER and PgR) IHC including Allred.  
8. 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. breast, pelvis, brain) using an appropriate method (CT scan, MRI).  The same radiographic procedure must be used throughout the study 
(See Section 5.1.2). Bone scans and correlative imaging should be performed when clinically indicated.  Assessment will be performed at screening and 
then every 6 weeks, calculated from the start of treatment (i.e. 2 courses). In the event of early discontinuation or an interruption/delay to treatment, the 
tumour assessment schedule should not be changed. Brain metastases are considered as non-target lesions. A brain MRI should be performed at baseline 
in cases of clinically known, stable brain metastases. Brain MRI should be done of the respective lesion(s) at baseline and subsequently at every 


Boehringer Ingelheim 
27 June 2013 
BI Trial No.: 1200.98 
Revised Trial Protocol 
Page 8 of 101 
 
 
imaging time-point. Tumour assessment does not need to be repeated at the screening visit if there are valid results available from assessments which 
were performed as part of routine clinical practice within 28 days prior to the start of treatment and the patient has given consent to utilising these 
results. Tumour assessment is not required at EOT visit if progressive disease has already been documented at scheduled imaging assessment. 
9. Only if treatment related or not resolved during 1st FU 
10. If patient has shown disease progression (based on the clinical judgement of the investigator) on BIBW 2992 (afatinib) monotherapy the patient must 
commence combination therapy (i.e. VPC1V1) as soon as possible but within 21 days of documented progression (unless radiotherapy is required – see 
section 3.2). Refer to Flow Chart B below.  


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Revised Trial Protocol 
Page 9 of 101 
 
 
FLOW CHART B (BIBW 2992 (AFATINIB) & PACLITAXEL/VINORELBINE COMBINATION TREATMENT)  
Follow this flow chart if 
paclitaxel or vinorelbine 
treatment added 
Treatment Course 1 * 
Treatment Course 2 and 
subsequent treatment courses * 
End of Treatment 
** 
Follow-up 
*** 
Additional 
Follow- up 
visits 
****
Visit abbreviation 
VPC1V1 
VPC1V2 
VPC1V3 
VPC2V1 
to 
VPCnV1 
VPC2V2 
to 
VPCnV2 
VPC2V3 
to 
VPCnV3 
EOT 
FU 1 
FU Vn 
Days 
Day 1 
(± 2 days) 
Day 8 
(± 2 days) 
Day 15  
(± 2 days) 
Day 1 
(± 2 days) 
Day 8 
(± 2 days) 
Day 15  
(± 2 days) 
0-14 days after 
permanent 
discontinuation of 
BIBW 2992 and 
Paclitaxel/ 
Vinorelbine # 
28 days after EOT 
visit  
(± 7 days) # 
Every 6 weeks 
after first FU 
Visit # 
Complete physical examination 
X 
X
Limited physical examination 1 
 
 
 
X 
 
 
 
X 
X 
Review Inclusion /exclusion 
criteria (for Part B – 
combination therapy part of 
study ) 
X 
 
 
 
 
 
 
 
 
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG performance status 
X 
 
 
X 
 
 
X 
X 
X 
12 Lead  ECG 2 
X 
 
 
X2 
 
 
X2 
 
 
ECHO or MUGA scan 3 
X 
 
 
X3 
 
 
X3 
 
 
Safety lab4 
X 
 
 
X 
 
 
X4 
X 
X 
Pregnancy test5 
X 
 
 
X 
 
 
X 
 
 
Tumour assessment 6 
X7 
 
 
See schedule below 
X6 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
Concomitant medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Compliance Check BIBW2992 
X 
 
 
X 
 
 
X 
 
 
Compliance check 
Paclitaxel/Vinorelbine 
X 
X 
X 
X 
X 
X 
 
 
 
Adverse events 
X 
X 
X 
X 
X 
X 
X 
X 
X9 


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Revised Trial Protocol 
Page 10 of 101 
 
 
CBC assessment prior to 
administering chemotherapy 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense Trial drugs 
X 
X 
X 
X 
X 
X 
 
 
 
BIBW 2992 (afatinib) 
treatment 
 
 
 
Continuous 
 
 
 
Paclitaxel/Vinorelbine weekly8 
X 
X
X
X
X
X
Termination of active treatment 
 
 
 
 
 
 
X 
 
 
Trial Completion 
 
 
 
 
 
 
 
X 
X 
 
Abbreviations for Visit types: VPC = Course of combination treatment with BIBW 2992 (Afatinib) + either Paclitaxel or Vinorelbine before the 3rd May 2013 
or Course of combination treatment with BIBW 2992 (Afatinib) + Paclitaxel only for patient starting in part B after the 3rd May 2013 or, V = Visit, EOT 
= End of Treatment, Visit, FU = Follow-up Visit  
* 
 All courses are 3 weeks in duration (21days). Patients may continue on treatment for unlimited courses, until the criteria for stopping medication are 
met- All patients who have been screened in the trial before protocol amendment 6 approval by IRBs and IECs will be able to enter in part B of 
the trial if they meet the inclusion/exclusion criteria for part B 
** 
If the decision to permanently discontinue trial treatment is taken during a scheduled visit, the EOT visit should be performed instead of the scheduled 
visit. From May 3rd, 2013, patients who will switch from the combination treatment Vinorelbine+Afatinib to Paclitaxel +Afatinib will have to 
undergo an EOT visit before the switch. Those patients will have a second EOT visit when they will permanently discontinue part B. See 
Section 3.1 
***    
 All patients should have a follow-up visit 28 days after the EOT visit. See section 5.2.2.2 for AEs reporting during this period. 
**** 
 Patients who have not progressed and not started further treatment should have further follow-up visits every 6 weeks until progression or start of 
further treatment. 
#  
The EOT, FU and all subsequent follow-up visits in Flow Chart B, are only applicable to patients who are permanently withdrawn from BIBW 2992 
(Afatinib) and vinorelbine/paclitaxel combination treatment.  
 
1. Includes height (at screening only), weight and body temperature. See section 5.2.1 for difference between a complete and limited physical examination 
2.  A 12-lead resting ECG will be performed on Day 1 of Course 1 of combination therapy and then on Day 1 of every third course (Day 1 of Course 4 
(VPC4V1), 7 (VPC7V1), 10 (VPC10V1) etc.), and at EOT (if not performed in the previous 8 weeks). 
3. ECHO or MUGA will be performed within 2 weeks of Day 1 of Course 1 of combination therapy and then on Day 1 of Course 4 (VPC4V1) and then at 
every third course (Course 7 (VPC7V1), 10 (VPC10V1), 13 etc.), and at EOT (if not performed in the previous 8 weeks).  
4. Includes haematology, serum biochemistry, coagulation and urinalysis (Baseline and EOT Visits only. See Section 5.2.3). Once patients are treated with 
paclitaxel or vinorelbine combination, weekly CBC need to be taken and results available and assessed prior to treatment.  
5. Pregnancy test is only to be performed if patient is of child bearing potential. Also refer to Sections 5.2.2.2 Pregnancy and 3.3.4 Removal of patients 
from therapy or assessments 


Boehringer Ingelheim 
27 June 2013 
BI Trial No.: 1200.98 
Revised Trial Protocol 
Page 11 of 101 
 
 
6. Tumour assessments should include CT scans of the chest and abdomen and, if clinically indicated, imaging of any other known or suspected sites of 
disease (e.g. breast, pelvis, brain) using an appropriate method (CT scan, MRI).  The same radiographic procedure must be used throughout the study 
(See Section 5.1.2). Bone scans and correlative imaging should be performed when clinically indicated. During combination therapy assessment will be 
performed every 6 weeks calculated from the start of combination therapy (i.e. 2 courses). In the event of early discontinuation or an interruption/delay 
to treatment, the tumour assessment schedule should not be changed. Brain metastases are considered as non-target lesions. A brain MRI should be 
performed at baseline in cases of clinically known, stable brain metastases. Brain MRI should be done of the respective lesion(s) at baseline and 
subsequently at every imaging time-point. Tumour assessment is not required at EOT visit if progressive disease has already been documented at 
scheduled imaging assessment. 
7. 
A tumour assessment is not required to be repeated at VPC1V1 if it has already been performed at the point when PD was determined on BIBW 2992 
(afatinib) (Monotherapy) in Flow Chart A and is within 3 weeks prior to starting combination treatment. If radiotherapy is given prior to commencing 
combination therapy, a tumour assessment must be performed at VPC1V1 to document the baseline status at start of combination therapy. 
8. 
Paclitaxel 80mg/m2 i.v. or Vinorelbine 25 mg/m² i.v. will be administered weekly once a patient progressed on BIBW 2992 (Afatinib) monotherapy. 
Special inclusion /exclusion criteria apply. Each administration should be preceded by CBC assessment and measurement of weight and body 
temperature. Pre-medications should be applied per product labelling.  Refer to Section 4.  
9. Only if treatment related or not resolved during 1st FU 
 
 
 


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Page 12 of 101 
 
 
TABLE OF CONTENTS 
TITLE PAGE ..................................................................................................... 1 
CLINICAL TRIAL PROTOCOL SYNOPSIS ............................................... 4 
FLOW CHART A (BIBW 2992 (AFATINIB) MONOTHERAPY) ............. 6 
FLOW CHART B (BIBW 2992 (AFATINIB) & 
PACLITAXEL/VINORELBINE COMBINATION 
TREATMENT) ....................................................................................... 9 
TABLE OF CONTENTS ................................................................................ 12 
ABBREVIATIONS .......................................................................................... 16 
1. 
INTRODUCTION ................................................................................ 19 
1.1 
MEDICAL BACKGROUND ............................................................................ 19 
1.2 
DRUG PROFILE ............................................................................................... 19 
2. 
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ...................................................................................... 21 
2.1 
RATIONALE FOR PERFORMING THE TRIAL ........................................ 21 
2.2 
TRIAL OBJECTIVES ....................................................................................... 22 
2.3 
BENEFIT - RISK ASSESSMENT .................................................................... 22 
3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION .......... 25 
3.1 
OVERALL TRIAL DESIGN AND PLAN ....................................................... 25 
3.1.1 
 Administrative structure of the trial ......................................................... 27 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP .......................................................................................... 27 
3.3 
SELECTION OF TRIAL POPULATION ....................................................... 28 
3.3.1 
Main diagnosis for study entry .................................................................... 28 
3.3.2 
Inclusion criteria ........................................................................................... 28 
3.3.3 
Exclusion criteria .......................................................................................... 29 
3.3.4 
Removal of patients from therapy or assessments .................................... 32 
3.3.4.1 
Removal of individual patients ................................................................. 32 
3.3.4.2  
Discontinuation of the trial by the sponsor .............................................. 33 
4. 
TREATMENTS .................................................................................... 34 
4.1 
TREATMENTS TO BE ADMINISTERED .................................................... 34 
4.1.1 
Identity of BI investigational product and comparator products ............ 34 
4.1.2 
Method of assigning patients to treatment groups .................................... 36 
4.1.3 
Selection of doses in the trial ....................................................................... 36 
4.1.4 
Drug assignment and administration of doses for each patient ............... 36 
4.1.5 
Blinding and procedures for unblinding .................................................... 39 
4.1.5.1 
Blinding .................................................................................................... 39 
4.1.5.2 
Procedures for emergency unblinding ...................................................... 39 
4.1.6 
Packaging, labelling, and re-supply ............................................................ 39 
4.1.6.1 BIBW 2992 (afatinib) ................................................................................... 39 
4.1.6.2 
Paclitaxel .................................................................................................. 40 
4.1.6.3 Vinorelbine ................................................................................................... 40 
4.1.7 
Storage conditions ........................................................................................ 41 


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4.1.8 
Drug accountability ...................................................................................... 41 
4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT .................................................................................................... 42 
4.2.1 
Rescue medication, emergency procedures, and additional 
treatments ...................................................................................................... 42 
4.2.2 
Restrictions .................................................................................................... 42 
4.2.2.1 
Restrictions regarding concomitant treatment .......................................... 42 
4.2.2.2  
Restrictions on diet and lifestyle .............................................................. 43 
4.2.2.3 
Management of diarrhoea following treatment with BIBW 2992 
(afatinib) ................................................................................................... 43 
4.2.2.4  
Management of nausea and vomiting following treatment with 
BIBW 2992 afatinib) ................................................................................ 44 
4.2.2.5 
Management of rash following treatment with BIBW 2992 
(afatinib) ................................................................................................... 45 
4.3 
TREATMENT COMPLIANCE ....................................................................... 46 
4.3.1 
BIBW 2992 (afatinib) ................................................................................... 46 
5. 
VARIABLES AND THEIR ASSESSMENT ..................................... 48 
5.1 
EFFICACY - CLINICAL PHARMACOLOGY OR 
PHARMACODYNAMICS .................................................................................. 48 
5.1.1 
Endpoints of efficacy .................................................................................... 48 
5.1.1.1 Primary endpoint ........................................................................................... 48 
5.1.1.2 Secondary endpoints ..................................................................................... 48 
.......................................................................................... 48 
5.1.2 
Assessment of efficacy .................................................................................. 49 
5.2 
SAFETY .............................................................................................................. 50 
5.2.1 
Endpoints of safety ....................................................................................... 50 
5.2.2 
Assessment of adverse events ...................................................................... 50 
5.2.2.1 
Definitions of adverse events ................................................................... 50 
5.2.2.2 
Adverse event and serious adverse event reporting ................................. 52 
5.2.3 
Assessment of safety laboratory parameters ............................................. 54 
5.2.4 
Electrocardiogram ........................................................................................ 54 
5.2.5 
Assessment of other safety parameters ...................................................... 55 
5.2.5.1 
Physical examination, ECOG performance score .................................... 55 
5.2.5.2 
Left ventricular function ........................................................................... 55 
5.2.5.3 
Vital signs ................................................................................................. 56 
5.3 
OTHER ................................................................................................................ 56 
 
 ............................................................................................ 56 
5.3.2 
Other assessments ......................................................................................... 56 
5.3.3  
Pharmacogenomic evaluation ..................................................................... 56 
5.4 
APPROPRIATENESS OF MEASUREMENTS ............................................. 56 
5.5 
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS .................................................................................. 57 
5.5.1 
Pharmacokinetic endpoints ......................................................................... 57 
5.5.2 
Methods of sample collection ....................................................................... 57 
5.5.3 
Analytical determinations ............................................................................ 57 
5.6 
BIOMARKERS .................................................................................................. 57 


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5.6.1 
Endpoints based on biomarkers .................................................................. 58 
5.6.2 
Methods of sample collection ....................................................................... 58 
5.6.3 
Analytical determinations ............................................................................ 58 
5.7 
PHARMACODYNAMICS ................................................................................ 58 
5.7.1 
Pharmacodynamic endpoints ...................................................................... 58 
5.7.2  
Methods of sample collection ....................................................................... 58 
5.8 
PHARMACOKINETIC - PHARMACODYNAMIC 
RELATIONSHIP ............................................................................................... 58 
6. 
INVESTIGATIONAL PLAN .............................................................. 59 
6.1 
VISIT SCHEDULE ............................................................................................ 59 
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................. 59 
6.2.1 
Screening and run-in period(s) (Up to 14 days before start of 
treatment) ...................................................................................................... 60 
6.2.2 
Treatment periods ........................................................................................ 61 
6.2.3 
End of trial and follow-up period ............................................................... 64 
7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE ..................................................................................... 66 
7.1 
STATISTICAL DESIGN - MODEL ................................................................ 66 
7.2 
NULL AND ALTERNATIVE HYPOTHESES ............................................... 66 
7.3 
PLANNED ANALYSES .................................................................................... 66 
7.3.1 
Primary analyses .......................................................................................... 66 
7.3.2 
Secondary analyses ....................................................................................... 67 
7.3.2.1 
Key secondary analyses .......................................................................... 67 
..................................................................................... 68 
..................................................................................... 69 
..................................................................................... 69 
7.3.4 
Interim analyses ............................................................................................ 70 
7.3.4.1 
Early stopping rule ................................................................................... 70 
7.3.5 
Pharmacokinetic analyses ............................................................................ 71 
7.3.6 
Pharmacodynamic analyses ......................................................................... 71 
7.3.7 
Pharmacogenomic analyses ......................................................................... 71 
7.4 
HANDLING OF MISSING DATA ................................................................... 71 
7.5 
RANDOMISATION ........................................................................................... 71 
7.6 
DETERMINATION OF SAMPLE SIZE ......................................................... 71 
8. 
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS............................................................................................. 72 
8.1 
STUDY APPROVAL, PATIENT INFORMATION, AND 
INFORMED CONSENT ................................................................................... 72 
8.2 
DATA QUALITY ASSURANCE ...................................................................... 73 
8.3 
RECORDS .......................................................................................................... 73 
8.3.1 
Source documents ......................................................................................... 73 
8.3.2 
Direct access to source data and documents .............................................. 73 
8.3.3 
Storage of records ......................................................................................... 73 
8.4 
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS .............................................................................................................. 73 
8.4.1 
Listedness ...................................................................................................... 73 


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8.4.2 
Expedited reporting to health authorities and IECs/IRBs ....................... 74 
8.5 
STATEMENT OF CONFIDENTIALITY ....................................................... 74 
8.6 
COMPLETION OF TRIAL .............................................................................. 74 
9. 
REFERENCES ..................................................................................... 75 
9.1 
PUBLISHED REFERENCES ........................................................................... 75 
9.2 
UNPUBLISHED REFERENCES ..................................................................... 77 
9.3 
POSTERS/ONLINE PUBLICATIONS ........................................................... 78 
10. 
APPENDICES ...................................................................................... 80 
10.1 
APPENDIX 1 COCKCROFT-GAULT FORMULA ...................................... 80 
10.2 
APPENDIX 2 ECOG SCALE ........................................................................... 81 
10.3 
APPENDIX 3 TUMOUR RESPONSE ASSESSMENT ACCORDING 
TO RECIST 1.1 .................................................................................................. 82 
10.4 
APPENDIX 4 LIST OF CYP3A4 SUBSTRATES, INHIBITORS, 
AND INDUCERS AND LIST OF POTENT INHIBITORS AND 
INDUCERS OF P-GLYCOPROTEIN ............................................................. 83 
10.4.1 List of CYP3A4 substrates, inhibitors, and inducers .................................... 83 
10.4.2. List of potent inhibitors and inducers of P-glycoprotein ............................. 84 
10.5 
APPENDIX 5 CLINICAL EVALUATION OF LIVER INJURY ................. 85 
10.5.1 
Introduction .................................................................................................. 85 
10.5.2 
Procedures ..................................................................................................... 85 
11. 
SUMMARY OF CLINICAL TRIAL PROTOCOL 
MODIFICATIONS .............................................................................. 87 


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ABBREVIATIONS 
 
AE 
Adverse Event 
ALT 
Alanine Amino Transferase 
ALTTO 
The Adjuvant Lapatinib and/Or Trastuzumab Treatment Optimisation 
study 
AUC 
Area under the Curve 
BC 
Breast Cancer  
CA 
Competent Authority 
CBC 
Complete Blood Count 
CI 
CK-ELPR 
Confidence Interval 
Creatinine Kinase Electrophoresis 
CPK 
Creatinine Phosphokinase 
CR 
Complete Response 
CML 
Clinical Monitor Local 
CRA 
Clinical Research Associate 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMF 
Clinical Trial Master File 
CTP 
Clinical Trial Protocol 
CTR 
Clinical Trial Report 
DDI 
Drug-Drug Interaction 
DILI 
Drug Induced Liver Injury 
DMC 
Data Monitoring Committee 
DNA 
Deoxyribonucleic Acid 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
ECG 
Electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EGFR 
ELPR 
Epidermal Growth Factor Receptor 
Electrophoresis 
EOT  
End of Treatment 
EORTC 
European Organisation for Research and Treatment of Cancer 
ER 
Estrogen Receptor 
EU 
Europe 
EudraCT 
European Clinical Trials Database 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FFPE 
Formalin Fixed Paraffin Embedded  
FU 
Follow-up 
GCP 
Good Clinical Practice 
GFR 
Glomerular Filtration Rate 
HPC 
Human Pharmacology Centre 
HER2 
Human Epidermal Growth Factor Receptor 
HR 
Hazard Ratio 


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HrR 
Hormone Receptor 
HRQoL 
Health Related Quality of Life 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IHC 
Immunochemistry 
INR 
International Normalised Ratio 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
ISF 
Investigator Site File 
i.v. 
intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web-based Response System 
LVEF 
Left Ventricular Ejection Fraction 
MAB 
Monoclonal antibody 
mBC 
Metastatic breast cancer  
MedDRA 
Medical Dictionary for Drug Regulatory Activities 
mg 
Milligram 
MOA 
Mode of Action  
MRI 
Magnetic Resonance Imaging 
MST 
Medical Subteam 
MUGA 
Multiple Gate Acquisition 
NeoALTTO 
The Neo Adjuvant Lapatinib And/Or Trastuzumab Treatment Optimisation 
study 
NIMP 
Non Investigational Medicinal Product  
NSCLC 
Non Small Cell Lung Cancer  
OPU 
Operative Unit 
OR 
Objective Response 
OS 
Overall Survival 
PD 
Progressive Disease 
PFS 
Progression Free Survival 
P-gp 
P-glycoprotein  
PgR 
Progesterone Receptor 
PI 
Prescribing Information 
PK 
Pharmacokinetic 
PR 
Partial Response 
p.o. 
per os (oral) 
PCC 
Protocol Challenge Committee 
q.d. 
quaque die (once a day) 
QLQ 
Quality of Life Questionnaire 
RDC 
Remote Data Capture 
RECIST 
Response Evaluation Criteria in Solid Tumours 
SAE 
Serious Adverse Event 
s.c. 
subcutaneous 
SD 
Stable Disease 
SmPC 
Summary of Product Characteristics 
TCM 
Trial Clinical Monitor 


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TDMAP 
Trial Data Management and Analysis Plan 
t.i.d. 
ter in die (3 times a day) 
TKI 
Tyrosine Kinase Inhibitor 
TMM 
Team Member Medicine 
tmax 
Time from (last ) dosing to the maximum measured concentration of the 
analyte in plasma 
TNM 
Tumour (lymph) Nodes, Metastasis 
TMW 
Trial Medical Writer 
TSAP 
Trial Statistical Analysis Plan 
US 
United States 
 


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1. 
INTRODUCTION 
1.1 
MEDICAL BACKGROUND 
Breast cancer is the most common malignant disease in women in the Western world. In the 
US, more than 200,000 women will be diagnosed with breast cancer every year, and 
approximately a fifth will eventually die of the disease (R09-5656). 
Aberrant Epidermal Growth Factor Receptor (EGFR) and Human Epidermal Growth Factor 
Receptor (HER2) signalling has been causally associated with cancer cell proliferation and 
decreased survival (R08-1376, R08-1380, R08-1386). The HER2 proto-oncogene encodes a 
185 kDa transmembrane receptor kinase which is amplified and/or overexpressed in 25% - 
30% of human breast cancers. Tyrosine phosphorylation of the HER2 receptor leads to 
activation of specific signal transduction pathways including the ras/MAP kinase cascade 
with transduction pathways ultimately converging on the cell nucleus with activation of the 
receptor (R01-0299). The association between HER2-overexpression and poor prognosis in 
node-positive and advanced breast cancer has been shown by a number of studies (R06-0964, 
R08-1382, R08-1384, R08-1392, R08-1393, R08-1394, R08-1395, and R08-1396). Recent 
studies have also shown the prognostic value of HER2-overexpression in patients with node-
negative breast cancer (R08-1397). 
Based on this association between the members of EGFR/HER2 family and worse clinical 
outcome, antibodies and small molecules that specifically target these receptor tyrosine 
kinases were developed for therapeutic use. 
1.2 
DRUG PROFILE  
BIBW 2992 (afatinib) is a novel oral EGFR/HER2 inhibitor that offers the chance to control 
both recurrent as well as distant metastatic disease on an outpatient basis with continuous 
treatment. It is a potent, irreversible, combined EGFR/HER2 inhibitor both in vitro and in 
vivo1. Receptor tyrosine kinases other than the ErbB (Class I) family and non-receptor type 
tyrosine kinases were not inhibited. Continuous treatment with BIBW 2992 (afatinib) has the 
potential to provide significant benefit to patients with advanced malignancies by inducing 
tumour responses or slowing of tumour progression and metastasis. Due to its mechanism of 
action, treatment with BIBW 2992 (afatinib) will result in a more selective antitumour 
activity than classical cytotoxic chemotherapeutics which have an indiscriminate effect on all 
proliferating cells. BIBW 2992 (afatinib) final formulation is available in 20, 30, 40 and 50 
mg film-coated tablets to be used for clinical trials up to Phase III.  
The available clinical efficacy data for BIBW 2992 (afatinib) is based on phase I and phase II 
studies and indicate that patients with advanced solid tumours may benefit from BIBW 2992 
(afatinib). Three phase IIb/III and phase III trials in patients with advanced non-small cell 
lung cancer (NSCLC) and a phase III trial in breast cancer are currently ongoing. Objective 
responses have been observed to date in patients with metastatic NSCLC, breast cancer (BC), 
____________________________ 
1 Since this clinical trial protocol was produced, the mechanism of action of BIBW 2992 (afatinib) has been 
updated (P12-09544) 


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 oesophageal cancer, cholangiocarcinoma and others in monotherapy and combination 
treatment in phase I and phase II trials (P09-10056,  P08-11756, P10-01317 and P09-10626). 
Ongoing and recently completed phase II studies show clinical activity of BIBW 2992 
(afatinib) in patients with EGFR mutation positive NSCLC and patients with HER2 positive 
breast cancer (U10-3047-01, U10-2018-01, U10-1598-01, U09-2463-03) 
Overall 14 patients with metastatic breast cancer were included in the Phase I BIBW 2992 
(afatinib) monotherapy trials. Of these 4 patients showed stable disease (SD) as best response 
to treatment with duration of at least 12 weeks in 3 patients and duration of 24 weeks in 1 
patient. Another five patients with metastatic breast cancer (mBC) were entered into Study 
1200.20, a Phase I BIBW 2992 (afatinib) trial in combination with docetaxel.  BIBW 2992 
(afatinib) was administered on days 2-4 following a docetaxel administration on day 1, in a 
21 day course. One mBC patient showed a complete response (CR), two a partial response 
(PR) while on BIBW 2992 (afatinib) treatment and another patient had stable disease.  
Full details of the clinical pharmacology, toxicology, clinical pharmacokinetics and safety 
data can be found in the current Investigator Brochure for BIBW 2992 (afatinib) (U03-3218)  


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2. 
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT 
2.1 
RATIONALE FOR PERFORMING THE TRIAL 
Patients who received neo-adjuvant and/or adjuvant HER2-targeted treatment will be 
recruited into this trial. Trastuzumab is currently registered as HER2-targeted treatment in the 
adjuvant and 1st line metastatic setting in combination with chemotherapy and as 
monotherapy in later lines of treatment of BC (R10-4385). Lapatinib is registered as 2nd line 
treatment in combination with capecitabine in HER2-pos. mBC patients after failure of 1st 
line trastuzumab therapy. Nevertheless both compounds are used outside of their registered 
indications (off-label) in earlier lines. One recently published trial showed benefit for the 
combination of both targeted agents even in heavily pre-treated mBC patients (U10-1491-01). 
The working hypothesis behind the combination of two targeted agents, trastuzumab, a 
monoclonal antibody (MAB) and lapatinib, a tyrosine kinase inhibitor (TKI), is the different 
mode of action (MOA) leading to additive efficacy on different levels of signal transduction 
pathways, thus causing total HER2-inhibition. Most recently several trials used trastuzumab 
and lapatinib alone or in combination in the neo-adjuvant setting (NeoALTTO, Gepar-Quatro 
– R10-5364) or in the adjuvant setting (ALTTO – R10-5362) in combination with paclitaxel. 
If HER2-positive BC-patients already receive taxanes and both registered targeted agents 
early on in therapy, treatment options in the metastatic setting are limited. Once these patients 
relapse, they have a high unmet medical need for innovative therapeutics and treatment 
algorithms. Currently there are no therapies available for patients who failed total HER2-
blockade and little is known about the pathological mechanisms involved. Accordingly there 
is an urgent need to develop treatments for this patient population.  
BIBW 2992 (afatinib) is a dual irreversible EGFR/HER2-inhibitor and has shown clinical 
efficacy in HER2-overexpressing patients with metastatic breast cancer who failed prior 
trastuzumab treatment. This trial provided proof of concept to further evaluate BIBW 2992 
(afatinib) in a larger cohort of HER2-positive metastatic breast cancer patients, who failed 
prior trastuzumab treatment. Moreover BIBW 2992 (afatinib) unlike lapatinib is an 
irreversible EFGR/HER2 inhibitor with clinical efficacy in EGFR driven tumours (P09-
06809). Preclinical data further support the efficacy of BIBW 2992 (afatinib) in trastuzumab 
resistant, HER2-positive (SUM 190 PT ) breast cancer cell lines and HER2-negative SUM 
149 PT): The latter suggests that heterodimerisation of ErbB receptors (HER2/EGFR) even in 
HER2-positive disease plays an important role (P09-08104, U09-1454-01, U09-1455-01) in 
tumour growth suppression of HER2-positive/trastuzumab resistant cell lines. BIBW 2992 
(afatinib) combines well with paclitaxel and vinorelbine preclinically and clinically (U03-
3218, U10-1491-01, P09-10626, and P09-05119) 
As BIBW 2992 (afatinib) has a different MOA from trastuzumab and lapatinib, shows 
monotherapy efficacy in heavily pre-treated patients comparable to that of 
trastuzumab/lapatinib combinations in the Blackwell trial (R09-4140) and clinically truly is a 
dual EGFR/HER2 inhibitor, BIBW 2992 (afatinib) monotherapy provides an interesting and 
rational treatment to these patients in 1st line mBC and the proposed trial design provides an 
interesting and rational alternative. In case patients don’t respond or relapse on monotherapy 
they may be “rescued” by addition of chemotherapy, i.e. paclitaxel weekly if the prior 


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paclitaxel-free interval is more than 12 months or vinorelbine in all other cases (only for 
patients commencing treatment with this combination prior to 03 May 2013). The latter 
is based on oncogene addiction which has let to the use of “Herceptin beyond progression” 
over the past two decades (R09-2787). The current trial will investigate the use of BIBW 
2992 (afatinib) beyond progression in breast cancer. 
2.2 
TRIAL OBJECTIVES 
This open label phase II study will investigate the efficacy and safety of BIBW 2992 
(afatinib) alone and in combination with weekly treatment with paclitaxel or vinorelbine (in 
patients who progress on BIBW 2992 (afatinib) monotherapy only) as a new treatment 
algorithm in patients with HER2-overexpressing, metastatic breast cancer, who failed HER2-
targeted treatment in the neoadjuvant and/or adjuvant setting. 
2.3 
BENEFIT - RISK ASSESSMENT 
HER2-positive breast cancer still has a poor prognosis despite recent advances which came 
with the introduction of targeted trastuzumab treatment into therapy. Trastuzumab is a 
standard component of HER2 positive breast cancer treatment although its use is associated 
with cardiotoxicity. Patients develop resistance to trastuzumab or display primary resistance 
to trastuzumab during therapy or upfront, but still most patients continue trastuzumab beyond 
progression in combination with other cytotoxic drugs with some therapeutic benefit as there 
are not many options available. Lapatinib, a small molecule reversible, dual EGFR/HER2-
TKI is registered in combination with capecitabine for the treatment of 2nd-line HER2-
positive mBC.  
Both trastuzumab and lapatinib seem to complement each other by a slightly different MOA 
thus combination of both targeted treatments is supposed to give added benefit to patients. 
Still lapatinib clinically is not being developed in EGFR-driven malignancies whereas BIBW 
2992 (afatinib), a small molecule irreversible, dual EGFR/HER2 RTKI not only showed 
preclinical and clinical efficacy in trastuzumab resistance, but also showed clinical efficacy in 
EGFR-driven malignancies (P09-06809). In trastuzumab resistance, alternative pathways, 
among those the EGFR-pathway, play an important role. In patients, who received various 
targeted treatment options early in treatment once relapse/resistance develops, targeting these 
alternative pathways may become crucial for patients’ prognosis. As such BIBW 2992 
(afatinib) monotherapy treatment may provide a reasonable therapeutic approach in a 
scenario, where patients early on in therapy have received both registered HER2-targeted 
treatments and nonetheless relapse: For these patients at present there are no treatment 
recommendation/ algorithms available.  


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BIBW 2992 (afatinib) combines well with paclitaxel and vinorelbine. Side effects observed for this 
combination are consistent with what is known for either compound alone (see IB, U03-3218, to 
vinorelbine interim report (U10-1491-01) and to SmPC).The Data Monitoring Committee 
(DMC) of the LUX-Breast 1* trial (EUDRA CT No.: 2009-015476-98, NCT01125566) 
conducted a benefit-risk analysis as pre-specified in the clinical trial protocol. A DMC 
recommendation which was issued on 26 April 2013 concluded, that based on the 
benefit-risk analysis, treatment in the experimental arm (afatinib  40 mg + vinorelbine 
25 mg/m2 weekly i.v.) should be discontinued.  
The benefit-risk analysis was based on data from over half of the planned number of 
patients enrolled. The DMC concluded that there is a low likelihood of study 1200.75 
meeting the pre-defined criteria for increased efficacy in terms of PFS. In addition, a 
high rate of treatment discontinuations and dose reductions as well as a higher rate of 
serious adverse events and deaths was observed in the experimental arm compared to 
the control arm trastuzumab + vinorelbine. 
Boehringer Ingelheim and the Executive Committee of the trial agreed to follow the 
DMC’s recommendation and decided to stop further randomisation into trial 1200.75 
and to discontinue further treatment with the combination of afatinib and vinorelbine.  


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Since one of the treatment options in Part B of Trial LUX-Breast 2 is the combination of 
afatinib + vinorelbine, and in light of the unfavourable benefit-risk observed in 1200.75 
Boehringer Ingelheim decided as a precautionary measure to stop the inclusion of new 
patients into the afatinib + vinorelbine combination in Part B of LUX-Breast 2 on the 
3rd May 2013. Continuation of vinorelbine+ BIBW2992 (afatinib) can only be allowed 
for patients already on treatment before the 3rd May 2013 and benefitting from the 
treatment combination. For new patients this combination will no longer be offered 
after the 3rd May 2013. Part A of the trial and continuation of treatment with paclitaxel 
in Part B were not affected.  
 
Furthermore a decision has been made to stop further enrolment of new patients in Part 
A: 
-Afatinib+VNR Treatment in part B is no longer an option,  as the latter showed an 
unfavourable benefit/risk ratio in trastuzumab pre-treated patients leading to 
termination of the pivotal trial 1200.75. As a consequence the eligible patient population 
to be included in part A will narrow down, as patients receiving adjuvant/neoadjuvant 
paclitaxel are not readily rechallenged with paclitaxel when receiving 1st line mBC 
treatment. This will generate further difficulties for recruitment.  
- In addition since the trial 1200.98 started, pertuzumab/trastuzumab + docetaxel 
intended for patients who have not received prior treatment for metastatic breast 
cancer with an anti-HER2 therapy or chemotherapy, has been approved in 2012 and is 
becoming standard of care  wherever available. This will establish further hurdles for a 
timely recruitment into part A of trial 1200.98. 
-Approximately 60 out of 69 patients enrolled to date in this trial have received 
trastuzumab only based regimens as prior treatment in the adjuvant and neoadjuvant 
setting. By the time of approval of amendment 6, it is expected that approximately 80 
patients will have been treated in this trial. As only 9 patients have received lapatinib or 
a combination of lapatinib and trastuzumab as prior treatment so far, the efficacy 
analysis will be driven by trastuzumab pretreated patients. 80 patients will address the 
efficacy of afatinib in the trastuzumab-pretreated patients with a high statistical 
probability (see section 7.6 for details) 
In conclusion, the potential benefits to be expected from BIBW 2992 (afatinib) 
monotherapy or its combination with paclitaxel weekly or vinorelbine weekly are likely 
to outweigh its risks in the population described. 


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3. 
DESCRIPTION OF DESIGN AND TRIAL POPULATION 
3.1 
OVERALL TRIAL DESIGN AND PLAN 
This is an open label study designed to investigate the efficacy and safety of  BIBW 2992 
(afatinib) alone and in combination with weekly paclitaxel or weekly vinorelbine as treatment 
in patients with HER2-overexpressing, metastatic breast cancer, who failed HER2-targeted 
treatment in the neoadjuvant and/or adjuvant setting. All patients will start on BIBW 2992 
(afatinib) monotherapy. In case of progression of disease on monotherapy they will 
commence combination therapy as described above (also compare Figure 3.1:1 below). 
 
 
Figure 3.1: 1 
Schematic of Trial Design 
All patients will initially undergo a 2 week screening period during which time their 
eligibility will be confirmed. Eligible patients will receive 40 mg/day BIBW 2992 (afatinib) 
monotherapy in 3-weekly treatment courses for treatment of HER2-overexpressing metastatic 
breast cancer (mBC) (1st line patients), until progression of disease (PD) assessed by 
RECIST (1.1) Refer to Flow Chart A and Figure 3.1:1 above. In the event of treatment-
** 
**    From the 3rd May 2013, patients will only be able to enter in the combination therapy 
BIBW2992 (Afatinib) and Paclitaxel i.v 80mg/m2 weekly 
***patient recruitment will be stopped after approval of protocol amendment 6, however 
patients who signed PIC before that date will proceed as per schedule described below 
*** 


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related adverse events, BIBW 2992 (afatinib) doses will be reduced according to Dose 
reduction scheme (Table 4.1.4: 1). 
Patients showing disease progression on BIBW 2992 (afatinib) monotherapy (then eligible 
for 2nd line mBC treatment) will then receive: 
- before the 3rd May 2013: chemotherapy, i.e. paclitaxel or vinorelbine weekly as 
decided by the investigator, which will be added to BIBW 2992 (afatinib).  
-after the 3rd May 2013: paclitaxel weekly, which will be added to BIBW 2992 
(afatinib). 
See Flow Chart B and Figure 3.1:1 above. Chemotherapy must commence as soon as possible 
but within 21 days of documented progression (unless radiotherapy is required – see section 
3.2). 
For patients on treatment with the combination of vinorelbine + BIBW 2992 (afatinib) 
in Part B of the trial on the 3rd May 2013, the investigator should perform a thorough 
benefit-risk analysis to assess whether the patients may continue on this combination. 
The investigator should then discuss and agree this with the patient whether the 
combination will be continued: 
• Should the decision be to continue treatment with vinorelbine + BIBW 2992 
(afatinib) or to change the chemotherapy regimen from vinorelbine to paclitaxel, 
the patients will remain on trial and the investigator should document this in the 
patient’s notes (the patients will need to met the inclusion and exclusion criteria 
for paclitaxel to be able to switch treatment regimen).  
• Should the decision be to discontinue treatment with the combination, the 
investigator should document this in the patient’s notes and an EOT visit should 
be conducted.  Patients will need to be followed up as per protocol after the EOT 
visit. 
With protocol amendment 6 the sponsor will stop recruitment into the trial (part A), 
pending approval by IRBs and IECs. (See section 3.3.4.2 and Section11section 11). All 
patients who already signed the PIS/PIC when the recruitment is stopped will proceed 
as planned per protocol 
An early stopping rule will be implemented to minimise the number of patients treated if 
BIBW 2992 (afatinib) was ineffective in the given therapeutic setting. See Section 7.3.4.1 for 
further details.  
All patients will attend an End of Treatment (EOT) Visit when they discontinue the study 
treatment permanently. All patients will then have a follow-up visit 28 days after the EOT 
Visit. Following this, patients who still have not experienced disease progression and not 
started further treatment, will have further follow- up visits every 6 weeks until disease 
progression or start of further treatment.  
After a patient has completed participation in the trial, information on post-trial treatment, 
best response and vital status will be collected, if available. 


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The end of the study is when the last patient entered has either experienced a second disease 
progression or started further treatment. 
3.1.1 
 
Administrative structure of the trial 
The investigators participating in the trial must have experience in this type of trial and 
investigations.  
The co-ordinating investigator, who will sign the clinical trial report of this trial, has been 
appointed by Boehringer Ingelheim. The co-ordinating investigator has experience in this 
type of trial and investigations.  
Safety laboratory assessments and tumour marker assessments are performed at the 
investigator site. Analysis of HER2- and HrR status will be performed centrally by an 
authorized laboratory. The results of HER2-analysis don’t need to be available to confirm the 
eligibility of the patient for trial participation. They will be used for retrospective analyses 
only.  
Tumour images have to be assessed by the investigator at the site and will be used for clinical 
decisions on whether or not to continue treatment on study. 
There will be no Steering Committee or Data Monitoring Committee for this trial. 
All trial relevant documentation is stored in Boehringer Ingelheim’s Clinical Trial Master 
File (CTMF). Trial relevant documentation which has to be at the trial site is filed in the 
investigator site file (ISF) at the investigator site. 
On-site monitoring will be performed by Boehringer Ingelheim or a CRO appointed by 
Boehringer Ingelheim. It is intended to have a discussion on the early stopping of the trial and 
that this will not be based on a discussion with all investigators.  
 
3.2 
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP 
The primary objective of this trial is to investigate the efficacy and safety of BIBW 2992 
(afatinib) alone and in combination with weekly treatment with paclitaxel or vinorelbine (in 
patients who progress on BIBW 2992 (afatinib) monotherapy only) as first line treatment in 
patients with HER2-overexpressing, metastatic breast cancer, who failed HER2-targeted 
treatment in the neoadjuvant and/or adjuvant setting. Patients must be HER2-positive by 
documented HER2-status in their files, have been treated with prior HER2-targeted treatment 
and have archived tissue samples available for central re-assessment of HER2-status.   
Patients meeting the eligibility criteria will receive BIBW 2992 (afatinib) monotherapy at a 
dose of 40 mg/d until progression of their disease whereupon patients will additionally 
receive either paclitaxel weekly at a dose of 80 mg/m2 or vinorelbine at a weekly dose of 25 
mg/m2. From the 3rd May 2013 after progression on BIBW 2992 (afatinib) monotherapy, 
patients will only be allowed to additionally receive paclitaxel weekly at a dose of 80 


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mg/m2 in part B of the trial. Patients will not be able to enter in the combination part of 
the trial (part B) and receive vinorelbine treatment (section 2.3). With protocol 
amendment 6 the sponsor will stop recruitment into the trial (part A), pending approval 
by IRBs and IECs. (See section 3.3.4.2 and section 11) 
Disease status will be assessed clinically by the investigator at the end of the first treatment 
course and each following treatment course. At the time of progression the investigator will 
decide which study chemotherapy treatment to add (i.e. paclitaxel or vinorelbine). Patients 
allocated to paclitaxel treatment must not have received paclitaxel treatment within a year of 
re-starting. Patients allocated to vinorelbine treatment should not have previously received 
vinorelbine treatment. 
If any metastatic sites associated with the first disease progression (i.e. progression on first 
line treatment with afatinib) require short course palliative radiotherapy, patients should 
continue on the afatinib monotherapy schedule (part A) whilst radiotherapy is administered. 
Details of the radiotherapy treatment administered should be documented on the CRF. 
Treatment with combination therapy (part B) should commence 3-4 weeks after completion 
of radiotherapy. Visit VPC1V1 should be performed prior to commencing combination 
therapy and should include a tumour assessment.  
Patients with clinical benefit will continue to receive BIBW 2992 (afatinib) monotherapy. If 
patients experience further disease progression after treatment with BIBW 2992 (afatinib) 
and chemotherapy i.e., paclitaxel, or vinorelbine, they will be withdrawn from the study. All 
patients will have a Follow-up Visit, 28 days after the End of Treatment Visit. Patients who 
have not progressed and not started further treatment should have further follow-up visits 
every 6 weeks until disease progression or start of further treatment.   
After a patient has completed participation in the trial, information on post-trial treatment, 
best response and vital status will be collected, if available. 
 
3.3 
SELECTION OF TRIAL POPULATION 
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not. 
3.3.1 
Main diagnosis for study entry  
All patients that will be included into the trial must have been diagnosed with histologically 
confirmed HER2-overexpressing disease breast cancer and must have stage IV metastatic 
disease. 
3.3.2 
Inclusion criteria  
These inclusion criteria apply to both mono and combination therapy (Parts A and B) 


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Inclusion criteria for Part A (Flow Chart A) 
1. 
Female patients ≥18 years. 
2. 
Proven diagnosis of HER2-overexpressing, histologically confirmed breast 
cancer. Patients must have an archived tissue sample available for central re-
assessment of HER2-status. (The results of this analysis are not required to be 
available to confirm the eligibility of the patient to take part in the study). 
3. 
Stage IV metastatic disease.  
4. 
At least one measurable lesion according to RECIST 1.1. Skin, bone and brain 
lesions are considered non-target lesions. 
5. 
Eastern Cooperative Oncology Group (ECOG) score of 0,1 or 2 (See 
Appendix 2). 
6. 
Life expectancy of at least six (6) months. 
7. 
Written informed consent that is consistent with ICH-GCP guidelines and 
local legislation. 
8. 
Must have failed or progressed on either trastuzumab or lapatinib or 
trastuzumab and lapatinib treatment in the neoadjuvant and/or adjuvant setting. 
 
Inclusion criteria for Part B (Flow Chart B) – BIBW 2992 (afatinib) combination 
therapy with paclitaxel and vinorelbine only 
 
9. 
Must have failed or progressed trastuzumab or lapatinib or trastuzumab and 
lapatinib treatment in the neoadjuvant and/or adjuvant setting and on BIBW 
2992 (afatinib) monotherapy in the 1st line metastatic setting. 
10. 
Must be eligible for re-treatment with paclitaxel,  refer to exclusion criterion 
(29). or vinorelbine, refer to exclusion criterion (30) 
3.3.3 
Exclusion criteria 
These exclusion criteria apply to both monotherapy and combination therapy (Parts A 
and B)  
Exclusion criteria for Part A – BIBW 2992 (afatinib) monotherapy only (See 
Flow Chart A) 
1. 
Requirement for treatment with any of the prohibited concomitant medications 
listed in Section 4.2.2 (restrictions).  


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2. 
Must not have quickly progressing visceral disease. 
3. 
Known pre-existing interstitial lung disease. 
4. 
Prior first line therapy for metastatic breast cancer 
5. 
Radiotherapy, chemotherapy, immunotherapy, trastuzumab or lapatinib 
treatment or surgery (other than biopsy) within 4 weeks prior to trial treatment. 
Treatment with palliative radiotherapy (short course to non-target lesions) is 
allowed. 
6. 
Hormone therapy for breast cancer within 2 weeks prior to trial treatment. 
7. 
Active brain metastases (defined as stable for <4 weeks and/or symptomatic 
and/or requiring changes of treatment with anticonvulsants or steroids and/or 
leptomeningeal disease). 
8. 
Any other current malignancy or malignancy diagnosed within the past five 
(5) years (other than bilateral primary breast cancer, metastases to the 
contralateral breast, non-melanomatous skin cancer and in situ cervical 
cancer). 
9. 
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. 
10. 
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.  
11. 
Myocardial infarction within 6 months prior to trial treatment. 
12. 
Cardiac left ventricular function with resting ejection fraction of less than 
50%. 
13. 
Any other concomitant serious illness or organ system dysfunction which in 
the opinion of the investigator would either compromise patient safety or 
interfere with  the evaluation of the safety of the test drug. 
14. 
Absolute neutrophil count (ANC) < 1.5 x 109/L  
15. 
Calculated Creatinine clearance < 60 ml / min (Cockcroft formula – Appendix 
1) or serum creatinine > 1.5 times upper limit of normal (Note that both values 
must be checked and both must be within the limits for inclusion) 
16. 
Bilirubin > 1.5 times upper limit of normal. 


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17. 
Aspartate amino transferase (AST) or alanine amino transferase (ALT) > three 
times the upper limit of normal (ULN) (if related to liver metastases > five 
times ULN). 
18. 
Women of childbearing potential, unwilling to use a medically acceptable 
method of contraception during the trial. Acceptable methods of contraception 
include surgical sterilisation (tubar ligation/hysterectomy), 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 intra-uterine device (IUD) 
(female and male condom, diaphragm and cervical cap must all 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 methods of 
contraception.  
NOTE: Women of child bearing potential, must also continue to use effective 
contraception for at least 1 month after treatment has ended if they have been 
treated with BIBW 2992 monotherapy, for at least 3 months after treatment 
has ended if they have been additionally treated with vinorelbine and for at 
least 6 months after treatment has ended, if they have been additionally treated 
with paclitaxel during the study. ). In any case continuing measures after 
ceasing study medication should be done based on the latest information 
available for the study drugs: IB (U03-3218) for BIBW2992 and SPC/PI for 
paclitaxel and vinorelbine.  
19. 
Pregnancy or breast-feeding (lactation). 
20. 
Patients unable to comply with the protocol. 
21. 
Known Hepatitis B infection, known hepatitis C infection or known HIV 
carrier. 
22. 
Known or suspected active drug or alcohol abuse. 
23. 
Any contraindications for therapy with paclitaxel or vinorelbine. 
24. 
Known hypersensitivity to BIBW 2992 (afatinib) or the excipients of any of 
the trial drugs including paclitaxel and vinorelbine. 
25. 
Treatment with an investigational drug within the previous 4 weeks prior to 
study or concurrent participation in another clinical trial. 
26. 
Prior treatment with EGFR/HER2-targeted small molecules or antibodies other 
than trastuzumab and lapatinib in the neoadjuvant and/or adjuvant setting. 
27. 
Platelet count < 100 x 109/L for BIBW 2992 (afatinib) monotherapy. 


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Exclusion criteria for Part B – BIBW 2992 (afatinib) combination therapy only 
(see Flow Chart B) – Exclusion criteria 12 and 14 has to be rechecked before starting 
treatment in part B 
28. 
Prior treatment with EGFR/HER2-targeted small molecules or antibodies other 
than trastuzumab and lapatinib in the neoadjuvant and/or adjuvant setting, 
and/or BIBW 2992(afatinib) in the 1st line setting. 
29. 
If treatment with paclitaxel is planned, Patient must not have received prior 
treatment with paclitaxel in the past 12 months.  The timeframe between 
paclitaxel treatments needs to be 12 months to allow re-start of paclitaxel.  
30. 
If treatment with vinorelbine is planned, patient must not have received prior 
vinorelbine treatment. 
30 
Platelet count of < 100000/mm3 for BIBW 2992 (afatinib) combination 
treatment with paclitaxel or BIBW2992 (afatinib) combination with 
vinorelbine. 
 
3.3.4 
Removal of patients from therapy or assessments 
3.3.4.1 Removal of individual patients 
A patient has to be withdrawn from study therapy in case any of the following applies: 
1. The patient withdraws consent to further study treatment.  
2. Documented progressive disease (see Appendix 3) on combination treatment of BIBW 
2992 (afatinib) and paclitaxel/vinorelbine, i.e. documented 2nd progression whilst on trial  
3. The patient is no longer able to receive any of the study treatments (e.g. adverse events, 
pregnancy, concomitant diagnoses, concomitant therapies or administrative reasons).  
4. Significant deviation from the protocol or eligibility criteria. The decision to continue or 
withdraw treatment will be made after discussion between the local clinical monitor of 
the sponsor and the investigator 
5. Diagnosis of interstitial lung disease 
6. If a patient experiences deterioration in left ventricular cardiac function (LVEF) to 
CTCAE Grade ≥3. 
7. Further dose reductions considered necessary but not allowed according to the protocol 
(for exceptions, refer to Section 4.1.4.) 
8. The patient receives any of the prohibited medications listed in the current SmPC or  
prescribing information (PI) for paclitaxel and vinorelbine (See Section 4.2)  
 
Except for reasons 1, 2, 5 and 6, it should be attempted to retain the patient in the study and 
to perform additional follow-up visits at the tumour assessment schedule until progression 
of disease or start of new treatment. 


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3.3.4.2  Discontinuation of the trial by the sponsor 
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons: 
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 if applicable (See section 2.3) 
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). 


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4. 
TREATMENTS 
4.1 
TREATMENTS TO BE ADMINISTERED 
Patients will initially be treated with BIBW 2992 (afatinib) 40mg/day monotherapy until 1st 
disease progression on trial. Upon the latter, patients will additionally receive either 
paclitaxel weekly at a dose of 80 mg/m2 or vinorelbine at a weekly dose of 25 mg/m2 ( See 
section 3.1). In case there is a timeframe of less than 12 months between paclitaxel 
treatments, patients can only receive vinorelbine, otherwise it will be investigator’s 
choice of combination treatment. The manufacturers for each of the products are listed in 
Section 4.1.1. All three study treatments will be supplied by Boehringer Ingelheim to the 
investigator for this study.  
4.1.1 
Identity of BI investigational product and comparator products 
Substance (INN):  
 
BIBW 2992 (afatinib)  
Pharmaceutical form:  
Film-coated tablets 
Source:  
 
 
Boehringer Ingelheim Pharma GmbH & Co. KG 
Unit strength:  
20mg, 30mg and 40mg film-coated tablets (the dose of BIBW 
2992 (afatinib)) in the film-coated tablets is related to the free 
base equivalent of BIBW 2992 (afatinib). 
Daily Dose:   
 
40mg  
Duration of use:  
Continuous daily dosing until disease 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 
Substance (INN) Paclitaxel 
Paclitaxel is a registered commercially available cytotoxic drug. Paclitaxel will be provided 
by the sponsor 
Pharmaceutical form:  
Vial containing 6mg/ml concentrate for solution for infusion   
Source:  
Commercially available paclitaxel will be provided by the 
sponsor 
Unit strength:  
Paclitaxel vials containing 30 mg and 150 mg paclitaxel as 6 
mg/ml solution for infusion 


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Weekly Dose:  
Paclitaxel 80 mg/m2 once weekly upon treatment failure on 
BIBW 2992 (afatinib) monotherapy in case there is a timeframe 
of > 12 months between this and any previous paclitaxel 
treatment 
Duration of use:  
Weekly in a 3-weekly course (21 days). Patients will be eligible 
for repeated treatment courses in the absence of clinical disease 
progression or undue adverse events. 
Route of administration:  
Intravenous 
Posology:  
 
 
Intravenous infusion over a period of 60 minutes.  
Additional information: 
Paclitaxel should be administered according to the Summary of 
Product Characteristics (SmPC). The SmPC recommendations 
for pre-administration laboratory assessments and supportive 
care should be followed. In the study Paclitaxel 80mg/m2 i.v. 
may be given in the combination treatment part.   
Substance (INN):  
 
Vinorelbine (Navelbine®)  
Vinorelbine is a registered commercially available cytotoxic drug. Vinorelbine will be 
provided by the sponsor. Patients will not receive vinorelbine after the 3rd May 2013 
unless they are already receiving vinorelbine treatment on that date and are showing 
benefit from the treatment in the opinion of the investigator. 
Pharmaceutical form:  
Concentrate for intravenous infusion 
Source:  
 
 
Pierre Fabre, Germany 
Unit strength:   
 
Vial containing 50mg as 10mg/ml solution for infusion 
Duration of use:  
Patients will be eligible for repeated treatment courses in the 
absence of clinical disease progression or undue adverse events. 
 
Route of administration:  
Intravenous, short infusion of about 10 minutes  
Vinorelbine reconstitution: Vinorelbine must be diluted prior to administration in a 20-50 
ml volume of normal saline solution for injection or in 5 % 
glucose solution for injection 
Posology:  
25 mg/m² once weekly 
Additional information: 
Vinorelbine should be administered according to the SmPC. In 
the study Vinorelbine 25 mg/m² i.v. once weekly may be given 
in the combination treatment part.   The SmPC 
recommendations for pre-administration laboratory assessments 
and supportive care should be followed. 


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4.1.2 
Method of assigning patients to treatment groups 
All patients will initially receive first line monotherapy with BIBW 2992 (afatinib) until 
disease progression (With protocol amendment 6 the sponsor will stop recruitment into 
the trial (part A), pending approval by IRBs and IECs. (See section 3.3.4.2 and section 
11)).  
If disease progression occurs at any time, then patients will receive additional paclitaxel 
(providing the patient has not received paclitaxel in the past 12 months) or vinorelbine 
treatment (providing patient has not previously received Vinorelbine) as second line therapy. 
The decision to treat the patient with either paclitaxel or vinorelbine is left to investigator 
judgement. Disease progression can occur at any time during the trial and the decision to 
commence combination therapy is always based on investigator judgement. It may be based 
on clinical assessment only (e.g. at the end of course 1) or on both clinical judgement and 
tumour imaging. In any case before combination treatment is started tumour imaging should 
take place. Combination therapy should commence as soon as possible but within 21 days of 
documented progression on monotherapy (unless radiotherapy is required – see section 3.2). 
If there are no signs of PD patients will continue on BIBW 2992 (afatinib) monotherapy. 
After the 3rd May 2013 after progression on BIBW2992 (afatinib) monotherapy, 
patients will only be able to additionally receive paclitaxel weekly at a dose of 80 mg/m2 
Patient will not be able to enter in the combination part of the trial (part B) and receive 
vinorelbine treatment. 
Patients are withdrawn from study treatment if their metastatic disease shows further 
progression whilst on the combination of BIBW 2992 (afatinib) and paclitaxel or BIBW 2992 
(afatinib) and vinorelbine (2nd progression on trial) and/or in case of undue AEs. 
4.1.3 
Selection of doses in the trial 
The Maximum Tolerated Dose (MTD) and recommended phase II dose for BIBW 2992 
(afatinib) in combination with either paclitaxel 80 mg/m2 or vinorelbine 25 mg/m2 weekly 
was determined at 40 mg in a continuous regimen. The decision to administer weekly 
paclitaxel is based on publications which demonstrate the efficacy of this regimen (R11-
0902). 
The starting dose of BIBW 2992 (afatinib) in this trial was determined at 40 mg/day for 
monotherapy. 20 mg and 30 mg tablets of BIBW 2992 (afatinib) are available in case a 
patients need to undergo dose reduction. See Section 4.1.4 below. (U03-3218, U10-1491-01) 
4.1.4 
Drug assignment and administration of doses for each patient 
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 40 mg BIBW 2992 
(afatinib) every day for the first course (21 days). 
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 (afatinib) tablets are film-coated and therefore should not 


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be chewed or crushed, but may if necessary, be administered via G-tube after dispersing the 
BIBW 2992 (afatinib) 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). 
Missed doses of BIBW 2992 can be made up if taken within 6 hours of the regularly schedule 
time. Otherwise, the dose should be skipped and patients should take the next scheduled dose 
at the usual time. Patients with emesis should not take a replacement dose. 
In the event of treatment-related adverse events, the treatment with BIBW 2992 (afatinib) 
should be handled according to the schedule in Table 4.1.4: 1 
Table 4.1.4: 1 
 
BIBW 2992 (afatinib) Dose Reduction Scheme 
AE type and grade 
Action 
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 anti-
emetic 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 (afatinib) 
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 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 
(afatinib). 
 
1 
Baseline is defined as the CTCAE grade at 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. 
 


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Dose reduction should always follow a treatment pause for drug related event. 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, 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.In the event of adverse events or serious adverse 
events which are not related to treatment, the investigator may choose to pause the trial 
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 trial medication for more than 7 days, the 
afatinib doses and/or vinorelbine doses and/or paclitaxel doses will be missed and reasons 
will need to be documented in the eCRF. Treatment will be resumed at regular schedule 
thereafter and no dose reduction should occur. 
 
Vinorelbine & Paclitaxel 
Paclitaxel and Vinorelbine chemotherapy will be administered at the investigator site and will 
be prepared and administered in accordance with the respective current SmPC.  
Weekly chemotherapy will be administered within treatment courses of 3 weeks. 
Haematology should be checked prior to commencing each weekly infusion and treatment 
should be delayed if platelet count < 100,000/mm3 for combination treatment with 
vinorelbine or <100,000/mm3 for combination treatment with paclitaxel.  
The patient must be given supportive care during chemotherapy in accordance with the 
current SmPC and institutional guidelines for both paclitaxel and vinorelbine.  
In the event of treatment related adverse events, the treatment dose of vinorelbine/paclitaxel 
will be missed (see below) in accordance with the guidance in the current SmPC. A summary 
of the current SmPC is provided in the ISF.  
In the event of a missed dose due to adverse events, subsequent infusions and assessments 
will be done according to schedule (see Flow Chart B). 
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 (i.e. to skip one dose 
of chemotherapy as well as BIBW 2992 (Afatinib) doses) allow the patient to recover, but no 
dose reduction should occur. If the investigator chooses to delay the medication for more than 
7 days, the dose (one chemotherapy dose as well as BIBW 2992 (Afatinib) doses) will be 
missed and reasons will need to be documented in the eCRF. Treatment will be resumed at 
regular schedule thereafter. 


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In the event of treatment related adverse events, the treatment dose of vinorelbine or 
paclitaxel will be skipped in accordance with the guidance in the current summary of product 
characteristics (SmPC). A summary of the current SmPC for paclitaxel and vinorelbine is 
provided in the ISF. In the event of a skipped infusion due to adverse events, subsequent 
infusions and assessments should be resumed according to the original schedule and the 
tumour assessment should be performed according to the original schedule. In case of 
myelotoxicity, administration of chemotherapy will be skipped until recovery, i.e. neutrophil 
counts >1500/mm³ and thrombocyte counts > 100000/mm³ for vinorelbine or for paclitaxel. 
In general, for vinorelbine no dose adaptations for liver metastases or renal insufficiency are 
needed. In cases of severe hepatic impairment a dose reduction of vinorelbine to 20 mg/m² is 
recommended per SPC/PI and may be applied after causes for severe hepatic impairment on 
trial have been discussed between the Sponsor and the investigator. Paclitaxel treatment 
needs to be adapted in case of hepatic impairment (see SmPC). Growth factor support will be 
allowed, following ASCO Guidelines (R09-0871). Treatment should be continued within the 
regular schedule. 
4.1.5 
Blinding and procedures for unblinding 
4.1.5.1 Blinding 
Not applicable in this trial. 
4.1.5.2 Procedures for emergency unblinding 
Not applicable in this trial. 
4.1.6 
Packaging, labelling, and re-supply 
4.1.6.1 BIBW 2992 (afatinib) 
BIBW 2992 (afatinib) will be supplied as film-coated tablets. Available dosage strengths will 
be 20mg, 30mg and 40mg. Tablets will be supplied in HDPE, a child-resistant, tamper-
evident bottles.  
 
Bottles will be labelled according to local regulations and will include the following as a 
minimum; 
• 
Study number (1200.98) 
• 
Product name BIBW 2992 
• 
Contents of the bottle (30 tablets) 
• 
Tablet strength 
• 
Batch number 
• 
Medication number 
• 
Use-by date 
• 
Storage information 


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• 
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. A 
new bottle of medication will be dispensed on Day 1 of each course, regardless of the number 
of tablets remaining in the bottle from the previous course. The patient will initially receive 
one bottle of 40mg tablets and in the event that dose reduction is necessary the patient will 
return to the clinic and new medication will be dispensed. 
For details of packaging and the description of the label, refer to the ISF. 
4.1.6.2 Paclitaxel 
Paclitaxel will be supplied as a vial containing 6mg/ml concentrate for solution for infusion. 
Vials/boxes will be labelled according to local regulations and will include the following as a 
minimum; 
• 
Study number (1200.98) 
• 
Product name (Paclitaxel) 
• 
Contents of the vial 
• 
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 
4.1.6.3 Vinorelbine 
Vinorelbine will be supplied as a vial containing 10mg/ml solution. This is a concentrate for 
the preparation of a solution for infusion. 
Vials/boxes will be labelled according to local regulations and will include the following as a 
minimum; 
• 
Study number (1200.98) 
• 
Product name (Vinorelbine) 
• 
Contents of the vial 
• 
Dose strength 
• 
Batch number 


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• 
Medication number 
• 
Use-by date 
• 
Storage information 
• 
Instructions for use 
• 
Sponsor name and address 
• 
A statement that the medication is for clinical trial use only 
4.1.7 
Storage conditions 
BIBW 2992 (afatinib) must be stored in the original packaging. 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. 
Paclitaxel and vinorelbine will be stored in accordance with the instructions on the current 
local label. 
4.1.8 
Drug accountability 
Drug supplies, which will be provided by Boehringer Ingelheim, must be kept in a secure, 
limited access storage area under the storage conditions defined by the sponsor. A 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature. 
The investigator, pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled: 
• approval of the study protocol by the IRB / ethics committee,  
• availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre, 
• approval/notification of the regulatory authority, e.g. competent authority, 
• availability of the curriculum vitae of the principal investigator, 
• availability of a signed and dated clinical trial protocol or immediately imminent 
signing of the clinical trial protocol,  
• If applicable, availability of the proof of appropriate licence(s) for the principal 
investigator 
The investigator, pharmacist or investigational drug storage manager must maintain records 
of the product’s delivery to the trial site, the inventory at the site, the use by each patient, and 
the return to the sponsor or alternative disposition of unused product(s).  
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational product(s) received from the sponsor. At the time of return to the 
sponsor or appointed CRO, the investigator, pharmacist or investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the investigator’s possession. 


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4.2 
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT 
4.2.1 
Rescue medication, emergency procedures, and additional treatments 
Symptomatic treatments of tumour-associated symptoms are allowed. Treatment with 
corticosteroids and bisphosphonates are allowed. Concomitant medications, or therapy to 
provide adequate care, may be given as clinically necessary. Restrictions in Section 4.2.2 
apply. 
All concomitant (non-oncological) therapies starting or changing during the trial are allowed 
but should be recorded in the e-CRF except for vitamins, appetisers or nutrient supplements. 
Trade name, indication, dose and dates of administration will be documented. If patients 
receive parenteral nutrition during the trial, the components need not be specified in detail. It 
should just be indicated as “parenteral nutrition”. If a patient requires anaesthesia, it will be 
sufficient to indicate “anaesthesia” without specifying the details. 
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude Interstitial 
Lung Disease (ILD). 
Rescue medications to reverse the actions of BIBW 2992 (afatinib), paclitaxel and 
vinorelbine are not available.  Please refer to the current SPC for paclitaxel and vinorelbine 
and to the IB (U03-3218) for BIBW 2992 (afatinib) for further information. Side effects of 
trial medications should be treated symptomatically. Growth factor support, if required, will 
be used following ASCO Guidelines (R09-0871). 
The investigator brochure lists the AEs expected for treatment with BIBW 2992 (afatinib) 
(U03-3218). Always refer to the most recent IB. Suggested treatments for diarrhoea, nausea, 
vomiting and rash/acne are described in Sections 4.2.2.3, 4.2.2.4 and 4.2.2.5. 
During study participation symptomatic treatment of tumour associated symptoms is allowed. 
Concomitant medications or therapy to provide adequate care may be given as clinically 
necessary. All concomitant (non-oncological) medications which are taken between trial   
informed consent and the last follow-up visit should be recorded in the electronic case report 
form (eCRF) with the start and end of treatment dates, the total daily dose, the respective unit 
and the reason for use. 
4.2.2 
Restrictions 
4.2.2.1 Restrictions regarding concomitant treatment 
Patients should not receive any additional experimental anti-cancer treatment, chemotherapy, 
immunotherapy, hormone treatment, maintenance therapy for metastatic breast cancer or 
radiotherapy within 4 weeks (within 2 weeks for hormone treatment) prior to receiving trial 
drug until the EOT Visit. Treatment with palliative radiotherapy (short course to non-target 
lesions) is allowed (see also section 3.2). 


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Patients should not receive any of the prohibited medications listed in the current SmPC or 
prescribing information (PI) for paclitaxel and vinorelbine.  
For BIBW 2992 (afatinib): Afatinib is a substrate of the P-gp transporter. Caution should be 
exercised when combining afatinib with P-gp modulators. For a list of potent P-gp inhibitors 
and inducers (see Appendix 4). 
For paclitaxel:  
Refer to current SmPC/PI (see ISF) 
For vinorelbine:  
Refer to current SmPC/PI (see ISF), special care should be taken when 
administered with inducers or inhibitors of CYP 3A4 (see Appendix 4) 
4.2.2.2  Restrictions on diet and lifestyle 
For BIBW 2992 (afatinib):  
In the event of diarrhoea, patients should be advised to avoid lactose-containing products or 
any foods known to aggravate diarrhoea. 
To prevent skin related adverse events: It is currently proactively recommended to avoid 
intense irradiation with UV light, e.g., sunbathing or visiting a solarium during the treatment 
period of the study and strict sun protection should be used. In case of sun exposure a 
sunscreen of Sun Protection Factor 15 (SPF 15) or higher, preferably containing zinc oxide 
should be used, preferably a thick, alcohol-free emollient cream. Harsh detergents should be 
avoided. 
For paclitaxel:  
Refer to the current SmPC/PI for details of any restrictions on diet and lifestyle. 
For vinorelbine: 
Refer to the current SmPC/PI for details of any restrictions on diet and lifestyle. 
4.2.2.3 Management of diarrhoea following treatment with BIBW 2992 (afatinib)  
Close monitoring and proactive management of diarrhoea is essential for successful treatment 
of patients with BIBW 2992 (afatinib). Early and appropriate intervention can prevent the 
development of more severe diarrhoea. In most cases, loperamide controls diarrhoea caused 
by BIBW 2992 (afatinib). 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 (afatinib). Loperamide is considered as a 
Non Investigational Medicinal Product (NIMP). For loperamide use, please refer to the 
current SmPC/ PI 
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). 
• 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 2 or 3 diarrhoea lasting ≥ 2 days (48 hours) despite adequate 
antidiarrhoeal treatment, BIBW 2992 (afatinib) must be paused until recovery to 
CTCAE ≤ Grade 1. Upon recovery, BIBW 2992 (afatinib) should be resumed at a 
reduced dose according to the dose reduction scheme outlined in Table 4.1.4:1. 
The occurrence of diarrhoea and the outcome of treatment will be recorded in the AE section 
of the eCRF.  
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 (afatinib) 
treatment. Restrictions given in Table 4.1.4:1, footnote 2 may apply. 
4.2.2.4  Management of nausea and vomiting following treatment with BIBW 2992 afatinib) 
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 4.2.2.4: 1. 


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Table 4.2.2.4: 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 
Antiemetic treatment if deemed necessary 
by the investigator 
Nausea = grade 2 
and 
Vomiting = grade 0 
 
Nausea = grade 0, 1 or 2 
and 
Vomiting = grade 1 or 2 
Antiemetic treatment1
 
Pause BIBW 2992 (afatinib) 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 (afatinib) 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 (afatinib) should be reduced according to the 
dose reduction scheme in Table 4.1.4:1. 
The occurrence of nausea and/or vomiting and the outcome of treatment will be recorded in 
the AE section of the eCRF.  
In case of nausea and/or vomiting ≥ CTCAE grade 2, appropriate hydration (1.5 L/m²/day 
plus hydration deficit) must be ensured. 
4.2.2.5 Management of rash following treatment with BIBW 2992 (afatinib) 
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: see Section 4.2.2.2 
• 
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. 


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• 
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 (e.g. doxycycline or minocycline etc.). 
 
2) Topical treatment (e.g. hydrocortisone 2.5% cream, clindamycin 1% gel, 
pimecrolimus  1% cream). 
 
And / or 
 
1) Antihistamines (e.g. diphenhydramine, etc.) 
 
2) Oral corticosteroid (low dose and short term i.e., <10 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 continued 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 (afatinib). 
• 
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 
(afatinib) should be paused until recovery to CTCAE Grade ≤1. Treatment should be 
resumed at a reduced dose (see Table 4.1.4:1). If CTCAE Grade ≥3 rash does not 
resolve to CTCAE Grade ≤1 within 14 days of stopping BIBW 2992 (afatinib) 
treatment and despite optimal supportive care, the patient should not receive any 
further treatment with BIBW 2992 (afatinib). Restrictions given in Table 4.1.4:1, 
footnote 2 may apply. 
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 (afatinib) 
BIBW 2992 (afatinib): Patients treated with BIBW 2992 (afatinib) should take the first dose 
of BIBW 2992 (afatinib) treatment at the trial site and subsequent doses will be taken at 
home. A compliance check of trial medication should be performed on Day 15 of Treatment 
Course 1 and Day 1 of each subsequent course to ensure that the medication is being taken 
correctly. 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 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.  


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Patients experiencing emesis should not take a replacement dose. BIBW 2992 (afatinib) 
should not be taken more than once a day under any circumstances. 
Paclitaxel and vinorelbine: Chemotherapy will be administered at the trial site under the 
supervision of the investigator and in accordance with the current SmPC for both products. In 
the event that the patient does not receive the full dose of chemotherapy or a dose of 
chemotherapy is skipped this should be documented and a reason given. The compliance 
check for both treatments will include the infusion dose, time and date trial medication 
administered.  


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5. 
VARIABLES AND THEIR ASSESSMENT 
5.1 
EFFICACY - CLINICAL PHARMACOLOGY OR PHARMACODYNAMICS 
5.1.1 
Endpoints of efficacy 
5.1.1.1 Primary endpoint 
The primary endpoint of this study for BIBW 2992 (afatinib) monotherapy and combination 
therapy is:  
-  
Objective Response (OR) assessed by RECIST 1.1 
5.1.1.2 Secondary endpoints 
The secondary endpoints for this study are:  
• Best overall response during each treatment period according to RECIST 1.1  
• Duration of objective response, defined as the time from first objective response to the 
time of progression or death. 
• Progression-Free Survival (PFS) will be defined for three time intervals: time from the 
date of the start of monotherapy to the date of 1st disease progression; time from the date 
of the start of combination therapy to the date of 2nd disease progression and the time 
from the date of the start of monotherapy to the date of 2nd disease progression. In each 
case, the date of death will be used if a patient died before the appropriate progression. 
The analysis will be based upon the evaluation of tumour imaging performed by the 
investigator using RECIST Version 1.1.  
• Safety assessed by the severity and incidence of adverse event according to Common 
Terminology Criteria for Adverse Events (CTC s, AE Version 3.0), changes in vital signs 
and safety laboratory parameters 


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5.1.2 
Assessment of efficacy 
Efficacy 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 (Ref: Appendix 3 for RECIST 1.1 criteria)  
Every effort should be made to objectively evaluate tumour response and confirm this at a 
minimum of 4 weeks later using RECIST (1.1) tumour progression with radiological tumour 
imaging for all patients who enter into the trial, including those who discontinue prematurely. 
(Ref: Appendix 3 for RECIST 1.1 criteria)   
One to five target lesions (not exceeding two lesions per organ) should be identified at 
screening by Computed Tomography (CT) or MRI.  
Individual lesions detected at screening will be numbered and recorded in the eCRF. 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. 
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. breast, pelvis, brain) 
using an appropriate method (CT scan, MRI).  The same radiographic procedure should be 
used throughout the study. Assessment will be performed at screening and every six weeks    
(i.e. 2 courses) thereafter. If a patient develops a condition that does not allow to continue 
tumour assessment with CT scans, these scans may be substituted by MRI. Tumour 
assessment (CT scans) does not need to be repeated at the Screening Visit if there are valid 
results available from assessments which were performed as part of routine clinical practice 
within 28 days prior to start of treatment and the patient has given consent to utilising these 
results. In the event of early discontinuation or an interruption/delay to treatment, the tumour 
assessment schedule should not be changed. Brain metastases are considered as non-target 
lesions.  
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 patient’s participation and will be taken into consideration when determining the patient’s 
response. Skin, brain and bone lesions should not be regarded as target lesions in this study. 
In case of skin lesions, these should be measured with a calliper and photographic 
documentation should be performed. However, skin lesion should not be considered as target 
lesions in this study. Patients exclusively showing skin metastasis will not be eligible for this 
study. 
Bone metastases are considered as non-target lesions. 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 phosphates). 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 


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imaging time-point. During study treatment, bone scans should be performed when medically 
indicated e.g. in case of suspected new bone metastases (Appendix 3). 
Brain metastases are considered as non-target lesions. A brain MRI should be performed at 
baseline in cases of clinically known, stable brain metastases. The brain MRI of the 
respective lesion(s) at baseline must be repeated subsequently at every imaging time-point.  
5.2 
SAFETY 
5.2.1 
Endpoints of safety 
Safety of BIBW 2992 (afatinib), paclitaxel and vinorelbine will be evaluated as indicated by 
intensity and incidence of adverse events, graded according to US NCI CTCAE Version 3.0 
(R04-0474).  
Safety endpoints include: 
• 
Events leading to permanent dose reduction 
• 
Events leading to permanent treatment discontinuation 
• 
The overall incidence and CTC criteria grade of adverse events, as well as relatedness 
of adverse events to treatment 
• 
Causes of death 
5.2.2 
Assessment of adverse events 
5.2.2.1 Definitions of adverse events 
Adverse event 
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment. 
Serious adverse event 
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions. 
Intensity of adverse event 
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0 in the (e)CRF. 
 
 


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Causal relationship of adverse event 
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms.  
Yes: 
There is a reasonable causal relationship between the investigational product 
 
administered and the AE.  
No: 
There is no reasonable causal relationship between the investigational product 
 
administered and the AE.  
The causal relationship must be provided by the investigator for all potential trial drugs, i.e. 
the BI trial drug (BIBW 2992 (afatinib)) and for all other trial drugs IMP or NIMP 
(paclitaxel, vinorelbine, loperamide). 
Worsening of the underlying disease or other pre-existing conditions 
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
AE in the (e)CRF. 
Changes in vital signs, ECG, physical examination, and laboratory test results 
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an AE in the (e)CRF, if they are judged clinically relevant by the investigator. 
Planned Hospitalizations 
Patients may be hospitalized during selected phases of the study as required per protocol, e.g., 
monitoring of trial drug administration or for administrative reasons. Hospitalizations for 
administrative reasons and other hospitalizations already planned at the Screening Visit need 
not be reported as an SAE in cases where they are performed "as planned". 
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 10.5.2 of this clinical trial protocol and the 
“DILI checklist” provided in the ISF. 


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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 10.5.2 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 – for details 
please see section 5.2.2.2. 
 
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. 
 
5.2.2.2 Adverse event and serious adverse event reporting 
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through the observational phase) will be 
collected, documented and reported to the sponsor by the investigator on the appropriate 
CRF(s) / eCRFs / SAE reporting forms. Reporting will be done according to the specific 
definitions and instructions detailed in the ‘Adverse Event Reporting’ section of the 
Investigator Site File.  
For each adverse event, the investigator will provide the onset date, end date, CTCAE grade, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in 
Section 5.2.2.1.  
Adverse events with onset within first administration of trial treatment and 28 days after last 
administration of chemotherapy and/or BIBW 2992 (afatinib) will be considered as on 
treatment. All AEs, including those persisting after end of study treatment must be followed 
up until they have resolved or have been sufficiently characterised or the clinical monitor and 
the investigator agree to not further pursue them. 
Serious and non-serious adverse events occurring later than 28 days after last administration 
of trial drug will only be reported in case they are considered drug-related or trial (procedure) 
related. 
The investigator also has the responsibility to report AEs occurring in a certain period (within 
28 days after last dose of trial medication or any drug related events) after a patient completes 
the trial. Any AEs reported to the sponsor during this phase must be documented in the safety 
database. 
If not stipulated differently in the ISF, the investigator must report the following events via 
telephone/fax or, if available in the trial, by Remote Data Capture (RDC) using the SAE form 
immediately (within 24 hours or the next business day whichever is shorter) to the sponsor: 
SAEs and non-serious AEs occurring at the same time as an SAE and/or which are medically 


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related to the SAE(s), and protocol-specified significant events. With receipt of any further 
information to these events, a follow-up SAE report has to be provided. SAEs and non-
serious AEs must include a causal relationship assessment made by the investigator. 
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non serious 
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the event.  If the event description is correct, the 
item “serious” needs to be ticked and an SAE has to be reported in expedited fashion 
following the same procedure as above. The list of these adverse events can be found via the 
RDC-system. 
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the Investigator Site File). This 
immediate report is required irrespective of whether the investigational product has been 
administered or not and irrespective of causal relationship. It also applies if new information 
to existing SAEs or protocol-specified significant events becomes available.  
No significant AEs have been defined for this trial 
Pregnancy 
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. In case of any doubt estradiol, LH and FSH levels should be 
assessed. 
All other patients are considered to have childbearing potential and should use effective 
contraception throughout the study (i.e. from screening until  the following time points after 
end of study drug treatment: for at least 1 month after treatment has ended if the patient has 
received BIBW 2992 (afatinib) monotherapy, for at least 3 months after treatment has ended 
if the patient has been additionally treated with vinorelbine and for at least 6 months after 
treatment has ended if the patient has been treated with paclitaxel during the study). In any 
case continuing measures after ceasing study medication should be done based on the latest 
information available for the study drugs: IB (U03-3218) for BIBW 2992  (afatinib) and 
SPC/PI for paclitaxel and vinorelbine. 
In rare cases, pregnancy might occur in clinical trials. Once a female subject has been 
enrolled into the clinical trial, after having taken study medication, the investigator must 
report immediately any drug exposure during pregnancy to the sponsor. The study drug 
should be stopped and drug exposure during pregnancy has to be reported immediately 
(within 24 hours or next business day whichever is shorter) to the defined unique entry point 
for SAE forms of the respective BI OPU (country-specific contact details will be provided in 
the Investigator Site File). The outcome of the pregnancy associated with the drug exposure 
during pregnancy must be followed up. In the absence of an (S)AE, only the Pregnancy 
Monitoring Form for Clinical Trials and not the SAE form is to be completed. Only if 
pregnancy is accompanied by a SAE the Pregnancy Monitoring Form and the SAE form must 
be completed. The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part 
A and Part B). 


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5.2.3 
Assessment of safety laboratory parameters 
Blood samples will be collected at the time points specified in Flow Chart A and Flow Chart 
B 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 all patients receiving paclitaxel or vinorelbine, the decision to receive the next paclitaxel 
or vinorelbine infusion 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 blood sampling should be taken within 48hrs prior infusion. 
Safety laboratory assessment may be performed according to local practice but must include 
at least the following parameters: 
Haematology (CBC) Red blood cell count (RBC), neutrophils, haemoglobin, white blood 
cell count (WBC) and differential, platelets. 
Biochemistry 
Sodium, potassium, calcium, magnesium, creatinine, aspartate amino-
transferase (AST), alanine amino transferase (ALT), alkaline 
phosphatase, lactate dehydrogenase, total bilirubin, urea, uric acid, 
creatine phosphokinase (CPK). In case of pathological CPK further 
evaluation (e.g., by Troponin assays, CK-ELPR and ECG exam) 
should be performed and the findings documented in the eCRF. 
Creatinine clearance will be estimated by the Cockcroft-Gault Formula 
utilising serum creatinine values (directly imputed in eCRF by data 
management). 
Coagulation 
International Normalised ratio (INR) 
Urinalysis 
pH, glucose, erythrocytes, leukocytes, protein, nitrite will be analysed 
by dipstick at baseline and EOT only. In case of abnormal findings, 
further evaluation (g/24 hrs urine sampling) should be performed and 
the findings documented in the eCRF. 
Pregnancy test 
β-HCG testing in urine or serum will be performed in women of  
 
 
 
childbearing potential. 
5.2.4 
Electrocardiogram 
A standard 12-lead resting ECG will be performed at the time-points specified in Flow Chart 
A and Flow Chart B i.e. at Screening, on Day 15 of Monotherapy Course 1, on Day 1 of 
every third monotherapy course (i.e. Day 1 of Course 4, 7, 10 etc.), on Day 1 of combination 
course 1 (VPC1V1), on Day 1 of every third combination therapy course (i.e. VPC4V1, 
VPC7V1 etc.) and at EOT (if not performed in the previous 8 weeks). The investigator 
should 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.  


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5.2.5 
Assessment of other safety parameters 
5.2.5.1 Physical examination, ECOG performance score 
A physical examination will be performed at screening and at the time points specified in 
Flow Chart A and Flow Chart B.  
A full physical examination serves as a clinical tumour assessment and should include a 
cardiopulmonary examination, examination of the regional lymph nodes, abdomen, and an 
assessment of the mental and neurological status of the patient. 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), body weight (in kg), respiratory rate and body temperature 
and the evaluation of the ECOG performance score will be performed at the time points 
specified in Flow Chart A and Flow Chart B.  
5.2.5.2 Left ventricular function 
Left Ventricular Ejection Fraction (LVEF) as measured by echocardiography or Multi Gated 
Acquisition Scan (MUGA) 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). 
(R06-1414) 
MUGA scan: The MUGA scan is recommended 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). 
Cardiac left ventricular ejection fraction assessment will be performed at screening. Further 
ECHO or MUGA scans will be performed on Day 1 of Monotherapy Course 4 and then at 
every third course during monotherapy (Course 7, 10, 13 etc.), at the start of combination 
therapy (VPC1V1) and then at every third course during combination therapy (VPC4V1, 
VPC7V1 etc.) and at EOT (if not performed in the previous 8 weeks). 
 
LVEF assessment does not need to be repeated at the Screening Visit if there are valid results 
available from assessments which were performed as part of routine clinical practice within 
28 days prior to start of treatment and the patient has given consent to utilising these results. 
 


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5.2.5.3 Vital signs 
Vital signs (blood pressure and pulse after 2 minutes supine rest) and temperature will be 
recorded at the screening visit and at the time points specified in the Flow Chart A and Flow 
Chart B. 
5.3 
OTHER 
5.3.2 
Other assessments 
Not applicable to this protocol  
5.3.3  
Pharmacogenomic evaluation 
 No pharmacogenomic evaluation is planned in this protocol 
5.4 
APPROPRIATENESS OF MEASUREMENTS 
The RECIST criteria 1.1 (R09-0262) to be used for evaluation of tumour response are well 
established and scientifically accepted. The US NCI CTCAE criteria version 3.0 (R04-0474) 
are used in the assessment of adverse events. 


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5.5 
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS 
Not applicable to this protocol 
5.5.1 
Pharmacokinetic endpoints 
Not applicable to this protocol  
5.5.2 
Methods of sample collection 
Not applicable to this protocol 
5.5.3 
Analytical determinations 
Not applicable to this protocol 
5.6 
BIOMARKERS  
There will be no on-trial biopsies. All biomarker evaluations will be used to retrospectively 
confirm the patient’s HER2/hormone receptor status and are performed on archival tissue 
samples. The results of these tests are not required to confirm the patients’ eligibility to take 
part in the study. 
Archived tissue: 
Earlier studies showed that there are discrepancies of up to 23% when comparing HER2-ICH 
and FISH analyses between local and central labs (R09-6008; R09-6009; R09-6011). To 
assure that patients who had received and failed prior HER2-targeted treatment were truly 
HER2-positive when they received this, confirmatory HER2-tests will be performed on 
archival tissue by a central laboratory. The hormone receptor status will also be determined. 
Formalin Fixed Paraffin Embedded (FFPE) tumour slides from the primary tumour or 
metastasis should be provided to confirm the patient segment. The following tests will be 
done by a central laboratory: HER2 IHC and reflex FISH testing using a FDA -approved 
DAKO kit. 
 


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5.6.1 
Endpoints based on biomarkers  
 There are no clinical trial endpoints based on biomarkers. 
5.6.2 
Methods of sample collection 
The FFPE tumour slides (minimum of 10 slides) from the primary tumour or metastasis 
should be provided and sent to the central laboratory for retesting to confirm the patient’s 
HER2 status. This is not required for screen failures. 
The following tests will be done: 
- HER2 IHC and reflex FISH testing using a Food and Drug Administration (FDA) -approved 
DAKO kit  
- HrR (ER and PgR) IHC including Allred 
All tests will be performed by a central laboratory according to standard procedures. For 
HER2 IHC, FDA approved kits will be used. Details will be provided in the ISF 
The method of sampling are described in the laboratory manual (see ISF)   
5.6.3 
Analytical determinations 
HER2 IHC/FISH, HrR IHC and Allred, will be performed according to standard procedures 
by the central lab. Details to be provided in the laboratory manual in the ISF. 
5.7 
PHARMACODYNAMICS 
5.7.1 
Pharmacodynamic endpoints 
 No pharmacodynamic endpoints planned 
5.7.2  
Methods of sample collection 
Not applicable to this protocol 
5.8 
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP 
Not applicable to this protocol 


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6. 
INVESTIGATIONAL PLAN 
6.1 
VISIT SCHEDULE 
This is an open-label study in patients with metastatic breast cancer. Patients meeting the 
inclusion and exclusion criteria and who have given their written informed consent are 
eligible for participation in the study.  
6.2 
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS 
Written informed consent must be obtained before any protocol specific screening 
assessments are performed.  
A treatment course lasts 21 days. Visit 1 takes place on the first day of each treatment course 
and will occur on the day after the preceding 21 day course. For BIBW 2992 (afatinib) 
monotherapy (see Flow Chart A) an intermediary visit is to be performed on Day 15 (+/- 2 
days) of the first treatment course only. If patients receive combination therapy with either 
paclitaxel or vinorelbine due to treatment failure on BIBW 2992 (afatinib) monotherapy, the 
timing of the treatment courses re-starts at VPC1V1 and subsequent visits will occur weekly 
for administration of these treatments (see Flow Chart B). When progression on monotherapy 
is documented, combination therapy should commence as soon as possible but within 21 days 
(unless radiotherapy is required – see section 3.2). 
Note: Patients will not receive vinorelbine after the 3rd May 2013 unless they are already 
receiving vinorelbine treatment on that date and are showing benefit from the 
treatment in the opinion of the investigator (section 2.3). 
Patients may continue on treatment for unlimited courses, until the criteria for stopping 
medication are met (see Section 3.3.4). 
If the decision to permanently discontinue the study treatment is taken during a scheduled 
visit, the End Of Treatment (EOT) Visit should be performed as soon as possible instead of 
the scheduled visit (within 0 to 14 days after last treatment administration). 
All entered and treated patients should have a follow-up visit 28 days (+/-7 days) after the 
EOT visit. 
If a patient misses a visit and the patient reports to the investigator between the missed visit 
and the next scheduled visit, the missed visit should be performed. The current date and the 
reason for the delayed visit should be noted in the patients chart. The next visit, however, 
should take place at the scheduled time after the first administration of the trial drug in the 
respective treatment course. In the event of any interruption/delay of treatment, the tumour 
assessment schedule should not be changed (Vinorelbine or paclitaxel infusions in this case 
may need to be skipped). 
The investigations, as outlined in the Flow Charts, will be performed at the respective visits 
as described in detail in the following sections. Flow Chart A refers to treatment with BIBW 
2992 (afatinib) monotherapy. Flow Chart B refers to: the combination of BIBW 2992 


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(afatinib) and either paclitaxel or vinorelbine treatment. The switch from Flow Chart A 
(monotherapy) to Flow Chart B (combination therapy) occurs when the patient has disease 
progression on BIBW 2992 (afatinib) monotherapy, which may occur at any stage during the 
patients’ participation in the study.  
PD on BIBW 2992 (afatinib) monotherapy must always be documented by imaging, 
regardless of when PD occurs. When PD is documented, combination therapy should 
commence as soon as possible but within 21 days (unless radiotherapy is required – see 
section 3.2) and the assessments performed at start of combination treatment should be for 
VPC1V1 (Flow Chart B).   
6.2.1 
Screening and run-in period(s) (Up to 14 days before start of treatment) 
Refer to Flow Chart A. 
All patients who signed the written informed consent before the approval of amendment 
6 by IRBs and IECs (See section 3.3.4.2 and section 11) may continue in the trial- After 
approval of protocol amendment 6, no new informed consent must be signed as patient 
recruitment in part A will be stopped. 
Assessments to perform at this visit:   
• 
Written informed consent  
• 
Patient demographics  
• 
Medical history and relevant non-oncological history. 
• 
Review patient eligibility to participate in study 
• 
Complete physical examination including body weight and height 
• 
Vital signs 
• 
Performance status (ECOG scale)  
• 
ECG 
• 
Echocardiogram or MUGA scan. Note: LVEF assessment does not need to be 
repeated at the Screening Visit if there are valid results available from assessments 
which were performed as part of routine clinical practice within 28 days prior to start 
of treatment and the patient has given consent to utilising these results. 
• 
Blood and urine sample for safety laboratory assessment  
• 
Provide archived tissue sample for HER2-retesting/ biomarker analysis  
• 
Obtain a urine or serum sample for pregnancy test (if woman is of child bearing 
potential).  
• 
Tumour assessments (CT Scan) Note: Tumour assessment does not need to be 
repeated at the screening visit if there are valid results available from assessments 
which were performed as part of routine clinical practice within 28 days prior to the 
start of treatment and the patient has given consent to utilising these results. 
• 
Record all concomitant therapies 
• 
Record AEs  
• 
Schedule next patient appointment in 0-14 days time (Visit C1V1)    


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6.2.2 
Treatment periods 
Course 1, Visit 1, Day 1 (Visit C1V1)   
Refer to Flow Chart A - (BIBW 2992 (afatinib) monotherapy) 
Assessments to complete at this visit:  
• 
Confirm patient eligibility 
• 
Limited physical examination including measurement of body weight  
• 
Vital signs  
• 
Performance status (ECOG scale) 
• 
Blood and urine sample for safety laboratory tests  
• 
 
• 
Urine or serum for pregnancy test (if applicable)  
• 
Record all concomitant therapies 
• 
Record AEs   
• 
Dispense sufficient trial drug BIBW 2992 (afatinib) for 21 days (3 week treatment 
course) 
• 
Schedule next patient appointment in 14 days time (On Course 1 Day 15) 
 
Course 1, Visit 2, Day 15 (± 2 days) (Visit C1V2)  
Assessments to complete at this visit: 
• 
Vital signs  
• 
Performance status (ECOG scale) 
• 
ECG 
• 
AEs since last visit  
• 
Record all concomitant therapies 
• 
BIBW 2992 (afatinib) medication compliance check  
• 
Schedule next patient appointment in 7 days time (Day 22)  
 
Treatment Course 2 (C2V1) and all subsequent treatment courses (CnVn) with BIBW 
2992 (afatinib) Monotherapy  
Assessments to complete at this visit (on day 1 of each course): 
• 
Limited physical examination including body weight  
• 
Vital signs 
• 
Performance status (ECOG scale) 
• 
ECG  (Perform on Day 1 of every third course (i.e. Day  1 of Course 4, 7, 10 etc.) and 
at EOT (if not  performed in the previous 8  weeks) 


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• 
Echocardiogram or MUGA scan (Perform on Day 1 of every third course (i.e. Day  1 
of Course 4, 7, 10 etc.) and at EOT (if not  performed in the previous 8  weeks) 
• 
Blood and urine sample for safety laboratory assessments 
• 
Urine or serum sample for pregnancy test (if applicable)  
• 
Tumour assessments (CT scan) every 6 weeks calculated from start of treatment 
• 
Record all concomitant therapies 
• 
BIBW 2992 (afatinib) medication compliance check  
• 
AEs since last visit  
• 
Dispense sufficient BIBW 2992 (afatinib) trial drug for 21 days 
• 
Schedule next patient appointment in 21 days time 
• 
Assess patient for Disease progression: 
o If a patient has not shown disease progression on BIBW 2992 (afatinib) 
monotherapy then continue to refer to Flow Chart A.  
o If a patient has shown disease progression on BIBW 2992 (afatinib) 
monotherapy at any time (based upon the clinical decision of the investigator) 
and treatment with either paclitaxel or vinorelbine is added (only Paclitaxel 
after the 3rd May 2013), then refer to Flow Chart B for visit scheduling and 
procedures (see below). If the patient subsequently shows disease progression 
whilst on the combination treatment, then the patient is to be withdrawn from 
study treatment.  
 
Combination Therapy Treatment Course 1 and all subsequent combination treatment 
courses (where paclitaxel or vinorelbine treatment have been added to BIBW 2992 
(afatinib)) (See Flow Chart B)  
Refer to Flow Chart B 
Visit VPC1V1 - Day 1(± 2 days) 
Assessments to complete at this visit are the same as those for Treatment Course 2 (C2V1) 
above with the addition of the following:  
• 
Tumour assessments (CT scan) at the start of combination treatment (VPC1V1) and 
every 6 weeks calculated from start of combination treatment. Note that a tumour 
assessment is not required to be repeated at VPC1V1 if it has already been performed 
at the point when PD was determined on BIBW 2992 (afatinib) (Monotherapy) and is 
within 3 weeks of starting combination treatment. 
• 
ECHO or MUGA at the start of combination treatment (VPC1V1) and then at every 
third course (Course 4 (VPC4V1), Course 7 (VPC7V1), 10 (VPC10V1), 13 etc.). 
Note: ECHO or MUGA can be performed within 2 weeks of Day 1 of Course 1 of 
combination therapy.  
• 
Complete physical examination including body weight and height 
• 
 
• 
Administer paclitaxel or vinorelbine: 


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- Before the 3rd May 2013: Paclitaxel 80mg/m2 i.v. or vinorelbine 25 mg/m² i.v. once 
weekly will be administered once weekly once a patient experiences disease 
progression whilst being treated with BIBW 2992 (afatinib) monotherapy.  
- After the 3rd May 2013: Paclitaxel 80mg/m2 i.v. will be administered once 
weekly once a patient experiences disease progression whilst being treated with 
BIBW 2992 (afatinib) monotherapy. Patients will not receive vinorelbine after 
the 3rd May 2013 unless they are already receiving vinorelbine treatment on that 
date and are showing benefit from the treatment in the opinion of the 
investigator. Should the decision be to change the chemotherapy regimen from 
vinorelbine to paclitaxel, the patient will remain on trial and undergo an EOT 
visit before the switch. Those patients will have a second EOT visit when they 
will permanently discontinue part B.   
 
Each administration should be preceded by CBC assessment and measurement of 
weight and body temperature. Pre-medications should be applied in accordance with 
the current SmPC  
• 
Perform paclitaxel or vinorelbine compliance check (See Section 4.3.1)  
• 
Schedule next patient appointment in 7 days time 
 
Visit VPC1V2 - Day 8 (± 2 days) 
Assessments to complete at this visit:  
• 
Administer paclitaxel or vinorelbine. 
 - for patients who performed VPC1V1 before the 3rd May 2013: Paclitaxel 
80mg/m2 i.v. or  vinorelbine 25 mg/m² i.v. once weekly  
- for patients who performed VPC1V1 after the 3rd May 2013:: Paclitaxel 
80mg/m2 i.v. once weekly will be administered weekly once a patient experienced 
disease progression whilst being treated with BIBW 2992 (afatinib) monotherapy.  
Each administration should be preceded by CBC assessment and measurement of 
weight and body temperature. Pre-medications should be applied in accordance with 
the current SmPC  
• 
Vital signs 
• 
Paclitaxel or vinorelbine compliance check  
• 
Record all concomitant therapies 
• 
Record occurrence of AEs since last visit  
• 
Schedule next patient appointment in 7 days time 
 
Visit VPC1V3 - Day 15 (± 2 days) 
Same procedures as for Visit VPC1V2 above and in addition:  
• Schedule next patient appointment in 7 days time (Day 22) 


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• Note: On day 22 the patient will commence the next Treatment Course (i.e. Visit 
VPC2V1) should patient continue treatment with study medications. The same applies to 
all subsequent treatment courses.  
 
6.2.3 
End of trial and follow-up period 
All patients should have an EOT visit when trial medication is permanently discontinued. 
Assessments to be performed at the EOT Visit are described below. 
End of Treatment Visit (EOT) - 0-14 days after permanent discontinuation of BIBW 
2992 (afatinib) monotherapy or combination therapy - See Flow Chart A and  Flow 
Chart B 
Assessments to complete at this visit:  
• 
Complete physical examination including body weight  
• 
Vital signs 
• 
Performance status (ECOG scale) 
• 
ECG (if not performed in previous 8 weeks) 
• 
Echocardiogram or MUGA scan. (if not performed in the previous 8 weeks) 
• 
Blood and urine sample for safety assessments 
• 
) 
• 
Blood or urine sample for a pregnancy test (if applicable)   
• 
Tumour assessment (not required at EOT visit if progressive disease has already been 
documented at scheduled imaging assessment). In case progressive disease is 
suspected, CT/MRI imaging needs to be done at any time when active treatment ends. 
(See Appendix 3) Bone scans and correlative imaging should be performed when 
clinically indicated 
• 
Record all concomitant therapies 
• 
AEs since last visit 
• 
BIBW 2992 (afatinib) medication compliance  
• 
Paclitaxel or vinorelbine compliance check (if applicable)  
• 
Termination of study medication – Record date of last administration of study drugs 
and reason for discontinuation 
 
All patients should have a follow-up visit 28 days after the End of Treatment (EOT) visit. 
Patients who have not experienced disease progression and not started further treatment 
should have further follow- up visits every 6 weeks after the first FU until disease 
progression or start of further treatment. See below for assessments to be performed at these 
visits. 
First follow-up visit (FU V1): 28 days after EOT visit (± 7 days) - See Flow Chart A and 
Flow Chart B 


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All patients should have a follow-up visit 28 days after the EOT visit and the following 
assessments should be completed:  
• 
Limited physical examination including body weight 
• 
Vital signs  
• 
Performance status (ECOG scale) 
• 
Blood and urine sample for safety assessments 
• 
Record all concomitant therapies 
• 
AEs since last visit. Follow-up on AEs which were ongoing at EOT. Please refer to 
section 5.2.2.2 for specific safety reporting obligations 
• 
Trial completion - If applicable (patients who have progressed or who have started 
new treatment) 
 
Additional Follow-Up Visit (where applicable) (FU Vn – every 6 weeks) 
Patients who have not shown disease progression and not started further treatment should 
have further follow-up visits every 6 weeks until disease progression or start of further 
treatment. The assessments performed and information collected are the same as that for the 
first Follow-Up Visit above, with the exception that new AEs are only recorded if they are 
serious and/or trial drug-related. 
Collection of data after patient has ended participation in the study 
Follow up information on further post-trial treatment, best response and vital status will be 
collected, if available, but no visits will be performed for study purposes. 


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7. 
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE 
7.1 
STATISTICAL DESIGN - MODEL 
The trial will be performed as a single arm open label study. Patients will receive BIBW 2992 
(afatinib) monotherapy until disease progression according to RECIST 1.1. Afterwards they 
will be treated with BIBW 2992 (afatinib) in combination with either paclitaxel or 
vinorelbine until a further disease progression according to RECIST 1.1. (See Figure 3.1:1)  
Note: Patients will not receive vinorelbine after the 3rd May 2013 unless they are already 
receiving vinorelbine treatment on that date and are showing benefit from the 
treatment in the opinion of the investigator (section 2.3). 
Patients will not be screened after protocol amendment 6 approvals by IRBs and IECs 
(See section 3.3.4.2 and section 11).  
 
7.2 
NULL AND ALTERNATIVE HYPOTHESES 
All analyses in this study are descriptive and exploratory by nature. Any statistical tests are 
performed only to provide a statistical framework from which to view the results and 
providing aid for planning further studies. No formal statistical inferences are foreseen. 
7.3 
PLANNED ANALYSES 
Treated analysis sets (TRT) are defined for mono- and combination-therapy separately. The 
TRT for monotherapy comprises all patients who received at least one single dose of BIBW 
2992 (afatinib), and the TRT for combination therapy comprises all patients who received at 
least one dose each of BIBW 2992 (afatinib) and paclitaxel or BIBW 2992 (afatinib) and 
vinorelbine. 
Separate baselines will be defined for mono- and combination therapy and no pooling will be 
performed across the two parts of the study unless otherwise stated.  
No per protocol population will be used for analyses. However important protocol violations 
will be described. 
7.3.1 
Primary analyses 
Objective Response 
The primary analysis will estimate the proportion of patients who achieve objective response 
according to the RECIST 1.1 criteria for mono- and combination therapy separately. The 
individual response criteria will be relative to the respective baselines in each part and the 
rates will be presented using the respective TRTs. Objective response is defined as CR or PR 
and only confirmed responses will be considered. An exact 95% Clopper-Pearson confidence 


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interval will be calculated for the proportion of responders (R06-1080). Also, similar point 
estimates and exact confidence intervals will be calculated for each category (CR, PR, SD, 
PD and NE). 
Each patient will be assigned to one of the following categories based upon their best 
response during treatment in each part, as determined according to RECIST 1.1. 
• 
1 = CR (complete response) 
• 
2 = PR (partial response) 
• 
3 = SD (stable disease) 
• 
4 = PD (progressive disease) 
• 
9 = Not evaluable 
Objective response, determined without requiring confirmation, will be tabulated separately.  
 
7.3.2 
Secondary analyses 
None of the secondary endpoints which use RECIST 1.1 require confirmation. 
7.3.2.1 Key secondary analyses 
Best overall response 
Frequency tables will be presented for the best RECIST assessment achieved by each patient 
during each of the treatment periods in the order (from best to worst): complete response, 
partial response, stable disease, disease progression. 
Duration of objective response 
Time to objective response is defined as the number of days from the start of treatment to the 
first recorded objective response in each part. Duration of objective response is measured 
from the time of first objective response to the time of progression or death (or date of 
censoring for PFS).  
Descriptive statistics will be produced for the duration of objective response for mono- and 
combination-therapy separately. 
Progression-free survival 
Disease progression will be evaluated according to the RECIST 1.1 criteria (R09-0262). 
For patients with known date of progression (or death): 
• 
PFS [days] = earlier of date of progression or death – date of first administration + 1. 
Date of progression and date of first administration is referring to the respective part of the 
study (mono- or combination therapy).  


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PFS will also be defined for the following time interval: 
• 
PFS [days] = earlier of date of death or second progression – date of first 
administration of monotherapy + 1. 
PFS will be assessed based on the Kaplan-Meier method for each part separately. Point 
estimates together with confidence intervals (based on Greenwood’s method) will be 
provided for median PFS. Details of time points and censoring rules will be provided in the 
TSAP. 
Safety endpoints : see section 7.3.3 
 
 


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7.3.4 
Interim analyses 
7.3.4.1 Early stopping rule 
An early stopping rule will be implemented in order to minimise the number of patients 
treated if BIBW 2992 (afatinib) were ineffective.  
When 20 evaluable patients (according to RECIST 1.1) have completed at least two courses 
of BIBW 2992 (afatinib) (or progressed during the first course), a meeting will be held to 
evaluate the objective tumour response rate and to decide whether to proceed with the trial or 
stop for futility. If at least 1 unconfirmed objective response is witnessed from all available 
information at the time, then the trial will continue to full accrual. If no unconfirmed 
responses are witnessed, the benefit-risk of continuing with the trial will be discussed. Details 
of the evaluation and decisions made at this meeting will be fully documented. The attendees 
at the meeting will be members of the BI trial team and the National Co-ordinating study 
investigators of each country.  As only one responder is required it is possible that this 
meeting may be held earlier.  
As long as assessment of the early stopping condition is still pending, recruitment of further 
patients will continue. 
Table 7.3.4.1: 1 shows that a minimal requirement of at least one responder (CR or PR) out of 
20 patients provides a chance greater than 87% of continuing to full accrual, if the underlying 
objective response rate is at least 10%. On the other hand, there would be a less than 19% 
chance of falsely continuing to full accrual, if the underlying objective response rate is below 
1%. 
Table 7.3.4.1: 1 
Operating characteristics of first-stage criteria 
20 patients in the first stage 
Number of responders required to continue to 
second stage 
Underlying response rate [%] 
1 
2 
3 
 
Probability for stopping* 
0.01 
0.8179 
0.9831 
0.9990 
0.05 
0.3585 
0.7358 
0.9245 
0.08 
0.1887 
0.5169 
0.7879 
 
Probability for continuing* 
0.10 
0.8784 
0.6083 
0.3231 
0.15 
0.9612 
0.8244 
0.5951 
0.20 
0.9885 
0.9308 
0.7939 
*Probabilities are based on the binomial distribution, Bin (20, p), where p is the underlying response rate  
 


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7.3.5 
Pharmacokinetic analyses 
Not applicable to this protocol  
7.3.6 
Pharmacodynamic analyses 
 Not applicable to this protocol 
7.3.7 
Pharmacogenomic analyses 
 Not applicable to this protocol 
7.4 
HANDLING OF MISSING DATA 
Patients will continue to be followed for progression after discontinuation of study treatment 
until they start new treatment. 
7.5 
RANDOMISATION 
This is an open-label non-randomised trial without a control group. No randomisation is 
involved in this trial. Eligible patients will be sequentially entered into the trial. 
7.6 
DETERMINATION OF SAMPLE SIZE 
40 patients would be expected to provide more than a 90% probability of observing at least 2 
responders and a nearly 80% probability of observing at least 3. This is based on a binomial 
probability with an assumed underlying ORR of 10%. 
Taking into account the additional condition that at least one responder needs to be among 
the first 20 patients, the probabilities change to approximately 85% for having at least 2 
responders among 40 patients overall and approximately 74% for having at least 3 responders 
overall. 
Taking into consideration the three lines of previous therapy from which patients are entered 
into this study (trastuzumab, lapatinib and trastuzumab +lapatinib), in order to have sufficient 
numbers to identify whether there is a previous therapy for which BIBW 2992 (afatinib) is a 
successful follow-on medication, it was planned that 120 patients will would be recruited. 
However, given that patients will not be enrolled/screened after protocol amendment 6 
approvals by IRBs and IECs (See section 3.3.4.2 and section 11), the total sample size is 
anticipated to be approximately 80 patients. 
A total sample size of 80 is expected to give an 82% probability of observing at least 6 
responders and a 91% probability of observing at least 5. 


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8. 
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS 
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, version as of October 1996 (as long as local laws do not require to 
follow other versions), in accordance with the ICH Harmonised Tripartite Guideline for Good 
Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). Standard 
medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient. 
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH GCP. 
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a general rule, no trial results should be 
published prior to finalisation of the Clinical Trial Report. 
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File). 
8.1 
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT 
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments. 
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative. 
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient. 
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities. 
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF (Investigator Site File). 


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8.2 
DATA QUALITY ASSURANCE 
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial. 
8.3 
RECORDS 
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, via 
remote data capture. For drug accountability, refer to Section 4.1.8. 
8.3.1 
Source documents 
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available. 
For eCRFs all data must be derived from source documents. 
8.3.2 
Direct access to source data and documents 
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents 
described in Section 8.3.1. 
8.3.3 
Storage of records 
The sponsor must retain the essential documents according to the sponsor's SOPs. When it is 
no longer necessary for the trial site to retain the source documents and essential documents 
the sponsor must notify the head of the trial site. 
8.4 
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS 
8.4.1 
Listedness 
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For BIBW 2992 (afatinib), this is the current version of the Investigator’s Brochure (U03-


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3218). For paclitaxel/ vinorelbine this is the current SmPC. The current versions of these 
reference documents are to be provided in the ISF.  
8.4.2 
Expedited reporting to health authorities and IECs/IRBs 
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File. 
8.5 
STATEMENT OF CONFIDENTIALITY 
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers. 
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities, i.e. the CA. 
8.6 
COMPLETION OF TRIAL 
The trial will be considered complete when the last patient completes the last follow-up 
visit.For EU countries: The EC/competent authority in each participating EU member state 
needs to be notified about the end of the trial (last patient/patient out, unless specified 
differently in Section 6.2.3 of the CTP) or early termination of the trial.  
 


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9. 
REFERENCES  
9.1 
PUBLISHED REFERENCES 
R01-0299 
Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. 
Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic 
breast cancer that over expresses HER2. N Engl J Med 2001; 344(11):783-
792. 
R04-0474 
Common terminology criteria for adverse events v3.0 (CTCAE) (publish date: 
December 12, 2003). See website ctep.cancer.gov/forms/CTCAEv3.pdf ; 
Cancer Therapy Evaluation Program, Common Terminology Criteria for 
Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS, March 31, 2003, 
Publish Date: December 12, 2003 
R06-0964 
Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human 
breast cancer: correlation of relapse and survival with amplification of the 
HER-2/neu oncogene. Science 1987; 235:177-182. 
R06-0986 
Antiemetic Subcommittee of the Multinational Association of Supportive Care 
in Cancer (MASCC). Prevention of chemotherapy- and radiotherapy-induced 
emesis: results of the 2004 Perugia International Antiemetic Consensus 
Conference. Ann Oncol 2006;17(1):20-28 
R06-1080  
Clopper CJ, Pearson ES. The use of confidence or fiducial limits illustrated in 
the case of the binomial. Biometrika 1934;26:404-413. 
R06-1414 
Thomas JD, Adams DB, DeVries S, Ehler D, Greenberg N, Garcia M, et al. 
Guidelines and recommendations for digital echocardiography: a report from 
the Digital Echocardiography Committee of the American Society of 
Echocardiography. J Am Soc Echocardiogr 2005;18(3):287-297 
website://asecho.org/Guidelines.php 
R08-1376 
Okano J, Gaslightwala I, Birnbaum MJ, Rustgi AK, Nakagawa H. Akt/protein 
kinase B isoforms are differentially regulated by epidermal growth factor 
stimulation. J Biol Chem 2000;275(40):30934-30942. 
R08-1380 
Riese DJ, Stern DF. Specificity within the EGF family/ErbB receptor family 
signaling network. BioEssays 1998; 20 (1):41-48. 
R08-1382 
Tsuda H, Hirohashi S, Shimosato Y, Hirota T, Tsugane S, Yamamoto H, et al. 
Correlation between long-term survival in breast cancer patients and 
amplification of two putative oncogene-co amplification units: hst-1/int-2 and 
c-erbB-2/ear-1. Cancer Res 1989; 49(11):3104-3108. 
R08-1384 
Wright C, Angus B, Nicholson S, Sainsbury JRC, Cairns J, Gullick WJ, et al. 
Expression of c-erbB-2 oncoprotein: a prognostic indicator in human breast 
cancer. Cancer Res 1989; 49:2087-2090. 


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R08-1386 
Amundadottir LT, Leder P. Signal transduction pathways activated and 
required for mammary carcinogenesis in response to specific oncogenes. 
Oncogene 1998; 16(6):737-746. 
R08-1392 
Walker RA, Gullick WJ, Varley JM. An evaluation of immunoreactivity for c-
erbB-2 protein as a marker of poor short-term prognosis in breast cancer. Br J 
Cancer 1989; 60:426-429. 
R08-1393 
Lovekin C, Ellis IO, Locker A, Robertson JFR, Bell J, Nicholson R, et al. c-
erbB-2 oncoprotein expression in primary and advanced breast cancer. Br J 
Cancer 1991; 63:439-443. 
R08-1394 
Gullick WJ, Love SB, Wright C, Barnes DM, Gusterson B, Harris AL, et al. c-
erbB-2 protein overexpression in breast cancer is a risk factor in patients with 
involved and uninvolved lymph nodes. Br J Cancer 1991; 63:434-438. 
R08-1395 
Varley JM, Swallow JE, Brammar WJ, Whittaker JL, Walker RA. Alterations 
to either c-erbB-2 (neu) or c-myc proto-oncogenes in breast carcinomas 
correlate with poor short-term prognosis. Oncogene 1987; 1(4):423-430. 
R08-1396 
May E, Mouriesse H, May-Levin F, Qian JF, May P, Delarue JC. Human 
breast cancer: identification of populations with a high risk of early relapse in 
relation to both oestrogen receptor status and c-erbB-2 overexpression. Br J 
Cancer 1990; 62(3):430-435. 
R08-1397 
Andrulis IL, et al, Toronto Breast Cancer Study Group. neu/erbB-2 
amplification identifies a poor-prognosis group of women with node-negative 
breast cancer. J Clin Oncol 1998;16(4):1340-1349. 
R09-0262 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et 
al. New response evaluation criteria in solid tumours: revised RECIST 
guideline (version 1.1). Eur J Cancer 2009; 45:228-247 
R09-0871 
Smith TJ, et al. 2006 update of recommendations for the use of white blood 
cell growth factors: an evidence-based clinical practice guideline. J Clin Oncol 
2006;24(19):3187-3205 
R09-2787  
Minckwitz G von, Bois A du, Schmidt M, Maass N, Cufer T, Jongh FE de, et 
al. Trastuzumab beyond progression in human epidermal growth factor 
receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast 
International Group 03-05 study. J Clin Oncol 2009. 27(12): 1999-2006. 
R09-4140 
J. O’Shaughnessy, K.L. Blackwell, H. Burstein, A.M. Storniolo, G. Sledge, J. 
Baselga, M. Koehler, S. Laabs, A. Florance and D. Roychowdhury. A 
randomized study of lapatinib alone or in combination with trastuzumab in 
heavily pre-treated HER2+ metastatic breast cancer progressing on 
trastuzumab therapy. Abstract. Journal of Clinical Oncology, 26, 2008 


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R09-5656 
SEER (Surveillance Epidemiology and End Results) stat fact sheets: cancer of 
the breast. http.//seer.cancer.gov/statfacts/html/breast.html (accessed August, 
2009) 2009 
R09-6008 
Gancberg D, Di Leo A, Cardoso F, Rouas G, Pedrocchi M, Paesmans M, et al. 
Comparison of HER-2 status between primary breast cancer and 
corresponding distant metastatic sites. Annals of Oncology 2002; 13: 1036-
1043 
R09-6009  
Perez E, Suman V, Davidson N, Martino S, Kaufmann P, Lingle W, et al. 
HER2 Testing by Local, Central, and Reference Laboratories in Specimens 
From the North Central Cancer Treatment Group N9831 Intergroup Adjuvant 
Trial. Journal of Clinical Oncology 2006; 24:  3032-3038 
R09-6011    
McCullough A, Dueck A, Chen B, Reinholz M, Wiktor A, Lingle W, et al. 
HER-2 central confirmatory testing using ASCO/CAP guidelines for 
trastuzumab/lapatinib trial MCCR RC0639. Journal of Clinical Oncology 
ASCO Annual Meeting Proceedings 2009; 27: No15S May 20 Supplement, 
2009: e11527 
R10-4385 
Kimberly L., Blackwell, Harold J. Burstein, Anna Maria Storniolo, Hope 
Rugo, Geroge Sledge, Maria Koehler, Catherine Ellis, Michelle Casy, 
Svetislava Vukelja, Joachim Bischoff, Jose Baselga and Joyce 
O’Shaughnessy. Randomized Study of Lapatinib Alone or in Combination 
With Trastuzumab in Women With ErbB2-Positive Trastuzumab-Refractory 
Metastatic Breast Cancer. Journal of Clinical Oncology, Vol 28, No 7, 1 
March 2010 
R10-5362 
GlaxoSmithKline ALTTO A Randomised, Multi-centre, Open-label, Phase III 
Study of Adjuvant Lapatinib, Trastuzumab, Their Sequence and Their 
Combination in Patients With HER2/ErbB2 Positive Primary Breast Cancer. 
Clinical Trials.gov Identifier: NCT00490139, 20 June 2007  
R10-5364 
GlaxoSmithKline Neo ALTTO (Neoadjuvant Lapatinib and/or Trastuzumab 
Treatment Optimisation) Study A Randomised, Multicenter Open-label Phase 
III Study of Neoadjuvant Lapatinib, Trastuzumab and Their Combination Plus 
Paclitaxel in Women With HER2/ErbB2 Positive Primary Breast Cancer. 
Clinical Trials.gov Identifier: NCT00553358, 01 November 2007 
R11-0902 
Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, Wolff AC, 
Sledge GW, Wood WC, Davidson NE. Weekly paclitaxel in the adjuvant 
treatment of breast cancer. N Engl J Med 2008;358(16):1663-1671 
9.2 
UNPUBLISHED REFERENCES 
U03-3218 
 Investigator's Brochure. BIBW 2992 
MA2. Version 9.  1200. P1 - 1200.P5. 24 April 2009 


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U09-1454-01 
. Anti-tumor activity of the EGFR/HER2 inhibitor BIBW 
2992 in a mouse model of human triple-negative breast cancer (cell line SUM-
149). BIRCV15-09. 07 September 2009 
U09-1455-01 
, Anti-tumour activity of the EGFR/HER2 inhibitor 
BIBW 2992 in a mouse model of human HER2-positive breast cancer (cell 
line SUM-190), BIRCV16-09. 07 September 2009 
U09-2463-03  
 Phase II trial of BIBW 2992 in patients with HER2-
positive metastatic breast cancer after failure of trastuzumab therapy. CTR 
1200.11 16 September 2010  
U10-1491-01 
 
Phase I open label trial to assess safety of BIBW 2992 in combination with 
Vinorelbine (i.v and oral) in patients with solid tumours historically known to 
overexpress HER2 and/or EGFR and not amenable to other treatment and with 
an indication for vinorelbine therapy, 1200.69 09 March 2010 
U10-1598-01  
 An open label phase 
II trial to assess the efficacy and safety of a once daily oral dose of 50 mg 
BIBW 2992 in two cohorts of patients with HER2-negative metastatic breast 
cancer after failure of no more than two chemotherapy regimen. 1200.10 30 
August 2010 
U10-2018-01 
 A Phase II study of BIBW 
2992 administration in patients with hormone refractory metastatic breast 
cancer. 1200.5. 20 August 2010 
U10-3047-01  
 LUX Lung 2 A Phase II single arm study of BIBW 2992 in NSCLC 
patients who have failed one line of chemotherapy or are chemotherapy naive 
and who have EGFR activating mutations. 1200.22 08 June 2010 
9.3 
POSTERS/ONLINE PUBLICATIONS 
P08-11756 
Spicer JF, Harris D, Ang J, Chau M, Vizor S, Shahidi M, Uttenreuther-Fischer 
M, Bono JS de 
A phase I study of daily BIBW 2992 , an irreversible EGFR/HER2 dual kinase 
inhibitor, in combination with weekly paclitaxel. 
33rd Ann Cong of the European Society for Medical Oncology (ESMO), 
Stockholm, 12 - 16 Sept 2008 (Poster) 
P09-05119 
A Phase I Study of Daily BIBW 2992, an irreversible EGFR/HER2 Dual 
Kinase Inhibitor, in Combination with Weekly Paclitaxel. J.F. Spicer, D. 
Harris, J. Ang, M. Chau, S. Vizor, M. Shahidi, M. Uttenreuther-Fischer, J.S. 
De Bono. 33rd Annual Congress of the European Society of Medical 
Oncology, 12-16th September, 2008, Stockholm, Sweden 


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P09-06809 
A Phase II Study of BIBW 2992 , a Novel Irreversible Dual EGFR and HER2 
TKI, in patients with Adenocarcinoma of the Lung and Activating EGFR 
Mutations after failure of  one Line of Chemotherapy (LUX-Lung 2). J-Y. 
Shih; C-H. Yang; W-C. Su; T-C. Hsia, C-M. Tsai; Y-M. Chen ; S-H.I Ou; H. 
Chang; Y. Zhao; E. Terlizzi; M. Shahidi; V.A. Mileer, on behalf of the LUX-
Lung 2 Clinical Study Team. 45th Ann Mtg of the American Society of 
Clinical Oncology (ASCO), Orlando, 29th May-2 June 2009. (Oral 
Presentation) 
P09-08104 
Hickish T, Wheatley D, Lin N, Carey L, Houston S, Mendelson D, Solca F, 
Uttenreuther-Fischer M, Jones H, Winer E. Use of BIBW 2992 , a novel 
irreversible EGFR/HER1 and HER2 tyrosine kinase inhibitor to treat patients 
with HER2-positive metastatic breast cancer after failure of treatment with 
trastuzumab.  45th Ann Mtg of the American Society of Clinical Oncology 
(ASCO), Orlando, 29 May - 2 Jun 2009, (2009). 
P09-10056 
Ang J, Mikropoulos C, Stavridi F, Rudman S, Uttenreuther-Fisher M, Shahidi 
M, Pemberton K, Wind S, Bono J de, Spicer JF 
A phase I study of daily BIBW 2992 , an irreversible EGFR/HER-2 dual 
kinase inhibitor, in combination with weekly paclitaxel. 
45th Ann Mtg of the American Society of Clinical Oncology (ASCO), 
Orlando, 29 May - 2 Jun 2009 J Clin Oncol 27 (15S) (Suppl), Abstr e14541 
(2009) 
P09-10626 
Stavridi F, Kristeleit R, Tobal K, Neat M, Forster M, Ang JE, Rudman S, 
Uttenreuther-Fischer M, Pemberton K, Solca F, Shahidi M, Bono J de, Spicer 
J. Activity of BIBW 2992 , an oral irreversible EGFR/HER1 and HER2 dual 
kinase inhibitor, in combination with weekly paclitaxel in non-small cell lung 
cancer. 13th World Conf on Lung Cancer, San Francisco, 31 Jul - 4 Aug 2009 
(Poster) 
P10-01317 
Stavridi F, Kristeleit R, Forster M, Ang JE, Rudman S, Uttenreuther-Fischer 
M, Pemberton K, Shahidi M, Bono J de, Spicer J 
Activity of BIBW 2992 , an oral irreversible EGFR/HER2 dual kinase 
inhibitor, in combination with weekly paclitaxel in non-small cell lung cancer. 
13th World Conf on Lung Cancer, San Francisco, 31 Jul - 4 Aug 2009 
J Thorac Oncol 4 (9) (Suppl 1), S444, Abstr PD3.1.5 (2009) 
P12-09544 
Solca F, Dahl G, Zoephel A, Bader G, Sanderson M, Klein C, Kraemer O, 
Himmelsbach F, Haaksma E, Adolf GR. Target binding properties and cellular 
activity of afatinib (BIBW 2992), an irreversible ErbB family blocker. Journal 
of Pharmacology and Experimental Therapeutics, Published online before 
print August 10, 2012, doi: 10.1124/jpet.112.197756 J Pharmacol Exp Ther 
2012 


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10. 
APPENDICES 
10.1 
APPENDIX 1 
COCKCROFT-GAULT FORMULA  
Estimated creatinine clearance rate (eCCR) using Cockcroft-Gault formula 
 
 
 
 
Or when serum creatinine is measured in µmol/L 
 
 
 
 
Where Constant is 1.23 for men and 1.04 for women 
 
eCCR = 
(140-Age)X Mass (in kilograms) X [0.85 if Female] 
72 X Serum Creatinine (in mg/dL) 
(140-Age)X Mass (in kilograms) X Constant 
eCCR = 
Serum Creatinine (in µmol/L) 


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10.2 
APPENDIX 2 
ECOG SCALE 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance without 
restriction. 
1 
Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory 
and able to carry out work of a light or sedentary nature (e.g., light housework, office 
work). 
2 
In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry 
out any work activities.  Up and about more than 50% of waking hours. 
3 
In bed >50% of the time.  Capable of only limited self-care, confined 
  to bed or chair more than 50% of waking hours 
4 
100% bedridden.  Completely disabled.  Cannot carry on any 
self-care.  Totally confined to bed or chair 
5 
Dead. 
 


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10.3 
APPENDIX 3 
TUMOUR RESPONSE ASSESSMENT ACCORDING TO 
RECIST 1.1 
Response criteria for target lesions 
1.   Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have a reduction in short axis 
to <10mm) 
2.   Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions 
taking as reference the baseline sum diameters 
3.   Progression (PD): 
At least a 20% increase in the sum of diameters of target lesions, 
taking as references the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of a least 5mm (note: the appearance of one or 
more new lesions is also considered progression). 
4.   Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as references the smallest sum 
diameters while on study 
 
Response criteria for non-target lesions 
1.   Complete Response (CR): 
Disappearance of all non-target lesions and normalization of 
tumour marker level. All lymph nodes must be non-pathological in 
size (<10mm short axis) 
2.   Non-CR/ Non-PD: 
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumour marker level above the normal limits. 
3.   Progression (PD): 
Unequivocal progression of existing non-target lesions (Note: the 
appearance of one or more new lesions is also considered 
progression) 
 
Time-point response 
Target lesions 
Non-Target lesions 
New lesions 
Overall response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 


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10.4 
APPENDIX 4 
LIST OF CYP3A4 SUBSTRATES, INHIBITORS, AND 
INDUCERS AND LIST OF POTENT INHIBITORS AND INDUCERS OF P-
GLYCOPROTEIN 
10.4.1 List of CYP3A4 substrates, inhibitors, and inducers  
 


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10.4.2. List of potent inhibitors and inducers of P-glycoprotein  
Inhibitors 
Inducers 
Amiodarone 
Azithromycin 
Captopril 
Carvedilol 
Clarithromycin  
Conivaptan 
Cyclosporine  
Diltiazem 
Dronedarone 
Erythromycin 
Felodipine 
Itraconazole 
Ketoconazole 
Lopinavir 
Nelfinavir 
Ritonavir 
Quinidine 
Ranolazine 
Saquinavir 
Tacrolimus 
Ticagrelor 
Verapamil 
Carbamazepine 
Phenytoin 
Rifampicin 
St John’s Wort 
Phenobarbital Salt 
Tipranavir 
Ritonavir 
 
As the information on potent inhibitors and inducers of P-glycoprotein may evolve, it is 
important for the investigator to assess the status of each concomittant therapies and in case 
of questions contact BI clinical monitor. 
 
While caution needs to continue to be exercised in concomitant use of P-gp 
inhibitors/inducers with afatinib, based on new data from two drug-drug interaction (DDI) 
trials (U03-3218 version 13) investigating the effect of ritonavir and rifampicin, respectively, 
on 40 mg afatinib, their use in patients needing such therapies is no longer prohibited. It 
cannot be excluded that the plasma exposure to afatinib may increase under concomitant 
treatment with strong P-gp inhibitors. Conversely, strong P-gp inducers may decrease the 
plasma concentrations of afatinib. However, maximum observed effects are rather mild to 
moderate and could even be avoided for the potent inhibitor ritonavir when given 
simultaneously or 6 h after afatinib. Therefore caution has to be exercised when combining 
afatinib with potent P-gp modulators. 
 


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10.5 
APPENDIX 5 
CLINICAL EVALUATION OF LIVER INJURY 
 
10.5.1 
Introduction 
Alterations of liver laboratory parameters, as described in section 5.2.2.1 (Protocol-Specified 
Significant Events), are to be further evaluated using the following procedures. 
10.5.2 
Procedures 
Any elevation of ALT/AST and bilirubin qualifying as laboratory alert should be confirmed 
using the initial sample if possible. 
 
If the alert is confirmed on initial sample, or it is not possible to repeat testing using initial 
sample, the following must be completed; 
 
1) Evaluate the patient within 48 hours and,  
 
2) Perform the following laboratory tests: 
   1. Repeat  of AST, ALT, bilirubin (with fractionation to total and direct)  
   2. Haptoglobin 
   3. Complete blood count and cell morphology 
   4. Reticulocyte count 
   5. CK 
   6. LDH 
   7.  Alkaline Phosphatase 
 
The results of these laboratory tests must be reported to BI as soon as possible. 
 
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” and results 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, 


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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), Anti-
nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) 
antibody, Anti-mitochondrial antibody, Epstein Barr Virus (VCA IgG, 
VCA IgM), cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, 
IgM)*, varicella (IgG, IgM)*, parvovirus (IgG, IgM)*  
• Hormones, tumormarker 
TSH* 
• Haematology 
Thrombocytes, eosinophils 
*If clinically indicated (e.g immunocompromised patients) 
 
− 
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).  
and report these via the eCRF. 


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11. 
SUMMARY OF CLINICAL TRIAL PROTOCOL 
MODIFICATIONS 
Summary of Clinical Trial Protocol Modifications Sheet (SOMS) 
Number of CTP modification 
 
1 
Date of CTP modification 
 
22nd December 2010 
EudraCT number 
 
2010-021945-29 
BI Trial number 
 
1200.98  
BI Investigational Product(s) 
 
BIBW 2992 (afatinib)  
Title of protocol 
 
An open label, phase II trial of BIBW 2992 
(afatinib) in patients with metastatic HER2-
overexpressing breast cancer failing HER2-
targeted treatment in the neoadjuvant and/or 
adjuvant treatment setting 
 
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities 
 
 
To be implemented 
immediately in order to 
eliminate hazard –  
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval 
 
 
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only 
 
 
 
Section to be changed 
 
1. Flow Charts A and B 
2. Abbreviations  
3. Section 3.3.3 Exclusion Criterion 17 
4. Section 3.3.3 Exclusion Criterion 30  
5. Section 3.3.4.1 
6. Section 4.1.1 
7. Section 5.2.2.2 
8. Section 5.2.2.1 
 
Description of change 
 
1. Clarified schedule for tumour assessments 
2. Corrected SmPC abbreviation 
3. Defined use of contraception post study 
for each of the trial medications used 


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4. Defined threshold values for platelet 
counts for combination treatment with 
paclitaxel and vinorelbine  
5. Included reason 1 as exception 
6. Vinorelbine infusion time 
7. Added requirements for post treatment 
requirement for contraception for BIBW 
2992, vinorelbine and paclitaxel 
8. Added explanation regarding handling of 
hospitalisations for administrative reasons
 
Rationale for change 
 
1. Clarification  
2. Corrected typographical error 
3. Change required by regulatory authority 
to align with SmPC for vinorelbine and 
paclitaxel 
4. Corrected typographical error  
5. Corrected typographical error 
6. Clarification  
7. Change required by regulatory authority 
to align with SmPC for vinorelbine and 
paclitaxel and to align with Exclusion 
Criterion 17 
8. Clarification 
 


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Number of CTP modification 
 
2 
Date of CTP modification 
 
27th April 2011 
EudraCT number 
 
2010-021945-29 
BI Trial number 
 
1200.98  
BI Investigational Product 
 
BIBW 2992 (afatinib)  
Title of protocol 
 
An open label, phase II trial of BIBW 2992 
(afatinib) in patients with metastatic HER2-
overexpressing breast cancer failing HER2-
targeted treatment in the neoadjuvant and/or 
adjuvant treatment setting 
 
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities 
 
 
To be implemented 
immediately in order to 
eliminate hazard –  
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval 
 
 
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only 
 
 
 
Section to be changed 
 
1. Title page 
2. Flow charts A and B 
3. Section 3.1 
4. Section 3.2 
5. Section 3.3.3 
6. Section 4.1.1 
7.Section  4.1.2 
8. Section 4.1.3 
9. Section 4.1.4 
10. Section 4.2.2.1 
11.Section 5.2.2.2 
12. Section 5.2.4 
13. Section 5.2.5.2 
14. Section 5.6.2 
15. Section 6.2 
16. Section 6.2.1, 6.2.2, 6.2.3 
17. Section 8.4.1 
18. Section 11 


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Description of change 
 
1. Change of Trial Clinical Monitor 
2. Clarification of timing of ECG, LVEF 
evaluation and tumour assessments. 
Clarification of timing of transition from part 
A to part B. Clarification that CBC results 
required prior to chemotherapy. 
3. Clarification of transition from part A to part 
B. Clarification of data collection after trial 
participation. 
4. Clarification of transition from part A to part 
B. New guidance on the use of radiotherapy 
during the trial. Clarification of data 
collection after trial participation. 
5. Exclusion criteria 4 amended to allow 
palliative radiotherapy. Exclusion criteria 14, 
17, 28 and 29 clarified. 
6. Vial size added for vinorelbine 
7. Clarification of transition from part A to part 
B. 
8. Addition of reference publications for weekly 
paclitaxel. 
9. Correction to the guidance on timing of study 
medication intake. Correction to footnote in 
table 4.1.4: 1.Addition of platelet count value 
required for treatment with paclitaxel. 
Clarification of handling of chemotherapy 
dosing in the event of treatment-related 
adverse events. 
10. Palliative radiotherapy is now allowed. 
11. Correction to adverse event reporting periods.
12. Clarification of timing of ECG assessments. 
13. Clarification of timing of LVEF assessments. 
14. Clarification of timing of sample collection. 
15. Clarification of timing of visits and of 
transition from part A to part B. Clarification 
of requirement to document progressive 
disease on BIBW 2992 monotherapy. 
16. Clarification on timing of visits, timing of 
assessments and assessments to perform. 
Clarification of data collection after trial 
participation. 
17. Clarification that the reference SmPC is not 
the local version. 
18. Correction to date of CTP modification 1 and 
addition of change number 8. 
Rationale for change 
 
1. Personnel change 


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2. Clarification 
3. Clarification 
4. Clarification and addition of guidance on use 
of radiotherapy in response to investigator 
request. 
5. Clarification and investigator request to allow 
palliative radiotherapy to non-target lesions. 
6. Omission from original protocol 
7. Clarification 
8. Investigator request for reference publication. 
9. Incorrect information in original protocol. 
Clarification required. 
10. Investigator request to allow palliative 
radiotherapy to non-target lesions. 
11. Incorrect information in original protocol. 
12. Clarification 
13. Clarification 
14. Clarification 
15. Clarification 
16. Clarification 
17. Clarification 
18. Incorrect and missing information 
 
 


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Number of CTP modification 
 
3 
Date of CTP modification 
 
29th July 2011 
EudraCT number 
 
2010-021945-29 
BI Trial number 
 
1200.98  
BI Investigational Product 
 
BIBW 2992 (afatinib)  
Title of protocol 
 
LUX-Breast 2; An open label, phase II trial of 
BIBW 2992 (afatinib) in patients with metastatic 
HER2-overexpressing breast cancer failing 
HER2-targeted treatment in the neoadjuvant 
and/or adjuvant treatment setting 
 
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities 
 
 
To be implemented 
immediately in order to 
eliminate hazard –  
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval 
 
 
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only 
 
 
 
Section to be changed 
 
Title page 
Description of change 
 
Addition of LUX-Breast 2 to trial title 
Rationale for change 
 
To indicate that this trial is part of the LUX-
Breast program 
 
Number of CTP modification 
 
4 
Date of CTP modification 
 
06th December 2011 
EudraCT number 
 
2010-021945-29 
BI Trial number 
 
1200.98  
BI Investigational Product 
 
BIBW 2992 (afatinib)  
Title of protocol 
 
LUX-Breast 2; An open label, phase II trial of 
BIBW 2992 (afatinib) in patients with metastatic 
HER2-overexpressing breast cancer failing 
HER2-targeted treatment in the neoadjuvant 
and/or adjuvant treatment setting 
 


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To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities 
 
 
To be implemented 
immediately in order to 
eliminate hazard –  
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval 
 
 
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only 
 
 
 
Section to be changed 
 
1  Abbreviations 
2. Section 2.1 
3.  Section 2.3 
4.  Section 3.2 
5.  Section 3.3.2 
6.  Section 3.3.3 
7.  Section 4.1.2 
8.  Section 4.1.4 
9.  Table 4.1.4: 1 
10. Section 4.2.2.1 
11.  Section 5.1.2 
12. Section 5.2.2.1 
13. Section 5.2.2.2 
14.  Section 7.3.1 
15. Section 7.3.2.3 
16. Section 7.3.2.4  
17. Section 7.3.2.7 
18. Addition of Appendix 10.5 
Description of change 
 
1. Addition of abbreviations CK-ELPR and DILI 
2. Addition of sentence to clarify treatment 
setting in trial 
3. Addition of text regarding drug-induced liver 
injury 
4. Clarification that study treatment is first line 
and that part A schedule is followed during 
radiotherapy 
5. Correction of cross-references to exclusion 
criteria.  
6. Addition of new exclusion criteria 4. Addition 


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of guidance to exclusion criteria 8 regarding 
bilateral breast cancer and metastases to the 
contralateral breast. 
7. Clarification of line of treatment in study 
8. Addition of guidance on missed doses 
9. Removal of ‘≥’ sign 
10. Clarification of time window 
11. Clarification that confirmation of tumour 
response must be at least 4 weeks after 
original assessment of response. 
12. Addition of text regarding drug-induced liver 
injury 
13. Addition of paragraph regarding adverse 
events which are considered to be ‘always 
serious’ 
14. Clarification of analyses to be performed 
15. Clarification of analyses to be performed 
16. Correction of cross-reference 
17. Clarification of analyses to be performed 
18. Addition of text regarding drug-induced liver 
injury 
Rationale for change 
 
1. Omission from original protocol 
2. Clarification 
3. New corporate standard for monitoring and 
assessment of drug-induced liver injury 
4  Clarification 
5  Correction 
6. Clarification that the intent of the protocol is 
to include patients requiring first-line 
treatment for metastatic breast cancer. 
Clarification regarding the inclusion of 
patients with bilateral breast cancer or 
metastases to the contralateral breast. 
7. Clarification 
8. Additional guidance added 
9. Removal of redundant symbol to clarify 
meaning 
10. Clarification 
11. Clarification in accordance with RECIST 
(1.1) 
12. New corporate standard for monitoring and 
assessment of drug-induced liver injury 
13. New corporate standard for events considered 
‘always serious’ 
14. Clarification 
15. Clarification 


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16. Correction 
17. Clarification 
18. New corporate standard for monitoring and 
assessment of drug-induced liver injury 
 
Number of CTP modification 
 
5 
Date of CTP modification 
 
06 Nov 2012 
EudraCT number 
 
2010-021945-29 
BI Trial number 
 
1200.98  
BI Investigational Product 
 
BIBW 2992 (afatinib)  
Title of protocol 
 
LUX-Breast 2; An open label, phase II trial of 
BIBW 2992 (afatinib) in patients with metastatic 
HER2-overexpressing breast cancer failing 
HER2-targeted treatment in the neoadjuvant 
and/or adjuvant treatment setting 
 
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities 
 
 
To be implemented 
immediately in order to 
eliminate hazard –  
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval 
 
 
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only 
 
 
 
Section to be changed 
 
1. Title page 
2. Flow chart A and B 
3. Flow chart B, Section 6.2.2 
4. Abbreviations 
5. Section 1.2 and 9.3 
6. Section1.2, 3.3.4.1, 4.2.2.1 and appendix 10.4 
7. Section 2.3 
8. Section 3.1 
9. Section 3.3.2 
10. Section 3.3.3 
11. Section 3.3.3 and 4.1.4 
12. Section 4.1.1 


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13. Section 4.1.4 
14. Section 5.2.2.1 
15. Section 5.2.2.2  
16. Section 5.2.3 
17. Section 6.2.3 
18. Section 7.3.2.1 and 7.3.2.2 
19. All protocol 
 
Description of change 
 
1. Change of Clinical Trial Monitor 
2. Clarification that the coagulation test is part 
of the safety assessment as described in 
section 5.2.3 and addition of reference to 
section 5.2.2.2 for safety  reporting during the 
follow up  period 
3. Clarification of time of Echo or MUGA during 
the combination therapy  
4. Addition of  abbreviation DDI 
5. Addition of reference on new publication on 
the mode of action of BIBW 2992 
6.  Updated guidance on the concomitant use of 
P-gp inhibitors and inducers- Deletion of 
withdrawal criteria 9 – addition in appendix 4 
of the list of potent inhibitors and inducers of 
P-glycoprotein (MDR1) in line with updated 
P-gp information (appendix 4.2). 
7. Information about incidence of Keratitis in 
licensed EGFR inhibitors. 
8. Clarification 
9. Clarification on inclusion criteria to be 
rechecked at the start of part B 
10. Clarification on exclusion criteria to be 
rechecked at the start of part B and 
clarification on pregnancy monitoring after 
the end of the trial 
11. Exclusion criteria amended: requirement for 
updated platelet count prior to the start of 
each vinorelbine infusion - Addition of a 
statement on vinorelbine dose adjustment for 
severe hepatic impairment due to the release 
of the updated vinorelbine SPC 
12. Removal of manufacturer name of Paclitaxel 
in the trial and updated dilution volume for 
vinorelbine  
13. Clarification on how to proceed with study 
treatment when patients do not have drug 
related adverse events. 


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14. Modification regarding the reporting of 
worsening of underlying disease or other pre-
existing conditions, change in vital signs, 
ECG, physical examination and laboratory 
test results. 
15. Clarification on pregnancy monitoring after 
the end of the trial. 
16. Clarification. 
17. Addition of reference to section 5.2.2.2 for 
safety reporting during the follow up period 
18. Alignement between section 5.1.1 (endpoints 
and efficacy) and Section 7.3 (planned 
analyses) 
19. Spell check (English UK) 
 
Rationale for change 
 
1. Personnel change  
2. Clarification 
3.  Clarification and addition of guidance for the 
time of Echo or MUGA during the 
combination therapy  
4. New abbreviation added in the amendment 
text 
5. Update on the mechanism of action of BIBW 
2992(afatinib) 
6. Updated guidance on the concomitant use of 
P-gp inhibitors and inducers (IB(U03-3218) 
version 13) 
7. Update 
8. Clarification 
9. Clarification  
10. Clarification  
11. Update following the release of the updated 
Vinorelbine SPC 
12. Following a shortage of Paclitaxel from 
Hospira UK on the market and in order to be 
able to provide Paclitaxel to the patients in 
the study, Boehringer-Ingelheim may need to 
purchase Paclitaxel from a different 
manufacturers -  Update on vinorelbine 
dilution due to SPC changes. 
13. Clarification  
14. Alignment with project standard definition 
15. Clarification 
16. Clarification 
17. Clarification 
18. Clarification 


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19. Spelling check 
 
Number of CTP modification 
 
6 
Date of CTP modification 
 
27 June 2013 
EudraCT number 
 
2010-021945-29 
BI Trial number 
 
1200.98  
BI Investigational Product 
 
BIBW 2992 (afatinib)  
Title of protocol 
 
LUX-Breast 2; An open label, phase II trial of 
BIBW 2992 (afatinib) in patients with metastatic 
HER2-overexpressing breast cancer failing 
HER2-targeted treatment in the neoadjuvant 
and/or adjuvant treatment setting 
 
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities 
 
  
To be implemented 
immediately in order to 
eliminate hazard –  
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval 
 
  
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only 
 
 
 
Changes related to Urgent Safety Information released on 03 May 2013 which were 
implemented at this time: 
 
Section to be changed 
 
1.  Protocol synopsis 
2. Flow chart B 
3. Abbreviations 
4. Section 2.1 
5. Section 2.3 
6. Section3.1 
7. Section3.2 
8. Section 3.3.2 and 3.3.3 
9. Section 3.3.4.2 
10. Section 4.1and 4.1.1 
11. Section 4.1.2 


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12. Section 6.2 
13. Section 6.2.2 
14. Section 7.1 
15 Section 7.6 
 
Description of change 
 
1 to 15. 
Stop the inclusion of new patients into 
the afatinib + vinorelbine combination in Part B 
of LUX-Breast 2 
 
Rationale for change 
 
1 to 15.   The Data Monitoring Committee (DMC) 
of the 1200.75 trial (LUX-Breast 1 - EudraCT # 
2009-015476-98, NCT01125566) conducted a 
benefit-risk analysis as pre-specified in the 
clinical trial protocol.  A 1200.75 DMC 
recommendation which was issued on 26 April 
2013 concluded,  that based on the benefit-risk 
analysis, treatment in the experimental arm 
(afatinib  40 mg + vinorelbine 25 mg/m2 weekly 
i.v.) should be discontinued.  
 
The benefit-risk analysis in trial 1200.75 was 
based on data from over half of the planned 
number of patients enrolled. The DMC concluded 
that there is a low likelihood of the study meeting 
the pre-defined criteria for increased efficacy in 
terms of PFS. In addition, a high rate of treatment 
discontinuations and dose reductions as well as a 
higher rate of serious adverse events and deaths 
was observed in the experimental arm compared 
to the control arm trastuzumab + vinorelbine. 
The sponsor and the Executive Committee of the 
trial agreed to follow the DMC’s recommendation 
and decided to stop further randomisation into 
the study and to discontinue further treatment 
with the combination of afatinib and vinorelbine.  
 
Since one of the treatment options in Part B of 
Trial LUX-Breast 2 is the combination of afatinib 
+ vinorelbine, BI decided as a precautionary 
measure to stop the inclusion of new patients into 
the afatinib + vinorelbine combination in Part B 
of LUX-Breast 2. Part A of the trial and 
continuation of treatment with paclitaxel in Part 
B was not affected by this urgent safety measure  
 
 


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Changes NOT related to Urgent Safety Information released on 03 May 2013 and 
only to be implemented after approval of this amendment: 
 
Section to be changed 
 
1.  Protocol synopsis 
2. Flow chart A and B 
3. Section 2.3 
4. Section3.1 
5. Section3.2 
6. Section 3.3.4.2 
7. Section 4.1.2 
8 Section 6.2.1 
9 Section 7.1 
10. Section 7.6 
11 Section 4.1.6.1 
Description of change 
 
1 to 10 Stop enrolment into the trial after protocol 
amendment 6 approval by IRBs and IECs 
 
11  Remove description of Afatinib bottle 
 
Rationale for change 
 
1 to 10 In addition the decision has been made to 
stop further enrolment of new patients in Part A 
as: 
-Afatinib+Vinorelbine Treatment in part B 
is no longer an option. This combination showed 
an unfavourable benefit/risk ratio in trastuzumab 
pre-treated patients leading to termination of the 
pivotal trial 1200.75. As a consequence the 
eligible patient population to be included in part 
A of trial 1200.98 will narrow down, as patients 
receiving adjuvant/neoadjuvant paclitaxel are not 
readily rechallenged with paclitaxel when 
receiving 1st line mBC treatment. This will 
generate further difficulties for recruitment.  
- In addition since the trial 1200.98 
started, pertuzumab/trastuzumab + docetaxel 
intended for patients who have not received prior 
treatment for metastatic breast cancer with an 
anti-HER2 therapy or chemotherapy, has been 
approved in 2012 and is becoming standard of 
care  wherever available. This will establish 
further hurdles for a timely recruitment even into 
part A of trial 1200.98. 
-Approximately 60 out of 69 patients 
enrolled to date in this trial have received 
Trastuzumab only based regimens as prior 
treatment in the adjuvant and neoadjuvant 


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setting. By the time of approval of amendment 6, 
it is expected that approximately 80 patients will 
have been treated in this trial. As only 9 patients 
have received lapatinib or a combination of 
lapatinib and trastuzumab as prior treatment so 
far, the efficacy analysis will be driven by 
trastuzumab pretreated patients. 80 patients will 
address the efficacy of afatinib in the 
Trastuzumab-pretreated patients with a high 
statistical probability (see section 7.6 for details)  
 
11  In the future, afatinib supplies for clinical 
trials might be switched to the marketed product. 
The bottle type might be different from an HDPE 
bottle (e.g. PP-bottle with more desicant ) 
 
 
 

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c01946576-03
BI Trial No.:
1200.98
Title:
LUX-Breast 2; An open label, phase II trial of BIBW 2992 
(afatinib) in patients with metastatic HER2-overexpressing breast 
cancer failing HER2-targeted treatment in the neoadjuvant and/or 
adjuvant treatment setting (including protocol revisions 1-7 1200-
0098--protocol-revision-07 [c02103088]).  
Investigational 
Product(s):
Giotrif®. afatinib
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
20 OCT 2014 SIGNED
Version:
Revised
Page 1 of  30
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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.


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1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................3
2.
LIST OF ABBREVIATIONS ...............................................................4
3.
INTRODUCTION..................................................................................5
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......6
5.
ENDPOINTS ..........................................................................................7
5.1
PRIMARY ENDPOINT ......................................................................................7
5.2
SECONDARY ENDPOINTS..............................................................................7
5.2.1
Key secondary endpoints................................................................................7
5.2.2
Other Secondary endpoints............................................................................8
............................................................................9
............................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................10
6.1
TREATMENTS..................................................................................................10
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................10
6.3
PATIENT SETS ANALYSED..........................................................................17
...................................................................................17
6.5
POOLING OF CENTRES ................................................................................17
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................17
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................18
7.
PLANNED ANALYSIS.......................................................................19
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........19
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................19
7.3
TREATMENT COMPLIANCE .......................................................................20
7.4
PRIMARY ENDPOINT ....................................................................................20
7.5
SECONDARY ENDPOINTS............................................................................20
7.5.1
Key secondary endpoints..............................................................................20
nts..........................................................................21
..............................................................................21
7.7
EXTENT OF EXPOSURE................................................................................21
7.8
SAFETY ANALYSIS.........................................................................................22
7.8.1
Adverse events ...............................................................................................22
7.8.2
Laboratory data.............................................................................................24
7.8.3
Vital signs.......................................................................................................25
7.8.4
ECG ................................................................................................................25
7.8.5
Others .............................................................................................................25
8.
REFERENCES.....................................................................................26
..27
...27
10.
HISTORY TABLE...............................................................................28


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LIST OF TABLES
Table 6.2: 1
Important protocol violations..........................................................................11
Table 10: 1
History table ....................................................................................................28


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
BSA
Body Surface Area
CR
Complete response
CTCAE
Common Terminology Criteria for Adverse Events  
CTP
Clinical Trial Protocol
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
ICH
International Conference on Harmonisation
IPV
Important protocol violation
MedDRA
Medical Dictionary for Regulatory Activities
NE
Not evaluable
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
PT
Preferred term
Q1
Lower quartile
Q3
Upper quartile
RECIST
Response Evaluation in Solid Tumours
SD
Stable disease
StD
Standard deviation
SOC
System Organ Class
TRT A
Treated set (Part A)
TRT B
Treated set (Part B)
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal


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3.
INTRODUCTION
As per the International Conference on Harmonisation (ICH E9) guideline (3), the purpose of 
this document is to provide a more technical and detailed elaboration of the principal features 
of the analysis described in the Clinical Trial Protocol (CTP), 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 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, randomisation.
SAS® Version 9.2 or higher will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Not applicable.


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5.
ENDPOINTS
All endpoints in this study, except where specified, will be assessed separately for the 
monotherapy part of the study (Part A) and for the combination part of the study (Part B). 
These parts are defined in Section 6.1.
5.1
PRIMARY ENDPOINT
Objective response (with confirmation):
Best overall response of confirmed complete response (CR) or confirmed partial response 
(PR) recorded since first administration of trial medication and until the earliest of disease 
progression, death or start of next treatment (either Part B combination therapy or new anti-
cancer therapy) in each part separately. Best overall response is the best overall response to 
trial medication (without clinical disease assessment) according to Response Evaluation in 
Solid Tumours (RECIST) version 1.1 (see Appendix 10.3 of the CTP) and is calculated 
relative to the baseline of each respective part.
Criteria for confirmation of best overall response are described by RECIST version 1.1 and in 
Section 5.1.2 of the CTP. 
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints 
Best overall response (with and without confirmation)
Defined as for objective response. For both confirmed and unconfirmed best overall response, 
stable disease (SD) needs to be observed >=35 days after the first dose in each part 
respectively.
See Section 6.6 for details on how missing or incomplete data (due to missed visits or 
blurred/unclear images) are handled for best overall response.
Progression-Free Survival (PFS)
Assessed for three time intervals (see Section 6.1 for the start of monotherapy and
combination therapy definitions): 

Part A: time from the date of the start of monotherapy to the date of 1st disease 
progression or death

Part B: time from the date of the start of combination therapy to the date of 2nd disease 
progression or death

Whole study (Part A + Part B): time from the date of the start of monotherapy to the date 
of 2nd disease progression or death.
And defined for patients presenting with disease progression (according to RECIST version 
1.1) or death before start of new anti-cancer therapy, as the shortest duration of the following:


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
Date of disease progression - date of first administration of trial medication + 1,

Date of death - date of first administration of trial medication + 1;
where date of disease progression is the earliest of the following:

Date of imaging documenting progressive disease (PD),

Date of progression of disease, recorded at the follow-up visits, occurring prior to 
commencement of other anti-cancer therapy.
For patients not presenting with disease progression according to RECIST version 1.1 or 
death before start of new anti-cancer therapy, censoring will be applied according to the 
following:

Date of last assessment where patient was known to be progression-free and alive before 
start of new anti-cancer therapy - date of first administration of trial medication + 1.
For patients not presenting with disease progression according to RECIST version 1.1 or 
death and lost to follow-up before start of new anti-cancer therapy, censoring will be applied 
according to the following:

Date of last assessment where patient was known to be progression-free - date of first 
administration of trial medication + 1.
Further censoring information with regards to missing or incomplete data (due to missed 
visits or blurred/unclear images) values is given in Section 6.6 of this document.
PFS will only be based on tumour imaging data, i.e. clinical disease progression will not be 
considered.
Duration of objective response (without confirmation) [days]:
For patients presenting with unconfirmed objective response, the shortest duration of the 
following:

Date of disease progression - date of first assessment indicating objective response + 1,

Date of death - date of first assessment indicating objective response + 1,

Date of censoring for PFS - date of first assessment indicating objective response + 1
where objective response, date of disease progression and censoring details for PFS are 
defined earlier on in this section of this document.
5.2.2
Other Secondary endpoints
Safety endpoints

Number of patients with highest CTCAE grade of 3 or higher 

Change from baseline to end of treatment in SBP

Change from baseline to end of treatment in DBP


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
Number of patients with possibly clinically significant laboratory values by functional 
group (Haematology, Differentials, Coagulation, Electrolytes, Enzymes and Substrates)


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
The following study periods based on actual start and stop dates of study treatment
administration are defined:

Screening: day of informed consent to day prior to starting afatinib monotherapy.

Part A: On-treatment (monotherapy): day of first administration of afatinib monotherapy
to day of last administration of afatinib monotherapy.

Post-treatment (monotherapy): day after last administration of afatinib monotherapy to 
either the 28th day after last administration of afatinib monotherapy or the day before the
first administration of study paclitaxel/vinorelbine, whichever occurs first.

Part B: On-treatment (combination therapy – if applicable): day of first administration of 
study paclitaxel/vinorelbine to day of last administration of afatinib or study 
paclitaxel/vinorelbine (whichever is later) in Part B.

Post-treatment (combination therapy – if applicable): day after last administration of 
afatinib or study paclitaxel/vinorelbine (whichever is later) in Part B to the 28th day after 
last administration of afatinib or study paclitaxel/vinorelbine (whichever is later) in Part 
B.

Post-study: 29th day after last administration of study treatment onwards. This includes 
patients in long-term follow-up.
For safety summaries data recorded up to and including 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
for mono- and combination therapy separately).
6.2
IMPORTANT PROTOCOL VIOLATIONS
The following table defines the different categories of important protocol violations (IPVs). 
The final column describes which PVs will be used to exclude patients from the different 
patient analysis sets. Since a per-protocol analysis set is not defined for the analysis of this 
trial, patients are either excluded from “All” or “None” of the analysis sets.


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Table 6.2: 1
Important protocol violations
Category/
Code
Description
Example/Comment
Excluded 
from
A
Entrance criteria not met
A1.1
Age out of range or patient 
not female
Inclusion criterion 1 answered ‘No’ or demography
eCRF page indicates patient is male and/or <18 
years old.
None
A1.2
Patient does not have 
proven diagnosis of trial 
disease or archived tissue
sample available for 
reassessment of HER2 
status
Inclusion criterion 2 answered ‘No’.
None
A1.3
Patient does not have stage 
IV metastatic disease
Inclusion criterion 3 answered ‘No’.
None
A1.4
Patient does not have at 
least one measurable lesion 
according to RECIST 1.1
Inclusion criterion 4 answered ‘No’ or patient 
doesn’t have at least one target lesion ≥ 10 mm if 
non-lymph node or ≥ 15 mm if lymph node on 
tumour evaluation (target lesions part A –
monotherapy) according to RECIST 1.1 eCRF 
page.
None
A1.5
Patient does not have 
ECOG score of 0, 1, or 2
Inclusion criterion 5 answered ‘No’ or ‘ECOG 
performance status’ > 2 on screening physical 
examination eCRF page.
None
A1.6
Patient does not have 
required life expectancy
Inclusion criterion 6 answered ‘No’.
None
A1.7
Patient has not failed on 
trastuzumab and/or 
lapatinib in the 
neoadjuvant and/or 
adjuvant setting.
Inclusion criterion 8 answered ‘No’ or neither ‘Was 
trastuzumab taken?’ nor ‘Was lapatinib taken?’ on 
the previous other anti-cancer therapies eCRF page 
answered ‘Yes’ with corresponding ‘Therapy 
mode’ neoadjuvant or adjuvant.
None
A1.8
Patient has not failed on 
trastuzumab and/or 
lapatinib in the 
neoadjuvant and/or 
adjuvant setting and 
afatinib monotherapy in 
the 1st line metastatic 
setting (only applicable to 
patients entering part B)
Inclusion criterion 9 answered ‘No’ or ‘date of 
progression’ is missing from completion part A
eCRF page.
None


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Table 6.2: 1
Important protocol violations (cont.)
A1.9
Patient is not eligible for 
re-treatment with either 
paclitaxel or vinorelbine
Inclusion criterion 10 answered ‘No’ or database 
indicates patient not eligible at entry to Part B for 
re-treatment with either paclitaxel or vinorelbine 
using previous systemic chemotherapies eCRF 
page:

the preferred term for the previous compound 
is ‘PACLITAXEL’, ‘PACLITAXEL 
LIPOSOME’ or ‘PACLITAXEL 
POLIGLUMEX’ but the date of last 
administration is ≤ 12 months prior to the 
VPC1V1 date
AND

the preferred term for the previous compound 
is ‘VINORELBINE’ or ‘VINORELBINE 
TARTRATE’
None
A2.1
Patient has a requirement 
for treatment with 
prohibited concomitant 
medications
Exclusion criterion 1 answered ‘Yes’.
None
A2.2
Previous or current 
excluded medical 
condition
Exclusion criterion 2, 3, 8, 9, 10, 11, 13 or 21
answered ‘Yes’ or medical review of baseline 
conditions eCRF page indicates excluded medical 
condition.
None


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Table 6.2: 1
Important protocol violations (cont.)
A2.3
Previous excluded 
treatment or therapy
Exclusion criterion 4, 5, 6, 25, 26 or 28 answered 
‘Yes’ or indication of excluded prior treatment or 
therapy by medical review of:

date of last chemotherapy (other anti-cancer 
therapies eCRF page) greater or equal to date 
of first appearance of metastasis (screening 
oncology/breast cancer eCRF page), or 
trastuzumab or lapatinib (previous other anti-
cancer therapies eCRF page) given as first line 
metastatic therapy

radiotherapy within 4 weeks prior to trial 
treatment (previous radiotherapies eCRF page)

chemotherapy within 4 weeks prior to trial 
treatment (previous systemic chemotherapies
eCRF page)

immunotherapy within 4 weeks prior to trial 
treatment (previous other anti-cancer therapies
eCRF page where therapy type=1 
(immunotherapy))

trastuzumab or lapatinib taken within 4 weeks 
prior to trial treatment (previous other anti-
cancer therapies eCRF page)

surgery (other than biopsy) within 4 weeks 
prior to trial treatment (previous surgeries for 
trial disease eCRF page)

hormone therapy within 2 weeks prior to trial 
treatment (previous other anti-cancer therapies
eCRF page where therapy type=2 (hormone 
therapy))

EGFR/HER2-targeted small molecules or 
antibodies other than trastuzumab and 
lapatanib in the neoadjuvant and/or adjuvant 
setting (based on medical review of previous 
other anti-cancer therapies eCRF page where 
therapy type=1 (immunotherapy) or 3 (other))
None
A2.4
Active brain metastases
Exclusion criterion 7 answered ‘Yes’ or ‘brain 
metastases status’ on screening oncology/breast 
cancer eCRF page = active.
None
A2.5
Cardiac left ventricular 
function with resting 
ejection fraction of less 
than 50%.
Exclusion criterion 12 answered ‘Yes’ or ‘LVEF’ < 
50% on left ventricular ejection fraction eCRF 
page.
None


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Table 6.2: 1
Important protocol violations (cont.)
A2.6
Abnormal laboratory 
measurement at Screening.
Exclusion criterion 14, 15, 16, 17, 27 or 31 
answered ‘Yes’ or database indicates criterion not 
met due to one of the following at screening, with 
no subsequent eligible value prior to first study 
drug administration:

Absolute neutrophil count (ANC) < 1.5 x 109/L

Calculated Creatinine clearance < 60 ml / min 
(Cockcroft formula – Appendix 1 CTP)

Serum creatinine > 1.5 times upper limit of 
normal

Bilirubin > 1.5 times upper limit of normal 
(ULN)

Aspartate amino transferase (AST) or alanine 
amino transferase (ALT) > 3 times the ULN 
where patient does not have liver metastases 
(oncology/breast cancer history eCRF page)

AST or ALT > 5 times the ULN where patient 
has liver metastases (oncology/breast cancer 
history eCRF page)

Platelet count < 100 x 109/L
or the following at the VPC1V1 visit (part B 
baseline):

Platelet count < 100,000/mm3 for afatinib
combination treatment with study paclitaxel

Platelet count < 75,000/mm3 for combination 
treatment with study vinorelbine.
Platelet counts which are ≥75,000/mm3 and 
<100,000/ mm3 prior to treatment with study 
vinorelbine will be compared against the local CTP 
approval dates to confirm whether a violation has 
taken place.
None
A2.7
Contraception, pregnancy 
or breast-feeding exclusion 
criteria met
Exclusion criterion 18 or 19 answered ‘Yes’ or 
pregnancy result at screening.is ‘positive’ or ‘Not 
done (although childbearing potential)’.
None
A2.8
Other exclusion criteria 
met
Exclusion criterion 20, 22, 23 or 24 met.
None
A2.9
Patient treated with study 
paclitaxel in Part B when 
eligibility criterion not met
Exclusion criterion 29 answered ‘Yes’ or the 
preferred term for the previous compound is 
‘PACLITAXEL’, ‘PACLITAXEL LIPOSOME’ or 
‘PACLITAXEL POLIGLUMEX’ but the date of 
last administration is ≤ 12 months prior to the date 
of first administration of study paclitaxel in Part B
None


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Table 6.2: 1
Important protocol violations (cont.)
A2.10
Patient treated with study 
vinorelbine in Part B when 
eligibility criterion not met
Original exclusion criterion 30 answered ‘Yes’ or 
the preferred term for the previous compound  is 
‘VINORELBINE’ or ‘VINORELBINE 
TARTRATE ’
None
B
Informed consent
B1
Informed consent not 
available
Inclusion criterion 7 answered ‘No’ or informed 
consent date missing
All
B2
Informed consent too late
Date of informed consent was after screening visit 
date 
None
C
Trial medication and 
randomisation
C1.1
Incorrect dose level of 
afatinib taken at first 
administration
At Visit C1V1:
Dose level from administration of BIBW 2992
eCRF page not ‘40’ or ‘medication number’ from 
medication dispensed record BIBW 2992 eCRF 
page indicates ‘unit strength’ is not ‘40’.
None
C1.2
Afatinib dose reduction 
scheme not followed or 
treatment not paused 
appropriately
Based on medical review of the trial medication 
compliance (BIBW 2992) and medication dispensed 
record BIBW 2992 eCRF pages for patients who 
had the AE type and grade as specified in Table 
4.1.4: 1 in the CTP.
None
C1.3
Increase in afatinib dose
Dose of afatinib increased after dose reduction has 
already occurred.
None
C2.1
Incorrect trial 
chemotherapy taken
In part B, study vinorelbine administered instead of 
study paclitaxel or vice versa. This will be assessed 
using ‘drug administered’ and ‘medication number’ 
from (first) administration of paclitaxel or 
vinorelbine eCRF page.
None
C2.2
Incorrect dose level of 
chemotherapy taken
From (first) administration of paclitaxel or 
vinorelbine eCRF page: 
Actual dose ≠ (planned dose level x body surface 
area [BSA] (m2)) ± 10%
None
C2.3
Incorrect exposure to 
combination therapy
Patient stopped afatinib more than 4 weeks before 
or after chemotherapy or no afatinib taken in Part B
None


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Table 6.2: 1
Important protocol violations (cont.)
C3
Trial medication non-
compliance
Medical review of ‘administration according to the 
protocol?’=’No’ and any associated comments from 
either of the following eCRF pages:

Administration of BIBW 2992

Trial medication compliance (BIBW 2992)
Review of ‘infusion according to the 
protocol?’=’No’ and any associated comments from 
either of the following eCRF pages:

First administration of paclitaxel or 
vinorelbine

Administration of paclitaxel or vinorelbine
None
D
Concomitant medication
D1
Prohibited medication use 
or radiotherapy during 
treatment period
Based on medical review of concomitant therapy.
None
G
Trial specific
G1
Incorrect timing of 
baseline tumour evaluation
Baseline tumour assessment is >4 weeks prior to 
study drug administration in Part A.
None
G2
Patient not withdrawn as 
per protocol
Patient met at least one of the withdrawal criteria 
identified in Section 3.3.4.1 of the CTP but was not 
withdrawn.
None
G3
Laboratory measurements 
out of range but 
chemotherapy not delayed
Most recent platelet count < 75,000/mm3 or most 
recent neutrophil count < 1500/mm³ prior to 
treatment with study vinorelbine
Platelet counts which are ≥75,000/mm3 and 
<100,000/ mm3 prior to treatment with study 
vinorelbine will be compared against the local CTP 
approval dates to confirm whether a violation has 
taken place.
OR
Most recent platelet count < 100,000/mm3
immediately prior to treatment with study 
paclitaxel.
None
G4
Gap between progression 
on Part A and start of Part 
B greater than 28 days 
with no radiotherapy.
Check ‘date of progression’ from completion part A
eCRF page vs date of first administration of study 
chemotherapy in Part B, taking start and end dates 
of radiotherapy into account.
None
G5
Other protocol violations 
affecting patients’ rights or 
safety
None


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6.3
PATIENT SETS ANALYSED
The following analysis sets will be defined for this trial:

SCR – Screened patients set
All patients screened for the trial who completed at least some screening procedures.

TRT A – Treated set (Part A)
This patient set includes all patients who were documented to have taken at least one dose 
of afatinib in Part A. 

TRT B – Treated set (Part B)
This patient set includes all patients who were documented to have had at least one dose 
of afatinib and one infusion of either study paclitaxel or study vinorelbine in Part B.
The treated sets for Part A and Part B will be used for all efficacy and safety analyses in parts 
A and B respectively.
6.5
POOLING OF CENTRES
All centres will be analysed together, with any centre effects being ignored. Country or 
region effects will also not be considered. 
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. If missing data do occur though, they will be handled as 
follows:
For PFS, patients will be censored using date of first administration of trial medication in the 
following situations:

Baseline tumour assessment missing,

First two post-baseline tumour assessments immediately preceding disease progression or 
death missing or not evaluable.
For PFS and duration of objective response, patients will be censored using date of last post-
baseline assessment where patient was known to be progression-free in the following 
situation:


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
Two consecutive post-baseline tumour assessments missing or not evaluable (not 
including first two) immediately preceding disease progression or death.
A patient’s best overall response will be set to not evaluable (NE) in the following situations:

Missing baseline tumour evaluations,

No post-baseline tumour evaluations prior to or on day of PD, last dose+1 or death,

No protocol-specified post-baseline tumour evaluations (unless unscheduled tumour 
evaluation indicates PD in which case patients will be assigned a best overall response of 
PD),

Two consecutive protocol-specified post-baseline tumour evaluations missing or NE 
(unless prior tumour evaluation indicates CR, PR or SD or subsequent tumour evaluation 
indicates PD).
If a patient has died and the death date is missing or incomplete, then the earliest conceivable 
date will be imputed, given the available information.
If day of first histological diagnosis or first appearance of metastases is missing it will be 
imputed using ‘15’. If month of first histological diagnosis or first appearance of metastases 
is missing it will be imputed using ‘June’.
Missing or incomplete AE dates are imputed according to BI standards (see reference 
document 001-MCG-156 “Handling of missing and incomplete AE dates”).(1)
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline values for Part A will be the measurements taken most recently prior to first 
administration of afatinib in Part A. For patients entering Part B, baseline values will be the 
measurements taken most recently prior to first administration of study paclitaxel or study 
vinorelbine on day 1 of the combination treatment period. Note that for some procedures (e.g. 
ECOG performance status, vital signs, laboratory tests), this may be the measurement taken 
on the same day the patient starts their treatment in each part, but since the assessments are 
made before study drug administration, these are acceptable to use as baseline measurements.
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. This will be 
performed separately for Parts A and B.
All data collected at a visit level will be presented according to the actual protocol visit it was 
measured at. 


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7.
PLANNED ANALYSIS
All analyses, except where specified, will be performed on the TRT A and TRT B analysis 
sets for parts A and B respectively.
Patient disposition (number of patients screened, treated in Part A etc.) will be presented for 
all patients in the screened set. If applicable, the number of patients who will continue 
treatment at the time of reporting will be reported in the disposition table, separately. A 
patient is deemed to have completed the trial once they show progressive disease according to 
RECIST in Part B.
The frequency of patients with IPVs will be presented.
Descriptive statistics for continuous variables will generally be n (number of patients with 
non-missing values), mean, standard deviation (StD), minimum, Q1 (lower quartile), median, 
Q3 (upper quartile), maximum. In general, means, StDs, medians, Q1 and Q3 will be 
presented to one more decimal place than the raw data. Minima and maxima will be 
presented to the same number of decimal places as the raw data.
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 population. As there are fewer than 100 patients in the study, percentages will 
generally be rounded to the nearest integer. A missing category will be displayed if there are 
actually missing values. Percentages will generally be based on all patients in the respective 
patient set whether they have non-missing values or not.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Descriptive statistics and/or frequency counts as described in Section 7 will be presented for 
the following eCRF pages:

Demographics

Oncology/breast cancer history

Target lesions (baseline sum) according to RECIST 1.1

Previous systemic chemotherapies Previous radiotherapies

Previous other anti-cancer therapies

Tumour biopsy
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
The frequency of patients with different concomitant diseases (baseline conditions) will be 
presented. This presentation will be categorised as follows:

Baseline conditions


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
Sign/Symptom of trial disease

ECG finding
Concomitant medications will be summarised according to whether they are concomitant 
with Part A or Part B. Medications which are prior to first study drug administration will be 
listed only.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
Compliance with afatinib will be calculated for parts A and B separately as follows:
100
*
study
of
part 
respective
in 
days
of
Number 
CTP
 the
 to
accordance
in 
not 
missed
 tablets
of
Number 
1







*Since posology is one tablet per day.
7.4
PRIMARY ENDPOINT
An exact binomial 95% confidence interval (Clopper-Pearson) will be calculated for the 
proportion of patients who achieve confirmed objective response (see Section 5.1) in each 
part separately. These point estimates and confidence intervals will be further presented by 
the subgroups defined in Section 6.4.
The objective response rate, determined without confirmation, will also be presented along 
with an exact 95% Clopper-Pearson confidence interval.
Additionally, confirmed objective response rates will be evaluated by a Bayesian approach. 
Further details are given in Appendix 9.1. 
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
None of the secondary endpoints which use RECIST 1.1 require confirmation, except for SD.
Best overall response
Frequency tables and exact binomial 95% confidence interval (Clopper-Pearson) will be 
presented for the best RECIST assessment achieved by each patient during each of the 
treatment periods in the order (from best to worst): CR, PR, SD, PD, NE. This will be 
presented for both confirmed and unconfirmed responses.
Progression-Free Survival (PFS)


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PFS (as described in Section 5.2.2) will be assessed based on the Kaplan-Meier method for 
each part separately and point estimates together with confidence intervals (based on 
Greenwood’s method) will be provided for median PFS.
See Section 6.6 for censoring rules.
Duration of objective response
Descriptive statistics will be produced for the duration of objective response (see Section 
5.2.2) for parts A and B separately. The duration will only be calculated for those patients 
with an objective response. Duration of objective response will also be summarised using 
Kaplan-Meier plots.
Frequency counts of time to objective response by planned imaging week will also be 
presented.
7.5.2
Other Secondary endpoints
Safety endpoints: See Sections 7.8.1, 7.8.2 and 7.8.3.
7.7
EXTENT OF EXPOSURE
Calculated in days for each part separately and overall:
Date of last administration of trial medication – date of first administration of trial medication 
+ 1.


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Total treatment time therefore includes time when treatment was temporarily discontinued 
and subsequently reintroduced. Categorisations for total treatment time are defined for Part A 
as follows:

1 - 21 days, 

22 - 42 days,

43 - 84 days,

85 - 126 days,

127 - 168 days,

>168 days
For Part B:

1 - 21 days,

22 - 42 days,

43 - 84 days,

>84 days
And for the overall summary:

1 - 21 days, 

22 - 42 days,

43 - 84 days,

85 - 126 days,

127 - 168 days,

169 - 210 days,

211 – 252 days,

>252 days
If there is discordance between the date of last intake of afatinib and study chemotherapy, the 
latest date will be used for the calculations in Part B and the overall summary.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the respective treated set and presented for parts A 
and B separately.
7.8.1
Adverse events
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of patients with AEs (not the number of AEs). For this purpose, AE data will be 
combined in a 2-step procedure into AE records.
In a first step, AE occurrences, i.e. AE entries on the CRF, will be collapsed into AE episodes 
provided that all of the following applies:

The same Medical Dictionary for Regulatory Activities (MedDRA) lowest level term was 
reported for the occurrences.


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
The occurrences were time-overlapping or time-adjacent (the second occurrence started 
before or one 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.
In a second step, AE episodes will be condensed into AE records provided that the episodes 
were reported with the same term on the respective MedDRA level and that the episodes are 
assigned to the same treatment. For further details on summarisation of AE data, please refer 
to the guideline 'Handling and summarization of adverse event data for clinical trial reports 
and integrated summaries' (2)
The analysis of AEs will be based on the concept of treatment emergent AEs. That means 
that all AEs occurring between first drug intake until 28 days after last drug intake will be 
assigned to either mono- or combination therapy (depending on the date of onset). Since 
times are not collected for AEs, any AEs occurring on the first day of Part B will be assigned 
to combination therapy. All adverse events occurring before first drug intake will be assigned 
to ‘screening’ and all adverse events occurring after last drug intake + 28 days will be 
assigned to ‘post-treatment’ and presented in listings only. For details on the treatment 
definitions, see Section 6.1.
An overall summary of AEs 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 maximum CTCAE’ grade.
The frequency of patients with adverse events will be summarised by maximum CTCAE
grade (and overall), treatment, primary system organ class (SOC) and preferred term (PT) for 
each of the following AE tables:

AEs overall.

Drug related AEs.

AEs leading to dose reduction.

AEs leading to treatment discontinuation.

Serious AEs.

Drug related AEs leading to treatment discontinuation.

Drug related and serious AEs

AEs leading to death.

Non-serious AEs
The PTs will be sorted by descending incidence within SOC.
The above tables except for AEs leading to death will be repeated replacing SOC and PT with
project defined grouping of AE terms for selected incidence rates. Details of the project 
defined groupings are defined in the technical TSAP.
Additional AE tables showing time at risk, frequency counts and 95% confidence intervals, 
outcomes, consequences, maximum CTCAE grade, time to first onset and time to 
discontinuation will be produced for three of the project defined groupings (diarrhoea, rash 


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and stomatitis), and for AEs of special interest including 'Renal insufficiency', 'Leukopenia', 
‘Neutropenia’ and 'Neuropathy'. Note that the leukopenia group will not contain cases of 
neutropenia since these are being presented separately.
All of the tables described above will be produced separately for AEs assigned to parts A and 
B. See Section 6.1 for the treatment period definitions.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (4). CTCAE grades will be applied to laboratory parameters using the current BI 
oncology standard as detailed in the document ‘Conversion of laboratory parameters to 
CTCAE grades within BI’ (5).
Descriptive statistics of all laboratory values by visit will be provided including changes from 
baseline. Frequency tables of transitions relative to the reference range and of possible 
clinically significant abnormalities will be produced. For those parameters that have CTCAE
grading, possible clinically significant abnormalities are defined as those laboratory values 
with a CTCAE grade ≥2 that have had an increase of ≥ 1 grade from baseline. For those 
parameters for which no CTCAE grade has been defined, standard BI project definitions will 
be used to decide on clinical significance.
Three further frequency tables will show:

the transition of CTCAE grade from baseline to worst value 

the transition from baseline to last value on treatment

the transition from worst value to last value on treatment.
In order to assess potential Hy’s law cases, scatter plots will be produced of peak ALT values 
versus peak total bilirubin values within 30 days of the ALT value. The following algorithm 
will be applied:

Identify all ALT values >= 3*ULN

Do any of these have a bilirubin value >= 2*ULN within 30 days of the observed peak 
ALT value?
→ if YES then keep the patient observation with the highest ALT value (along with the 
highest bilirubin value within 30 days).
→ if NO then keep the patient observation with the highest bilirubin value (along with the 
highest ALT value 30 days prior to this).
Similar plots will be produced for peak AST versus total bilirubin.
The focus of the laboratory data analysis will be on the following laboratory parameters:

Low values: haemoglobin, neutrophils, platelets, white blood cell count, magnesium, 
potassium.

High values: International Normalised Ratio, creatinine, AST, ALT, total bilirubin, 
alkaline phosphatase.


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The tables described above will be produced for laboratory data recorded during parts A and 
B separately.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
No data. Any clinically relevant findings were to be reported as AEs.
7.8.5
Others
Left ventricular ejection fraction:
Only descriptive statistics are planned for this section of the report.


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8.
REFERENCES
1
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
2
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON.
3
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version.
4
001-MCG-157: "Display and Analysis of Laboratory Data", current version, IDEA 
for CON.
5
BI Guidance document ‘Conversion of laboratory values to CTCAE grades within
Boehringer Ingelheim’


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10.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP:
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
13-Jul 12
None
This is the final TSAP without any 
modification
Revised
20-Oct-14
Title 
page
Date and referenced protocol version 
updated. 
 
 
3
Clarified SAS® version 9.2 or higher
5.1
Efficacy was only to be assessed until 
the end of treatment in each respective 
part but to fully utilise all data 
collected, efficacy will now be assessed 
from start of treatment in each part to 
the start of next treatment (Part B or 
new anti-cancer therapy).
Missing data detail removed since 
covered in Section 6.6.
5.2.1 
and 
5.2.2
Moved endpoints from Secondary to 
Key Secondary in accordance with 
Section 7.3.2.1 of the CTP.
Added detail on confirmation for SD.
Removed ‘date of detection of new 
lesions’ from PFS section since this is 
covered by the ‘progressive disease’ 
bullet.
Removed “Date of last administration 
of trial medication-date of first 
assessment indicating objective 
response+1” bullet from “Duration of 
objective response” section since 
covered by censoring for PFS bullet.
Made other secondary endpoint 
definitions more specific.
 
 
 
6.1
Removed reference to radiotherapy 
period since it’s not a study treatment 
and the data are very limited.


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Table 10: 1
History table (cont)
6.2.1
Removed check for stage IV metastatic 
disease based on TNM classification at 
study inclusion (PV A1.3), for 
consistency within project and between 
projects for this compound.
Corrected limits for measurable disease 
according to RECIST 1.1 (PV A1.4).
Added PVs C2.3 “incorrect exposure to 
combination therapy” and G5 “Other 
protocol violations affecting patients’ 
rights or safety”.
Altered platelet count limit in G3 from 
75,000 to 100,000 /mm3 for treatment 
with vinorelbine in accordance with 
CTP amendment 5 (06 Nov 2012).
6.3
Removed requirement to have been 
dispensed study medication since this is 
implied by the documentation of 
administration.
6.6
Added details on when a patient’s best 
overall response will be ‘not 
evaluable’.
Added detail on imputation of date of 
death.
6.7
Removed summaries during 
radiotherapy period.
Removed detail on visit labelling –
more appropriate for technical TSAP.
7
Added definition of patients who 
complete the trial.
Changed number of decimal places for 
percentages.
7.3
Removed calculation for treatment 
compliance since this is how they 
calculate compliance at site and only 
the percentage is provided on the 
database.
7.4
Removed analysis of best overall 
response since covered later in the 
document.
7.5
Moved endpoints from Secondary to 
Key Secondary in accordance with 
Section 7.3.2.1 of the CTP.


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Table 10: 1
History table (cont)
7.5.1
Added 95% Clopper-Pearson 
confidence interval for best overall 
response for consistency within project.
Removed text stating that a 
proportional hazards model will 
explore the subgroups since only one 
treatment group in each part.
Added Kaplan-Meier plots for duration 
of objective response and frequency 
counts by planned imaging week.
7.7
Added an extra qualitative exposure 
category.
7.8.1
Removed summaries based on the 
radiotherapy period.
Added detail on AEs of special interest 
and project-defined groupings.
7.8.2
Added detail on Hy’s law assessments.
7.8.4
Clarified that clinically relevant ECG 
findings were to be reported as AEs 
and no specific ECG data were to be 
collected.
All
Administrative changes.


 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Version Number:
Document Name: 
 
 
 
                                                                                                                      
 
Title: 
 
 
 
 
                                                                                                                     
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c01946576
3.0
8-01-tsap
LUX-Breast 2; An open label, phase II trial of BIBW 2992 (afatinib) in patients with
metastatic HER2-overexpressing breast cancer failing HER2-targeted treatment in the
neoadjuvant and or adjuvant treatment setting
Author-Trial Statistician
20 Oct 2014 21:50 CEST
Approval-Trial Clinical Monitor
21 Oct 2014 10:06 CEST
Approval-Project Statistician
28 Oct 2014 08:07 CET


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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.0