Clinical trial NCT02780687
Conditions: Urologic Neoplasms
Sponsor: Boehringer Ingelheim
Start date: 2016-06-09; Completion date: 2019-09-02
Enrollment: 42 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of this trial is to assess the anti-tumour activity and safety of afatinib monotherapy in patients with urothelial tract carcinoma carrying ERBB2 or ERBB3 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors) mutations or ERBB2 amplifications (Cohort A), and EGFR (Epidermal Growth Factor Receptor) amplification positive tumours (Cohort B), progressing despite previous platinum based chemotherapy, and thereby to improve their prognosis.

The antitumour activity of afatinib monotherapy in these patients will be assessed by progression free survival rate at 6 months (PFS6). This will be the primary endpoint of the trial. A key secondary endpoint will also be defined, the objective response rate (ORR).

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Afatinib
Intervention descriptions: intervention 1: None

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c03510257-02
EudraCT No.:
2015-005427-10
BI Trial No.:
1200.261
BI Investigational 
Product(s):
   Afatinib (Giotrif, Gilotrif)
Title:
LUX-Bladder 1: Phase II open label single arm exploratory trial 
of oral afatinib monotherapy following platinum failure for 
patients with advanced/metastatic urothelial tract carcinoma 
with genetic alterations in ERBB receptors.
Brief Title:
Afatinib monotherapy in patients with ERBB-deregulated 
metastatic urothelial tract carcinoma after failure of platinum 
based chemotherapy.  
Clinical Phase:
II
Trial Clinical 
Monitor:
Phone: 
Fax: 
Coordinating 
Investigator:
Phone: 
Fax: 
Status:
Final protocol (Revised Protocol (based on Global amendment 
1))
Version and Date:
Version: 2.0
Date: 13 Mar 2017
Page 1 of 90
Proprietary confidential information.
2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Giotrif, Gilotrif
Name of active ingredient:
Afatinib (BIBW 2992)
Protocol date:
17 FEB 2016
Trial number:
1200.261
Revision date:
13 MAR 2017
Title of trial:
LUX-Bladder 1: Phase II open label single arm exploratory trial of 
oral afatinib monotherapy following platinum failure for patients 
with advanced/metastatic urothelial tract carcinoma with genetic 
alterations in ERBB receptors.
Coordinating
Investigator:
Phone: 
- Fax: 
Trial site(s):
Multicentre trial conducted in Europe with participation of SOGUG
and CNIO
Clinical phase:
Phase II 
Objective(s):
To investigate the efficacy in terms of 6 month progression free 
survival (PFS6) and objective response rate (ORR) of afatinib, in 
patients with advanced/metastatic urothelial tract carcinoma who 
have progressed despite prior platinum based chemotherapy. Two 
cohorts will be analysed separately: Cohort A will investigate 
patients with ERBB2 amplification and ERBB2 or ERBB3 
mutations; Cohort B will investigate patients with EGFR 
amplification.
Other measures of efficacy include progression free survival (PFS), 
overall survival (OS), disease control rate (DCR), duration of 
objective response (DOR), and tumour shrinkage.
Safety will be assessed throughout the trial by AEs according to 
NCI CTCAE v. 4.03. 
Methodology:
Un-controlled, open–label phase II trial using a  two stage design 
for Cohort A. Cohort B will be hypothesis generating. Patients will 
be assigned to Cohort A (ERBB2/3 genetic alterations) or Cohort
B (EGFR amplification) based on screening biomarkers. In case of 
competing recruitment, Cohort A will be accrued first.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Giotrif, Gilotrif
Name of active ingredient:
Afatinib (BIBW 2992)
Protocol date:
17 FEB 2016
Trial number:
1200.261
Revision date:
13 MAR 2017
No. of patients: 
Approximately 350 patients will need to be screened to allow for 80
patients who are entered and treated in Cohort A (up to 70 patients) 
and Cohort B (up to 10 patients) and evaluable for PFS6
total entered:
Approximately 350 patients to be screened
Up to 80 patients to be treated
each treatment:
Approximately 350 patients to be screened
Cohort A: up to 70 patients treated 

Stage 1:
25 patients

Stage 2:
45 patients
Cohort B: up to 10 patients treated
Diagnosis :
Patients with histologically confirmed advanced/metastatic urothelial 
tract carcinoma who progressed despite platinum based therapy, and 
show mutations in ERBB2 or ERBB3 or amplification in ERBB2
(Cohort A), or EGFR amplification (Cohort B).
Main criteria
for inclusion:

Histologically confirmed urothelial tract carcinoma of the 
bladder, upper tract or urethra 

Locally advanced or metastatic urothelial tract carcinoma not 
amenable to surgical treatment

Progressed on or after platinum based therapy prior to 
enrolment and not candidate for another platinum therapy. 

Measurable disease per RECIST 1.1

Archival tissue sample available for biomarker testing and 
tissue banking
o
Cohort A: ERBB2 or ERBB3-mutation(s) or ERBB2-
amplification
o
Cohort B: EGFR amplification

ECOG performance status 0-1

Adequate bone marrow, hepatic and renal function
Test product(s):
Afatinib (Giotrif, Gilotrif)
20 mg, 30 mg, 40 mg afatinib film coated tablets
dose:
40 mg once daily given continuously; the dose can be reduced in 10 
mg decrements down to 20 mg daily in case of intolerable AEs.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Giotrif, Gilotrif
Name of active ingredient:
Afatinib (BIBW 2992)
Protocol date:
17 FEB 2016
Trial number:
1200.261
Revision date:
13 MAR 2017
mode of 
administration:
Oral, p.o
Comparator products:
Not applicable
dose:
Not applicable
mode of 
administration:
Not applicable
Duration of treatment:
Therapy with afatinib will continue until progression of disease as 
confirmed by imaging according to RECIST 1.1, or patient´s 
withdrawal of consent for continuation of treatment, or other reasons 
requiring treatment discontinuation (see Section 3.3.4.1).
It is anticipated that the average time on treatment will be ≥ 6 
months.
Endpoints
Primary endpoint: Progression free survival rate at 6 months (PFS6)
for Cohort A patients.
Key secondary endpoint: ORR for Cohort A patients
Other secondary endpoints: PFS, OS,  DCR, DOR, tumour shrinkage
for Cohort A patients. Cohort A and Cohort B will be analyzed 
separately.
Safety criteria:
Evaluation of safety and tolerability of afatinib by incidence and 
severity of adverse events according to NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.03
Statistical methods:
Cohort A: Will be evaluated with a two stage design based on PFS6. 
PFS6 will be calculated as the proportion of patients who are alive 
and without disease progression at the 24-week tumour assessment. 
Objective response rate will be calculated as the proportion of 
patients with confirmed complete response or confirmed partial 
response. Further, PFS and OS will be evaluated using the Kaplan-
Meier estimate. Duration of objective response will be summarized 
descriptively. All analyses will be descriptive in nature.
Cohort B: The analyses will be exploratory and descriptive in nature.


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FLOW CHART
Trial periods
Pre-screening
Screening
Treatment courses
EOT1
EoR2
Follow-up for 
progression3
Follow-ip for OS4
Course5
1
2
3
4 and 
onwards
Visit
1
2
3
1
2
1
1
Day of period
Any time prior 
to day
-296
-28 to -
1
1
8
±2
15
±27
1
±2
8
±27
1
±2
1
±2
Pre-screening consent
X8
Tumour sample tissue 
availability
X9
Informed consent 
X10
Demographics
X
Medical history
X
Physical examination 
X
X
X
X
X
X
X
Performance score11
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
Height 
X
Weight
X
X
X
X
X
X
X
Safety laboratory tests12
X
X
X
X
X
X
X
Pregnancy test (if appl.)13
X
X
12 lead-ECG14
X
X
X
X
Disease assessment
imaging15
X
X
X
Review in-/ex- criteria
X
Blood and urine for 
biomarker testing16
X
X
X
X
Blood for PGx
X17
Dose assessment
X
X
X
X
Dispense trial drug18
X
X
X
X
Afatinib administration
X
Adverse events19
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant therapies
X
X
X
X
X
X
X
X
X
X
X
Compliance check
X
X
X
X
Eligibility for treatment 
continuation
X
X
X
Conclusion of treatment
X
Conclusion  of patient 
participation20
X
X
X
Survival status
X
1
Subsequent anti-cancer 
therapy
X
X
1.
EOT = End of treatment – When the decision is taken to permanently discontinue the study medication, the EOT 
visit must be performed within 7 days after last administration of afatinib. If the decision is taken at a scheduled 
visit, the EOT visit will be performed instead of the scheduled visit. Examinations performed at this time may need 
to be renamed for the actual visit conducted
2.
EoR = End of residual effect period. Safety follow-up visit not earlier than 30 days (+7 days) after last afatinib 
administration. 
3.
Follow-up for progression = Additional follow-up visit. Patients who have not progressed at EOR should have 
additional limited follow-up visits at scheduled tumour assessment timepoints until progression, consent 
withdrawal, lost to follow-up or death.
4.
Follow-up for OS= Follow-up for overall survival: collection of information on vital status every 90 days. 
Information could be collected from the patient’s notes or by telephone contact. A formal visit is not required
5.
All courses are of 4 weeks duration (28 days). Day 1 of a new course should take place on day 29. Patients may 
continue on treatment for unlimited courses until the criteria for stopping medication are met (see Section 3.3.4).
Two additional visits are performed during course 1 to assess tolerability. From course 3 onwards, only one visit 
per course is required


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6.
Pre-screening period can start at any time after signature of pre-screening consent, but please allow at least 4 
weeks for assessment of biomarkers and delivery of results.
7.
Patient contact to be done 15 days after starting study medication, and one week after starting treatment Course 2, 
to check for Adverse Events and Concomitant medication. Information could be collected by telephone contact. A 
formal visit is not required if not needed.
8.
Before tumour tissue sample collection for assessment of eligibility into the trial the patient has to give informed 
consent according to the local regulatory requirements. This consent includes consent to maintain 5x1 mm cores 
for TMAs of tissue sample when the patient is not eligible, or the tissue block if the patient is eligible.
9.
Patient must consent for collection of tumour sample, to (i) perform pre-screening for inclusion into the trial and 
(ii) archiving of tissue for bridging of companion diagnostics assay if needed. 
10. Once the patient was eligible for the trial by pre-screening, before to commence any additional trial procedure the 
patient has to give informed consent/assent for trial participation according to the local regulatory requirements. At 
each moment along the trial, the site staff must disclose and discuss any new information that might affect 
willingness to continue trial participation with the patient and/or legal guardian.
11. Performance score will be assessed according to ECOG
12. Safety lab tests to be performed as described in Section 5.3.3, but should not be repeated if previous tests are older 
than 48 hours
13. Mandatory for female patients of child bearing potential (post menarchal) within 7 days prior to first treatment and 
at EOT. To ensure early detection of pregnancy, test might be repeated as necessary during the treatment period 
depending on the local law
14. ECG is required at screening, at C1V2, and V1 of every third course thereafter (i.e. C4V1, C7V1…) and EOT
15. Tumour assessment by Imaging (CT or MRI)  should be performed every 8 weeks (+/- 1 week) calculated from the 
first treatment day  to the end of study treatment. If  treatment discontinuation is for other reason than disease 
progression, further tumour assessments should be obtained as follows: every 8 weeks (+/-1 week) until month 6, 
and  every 12 weeks (+/-2 weeks) from 6 months onwards, until documented progression of disease. Baseline 
CT/MRI must be performed within 28 days before start of study treatment (if an assessment was performed within 
this timeframe, patient would not need to repeat this test).
16. Blood and urine for biomarker testing will be collected at screening, then every 4th cycle during treatment, and 
also at End of Treatment. If a patient has not progressed at End of Treatment then samples should continue to be 
collected at every 4th follow-up visit and also at the last follow-up visit (as described in Section 5.5).
17. Pharmacogenetics: one optional blood sample, to be obtained only after signing of PGx consent at any treatment 
visit.
18. New kit(s) of trial drug must be dispensed at visit1 of each course. If needed (e.g. in case a dose adaptation has to 
be applied during treatment course), new kit(s) of trial drug might be dispensed outside of the planned visit 
schedule
19. AE/SAE should be reviewed at every treatment visit,at EOT, EOR and thereafter as described in section 5.3.6.
20. Conclusion of patient participation: should be recorded at the last follow-up visit, when PD/Death occurs, consent 
withdrawal or death
21. All patients will be followed-up for overall survival at 90 days intervals. For patients who progressed on treatment, 
the observation period for overall survival starts after the EoR. For patients who have not progressed on treatment, 
this period starts after the last follow-up for progression visit. The End of the Trial will be achieved as described in 
Section 8.6.


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TABLE OF CONTENTS
CLINICAL TRIAL PROTOCOL..........................................................................................1
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................7
ABBREVIATIONS................................................................................................................11
1.
INTRODUCTION...............................................................................................14
MEDICAL BACKGROUND.............................................................................14
1.1
DRUG PROFILE................................................................................................15
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....17
RATIONALE FOR PERFORMING THE TRIAL.........................................17
2.1
TRIAL OBJECTIVES........................................................................................17
2.2
BENEFIT - RISK ASSESSMENT.....................................................................18
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................20
OVERALL TRIAL DESIGN AND PLAN .......................................................20
3.1
3.1.1
Administrative structure of the trial .................................................................21
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................22
SELECTION OF TRIAL POPULATION .......................................................22
3.3
3.3.1
Main diagnosis for trial entry ............................................................................23
3.3.2
Inclusion criteria .................................................................................................23
3.3.3
Exclusion criteria ................................................................................................24
3.3.4
Removal of patients from therapy or assessments...........................................25
Removal of individual patients .............................................................................25
3.3.4.1
Discontinuation of the trial by the sponsor...........................................................26
3.3.4.2
4.
TREATMENTS...................................................................................................27
TREATMENTS TO BE ADMINISTERED.....................................................27
4.1
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........27
4.1.2
Method of assigning patients to treatment groups...........................................27
4.1.3
Selection of doses in the trial..............................................................................27
4.1.4
Drug assignment and administration of doses for each patient......................28
Administration of afatinib.....................................................................................28
4.1.4.1
4.1.4.1.1 Dose reduction for afatinib .......................................................................................29
4.1.5
Blinding and procedures for unblinding...........................................................30
Blinding.................................................................................................................30
4.1.5.1
Unblinding and breaking the code ........................................................................30
4.1.5.2


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4.1.6
Packaging, labelling, and re-supply...................................................................30
4.1.7
Storage conditions...............................................................................................30
4.1.8
Drug accountability.............................................................................................30
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................31
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....31
4.2.2
Restrictions ..........................................................................................................32
Restrictions regarding concomitant treatment ......................................................32
4.2.2.1
Restrictions on diet and life style..........................................................................32
4.2.2.2
Restrictions regarding women of child-bearing potential.....................................32
4.2.2.3
4.2.3
Management of expected adverse events ..........................................................33
4.2.3.1
Management of diarrhoea and hydration status following treatment with afatinib
...............................................................................................................................33
4.2.3.2
Management recommendations for dermatological AEs following treatment with 
afatinib ..................................................................................................................35
4.2.3.3
Management of mucositis/stomatitis ....................................................................38
4.2.3.4
Management of interstitial lung disease (ILD) and keratitis.................................40
TREATMENT COMPLIANCE........................................................................40
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................41
TRIAL ENDPOINTS..........................................................................................41
5.1
5.1.1
Primary Endpoint ...............................................................................................41
5.1.2
Secondary Endpoints..........................................................................................41
ASSESSMENT OF EFFICACY........................................................................41
5.2
ASSESSMENT OF SAFETY.............................................................................42
5.3
5.3.1
Physical examination ..........................................................................................42
5.3.2
Vital Signs............................................................................................................42
5.3.3
Safety laboratory parameters ............................................................................42
5.3.4
Electrocardiogram ..............................................................................................43
5.3.5
Assessment of adverse events.............................................................................44
Definitions of AEs ................................................................................................44
5.3.5.1
5.3.6
Adverse event collection and reporting.............................................................46
DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS...................................................................................49
5.4.1
Assessment of Pharmacokinetics.......................................................................49
5.4.2
Methods of sample collection .............................................................................49
5.4.3
Analytical determinations ..................................................................................49
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship.......................................49
BIOMARKER ASSESSMENTS .......................................................................49
5.5
5.5.1
Screening biomarkers.........................................................................................49
Method of Sample Collection ...............................................................................50
5.5.1.1
Analytical Determinations ....................................................................................50
5.5.1.2
5.5.2
Exploratory Biomarkers.....................................................................................51
Exploratory Tumour Tissue Analyses...................................................................51
5.5.2.1
Exploratory Biomarker assessments in Plasma and Urine....................................51
5.5.2.2


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5.5.3
Pharmacogenetics................................................................................................52
5.5.4
Sample Storage....................................................................................................52
OTHER ASSESSMENTS...................................................................................53
5.6
APPROPRIATENESS OF MEASUREMENTS..............................................53
5.7
6.
INVESTIGATIONAL PLAN.............................................................................54
VISIT SCHEDULE.............................................................................................54
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................54
6.2
6.2.1
Screening period..................................................................................................54
6.2.2
Treatment period(s)............................................................................................55
6.2.3
Follow Up Period and Trial Completion...........................................................56
End of treatment visit (EOT) ................................................................................56
6.2.3.1
End of Residual effect period (EoR)....................................................................56
6.2.3.2
Extended follow-up period....................................................................................56
6.2.3.3
6.2.3.3.1
Follow-up for progression.....................................................................................56
6.2.3.3.2
Follow-up for Overall Survival.............................................................................57
Trial completion for an individual patient ............................................................57
6.2.3.4
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................58
STATISTICAL DESIGN - MODEL.................................................................58
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................58
7.2
PLANNED ANALYSES.....................................................................................58
7.3
7.3.1
Primary endpoint analyses.................................................................................58
7.3.2
Secondary endpoint analyses .............................................................................59
7.3.4
Safety analyses.....................................................................................................59
7.3.5
Pharmacokinetic analyses ..................................................................................61
INTERIM ANALYSES ......................................................................................61
7.4
HANDLING OF MISSING DATA ...................................................................61
7.5
RANDOMISATION ...........................................................................................61
7.6
DETERMINATION OF SAMPLE SIZE .........................................................61
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........64
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................64
DATA QUALITY ASSURANCE ......................................................................65
8.2
RECORDS...........................................................................................................65
8.3
8.3.1
Source documents ...............................................................................................65
8.3.2
Direct access to source data and documents.....................................................65
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS66
8.4
8.4.1
Listedness.............................................................................................................66
8.4.2
Expedited reporting of Adeverse Events ..........................................................66
STATEMENT OF CONFIDENTIALITY........................................................66
8.5
TRIAL MILESTONES.......................................................................................66
8.6
9.
REFERENCES....................................................................................................68


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PUBLISHED REFERENCES............................................................................68
9.1
UNPUBLISHED REFERENCES......................................................................74
9.2
10.
APPENDICES.....................................................................................................75
APPENDIX 1: PGP INHIBITORS AND INDUCERS....................................75
10.1
APPENDIX 2: COCKCROFT-GAULT FORMULA .....................................76
10.2
APPENDIX 3: ECOG PERFORMANCE STATUS........................................76
10.3
APPENDIX 4: CLINICAL EVALUATION OF LIVER INJURY ................77
10.4
10.4.1
Introduction.........................................................................................................77
10.4.2
Procedures ...........................................................................................................77
APPENDIX 5: RECIST 1.1 CRITERIA...........................................................78
10.5
APPENDIX 6: NYHA CLASSIFICATION OF HEART FAILURE.............82
10.6
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................83


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ABBREVIATIONS
ADL
Activity of Daily Life
AEs
Adverse Events
AESI
Adverse Event of Special Interest
ALT
Alanine Aminotransferase
ANC
Absolute Neutrophil Count
aPTT
Activated Partial Thromboplastin Time
AST
Aspartate Aminotransferase
AUC
Area under the Curve
BCRP
Breast Cancer Resistance Proteins
BI
Boehringer Ingelheim
b.i.d.
bis in die (twice daily dosing)
BSA
Body Surface Area
BSC
Best Supportive Care
BUN
Blood Urea Nitrogen
CA
Competent Authority
CDx
Companion Diagnostics
Cmax
Maximum measured concentration of the analyte in plasma
CML
Local Clinical Monitor 
CMV
Cisplatin, methotrexate, and vinblastine
CYP
cytochrome P450
CNIO
National Center for Oncology investigations
CPK
Creatine Phosphokinase
CR
Complete Response
CRA
Clinical Research Associate
CRF
Case Report Form
CRO
Clinical Research Organization
CT
Computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
DDMVAC
Dose-Dense Methotrexate, Vinblastine, Doxorubicin, and Cisplatin
DILI
Drug Induced Liver Injury
DNA
Desoxyribonucleic Acid
DOR
Duration of Objective Response
eCCR
Estimated Creatinine Clearance Rate
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EGFR
Epidermal Growth Factor Receptor
EMA
European Medicines Agency
EoFU
End of Follow Up
EoR
End of residual effect period
EOT
End of Treatment
ERBB
Erythroblastic leukaemia viral oncogene homolog of the human 
EGFepidermal growth factor family of receptors


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EU
European Union
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FISH
Fluorescence In Situ Hybridation
FOXA1
Forkhead box protein A1
FU
Follow-up
GATA
GATA Binding protein
GCP
Good Clinical Practice
GFR
Glomerular Filtration
GGT
Gamma-Glutamyl Transferase
Hb
Haemoglobin
HCG
Human chorionic gonadotropin
HCO
Bicarbonate
HER2
Human epidermal growth factor receptor 2
HER3
Human epidermal growth factor receptor 3
HIV
Human immunodeficiency virus
HLT
HNSCC
High Level Term
Head and Neck Squamous Cell Carcinoma
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IHC
Immunohistochemistry
ILD
Interstitial lung disease
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
i.v.
Intravenous
KG
Kilogram
KRT
Keratin
LD
Longest Diameter
LDH
Lactate dehydrogenase
MedDRA
Medical Dictionary for Drug Regulatory Activities
MIBC
Muscle-invasive bladder cancer
MQRMs
Medical and Quality Review Meetings
MRI
Magnetic resonance imaging
MTD
Maximum Tolerated Dose
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NGS
Next Generation Sequencing
NMIBC
Non Muscle-invasive bladder cancer
NSCLC
Non-Small Cell Lung Cancer
NYHA
New York Heart Association
OR
Objective Response
ORR
Objective Response Rate


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OS
Overall Survival
PABA
Para-aminobenzoic Acid
PC
Patient Completion
PD
Progressive Disease
PFS
Progression Free Survival
P-gp
P-glycoprotein
PGx
Pharmacogenetics
PK
Pharmacokinetics
p.o.
per os (oral)
PR
Partial response
q.d.
Quaque die (once a day)
PT
Preferred Term
RBC
Red Blood Cell Count
RDC
Remote Data Capture
RECIST
Response evaluation criteria in solid tumours
REP
Residual effect period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
RNA
Ribonucleic acid
RT-PCR
Reverse Transcription Polymerase Chain Reaction
SAE
Serious Adverse Event
sAG
Surface Antigen
SOC
System Organ Class
SD
Stable Disease
SEER
Surveillance, Epidemiology and End Results program
SOGUG
Spanish Oncology Genito-Urinary Group
SOP
Standard Operation Procedure
SmPC
Summary of Product Characteristics
SMQ
Standarised MedDRA Queries
SPF
Sunscreen Protection Factor
SUSAR
Suspected Unexpected Serious Adverse Reaction
TCCU
Urothelial Carcinomas
TCM
Trial Clinical Monitor
TKIs
Tyrosine Kinase Inhibitor
TMAs
Tissue Microarrays
TSAP
Trial Statistical Analysis Plan
UC
Urothelial Cancer
ULN
Upper Limit of Normal
US
United States
WBC
White blood cells
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
Afatinib (Giotrif®, Gilotrif®) is an irreversible ERBB-family blocker. It binds to and 
efficaciously blocks signalling from all homo- and heterodimers formed by the ERBB family 
members ERBB1 (EGFR), ERBB2 (HER2), ERBB3 and ERBB4. Afatinib demonstrated a 
significant therapeutic effect in patients with non-small cell lung cancer (NSCLC) harbouring 
EGFR activating mutations and is currently an approved treatment for TKI-naïve adult 
patients with locally advanced or metastatic NSCLC with activating EGFR mutation(s) (R14-
5311) and by US FDA as first-line treatment of patients with metastatic NSCLC whose 
tumours have epidermal growth factor receptor (EGFR) exon 19 deletions or exon 21 
(L858R) substitution mutations as detected by an FDA-approved test (R15-4558).
Lately various molecular profiling programmes have been integrated into adult oncology 
clinics aiming to enrich trials with patients whose tumours carry certain molecular pathway 
defects (R14-4189; R14-4191; R14-4174; R14-4175; P15-08257). Molecular profiling of 
tumours has increased the knowledge regarding genomic and proteomic aberrations and 
offers more options to target actionable mutations and to provide new treatment options
(R15-3968; R15-3974).
As part of “The Cancer Genome Atlas Project”, several very recent publications have 
highlighted the importance of the ERBB pathway for patients with various subtypes of 
urothelial cancer and render ERBB pathway genetic alterations, i.e. ERBB2 or ERBB3 gene 
copy number variations, ERBB2 and ERBB3 mutations, as well as EGFR amplifications 
suitable targets for ERBB family blockers (R15-3968; R15-3974). EGFR amplifications are 
also frequently observed in patients with basal like histology of urothelial cancer, a form of 
high-grade muscle-invasive tumour that harbors distinct gene expression patterns and shares 
common biological features as well as the poor prognosis of basal like breast cancer (R15-
5167, R15-5166). These dismal tumours pose a therapeutic challenge but due to EGFR 
amplification may be targetable by ERBB family inhibitors.
MEDICAL BACKGROUND
1.1
Bladder cancer is the most common cancer of the urinary tract with ~380,000 new cases and 
~150,000 deaths per year worldwide (R13-1113). It is the fifth most prevalent among cancers 
in men in Western countries and >90% of bladder cancers are transitional cell carcinomas of 
the urothelium (TCCU), or, to simplify, urothelial carcinomas(R15-3970). In 2012, there 
were an estimated 577,403 people living with bladder cancer in the US and the number of 
new cases of bladder cancer was 20.3 per 100,000 men and women per year with 4.4 deaths 
per 100,000 men and women per year. These rates are age-adjusted and based on 2008-2012 
cases and deaths (R15-5922). Muscle-invasive bladder cancers (MIBC) account for 33% of 
all bladder cancers, i.e about 125,400 patients per year are diagnosed with this subtype, and 
an additional 15-30% (37,620 to 75,240) of patients’with non muscle-invasive bladder 
cancers (NMIBC) progress into MIBC. As described by Knolwes et al and Rebouissou et al 
(R15-3968; R15-3974) about 20% of patients with urothelial cancer carry ERBB genetic 
alterations.


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Adjuvant treatment consists of neoadjuvantly or adjuvantly applied chemotherapy with 
DDMVAC, gemcitabine and cisplatin or CMV with or without radiotherapy and surgical 
cystectomy. Treatment in 1st line metastatic setting is largely confined to chemotherapy 
utilizing the regimes given in adjuvant setting (R15-3966). Treatment for patients with 
platinum refractory locally advanced or metastatic TCCU has not advanced for several 
decades, and at present no established standard of care nor an approved therapy by FDA or 
EMA exists and patients are generally entered into clinical trials (R15-3966, R15-5942). 
Median PFS published from various trial settings ranges between 2.9 and 4.0 months, median 
OS between 5.0 to 9.6 months (R15-3967; R15-3969; R15-3971; R15-3972; R15-3973).
Until recently chemotherapeutic agents of randomized trials have not been able to show OS 
benefit when compared to best supportive care (BSC), and have had the added burden of 
toxicity. New therapies for this disease, which has a very dismal prognosis, are needed. 
A recently published trial by Choudhury et al showed that five patients who carried 
ERBB2/ERBB3 mutations or ERBB2 gene amplifications had a prolonged time to 
progression/treatment discontinuation of 6.6 months on average compared to the remaining 
18 patients in the cohort without ERBB alterations whose disease progressed after only 1.4
months (P16-03913).
Recently, treatments with checkpoint inhibitors (antiPD1, antiPD-L1) such as Atezolizumab, 
Pembrolizumab and Nivolumab, have demonstrated benefit in this patient population mainly 
for those who were PD-L1 positive (R16-1588, R17-0679, R17-0602).
DRUG PROFILE
1.2
For the latest information on the drug profile of afatinib, please refer to the current
Investigators´ Brochure (IB) (c01617169-04) and/or local product label information. All
references in this protocol concerning afatinib refer to the free base compound which is used
as the oral formulation.
Afatinib (Giotrif®, Gilotrif®) is a small molecule, selective and irreversible ERBB family 
blocker. In preclinical models it effectively inhibits signaling from all homo- and 
heterodimers formed by the ERBB family members EGFR (ERBB1), ERBB2 (HER2), 
ERBB3 and ERBB4 resulting in tumour growth inhibition and regression of established 
subcutaneous tumours derived from four human cell-lines known to co-express ERBB 
receptors.
Afatinib is moderately fast absorbed after oral administration. Maximum plasma
concentrations of afatinib were achieved mainly at 2 to 5 hours after oral drug administration.
Afatinib maximum plasma concentrations and area under the curve increased slightly over-
proportional with increasing doses in the therapeutic range of 20-50mg. Moderate to high
inter- and intra-individual differences in plasma concentration were seen. Afatinib is highly
distributed out of the blood and has a moderate to high clearance. The overall gMean terminal
half-life at steady state was 37.2 hours in cancer patients. Steady state was reached no later
than 8 days after the first administration. The major route of elimination of afatinib was via
faeces. After food intake, a decreased systemic exposure was observed compared to
administration under fasted conditions. The PK characteristics in Caucasian cancer patients
were comparable to those observed in Japanese cancer patients.


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Afatinib is bound covalently to proteins to a variable extent and covalent protein adducts
were the major circulating metabolites in the plasma. Afatinib did not show relevant
inhibition or induction of cytochrome P450 isoenzymes, and it appears unlikely that drug-
drug interactions based on this mechanism will occur.
Afatinib is a substrate of the P-gp transporter. Concomitant administration of the potent P-gp
inhibitor ritonavir did not relevantly change the exposure to 40 mg afatinib when taken 
simultaneously with or 6 h after afatinib but increased the bioavailability of afatinib (single 
dose of 20 mg) by 48% and 39% for AUC0-∞ and Cmax when given 1 h before afatinib, 
respectively. Pretreatment with the potent P-gp inducer rifampicin decreased the plasma
exposure of 40 mg afatinib by 34 % afatinib (AUC0-∞) and 22 % (Cmax), respectively.
Caution should be exercised when combining afatinib with potent P-gp modulators.
In pre-clinical studies afatinib is not irritant to intact skin but an ocular irritant. Afatinib is 
mutagenic in a single bacteria strain, but did not show genotoxic potential in vivo when tested 
up to overt toxic/lethal doses. Studies on embryo-foetal development in rats and rabbits up to 
life-threatening doses have revealed no indication of teratogenicity.
Two phase I open label dose-escalation studies determined the MTD with continuous dosing 
of afatinib in patients with advanced solid tumours at 40mg and 50mg daily, respectively
(U07-3128 and U08-1023). Both daily doses (40mg and 50mg) have been used in phase II 
and phase III trials depending on the patient population evaluated. Adverse events (AE) 
observed with afatinib are consistent with those reported for EGFR and dual EGFR/ERBB2 
inhibitors. The most common AEs in afatinib monotherapy trials were associated with 
gastrointestinal disorders (including diarrhoea and stomatitis), skin and subcutaneous tissue 
disorders (rash/acne, dry skin, pruritus), nail effects, fatigue, and decreased appetite. Early 
and proactive management of diarrhoea, mucositis/stomatitis and skin rash together with 
treatment interruptions and dose reductions is recommended in line with recent guidelines in 
the management of common toxicities of EGFR and EGFR/ERBB2 TKIs and monoclonal
antibodies (R07-4077; P07-11507; R07-4078; P13-03658 and P13-03659).
Afatinib was approved as monotherapy to treat patients with advanced or metastatic non-
small cell lung cancer (NSCLC) whose tumours have epidermal growth factor receptor
(EGFR) mutations.
Giotrif® (Afatinib) has been approved in EU to treat patients with locally advanced or 
metastatic NSCLC of squamous histology progressing on or after platinum-based 
chemotherapy. In the US, Gilotrif® (Afatinib) has also been approved to treat patients with 
metastatic squamous NSCLC progressing after platinum-based chemotherapy.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
As described in Chapter 1.1 the prognosis of second line metastatic or recurrent urothelial 
cancer after platinum therapy is dismal and in light of no standard therapy, new treatment 
options are urgently needed. So far, no molecularly targeted agents have been approved for 
treatment of urothelial cancer. As part of “The Cancer Genome Atlas Project”, however, an
integrated analysis of 131 urothelial carcinomas provided a comprehensive landscape of 
molecular alterations, showing ERBB2 and ERBB3 gene copy number variations, ERBB2 
and ERBB3 mutations and EGFR amplifications in various subtypes (R15-5165; R15-3968;
R15-3974). Thus irreversible blockade of ERBB signalling with afatinib, is therefore an 
attractive therapeutic strategy for such patients.
Further support comes from a recently published trial by Choudhury et al, who demonstrated 
that in the first part of this trial 5 of 23 patients treated with afatinib, who carried ERBB3 
mutations or showed ERBB2 gene amplifications achieved PFS3. These patients had a 
prolonged time to progression/treatment discontinuation of 6.6 months on average, compared
to the cohort of patients without any ERBB alterations who did not achieve PFS3 and whose 
disease progressed after a median of 1.4 months (P16-03913).
Considering advances in tumour genotyping indicating the ERBB pathway as an actionable 
target and early clinical signal with afatinib in a biomarker-selected population with bladder 
cancer, this trial aims to provide further evidence of afatinib activity in patients with 
urothelial cancer harbouring ERBB2/3 mutations or ERBB2 amplification ( Cohort A). 
Furthermore due to EGFR amplifications being frequently observed in patients with high-
grade muscle-invasive urothelial cancer of basal like histology (R15-5166), ERBB family 
inhibitors may provide a suitable new option for targeted treatment of these poor prognostic 
tumours.
TRIAL OBJECTIVES
2.2
The purpose of this trial is to assess the anti-tumour activity and safety of afatinib 
monotherapy in patients with urothelial tract carcinoma carrying ERBB2 or ERBB3 
mutations or ERBB2 amplifications (Cohort A), and EGFR amplification positive tumours
(Cohort B), progressing despite previous platinum based chemotherapy, and thereby to 
improve their prognosis.
The antitumour activity of afatinib monotherapy in these patients will be assessed by 
progression free survival rate at 6 months (PFS6) (R17-0395). This will be the primary 
endpoint of the trial. A key secondary endpoint will also be defined, the objective response 
rate (ORR).
Further evaluation criteria for efficacy include progression free survival (PFS), Overall 
Survival (OS), disease control rate (DCR), duration of objective response (DOR) and tumour 
shrinkage. Safety will be assessed throughout the trial by the monitoring of AEs.
Trial objectives will be analysed separately for Cohorts A and B.


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BENEFIT - RISK ASSESSMENT
2.3
Safety and efficacy of afatinib are well described in adults. A positive benefit/risk assessment 
for afatinb in adult patients with EGFR M+ NSCLC has been demonstrated in a 
comprehensive development program which led to registration of this compound. Additional 
efficacy was shown in metastatic squamous cell lung cancer patients (P15-06906; P15-05707;
P14-14349) recurrent and metastatic head and neck squamous cell carcinoma (P15-03867)
and clinical activity was observed in ERBB2 positive metastatic breast cancer patients (P15-
00660; P14-14350; P14-09513).
In clinical studies, the pattern of AEs observed for afatinib was as expected for EGFR 
inhibitors, including predominantly gastrointestinal and dermatological AEs which were 
dose-dependent. Early and effective management of these AEs is mandated in ongoing and 
forthcoming clinical trials with the opportunity to reduce the dose where appropriate. Typical 
AEs associated with afatinib treatment are diarrhoea (which in severe cases may lead to 
dehydration with or without renal insufficiency) and effects on skin and its appendages: 
rash/acne, paronychia, pruritus, dryness and eczema. Besides diarrhoea, other gastrointestinal
AEs observed were stomatitis, mouth ulceration, dry mouth, and oral pain. Additional AEs 
seen in Afatinib clinical trials were  mucosal inflammation; respiratory disorders such as 
epistaxis and rhinorrhoea; eye disorders such as conjunctivitis .
The most common effect on the liver is a transient, reversible transaminase elevation, 
although hepatic failure, including fatalities, has been reported during treatment with afatinib 
in less than 1% of patients. Afatinib does not appear to have adverse effects on cardiac 
contractility or QTcF. The frequency of interstitial lung disease (ILD) -like AEs in all afatinib 
treated patients was low (approximately 1.5%) and similar to that observed with other EGFR 
TKIs (c01617169-04). However, several cases of ILD have been reported with administration 
of EGFR TKIs in NSCLC patients that had been previously treated with immunotherapy. It is 
unclear whether the extended use of EGFR TKIs after administration of immunotherapy
increases the risk of ILD (R16-4467, P16-11904).
For an early detection of rare but potential AEs, patients in this trial will be monitored for:

Interstitial lung disease (ILD), a rare and serious (potentially fatal) AE that has been 
reported with administration of EGFR TKIs in NSCLC patients that had been previously 
treated with immunotherapy (R16-4467, P16-11904). It is unclear whether the extended 
use of EGFR TKIs after administration of Nivolumab increases the risk of ILD. In case of 
suspected ILD on treatment please refer to Section 4.2.3.4.

Although rare, a potential for drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. Therefore, this trial requires timely detection, 
evaluation, and follow-up of laboratory alterations of selected liver laboratory parameters 
to ensure patients´ safety, see also Section 5.3.5.
Exposure of afatinib was similar in patients with mild and moderate liver impairment and in 
healthy controls. Subjects with moderate renal impairment had approximately 20% higher 
total exposure and similar peak exposure to afatinib when compared with matched healthy 
control subjects. In subjects with severe renal impairment, total afatinib exposure was
approximately 50% higher and peak exposure approximately 20% higher than that for healthy 
matched controls. Drug drug interactions of afatinib with Pgp- modulators, CYP-inhibitors 


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and BCRP were thoroughly investigated and information is summarized in the IB, SmPC and 
Patient Information (c01617169-04; R14-5311). 
The trial medication is available as oral formulation, i.e. film coated tablets of 40 mg, 30 mg 
and 20 mg strength which allows for dose reduction in case of adverse events. Afatinib 40 mg 
is the preferred dose. In human PK studies Cmax at a daily dose of 40 mg afatinib was 
determined to be 78 nM (P13-07487). As the compound demonstrates efficacy at 4-12 nM in 
ERBB2AMP driven cell lines (c01617169-04) an EC50 between 10-20 nM in the ERBB2
mutated lung cancer cell line H1787 (P09-00886), and due to its irreversible and covalent 
binding (P12-09544) plasma levels reached in patients treated with 40 mg afatinib daily 
should be sufficient to treat ERBB2 driven tumours.
Considering the (i) well established side effect profile of afatinib in adult patients which is
consistent with the observed side effect profile in a previous trial conducted in the target 
population of urothelial cancer patients (P15-03441), (ii) the established concomitant 
treatment algorithms for afatinib related side effects, (iii) close safety monitoring as 
performed during the conduct of this trial and (iv) early signs of clinical anti-tumour activity 
observed in the target population, the lack of treatment options and dismal prognosis of the 
disease, pre-selection of patients by ERBB genetic alterations is expected to maximize 
patients’ benefit from afatinib in both treatment cohorts. Overall the expected benefits from 
afatinib treatment for the patients included in this trial will outweigh anticipated risks.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This will be an exploratory open label phase II trial to assess the anti-tumour activity of 
afatinib monotherapy in patients with urothelial tract carcinoma and genetic alterations in 
ERBB receptors 1-3 who have previously progressed despite platinum based therapy.
As described in Sections 2.1 and Section 2.2, patients will be recruited into two cohorts (A 
and B) which will be analysed separately. Assignment into the respective cohorts will be 
according to biomarkers assessed in tumour biopsies.
Prior to biomarker testing, all patients will need to sign a pre-screening informed consent 
form (see Section 3.3.1). An archival tissue sample will be required from all patients at pre-
screening. All patients must have genetic alterations in ERBB receptors 1-3 present in their 
respective tumours and patients with ERBB2 and ERBB3 mutation and ERBB2 amplification
will be included into Cohort A, while  patients with EGFR amplifications into Cohort B. For 
details on biomarker assessment refer to section 5.5. The remaining tumour sample of eligible 
patients will be stored for exploratory and potential future biomarker analyses (see section 
5.5.2). For patients not eligible to participate in the trial, 3 x 1mm cores from the tissue 
sample will be archived as TMAs and the remaining tumour sample will be repatriated to the 
site.
Approximately 350 patients are expected to be pre-screened to identify up to 80 eligible 
patients. 
Pre-screening will be performed by a GCP validated lab authorized by BI. A summary report 
of all pre-screening biomarkers will determine if the patient was “a screening failure” , will 
be eligible for recruitment into “Cohort A “ or “Cohort B”. The report will be sent to the 
investigator by the central lab.
Cohort A will be recruited using a two-stage design. Differentiation per prognostic factors 
such as visceral metastases, ECOG and Hemoglobin will be done during the final analysis
(R15-6019). These factors will be defined in the TSAP.
Recruitment of 45 patients into stage 2 will depend on the anti-tumour activity demonstrated
in the first 25 patients included into stage 1.
Cohort B will include 10 patients in an exploratory design. 


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Figure 3.1:1 Trial design
All patients recruited will continue trial treatment until disease progression as confirmed by 
imaging according to RECIST 1.1, or patient´s withdrawal of consent for continuation of 
treatment, or other reasons requiring treatment discontinuation (see section 3.3.4.1). 
The active treatment phase will be followed by a Residual effect Period, a follow up for 
progression (when needed), and a follow up for overall survival (see Section 6.2 and 
flowchart). 
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
A Coordinating Investigator is responsible to coordinate investigators at different centres 
participating in this multicentre trial. Tasks and responsibilities will be defined in a contract. 
Relevant documentation on the participating investigators and other important participants, 
including their curricula vitae, will be filed in ISF.
The trial will be conducted in collaboration with SOGUG a Spanish Cooperative group 
specialized in the treatment of genitourinary cancers and CNIO the National Center for 
Oncology investigations in Spain. About 30-35 trial sites in Europe are expected to screen 
and recruit patients into in this trial. The actual recruitment period is anticipated to be 21 
months, i.e. 9 months for stage 1 and 12 months for stage 2. There will not be interruption in 


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enrolment after completing Cohort A. Therefore by the time of PFS6 and ORR evaluation on 
the first 25 patients is available, there may be additional patients enrolled into the study.
Biomarker analyses for pre-screening purposes will be performed by a CRO or central lab 
authorised by BI.
BI has appointed a Trial Clinical Monitor (TCM), responsible for coordinating all required
activities, in order to 

manage the trial in accordance with applicable regulations and internal SOPs,

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Safety and efficacy will be continuously monitored by the investigator, and sponsor. 
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons and relevant local information
can be found in the ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
This trial will be a single arm open label trial of afatinib monotherapy. No control group will 
be included as there are no standard treatments available for the patient population 
investigated.
Patients with metastatic urothelial cancer after failure of, or progression on platinum-
containing regimens were selected because they lack treatment options. However, these 
patients are deemed to benefit from ERBB inhibition if their tumours express ERBB genetic 
alterations (for details refer to Sections 2.1 and 2.2).
The assignment of patients into 2 separate cohorts is based on observations of anti-tumour 
activity and biomarker profiles described by Choudhury et al (P15-03441) for Cohort A and 
on biomarker profiles demonstrated by Jaegil Kim et al (R15-6019).
Up to 70 patients will be included into Cohort A using a two stage design which will test the 
working hypothesis that the true PFS6 rate is >40% at the end of stage 2. The trial will be 
stopped if <11/25 patients at stage 1 show PFS 6 and <1 patient has a confirmed response.
Cohort B will be exploratory in nature and only include 10 patients. 
SELECTION OF TRIAL POPULATION
3.3
Two logs, one for all patients who signed pre-screening consent and one for all patients 
enrolled into the trial (i.e. who have signed the screening informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.


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3.3.1
Main diagnosis for trial entry
Patients to be recruited into this trial must have advanced or metastatic urothelial tract 
carcinoma that is not amenable to surgical treatment and must have progressed despite 
previous platinum based chemotherapy. Elegibility for trial participation is also based on 
positive pre-screening biomarkers – for details refer to Section 3.1. Patients who consent for 
pre-screening must be willing to provide tumor tissue (including tumour banking) for 
biomarker analyses (for details refer to Section 5.5) and storage of 3 x 1mm cores for TMAs. 
Patients who are eligible to receive treatment on the trial must fulfill the below inclusion 
criteria (See Section 3.3.2) and must not meet any exclusion criteria (Section 3.3.3).
3.3.2
Inclusion criteria
1. Adult patients ≥18 years old 
2. Patients must have histologically confirmed urothelial tract carcinoma. Patients with 
urothelial carcinoma of the bladder, upper tract or urethra are eligible.
3. Locally advanced or metastatic urothelial tract carcinoma that is not amenable to 
surgical treatment.
4. Progressive disease on or after platinum-containing regimen and is not a candidate for 
another platinum therapy. Following cases will be considered as one line of chemo:
-
Patients receiving platinum-based regimen in the peri-operative setting and 
subsequently in the metastatic setting
-
Patients who are not refractory to platinum based chemotherapy after one line 
in metastatic setting (defined as more than 6 months without clinical or 
radiological PD after the end of first line platinum based chemotherapy) and 
subsequently receive another line of platinum based chemotherapy in 
metastatic setting
5. Received no more than one line of prior systemic chemotherapy for 
recurrent/metastatic disease, and this previous chemotherapy should be platinum 
based (immunotherapy is not considered as a systemic chemotherapy). If platinum 
based chemotherapy was administered in the peri-operative setting, patient should 
have progressed during  or within 12 months after treatment . 
6. Measurable disease according to RECIST 1.1.
7. ECOG performance status 0 or 1
8. Life expectancy of at least 3 months (12 weeks)
9. Archival tissue biopsies (blocks) available for biomarker testing at pre-screening and 
for tissue banking for a potential bridging study for CDx (for details refer to Section 
5.5).
10. Patients should complete a pre-screening biomarker analysis and should fulfill the 
following:
-
Cohort A: Tumour with a ERBB2 or ERBB3 mutation, or ERBB2 gene 
amplification (for definitions please refer to section 5.5.1) 
-
Cohort B: Tumour with EGFR amplification (for definitions please refer 
to section 5.5.1)
11. Adequate organ function, defined as all of the following:
a.
Absolute neutrophil count (ANC) ≥1500 / mm3. 
b. Platelet count ≥75,000 / mm3.


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c.
Estimated creatinine clearance > 45ml / min. Refer to Appendix 10.2.
d. Total Bilirubin ≤ 1.5 times upper limit of (institutional/central) normal 
(Patients with Gilbert’s syndrome total bilirubin must be ≤4 times institutional 
upper limit of normal).
e.
Aspartate amino transferase (AST) or alanine amino transferase (ALT) ≤ three 
times the upper limit of (institutional/central) normal (ULN) (if related to liver 
metastases ≤ five times ULN).
12. Recovered from any previous therapy related toxicity to ≤Grade 1 at study entry 
(except for stable sensory neuropathy ≤Grade 2 and alopecia)
13. Written informed consent for pre-screening that is consistent with ICH-GCP 
guidelines for tissue, blood, urine collecting and biomarker assessment to confirm 
eligibility for enrollment into pre-screening phase. 
14. Written informed consent that is consistent with ICH-GCP guidelines to confirm 
eligibility for enrollment into the trial once pre-screening was successfully completed.
3.3.3
Exclusion criteria
1. Chemotherapy within 4 weeks prior to the start of study treatment. Biological therapy 
or investigational agents within 4 weeks prior to the start of study treatment or prior 
to passing 5 half-lives(i.e. systemic clearance), whatever comes first.
2. Prior use of EGFR, ERBB2 or ERBB3 targeted treatment
3. Major Surgery within 4 weeks before starting study treatment or planned surgery 
during the projected course of the study which compromises patient's trial 
participation by investigator judgement.
4. Radiotherapy within 4 weeks prior to start of study treatment , except palliative 
radiation to non-target lesions, which may be allowed up to 2 weeks prior to start of 
study treatment. Tumour lesions situated in a previously irradiated area are usually 
not considered target lesions unless there has been demonstrated progression in the 
lesion.
5. Known hypersensitivity to afatinib or its excipients 
6. History or presence of clinically relevant cardiovascular abnormalities such as but 
not limited to uncontrolled hypertension, congestive heart failure NYHA 
classification of ≥ 3 (Refer to Appendix 10.6), unstable angina or poorly controlled 
arrhythmia as by the investigator judgement. Myocardial infarction within 6 months 
prior to start of study treatment.
7. Any history of or concomitant condition that, in the opinion of the investigator, 
would compromise the patient’s ability to comply with the study or interfere with the 
evaluation of the efficacy and safety of the test drug 
8. Previous or concomitant malignancies at other sites, except effectively treated non-
melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ, 
non-invasive urothelial cancer at a different site than the primary tumour or 
effectively treated malignancy that has been in remission for more than 3 years and is 
considered to be cured, or incidental localized prostate cancer not requiring treatment 


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according to investigator´s judgement.
9. Requiring treatment with any of the prohibited concomitant medications as described
in Section 4.2.2.1 that cannot be stopped for the duration of trial participation
10. Known pre-existing interstitial lung disease or signs and symptoms indicative of the 
latter as per investigator judgement
11. Any history or presence of poorly controlled gastrointestinal disorders that could 
affect the intake/absorption of the study drug (e.g. Crohn’s disease, ulcerative colitis, 
chronic diarrhoea, malabsorption) as per investigator judgement
12. Active hepatitis B infection (defined as presence of HepB sAg and/ or Hep B DNA), 
active hepatitis C infection (defined as presence of Hep C RNA) and/or known HIV 
carrier.
13. Known brain metastases or signs hereof, uncontrolled spinal cord compression or 
leptomeningeal carcinomatosis
14. Female patients who are nursing or are pregnant or are planning to become pregnant 
on this trial
15. Women of child-bearing potential (WOCBP) and men who are able to father a child, 
unwilling to be abstinent or use highly effective methods of birth control that result in 
a low failure rate of less than 1% per year when used consistently and correctly prior 
to study entry*, for the duration of study participation and for at least 2 weeks after 
treatment has ended. Patients will be considered to be of childbearing potential unless 
surgically permanently sterilized (e.g. hysterectomy, bilateral oophorectomy, 
bilateral salpingectomy), or post-menopausal for at least 12 months without an 
alternative medical cause.
*A list of contraception methods meeting these criteria is provided in the patient information sheet, and Section 4.2.2.3.
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
An individual patient is to be withdrawn from trial treatment if the patient:
1. Withdraws consent for study participation, without the need to justify the decision.
2. Has radiologic documentation by CTscan or MRI of progressive disease (Section 
5.1.2) and is no longer receiving clinical benefit, in the opinion of the investigator.
3. Can no longer be treated with trial medication for other reasons (e.g. AE, pregnancy, 
surgery, concomitant diagnoses, or concomitant therapies) or administrative reasons. 
4. Is diagnosed with ILD
5. Has the need for further dose reductions considered necessary but not allowed 
according to the protocol (Section 4.1.4)
Given the patient’s agreement, the patient will undergo the procedures for treatment 
discontinuation and/or EoR as well as follow up such as vital status collection as outlined in 
the flow chart and Section 6.2.3. For all patients the reason for withdrawal (e.g. adverse 


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events) must be recorded in the (e)CRF. These data will be included in the trial database and 
reported.
The sponsor may remove patients from the study after completion of the primary efficacy 
analysis if the patient has access to afatinib study treatment via options included but not 
limited to an alternative clinical trial, marketed product, an expanded-access program, named 
patient use program, or compassionate use protocol or other means based on local regulation.
This may mean a change in packaging and labelling. The cost of any ongoing supply of study 
medication will be incurred by the sponsor until disease progression occurs. If a patient is 
removed from the study treatment, an end of treatment and a follow up visit 30 days later will 
be performed to ensure all adverse events are followed up and then the patient will be 
considered to have completed the trial.
Discontinuation of the trial by the sponsor
3.3.4.2
The sponsor may suspend recruitment after completing enrolment of the predefined 25 
patients into stage 1 in the event of low likelihood to meet the criteria to move from Stage 1 
to Stage 2.
Further to this, BI reserves the right to discontinue the trial overall or at a particular trial site 
at any time for the following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site

Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial

Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial

The primary analysis has been completed and all patients have either ended study 
treatment or are eligible to receive afatinib under the conditions indicated in section 
3.3.4.1.
The Investigator/the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
Patients will be treated with once daily oral dosing of afatinib. Patients will initially receive 
40 mg tablets q.d.
4.1.1
Identity of BI investigational product(s) and comparator product(s)
Table 4.1.1: 1
Test product: afatinib
Substance (Brand Name):
Afatinib (Giotrif® / Gilotrif®)
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer-Ingelheim Pharma GmbH & Co. KG
Unit strength:
20 mg, 30 mg, 40 mg film-coated tablets (the dose of 
afatinib in the film-coated tablets is related to the free 
base equivalent to afatinib)
Posology
Once daily
Route of administration:
Oral
4.1.2
Method of assigning patients to treatment groups
After assessment of all in- and exclusion criteria, the medication number for each eligible 
patient will be assigned via Interactive Response Technology (IRT). Note that the medication 
number is different from the patient number (the latter is assigned at trial entry). To facilitate 
the use of the IRT, the investigator will receive all necessary instructions.
4.1.3
Selection of doses in the trial
Based on early phase clinical trials, a daily dose of 50mg in the monotherapy setting was
identified as the dose for further development. This was used initially in EGFR TKI 
refractory population and several other phase II/III and proof of concept trials. Given a higher 
propensity of grade 3/4 AEs (especially diarrhoea), and no loss of efficacy especially in the 
EGFR mutation positive population dose was reduced to 40 mg in the pivotal phase III trials 
in EGFR mutated population (P10-12524, P10-12525, P10-12529). The 1200.22 (LUX- Lung
2) study enrolled 99 patients who started afatinib at 50 mg, and 30 patients starting at 40mg. 
While there was no substantial change in the occurrence of all AE grades for the two most 
frequent AEs, diarrhoea (96.7% in the 40 mg group compared to 93.9% in the 50 mg group) 
and rash/acne (90.0% in the 40 mg group compared to 94.9% in the 50mg group); there was a 
substantial difference in the occurrence of grade 3 AEs for diarrhoea (6.7% in the 40 mg 
group vs. 24.2% in the 50mg group) and rash/acne (6.7% in the 40 mg group and 28.3% in 
the 50 mg group). Neither group had grade 4 or 5 AEs reported for these terms (P10-12524).


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In NSCLC and other indications, durable responses (>20 months) have been observed with
daily dosing of afatinib of 40 mg and less (P10-09678) in a sensitive biomarker-positive 
population. The compound demonstrates efficacy at 4-12 nM in ERBB2AMP driven cell 
lines ( c01617169-04), an EC50 between 10-20 nM in the ERBB2 mutated lung cancer cell 
line H1787, (P09-00886) irreversibly and covalently binds to its targets (P12-09544). Plasma 
levels reached in patients treated with 40 mg afatinib daily should be sufficient to treat 
ERBB2 driven tumours. The population in the trial will be naive to EGFR, ERBB2, ERBB3 
targeted treatment. Patients with urothelial cancer will suffer from disease-associated co-
morbidities such as proteinuria, renal insufficiency, and side effects from previous anti-
cancer treatment such as polyneuropathy or long-term effects from prior abdominal 
irradiations. Therefore afatinib will be used at a dose of 40 mg to optimize the tolerability and 
efficacy balance. The daily dose will be modified following careful monitoring of patient’s 
drug-related adverse events and medication compliance.
4.1.4
Drug assignment and administration of doses for each patient
Administration of afatinib
4.1.4.1
Patients will take a single oral dose of afatinib each day starting at a dose of 40 mg, 
continuously, until progression of disease as confirmed by imaging according to RECIST 
1.1 or patient´s withdrawal of consent for continuation of treatment or other reasons 
requiring treatment discontinuation (see section 3.3.4.1).. Dose reductions of afatinib can 
occur. See Section 4.1.4.1.1.
The medication should be taken at approximately the same time each day without food (at
least one hour before or at least three hours after a meal).
Missed doses of afatinib can be made up during the same day as soon as the patient 
remembers. However, if the next schedule dose is due within eight hours then the missed 
dose must be skipped. Patients with emesis must not take a replacement dose.
Medication will be dispensed in bottles containing 30 tablets at the beginning of each
treatment course. For administrative purposes, a treatment course is defined as 28 days. 
Treatment will start when the patient is taking the first dose of medication and stop when the 
patient is diagnosed with disease progression or for any reason detailed in Section 3.3.4, 
unless clinical benefit is obtained beyond PD (see Section 3.2). Study drug will be prescribed 
by the investigator through IRT system, and may be dispensed either by the investigator, site 
staff or affiliated pharmacy.
If dosing of whole tablets is not possible, afatinib tablets can also be dispersed in 
approximately 100 ml of non-carbonated drinking water. No other liquids should be used. 
The tablet should be dropped in the water, without crushing it, and occasionally stirred for up 
to 15 min until the tablet is broken up into very small particles. The dispersion should be 
drunk immediately. The glass should be rinsed with approximately 100 ml of water which 
should also be drunk. The dispersion can also be administered through a naso-gastric tube. 


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4.1.4.1.1 Dose reduction for afatinib
Treatment related AEs will be managed by treatment interruptions and subsequent dose 
reductions of afatinib according to the schedule described in Table 4.1.4.1.1: 1. Dose 
reductions will apply to individual patients only. Once the dose has been reduced, it cannot 
be increased later.
To prevent the development of more severe adverse events, treatment related diarrhoea, 
nausea and vomiting or rash should be managed early and proactive as described in Section
4.2.
Table 4.1.4.1.1: 1 Dose reduction scheme for afatinib
1 Baseline is defined as the CTCAE Grade at the start of treatment
2 In the event that the patient is deriving obvious clinical benefit according to the investigator’s judgement, further treatment 
with afatinib will be decided in agreement between BI Clinical Monitor and the investigator.
AE Type and CTCAE Grade
Action
Dose reduction scheme
Events related to study drug:

Diarrhoea
Grade 2 persisting for 2 or 
more consecutive days (48 
hours) despite adequate anti-
diarrhoeal 
medication/hydration

Reduced renal function 
caused by dehydration 
secondary to diarrhea to
Grade 2 as measured by 
serum creatinine, proteinuria 
or decrease in glomerular 
filtration rate of more than 
50% from baseline

Any drug related AE Grade 
≥3
Pause treatment until 
patient has recovered to 
Grade ≤1 or baseline1.
Resume treatment at 
reduced dose according 
to schedule opposite.
If patient has not 
recovered to Grade ≤1 
or baseline1 within 14 
days study treatment 
must be permanently 
discontinued2.
If patient was receiving 40 mg, 
resume treatment at a dose of 
30 mg.
If patient was receiving 30 mg, 
resume treatment at a dose of 
20 mg.
If patient was receiving 20 mg, 
discontinue afatinib.
Acute onset and/or unexplained
worsening of pulmonary 
systems
(dyspnoea, cough, fever)
Pause afatinib while
clinical assessment to 
exclude ILD is
completed.
If ILD is ruled out as a cause of 
symptoms, grade symptoms 
and relatedness and report as 
AEs. If AEs are not related, 
resume afatinib at current dose.  
If AEs are drug related, follow 
directions in row above.
If ILD is confirmed,
discontinue afatinib


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In the event of any unrelated adverse events, the investigator may choose to interrupt the
medication for up to 14 days, but no dose reduction should occur. If the medication is 
interrupted for more than 14 days, the decision to continue with afatinib will be made by the
BI clinical monitor in agreement with the investigator.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
Not applicable. 
Unblinding and breaking the code
4.1.5.2
Not applicable.
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Afatinib tablets will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation to be certain that the drug supplies are 
stored at proper temperature.
4.1.8
Drug accountability
The Investigator or Pharmacist or investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB/ethics committee, 

Availability of a signed and dated clinical trial contract between the Sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol
The Investigator or Pharmacist or investigational drug storage manager must maintain 
records of the product’s delivery to the trial site, the inventory at the site, the use by each 
patient, and the return to the Sponsor or alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator/Pharmacist/investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. At the time of return to the 
Sponsor, the Investigator/Pharmacist/investigational drug storage manager must verify that 


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all unused or partially used drug supplies have been returned by the clinical trial patient and 
that no remaining supplies are in the Investigator’s possession.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
Rescue medication
Rescue medications to reverse the actions of afatinib are not available. There is no specific
antidote for overdosage with afatinib. In cases of suspected overdose, afatinib should be 
withheld and supportive care initiated. If indicated, elimination of unabsorbed afatinib may 
be achieved by emesis or gastric lavage. Potential adverse events should be treated 
symptomatically.
Common adverse
events
of treatment with afatinib
with specified management 
recommendations and/or requirements
include diarrhoea, stomatitis/mucositis, and 
rash/acne. To improve tolerability and the probability of clinical benefit, patients should 
receive prompt and appropriate supportive care at the first signs of symptoms. Suggested 
treatments for AEs are described below.
Concomitant treatments
Concomitant medications or therapy to provide adequate supportive care may be given as
clinically necessary.
After study enrollment, palliative radiotherapy may be given for bone pain or for other 
reasons (e.g. bronchial obstruction, skin lesions), provided that the total dose delivered is in a 
palliative range according to institutional standards. The irradiated area cannot be used for 
tumor response assessment. During palliative radiotherapy, study treatment should be 
delayed and may be resumed once the patient has recovered from any radiation associated 
toxicity. If medication is interrupted for more than 14 days, the decision to continue will be 
made by the BI clinical monitor in agreement with the investigator. Continuous interruption 
of >28 days due to palliative radiotherapy will not be allowed.
All concomitant therapy, including anaesthetic agents, vitamins, homeopathic/herbal 
remedies, nutritional supplements, must be recorded in the eCRF during the screening and 
treatment period, starting from the date of signature of informed consent, and ending at the 
EOT visit. After the EOT visit, only concomitant therapy indicated for treatment of an AE 
has to be reported.
In case of major surgery (as judged by the investigator), it is recommended to stop treatment 
with afatinib around one week prior to the surgery, and to restart treatment after complete 
wound healing. If afatinib is interrupted for more than 14 days, the decision to continue will
be made by the BI Clinical Monitor in agreement with the investigator.


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4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
Concomitant medications, or therapy to provide adequate supportive care, may be given
as clinically necessary.
Palliative radiotherapy may be given as described in Section 4.2.1.
Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy, 
hormone treatment or radiotherapy (other than palliative radiotherapy for 
symptom 
control) is not allowed concomitantly with the administration of study treatment.
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
and further recommendations see Appendix 10.1. More details and explanations on afatinb´s 
interactions can be found in the IB (c01617169-04).
Restrictions on diet and life style
4.2.2.2
Patients should be advised to avoid any foods known to aggravate diarrhoea.
To prevent skin related adverse events it is recommended to avoid intense irradiation with
UV light and harsh detergents, see also Section 4.2.3.2.
Restrictions regarding women of child-bearing potential
4.2.2.3
Patients who are not of childbearing potential due to being postmenopausal (i.e. 12 months 
with no menses without alternative medical cause, predefined hormonal level according to 
local regulation or etc.) or being permanently sterilized (bilateral oophorectomy, bilateral 
salphingectomy, or hysterectomy ) do not need to use contraception to be eligible for the trial.
All other patients are considered to have childbearing potential and must use adequate 
contraception throughout the trial (from screening until end of trial participation or 2 weeks
after last dose of trial medication, whichever is later).
Highly effective methods of birth control should be applied to women of childbearing 
potential as those, alone or in combination, that result in a low failure rate (i.e., less than 1% 
per year) when used consistently and correctly, and must be in accordance with local 
regulations where applicable.
Highly effective method of birth control include: 
-
hormonal methods of contraception associated with inhibition of ovulation (oral, 
intravaginal or transdermal combined – estrogen and progestogen containing - hormonal 
contraception; or, oral, injectable or implantable progestogen-only hormonal contraception), 
-
placement of intrauterine device or intrauterine hormone releasing system, 
-
bilateral tubal occlusion, vasectomized sexual partner or complete sexual abstinence 
(when this is in line with the preferred and usual lifestyle of the study participant). 
This list of contraception methods meeting the ICH M3 criteria is provided in the patient 
information.


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Women who become pregnant while participating in the study must discontinue study 
medication immediately. The pregnancy .must be reported following procedures detailed in
Section 5.3.5.1.
4.2.3
Management of expected adverse events
Dermatologic adverse events, diarrhoea and stomatitis are the most common side-effects 
associated with treatment with afatinib. Treatment of these side-effects should be proactive 
and should be started as early as possible after onset of symptoms.
4.2.3.1
Management of diarrhoea and hydration status following treatment with 
afatinib
Diarrhoea occurs at a high frequency and generally begins within 2 weeks of exposure to 
afatinib. Although usually mild to moderate, diarrhoea may lead to dehydration and compel
treatment modification or discontinuation, so early management is essential (Table 4.2.3.1:1). 
At the time of initiation of treatment with afatinib patients should be given a supply of 
loperamide to keep with them at all times or access to loperamide should be confirmed; and 
patients should be counselled on the appropriate use.
Patients must be advised to drink an adequate amount of fluids to make up for the fluid lost 
through diarrhoea.
Table 4.2.3.1: 1 Grade specific treatment recommendations for afatinib related diarrhoea
Severity 
(CTCAE 
Grading)
Description
Intervention 
concerning 
afatinib treatment
Specific 
intervention
Mild (Grade 1)
Increase of < 4 
stools per day over 
baseline; mild 
increase in ostomy 
output compared 
with baseline
Continue same dose
Stop laxatives and 
advise patient to 
drink at least 8-10 
glasses of water of 
clear fluids per day;
4 mg (2 tablets) of 
loperamide to be 
taken immediately, 
followed by 2 mg (1 
tablet) after each 
loose stool until 
bowel movements 
cease for 12 hours


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Table 4.2.3.1: 1 Grade specific treatment recommendations for afatinib related diarrhea 
(continued)
Severity 
(CTCAE 
Grading)
Description
Intervention 
concerning 
afatinib treatment
Specific 
intervention
Moderate (Grade 2)
Increase of 4-6 
stools per day over 
baseline; i.v. fluids 
indicated < 24 
hours; moderate 
increase in ostomy 
output compared 
with baseline; not 
interfering with 
ADL
Continue same dose
unless Grade 2 
diarrhoea continues 
for ≥ 2 days (48 
hours) in which case 
treatment must be 
interrupted
until recovered to ≤
Grade 1 followed by
dose reduction
Continue 
loperamide; assess 
for dehydration and 
electrolyte
imbalance; consider 
IV fluids and
electrolyte 
replacement
Severe (Grade 3)
Increase of ≥ 7 
stools per day over 
baseline;
incontinence; IV 
fluids > 24 hours; 
hospitalization; 
severe increase in 
ostomy output 
compared with 
baseline; interfering 
with ADL
Dose interruption 
until recovered to 
≤Grade 1 followed 
by dose reduction*
See Grade 2; plus:
an infectious process 
should be ruled out 
with stool cultures; 
aggressive iv fluid 
replacement
≥ 24 hours; 
hospitalization to 
monitor progress;
Consider
prophylactic 
antibiotics if patient 
is also neutropenic
Life threatening 
(Grade 4)
Life-threatening
consequences (e.g.
haemodynamic 
collapse)
Dose interruption 
until recovered to 
≤Grade 1 followed 
by dose reduction*
See Grade 3
* If despite optimal supportive care and a treatment interruption, diarrhoea does not resolve to CTCAE Grade ≤1 within 14 
days, treatment with afatinib must be permanently discontinued. In the event that the patient is deriving obvious 
clinical benefit according to the investigator’s judgement, further treatment with afatinib will be decided in agreement 
between BI Clinical Monitor and the investigator.


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4.2.3.2
Management recommendations for dermatological AEs following treatment 
with afatinib
Dermatologic AEs of afatinib include rash, acne, dermatitis acneiform, and dry skin. General 
recommendations for prophylaxis are summarized in Table 4.2.3.2: 1 and grade-specific 
treatment recommendations are summarized in Table 4.2.3.2: 2. For dose adjustment of 
afatinib refer to Table 4.1.4.1.2: 1.
Specific interventions should be reassessed at least after 2 weeks or at any worsening of 
symptoms, in which case the specific intervention should be adjusted and, depending on own 
clinical experience, early involvement of a dermatologist should be considered. (Adapted 
from R11-0826)
Table 4.2.3.2: 1 General recommendations for dermatological AE prophylaxis while 
receiving afatinib
Personal hygiene
Use of gentle soaps and shampoos for the body, e.g. pH5 neutral 
bath and shower formulations and tepid water.
Use of very mild shampoos for hair wash.
Only clean and smooth towels are recommended because of 
potential risk of infection. The skin should be patted dry after a 
shower, whereas rubbing the skin dry should be avoided.
Fine cotton clothes should be worn instead of synthetic material. 
Shaving has to be done very carefully.
Manicure, i.e. cutting of nails, should be done straight across until 
the nails no longer extend over the fingers or toes. Cuticles are not 
allowed to be trimmed because this procedure increases the risk of 
nail bed infections
Sun protection
Sunscreen should be applied daily to exposed skin areas regardless 
of season.
Hypoallergenic sunscreen with a high SPF (at least SPF30, PABA 
free, UVA/UVB protection), preferably broad spectrum containing 
zinc oxide or titanium dioxide are recommended
Patients should be encouraged to consequently stay out of the sun.
Protective clothing for sun protection and wearing a hat should be 
recommended.
Moisturizer treatment
It is important to moisturize the skin as soon as anti-EGFR therapy 
is started.
Hypoallergenic moisturizing creams, ointments and emollients 
should be used once daily to smooth the skin and to prevent and 
alleviate skin dryness.
Note: avoid greasy creams (e.g. petrolatum, soft paraffin, mineral 
oil based) and topical acne medications.


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Table 4.2.3.2: 1 General recommendations for dermatological AE prophylaxis while 
receiving afatinib (continued)
Prevention of 
paronychia
Patients should keep their hands dry and out of water if ever 
possible.
They should avoid friction and pressure on the nail fold as well as 
picking or manipulating the nail.
Topical application of petrolatum is recommended around the nails 
due to its lubricant and smoothing effect on the skin.
Table 4.2.3.2: 2 
Grade specific treatment recommendations of skin reactions to 
afatinib
Severity 
(CTCAE Grading)
Description
Specific intervention
ACNEIFORM RASH
Mild (Grade 1)
Macular or papular eruptions 
or erythema without 
associated symptoms
Consider topical antibiotics, e.g.
clindamycin 2% or topical 
erythromycin 1% cream of 
metronidazole 0.75% or topical 
nadifloxacin 1%;
Isolated scattered lesion: cream 
preferred
Multiple scattered areas: lotion 
preferred
Moderate (Grade 2)
Macular or papular eruptions 
with pruritus or other 
associated symptoms; 
localized desquamation or 
other lesions covering <50% 
of BSA
Topical treatment as for Grade 
1 plus short term topical 
steroids, e.g. prednicarbate 
cream 0.02% plus an oral 
antibiotic (for at least 2 weeks) 
e.g. Doxycycline 100mg b.i.d. 
or Minocycline hydrochloride 
100mg b.i.d
Severe (Grade 3)
Severe, generalized 
erythroderma or macular, 
popular or vesicular eruption; 
desquamation covering ≥50% 
of BSA; associated with pain, 
disfigurement, ulceration or 
desquamation
Topical and systemic treatment 
as for Grade 2.
Consider referral to 
dermatologist
Consider systemic steroids
Life threatening 
(Grade 4)
Generalized exfoliative, 
ulcerative, or bullous 
dermatitis
See Grade 3
Systemic steroids are 
recommended


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Table 4.2.3.2: 2
Grade specific treatment recommendations of skin reactions to afatinib
(continued)
Severity 
(CTCAE Grading)
Description
Specific intervention
EARLY AND LATE XEROTIC SKIN REACTIONS – PRURITUS
Mild (Grade 1)
Mild or localized
Topical polidocanol cream. 
Consider oral antihistamines, 
e.g. diphenhydramine, 
dimethindene, cetirizine, 
levocetirizine, desloratidine, 
fexofenadine or clemastine
Moderate (Grade 2)
Intense or widespread
See Grade 1 plus oral 
antihistamines; consider topical 
steroids, e.g. topical 
hydrocortisone.
Severe (Grade 3)
Intense or widespread and 
interfering with activities of 
daily living (ADL)
See Grade 2.
XEROSIS (DRY SKIN)
Mild (Grade 1)
Asymptomatic
Soap-free shower gel and/or 
bath oil.
Avoid alcoholic solutions and 
soaps.
Urea- or glycerin-based 
moisturizer.
In inflammatory lesions 
consider topical steroids (e.g. 
hydrocortisone cream)
Moderate (Grade 2)
Symptomatic, not interfering 
with ADL
See Grade 1.
In inflammatory lesions 
consider topical steroids (e.g. 
hydrocortisone cream)
Severe (Grade 3)
Symptomatic,
interfering with ADL
See Grade 2.
Topical steroids of higher 
potency (e.g. prednicarbate, 
mometasone furoate)
Consider oral antibiotics


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Table 4.2.3.2: 2 
Grade specific treatment recommendations of skin reactions to 
afatinib (continued)
Severity 
(CTCAE Grading)
Description
Specific intervention
FISSURES
Mild (Grade 1)
Asymptomatic
Petroleum jelly, Vaseline® or 
Aquaphor for 30 minutes under 
plastic occlusion every night, 
followed by application of
hydrocolloid dressing; antiseptic 
baths (e.g.
potassium permanganate 
therapeutic baths, final 
concentration of 1:10,000, or 
povidone-iodine baths).
Topical application of aqueous 
sliver nitrate solutions to 
fissures.
Moderate (Grade 2)
Symptomatic, not interfering 
with ADL
See Grade 1.
Consider oral antibiotics.
Severe (Grade 3)
Symptomatic, interfering 
with ADL
See Grade 2.
If Grade 2 rash persists for ≥7 days despite treatment and is poorly tolerated by the patient, 
the investigator may choose to pause treatment up to 14 days followed by a reduction in the 
dose of afatinib according to the dose reduction scheme in Table 4.1.4.1.2:1.
4.2.3.3
Management of mucositis/stomatitis
General and grade specific recommendations are described in Table 4.2.3.3: 1. For dose
adjustment refer to Section 4.1.4.1.1 and for restrictions on concomitant therapies refer to
Sections 4.2.2 and 10.1.
Treatment is supportive and aimed at symptom control. These may include atraumatic
cleansing and rinsing with non-alcoholic solutions such as normal saline, diluted salt and
baking soda solution (e.g. one-half teaspoonful of salt and one teaspoon of baking soda in one
quart of water every four hours); avoidance of agents containing iodine, thyme derivatives
and prolonged use of hydrogen peroxide; dietary manoeuvres such as promotion of soft, non-
irritating foods like ice-creams, mashed/cooked vegetables, potatoes and avoidance of spicy,
acidic or irritating foods such as peppers, curries, chillies, nuts and alcohol. If the patient is
unable to swallow foods or liquids, parenteral fluid and/or nutritional support may be needed.
Examples of some of the agents suggested in Table 4.2.3.3:1 include: topical analgesics –


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viscous lidocaine 2%; mucosal coating agents - topical kaolin/pectin; oral antacids,
maltodextrin, sucralfate; topical antifungals – nystatin suspension. (Adapted from P11-
09424).
Table 4.2.3.3: 1
Grade specific treatment recommendations of study-drug related
mucositis/stomatitis
Severity 
(CTCAE 
grading)
Description
Treatment 
recommendations
Intervention 
concerning afatinib 
treatment/dose 
modification
Mild (Grade 1)
Minimal 
symptoms; 
normal diet
Oral rinses with agents 
such as non-alcoholic 
mouth wash, normal 
saline, diluted salt and 
baking soda solution
No change
Moderate 
(Grade 2)
Symptomatic, but 
can eat and 
swallow modified 
diet
Addition of topical 
analgesic mouth
treatments, topical 
corticosteroids,
antiviral therapy if 
herpetic infection
confirmed, antifungal 
therapy preferably 
topical on a case by 
case basis.
Maintain dose if 
tolerable;
Hold dose if 
intolerable until 
recovery to grade ≤
1, then restart at the 
same dose.
Severe (Grade 3)
Symptomatic and 
unable to 
adequately aliment 
or hydrate orally
Same as for Grade 2; 
institute additional
symptomatic therapy 
(topical or systemic) as 
clinically indicated.
Hold dose until 
recovery to
grade ≤1 or baseline, 
then restart at the 
reduced dose
according to Section 
4.1.4.
Life threatening 
(Grade 4)
Symptoms
associated with
life-threatening
consequences
Same as for Grade 2; 
institute additional 
symptomatic therapy 
(topical or systemic) as 
clinically indicated .
Hold dose until 
recovery to
grade ≤1 or baseline, 
then restart at the 
reduced dose
according to Section 
4.1.4


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4.2.3.4
Management of interstitial lung disease (ILD) and keratitis
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude interstitial 
lung disease (ILD). Study drugs should be interrupted pending investigation of these 
symptoms. If interstitial lung disease is diagnosed, study drug must be permanently 
discontinued and appropriate treatment instituted as necessary.
Patients who present with symptoms of keratitis, such as acute or worsening eye 
inflammation, lacrimation, light sensitivity, blurred vision, eye pain and/or red eye should be 
referred promptly to an ophthalmic specialist. If a diagnosis of ulcerative keratitis is 
confirmed, treatment with afatinib should be interrupted or discontinued. If keratitis is 
diagnosed, the benefits and risks of continuing treatment with afatinib should be carefully 
considered. Afatinib should be used with caution in patients with a history of keratitis, 
ulcerative keratitis or severe dry eye. Contact lens use is a risk factor for keratitis and
ulceration.
TREATMENT COMPLIANCE
4.3
The appropriate number of afatinib tablets for each cycle of treatment will be provided to
patients to be self-administered at home. 
Patients will be asked to bring the remaining trial medication at the end of each treatment 
cycle to the investigator site for a compliance check. The remaining film- coated tablets will 
be counted by the investigator/site staff and recorded at the investigator site. Discrepancies 
between the number of tablets remaining and the calculated number of tablets the patients 
should have taken must be documented and explained. At the end of each treatment course, 
any remaining medication will be collected. If the patient is eligible for further treatment, a 
new bottle of study medication must be dispensed.
The investigator and/or the sponsor can withdraw a patient from the study in the event of 
serious and persistent non-compliance which jeopardizes the patient’s safety or render study 
results for this patient unacceptable. Patients who do not attend a minimum of 75% of 
scheduled study visits, unless due to exceptional circumstances (e.g. vacation), should be 
discussed with the BI trial monitor and be evaluated for compliance. For afatinib, a maximum 
of 25% of the dispensed afatinib doses may be missed for other reasons than recovery from 
drug-related AEs. Patients who miss afatinib treatment more frequently are considered non-
compliant.


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5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
5.1.1
Primary Endpoint
Progression Free Survival rate at 6 months (PFS6) in Cohort A defined as the proportion of 
patients who does not show disease progression by the 24-week tumour assessment. Disease 
progression will be determined according to Response Evaluation Criteria in Solid Tumours 
(RECIST) 1.1. for Cohort A and Cohort B.
5.1.2
Secondary Endpoints
A Key Secondary Endpoint will be assessed for Cohort A patients, the
Objective response 
rate (ORR), defined as number of complete response (CR) or partial response (PR) according 
to RECIST 1.1.
Further secondary endpoints of efficacy will be assessed for Cohort A patients, and include:

Progression free survival (PFS), defined as the time from first drug administration to the 
date of disease progression, or date of death whichever is earlier. Disease progression 
will be determined according to RECIST 1.1.

Overall Survival (OS), defined as the time from first drug administration to the date of 
death.

Disease Control Rate (DCR), defined as CR, PR, stable disease (SD) or Non-CR/Non-PD 
(NN) according to RECIST 1.1

Duration of objective response (DOR), according to RECIST 1.1  

Tumour shrinkage for each patient, measured as the maximum percentage decrease from 
baseline sum of target lesion diameters after treatment until disease progression.
None of the primary or secondary endpoints are related to safety issues.
ASSESSMENT OF EFFICACY
5.2
Response and progression will be evaluated in this study using Response Evaluation Criteria
in Solid Tumours (RECIST) guideline (version 1.1) (R09-0262). Tumour response will be
assessed by investigator review. Images will be stored in case independent radiology review 
may need to be introduced at stage 2.


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It is critical to continue response evaluation until progression if patients withdrew consent 
from continuation of treatment but agreed to participate in follow-up tumour assessment.
See Appendix 10.5, RECIST 1.1 Criteria for details on lesion measurements and response
assessment.
Tumour assessment by Imaging (CT or MRI) should be performed at screening, and then 
every 8 weeks (+/- 1 week) calculated from the first treatment day to the end of study 
treatment . If  treatment discontinuation is for other reason than disease progression, further 
tumour assessments should be obtained as follows: every 8 weeks (+/-1week) until month 6, 
and  every 12 weeks (+/-2 week) from 6 months onwards, until documented progression of 
disease.
ASSESSMENT OF SAFETY
5.3
Safety will be assessed throughout the trial by AEs determined according to NCI CTCAE 
(Version 4.03). 
5.3.1
Physical examination
A full physical exam must include: vital sign measurements, cardiopulmonary examination, 
examination of the regional lymph nodes, an examination of the abdomen and an assessment 
of the mental and neurological status. Additional symptoms which have not been reported 
during a previous examination must be clarified. Wherever possible the same investigator 
should perform this examination.
Measurement of height (in cm), body weight (in kg) and the evaluation of the performance 
score ECOG will be conducted at the times specified in the Flow Chart.
5.3.2
Vital Signs
Vital sign measurements include blood pressure (systolic blood pressure, diastolic blood 
pressure), pulse rate, temperature.
5.3.3
Safety laboratory parameters
Safety lab will be performed locally at each participating site. Following parameters should 
be evaluated at each timepoint:


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Table 5.3.3: 1
Safety laboratory parameters
Category
Parameters
Hematology
Red blood cell count (RBC), haemoglobin,
haematocrit, platelet count, white blood cell count 
(WBC), with differential (neutrophils, lymphocytes, 
monocytes, eosinophils, basophils)
Coagulation
International Normalized Ratio (INR), activated Partial 
Thromboplastin Time (aPTT), Fibrinogen.
Chemistry
Electrolytes
Sodium, potassium, calcium, magnesium, chloride, 
bicarbonate (HCO3)
Liver function tests
alkaline phosphatase, aspartate aminotransferase
(AST), alanine aminotransferase (ALT), γ-
glutamyltransferase (GGT), total bilirubin
Renal function parameters
Blood urea/blood urea nitrogen (BUN),
creatinine; Creatinine clearance (see Appendix 10.2).
Other
glucose, albumin, cholesterol, triglycerides,
phosphorus, lactate dehydrogenase (LDH), total
protein, uric acid, creatine phosphokinase (CPK); in case 
of pathological CPK further evaluation (e.g by 
determination of isoenzymes, troponin assays, ECG 
exam) should be performed as clinically indicated
Urinalysis
pH, protein, glucose, ketones, blood, leucocytes,
nitrite; in case of pathological finding further evaluation
should be performed and results documented.
Proteinuria per se will only result in treatment 
interruptions if associated to other renal pathology which 
would qualify for treatment interruption i.e. CTCAE >/= 
3 AE, or decrease in renal clearance to < 45 ml/min GFR
Pregnancy test
β-HCG testing in urine or serum in women of
childbearing potential (WOCBP)
The investigator should complete additional evaluations of laboratory tests as clinically 
indicated.
5.3.4
Electrocardiogram
12-lead ECG will be taken at the time points specified in the Flow Chart. The investigator 
will review the ECG recording, comment on any clinical significance and if applicable record 
any ECG abnormality that meets AE criteria.


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5.3.5
Assessment of adverse events
Definitions of AEs 
5.3.5.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and
unintended. Response in this context means that a causal relationship between a medicinal
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise
from use of the product within or outside the terms of the marketing authorisation or from
occupational exposure. Conditions of use outside the marketing authorization include offlabel
use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect, or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions.
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
If cancer is the indication for treatment, only cancers of new histology qualify as a serious 
event. Every new occurrence of cancer must be reported as a serious event regardless of the
duration between discontinuation of the drug and the occurrence of the cancer.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.


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The latest list of “Always Serious AEs” can be found in the RDC. These events should 
always be reported as SAEs as described in Section 5.3.6.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.6.
The following are considered as AESIs:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:

For patients with normal liver function at baseline (ALT, AST, and bilirubin within
normal limits at baseline):
-
an elevation of AST and/or ALT ≥3 fold ULN combined with an elevation of total
bilirubin ≥2 fold ULN measured in the same blood draw sample, and/or
-
Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN

For patients with abnormal liver function at baseline (AST and/or ALT>ULN)
-
an elevation of AST and/or ALT ≥ 5 fold ULN combined with an elevation of total 
bilirubin ≥2 fold ULN measured in the same blood draw sample, with the exclusion of 
the causes due to underlying diseases.
These lab findings constitute a hepatic injury alert and the patients showing these lab
abnormalities need to be followed up according to the “DILI checklist” provided via the RDC 
system. In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity of AEs
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 in the (e)CRF.
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal
relationship between a suspected medicinal product and an adverse event. An adverse
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship
between a medicinal product and an occurrence is suspected.


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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.
Arguments that may suggest that there is a reasonable possibility of a causal relationship
could be:
• The event is consistent with the known pharmacology of the drug
• The event is known to be caused by or attributed to the drug class.
• A plausible time to onset of the event relative to the time of drug exposure.
• Evidence that the event is reproducible when the drug is re-introduced
• No medically sound alternative aetiologies that could explain the event (e.g. pre-existing or 
concomitant diseases, or co-medications).
• The event is typically drug-related and infrequent in the general population not exposed to 
drugs (e.g. Stevens-Johnson syndrome).
• An indication of dose-response (i.e. greater effect size if the dose is increased, smaller effect 
size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship
could be:
• No plausible time to onset of the event relative to the time of drug exposure is evident (e.g. 
pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of drug 
administration; an allergic reaction weeks after discontinuation of the drug concerned)
• Continuation of the event despite the withdrawal of the medication, taking into account the 
pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged despite 
removing the original trigger.
• Additional arguments amongst those stated before, like alternative explanation (e.g.
situations where other drugs or underlying diseases appear to provide a more likely
explanation for the observed event than the drug concerned).
• Disappearance of the event even though the study drug treatment continues or remains
unchanged.
5.3.6
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs in their patient files.
The following must be collected and documented on the appropriate CRF(s) by the 
Investigator:
•
From signing the screening informed consent onwards until the end of treatment 
(including the Residual Effect period, REP):
- all AEs (non-serious and serious) and all AESIs.
•
After the end of treatment (including the REP) until the individual patient’s end of 
trial: all related SAEs and related AESIs.
•
After the individual patient’s end of the trial:


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the Investigator does not need to actively monitor the patient for AEs but should only
report relevant SAEs and relevant AESIs of which the Investigator may become aware 
of. The rules for Adverse Event Reporting exemptions still apply.
The REP is defined as 30 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment. Events which occurred after the REP will be considered as post treatment events.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
(e)CRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug(s). The Investigator 
should determine the causal relationship to the trial medication.
The following should also be recorded as an (S)AE in the (e)CRF and SAE form (if 
applicable):

Worsening of pre-existing conditions other than underlying disease will be recorded as an 
(S)AE in the eCRF. 

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.


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All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into
this clinical trial and has taken trial medication, the Investigator must report immediately
(within 24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s
unique entry point (country-specific contact details will be provided in the ISF). The
Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE
form must be completed in addition.
Exemptions to SAE Reporting
Disease Progression in oncology trials is a study endpoint for analysis of efficacy, and as 
such is exempted from reporting as a (S)AE. Progression of the patient's underlying
malignancy will be recorded in the appropriate pages of the (e)CRF as part of efficacy data
collection and will not be reported on the (S)AE form. Death due to disease progression is 
also to be recorded on the appropriate (e)CRF page and not on a SAE form. It will therefore 
not be entered in the safety database and hence not get expeditiously reported.
However, when there is evidence suggesting a causal relationship between the study drug and 
the progression of the underlying malignancy, the event must be reported as (S)AE on the
eCRF and on the SAE form.
Examples of exempted events of PD are:

Progression of underlying malignancy (Progressive disease PD): if PD is clearly 
consistent with the suspected progression of the underlying malignancy as defined by 
the respective response criteria.

Hospitalization/Procedures due solely to the progression of underlying malignancy
(PD)

Clinical symptoms and/or signs of progression (with or without confirmation by 
objective criteria e.g. imaging, clinical measurement): if the symptom can exclusively 
be determined to be due to the progression of the underlying malignancy and does 
meet the expected pattern of progression for the disease under study.
Exempted events are monitored at appropriate intervals by Medical and Quality Review 
Meetings (MQRMs).


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DRUG CONCENTRATION MEASUREMENTS AND 
5.4
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
Pharmacokinetic analyses are not planned to be part of this trial.
5.4.2
Methods of sample collection
Not applicable.
5.4.3
Analytical determinations
Not applicable.
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
Not applicable.
BIOMARKER ASSESSMENTS
5.5
Three mandatory biomarker activities will be performed in the course of the trial. 
1.
Screening biomarkers: As described in Section 3.3, all patients must provide a 
tumour sample which will be screened in a central laboratory for biomarkers of 
ERBB deregulation. Local testing will not be permitted. Patients whose tumour is 
positive for one or more of the screening biomarkers will be eligible for inclusion. 
The biomarker screening assessments are described in more detail in Section 5.5.1. 
2.
Exploratory biomarkers:
Exploratory, retrospective, evaluation of several 
biomarkers will be performed in a descriptive way. The exploratory biomarker 
assessments are described in more detail in Section 5.5.2.. 
3.
Sample Storage: Storage of tumour tissue and of plasma and serum prepared from a 
venous blood sample and urine for confirmatory testing of biomarkers will be
performed and is described in Section 5.5.4. In addition a sample of whole venous 
blood will be optionally collected and banked in order to enable unspecified
pharmacogenetic analyses as indicated in the flow chart. The provision of the 
banking sample for pharmacogenetics is described in Section 5.5.3.
No formal endpoints based on these biomarkers have been defined. 
5.5.1
Screening biomarkers
Tumour tissue is required from each patient at screening in order to pre-screen for the 
presence of the following molecular markers. 
1.
Non-synonymous somatic mutation of either the ERBB2 or ERBB3 gene. 
2.
Amplification of the ERBB2 gene. 


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Amplification of the ERBB2 gene will be defined according to the ASCO-CAP guidelines for 
ERBB2 FISH analysis (R15-6055): after counting at least 20 cells. 
-
Dual-probe ERBB2/CEP17 ratio ≥2.0 with an average ERBB2 copy number ≥4.0
signals/cell
-
Dual-probe ERBB2/CEP17 ratio ≥2.0 with an average ERBB2 copy number <4.0 
signals/cell
-
Dual-probe ERBB2/CEP17 ratio < 2.0 with an average ERBB2 Copy number ≥6.0 
signals/cell
If the patient’s tumour is positive for either marker 1 or 2 then the patient is eligible for 
inclusion in cohort A. 
3.
Amplification of the EGFR gene.
Amplification of the EGFR gene will be defined using an exploratory threshold: after 
counting 50 cells a case will be considered to be amplified when there are > 6 EGFR copies
in >20% of evaluated cells.
If the patient’s tumour is positive for marker 3 then the patient is eligible for inclusion in 
cohort B. 
Method of Sample Collection
5.5.1.1
The provision of tumour tissue for biomarker screening is mandatory. Each patient should 
provide a formalin-preserved, paraffin embedded tumour block of sufficient size to allow for 
sections to be cut in order for all screening assessments to be performed. 
If it is not possible to provide a tumour block then it is acceptable to provide 1 H/E slide plus 
14 x 3-4 microns thickness tissue sections for FISH studies,  and 5 x10 microns tissue 
sections on untreated glass slides for DNA extractions and repetitions. 4 of these sections of 
3-4 micron thickness for use in biomarker screening. Please note that in addition to the tissue 
required for screening, additional tissue sections are required for exploratory analyses and for 
assay validation purposes (n=10; this is more fully described in sections 5.5.2 and 5.5.4.).
Detailed instructions for sampling, handling, storage, and shipment of the biomarker samples
will be provided in the laboratory manual included in the ISF. All material such as test tubes
and labels will be provided. Date of sampling will be recorded in the eCRF.
Biomarker screening will be performed in a single central laboratory and the result of the 
screening will be made available to the investigator within a maximum of 26 days. 
Analytical Determinations
5.5.1.2
DNA will be extracted from the tumour tissue and will be used to sequence the coding 
regions of the ERBB2 and ERBB3 genes. Patients whose tumour contains a non-synonomous
mutation in either ERBB2 or ERBB3 will be eligible for inclusion in Cohort A. 
The number of copies of the EGFR and ERBB2 genes contained in the tumour cells will be 
counted using FISH (Fluorescence in-situ Hybridisation). Patients whose tumour contains 
cells with an elevated number of copies of ERBB2 will be eligible for inclusion in cohort A. 


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Patients whose tumour contains cells with an elevated number of copies of EGFR will be 
eligible for inclusion in Cohort B. 
5.5.2
Exploratory Biomarkers
Exploratory Tumour Tissue Analyses 
5.5.2.1
The provision of tumour tissue for exploratory biomarker assessments is mandatory. It is 
preferred that each patient provides a formalin-preserved, paraffin embedded tumour block of 
sufficient size to allow for sections to be cut in order for all exploratory assessments to be 
performed. In addition 3 cores of 1mm2 cross section will be taken from the block in order to 
prepare a tissue microarray (TMA). 
If it is not possible to provide a tumour block then it is acceptable to provide 10 sections of 3-
4 micron thickness for use in exploratory biomarker assessments. This tissue is in addition to 
the tissue provided for use in biomarker screening (section 5.5.1.1). 
The exploratory evaluation of the following biomarkers will be performed in a descriptive 
way: 
DNA will be extracted from the tumour tissue and will be used to sequence the coding 
regions of the EGFR and ERBB4 genes in order to identify the frequency of non-synonomous 
somatic mutation in these genes in the trial population and to clarify the frequency of the co-
occurrence of these mutations with the other biomarkers which will be measured in these 
patients. 
Exploratory Biomarker assessments in Plasma and Urine 
5.5.2.2
As described in Section 5.5.4, tissue and serum and plasma and urine from patients included 
in the trial will be stored and will be available for additional exploratory testing of 
biomarkers which may be prognostic or predictive of response to drug treatments such as 
afatinib or other therapies. This is necessary due to the emerging scientific understanding of 


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the biology of urothelial cancers and the emergence of new treatment strategies in this 
setting.
Blood samples for circulating tumour DNA (ctDNA) analysis and urine samples should be 
taken as specified in the flowchart. 20 mL of blood should be taken for ctDNA analyses. Up 
to 50 mL of urine should be obtained. Full instructions for the processing of the blood and 
urine samples will be provided in the laboratory manual included in the ISF. 
A Screening Visit sample of blood and of urine is to be taken. Subsequent samples should 
then be obtained every 4th cycle during treatment and also at End of Treatment. If a patient 
has not progressed at End of Treatment then samples should continue to be collected at every 
4th follow-up visit and also at the last follow-up visit. 
These blood and urine samples will be primarily used for the extraction and analysis of 
circulating DNA. The use of the samples will be at the discretion of the trial sponsor but 
could include the sequencing of genes relevant to cancer by NGS in order to research the 
mutations occurring in urothelial cancer and how urothelial tumours evolve upon drug 
treatment.  In addition the samples may be used in the development of a diagnostic test for 
patients eligible for treatment with afatinib. They may also be utilized for the measurement of 
proteins whose levels may be of prognostic relevance to the patients’ response to the study 
medications. 
Plasma,serum, urine or the derived DNA collected from all subjects, irrespective of their 
tumour’s ERBB biomarker status and their subsequent participation in the trial, will be stored 
for up to 15 years following the completion of the trial.
5.5.3
Pharmacogenetics
Pharmacogenetics (PGx) investigates genetic variations in patients to explain and to predict 
their individual response to drugs.
Collection of the unspecified blood sample for DNA banking for PGx is optional. All patients 
will be asked to provide a blood sample for DNA banking at C1V1, after a separate informed 
consent has been obtained in accordance with local ethical and regulatory requirements.
The DNA Banking sample, derived from the original blood sample, will be stored by 
Boehringer Ingelheim for up to 15 years after the end of the clinical trial. 
The stored DNA may be retrospectively analysed, e.g., to identify whether there are genetic 
factors that could contribute to a better therapeutic outcome or a higher risk of developing 
treatment-related adverse drug reactions.
5.5.4
Sample Storage
Samples will be stored at a central location in complicance with best clinical practice and will 
be used for CDx test development and for exploratory biomarker analyses as described 
elsewhere in section 5.5. Full instructions for the collection of samples for storage are 
provided in the laboratory manual. 
Samples may be stored for up to 15 years upon completion of the trial. 
The samples to be stored comprise:


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1.
Tissue blocks or tissue slides provided for the development of a CDx assay and to 
perform exploratory biomarker analyses. See 5.5.1.1 and 5.5.2. 
2.
Blood samples or the derived plasma or serum for circulating tumour DNA (ctDNA) 
analysis. 
3.
Urine samples or the derived sediments for biomarker assessments. 
OTHER ASSESSMENTS
5.6
Not applicable.
APPROPRIATENESS OF MEASUREMENTS
5.7
All clinical assessments are standard measurements commonly used in studies of advanced
solid tumours. Response evaluation criteria in solid tumours (RECIST) version 1.1 are used 
for assessment of the change in tumour burden. These criteria are well established and well 
received by the regulatory authorities and scientific community. Frequency of assessment is 
accordingly to standard clinical routine in advanced cancer patients.
The CTCAE criteria are used in the assessment of adverse events in cancer patients. In the 
present trial CTCAE version 4.03 will be used although an updated version is published. 
Since several pivotal oncology trials are currently ongoing with the investigational product 
it is considered more appropriate to continue to collect safety data using the same criteria.


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6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
As described in Section 3, patients will attend a screening period divided in two visits: the 
pre-screening visit where a mutation analysis will be completed in order to determine the 
eligibility of the patient, and when all subjects should sign a pre-screening informed consent 
to allow the analysis of their tumour samples; and a screening visit once the eligibility of the 
patient for either Cohort A or Cohort B has been determined, and subject will undergo the 
rest of screening tests. After the screening visit, patients will have to come to the 
investigational site on the days provided in the Flow Chart. More visits can be performed if 
deemed necessary by patient or investigator. 
A diagram of the stages of a patient´s participation in this trial is included in Section 3.1, and 
permitted time windows for visits are included in the Flow Chart.
Afatinib will be dispensed at the first visit of each treatment course according to the flow 
chart, and patients will receive continuous daily treatment with afatinib until the criteria for 
stopping medication are met (Section 3.3.4). As soon as the treatment with afatinib will be 
permanently discontinued, the patient has to undergo the end of treatment visit (i.e within 7 
days of last afatinib administration). A new visit will be performed at the end of the residual 
effect period (i.e. no earlier than 30 days after the last afatinib administration) for safety 
follow-up (EoR). After this visit, patients who have not progressed on treatment will have 
additional follow-up visits at scheduled tumour assessment timepoints until progression, 
withdrawal of consent for participating in the study, lost to follow-up or death. 
After progression, all patients will enter an observational period where they will be followed-
up for overall survival at 90 days intervals. 
Concomitant medication must be collected starting from Screening Visit until the EoR visit.
For adverse events refer to Section 5.3.6.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
6.2.1
Screening period
Pre-screening visit
During this visit, patient will be asked to review and sign a pre-screening consent, and his/her 
archived tumor material wll be taken and sent to a central laboratory for biomarker analysis. 
Further to this, 3 x1 mm cores of all pre-screened patients, and the remaining tissue 
block/slides for patients eligible to continue on trial will be banked. For details refer to 
Section 5.5. Only patients who test positive for either Cohort A or Cohort B will proceed to 
Screening Visit.


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Screening visit
Before starting the screening visit, a new informed consent should be delivered to patients
who were eligible for recruitment into Cohorts A or B based on biomarker results (see 
Section 5.5). After signature of this new consent, all screening assessments including tumor 
imaging scan and ECG must be completed in the 28 days prior to the first administration of 
study medication. However, if a tumour assessment (CT scan or MRI) was performed within 
this timeframe, patient would not need to repeat it.
Patients who failed screening may repeat the screening after discussion between investigator 
and BI Clinical Monitor providing that reasons for screening failure were reversible and have 
resolved.
Patients who meet the eligibility criteria (See section 3.3) will be allowed to start study 
treatment.
6.2.2
Treatment period(s)
Every treatment course is defined as 28 days. All subsequent visit dates should be calculated 
based on Course 1 Visit 1 date. If a visit is missed there will be no re-scheduling; if a patient 
should attend the study site between the “missed” and the next scheduled visit, then the 
missed visit assessments should be performed.
The investigations are outlined in the Flow Chart and will be performed at the respective visit, 
but are described in detail in the following sections.
During the first visit of each treatment course, the following procedures will be performed:

Physical examination: complete medical examination including body weight

ECOG performance status

Vital signs

Safety lab: haematology, biochemistry, coagulation parameters and urine analysis as 
described in Section 5.3.3. 

Dispense study medication, and dose assessment

Review of adverse events and concomitant medication
During Course 1, an additional visit will be performed 8 days after the start of treatment
(C1V2). The main objective of this visit is to assess the safety profile of trial drug. The exact 
procedures to be done are described in the study flowchart.
Additionally, a patient contact is to be done 15 days after starting study medication, and one 
week after starting treatment Course 2, to check for adverse events and concomitant 
medication. Information for these contacts could be collected by phone. A formal visit is not 
required if not needed.
Additionally, the following procedures will be done at specific timeponts:

12-lead ECG, to be performed at screening, C1V2, C4V1, and every third course 
thereafter (C7V1, C10V1,…)

At the end of second treatment cycle, i.e. 8 weeks after the start of study medication and 
every 8 weeks thereafter, tumour imaging to assess response to treatment must be 


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performed. In case of objective response, the latter has to be confirmed 4 to 6 weeks after 
initial OR observation.

A plasma and an urine sample will be stored for exploratory analyses – for details see 
Section 5.5.
6.2.3
Follow Up Period and Trial Completion
End of treatment visit (EOT)
6.2.3.1
The EOT visit will be performed after permanent discontinuation of trial medication for
any reason as soon as possible, but no later than 7 days after permanent discontinuation
of the trial medication or when the investigator decided with the patient to permanently
discontinue the trial medication or became aware that the trial medication had been 
terminated.
Refer to the Flow Chart for details. The patient must return all study drugs, and the site must
document the reason for permanent discontinuation of study medication. If permanent
discontinuation of study drug occurs during a scheduled visit, examinations as defined for
EOT visit should be performed instead of the examinations for the scheduled visit.
End of Residual effect period (EoR)
6.2.3.2
The EoR is defined in Section 5.3.6. The EoR visit should not be performed earlier than 
30 days (+7 days) after permanent discontinuation of the trial medication. The information 
collected at this visit should include all new AEs that occurred after EOT and a follow-up of 
adverse events ongoing at EOT.
Extended follow-up period
6.2.3.3
6.2.3.3.1
Follow-up for progression
Additional follow-up visits after the EoR visit will be performed for patients who did not 
progress on treatment, every 8 weeks (+/- 1week) until month 6, and every 12 weeks (+/-2 
weeks) from 6 months onwards.
The follow-up for progression period will end at the earliest if one of the following events is 
met:

Completion of the predefined FU for progression period

Lost to follow-up

Disease progression

Death

End of whole trial as specified in Section 8.6
At the end of the follow-up period, the EoFU (End of Follow-Up) visit has to be performed. 
The following will be obtained and / or performed during the follow-up visits and the EoFU  
visit:

Record AESI or SAEs, if assessed as related by the investigator, and a follow-up of 
adverse events ongoing since EoR to EoFU as entered in source data


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
Concomitant medications for treatment of an adverse event reported in the (e)CRF 
including trade name, indication and dates of administration

Record performance score (e.g. ECOG)

Perform tumour assessment and imaging if applicable

Treatment and date with any other anti-cancer drug including the name and type of the 
anti-cancer drug and/or best supportive care (if applicable)

PD (the actual date of PD shall be recorded)
6.2.3.3.2
Follow-up for Overall Survival
All patients will be followed-up for overall survival at 90 days intervals after the EoR visit or 
last follow-up for progression visit (as specified in Section 6.2.3.3.1) until death, lost to 
follow-up or completion of the whole trial (as specified in Section 8.6) whatever occurs 
earlier. For patients who progressed on treatment, the observation period for overall survival 
starts after the EoR visit. For patients who have not progressed on treatment, this period starts 
after the last FU for progression visit.
These visits may also be performed by e.g. telephone interview or via written correspondence 
in case the patient is unable to visit the investigator.
The following information will be collected during the follow-up for survival period:

Date of contact

Further anti-cancer treatment: regimen and drug name, start and stop dates, reason for 
stopping this treatment and/or best supportive care (if applicable)

Outcome event (e.g. death: Record date of and reason for outcome event)

Follow-up of adverse events in case they were not yet recovered at EoR, and AESI or 
SAEs if assessed as related by the investigator.
Trial completion for an individual patient
6.2.3.4
A patient is considered to have completed the trial in case any of the following applies:

Completion of planned follow-up period (or follow-up for overall survival if applicable)

Lost to follow-up

Refusal to be followed-up

Death


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN - MODEL
7.1
This is an open label, uncontrolled, exploratory phase II trial with two patient cohorts. Cohort 
A of the study follows a  two stage design where an analysis for futility will be performed at 
the end of stage 1 to determine if the stage 2 of cohort A will be carried out. Cohort B of the 
study will include up to 10 patients with EGFR amplification. Analysis will be conducted in 
parallel to, and independent of cohort A.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The exploratory null and alternative hypotheses were set up for the primary endpoint PFS6
based on a two-stage design with H0: PFS6 ≤ 40% and Ha: PFS6 >40%. PFS6 is defined as 
patient being alive and without disease progression at the 24-week tumour assessment.
The null hypothesis for key secondary endpoint ORR is H0: ORR ≤ 5% and Ha: ORR >5%. 
A Hochberg multiple adjustement procedure will be used to control the family-wise error rate
at 0.05 (one-sided) for testing PFS6 and ORR.
PLANNED ANALYSES
7.3
All eligible patients, who take at least one dose of afatinib will be included in the analysis 
dataset.
7.3.1
Primary endpoint analyses
The primary endpoint of the study is PFS rate at 6 months (PFS6). This will be calculated as 
the proportion of patients who are alive and without disease progression at the 24-week 
tumour assessment, out of all analysed patients. Patient prematurely discontinued without the 
24-week assessment will be considered as not achieving PFS6 regardless of the reason for 
discontinuation.
For Cohort A, the first stage will include 25 patients treated with Afatinib, as described in 
Section 7.4. When the criteria for transition into the second stage are met, the study will 
move on to the full accrual and there will be up to 70 patients  treated in Cohort A. 
At the end of the second stage, the significance level for testing the null hypothesis H0: PFS6 
≤ 40% will be calculated as the exact binomial probability i.e. Prob(X>s| n, p=0.40), where ‘s’ 
is the observed number of patients achieving PFS6 and ‘n’ is the total number of patients.  A 
Wilson 90% confidence interval will be provided also.
PFS6 for Cohort B patients will be analysed descriptively when all patients in Cohort B have 
completed the 24-week tumour assessment.


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7.3.2
Secondary endpoint analyses
Key Secondary Endpoint
Objective response rate (ORR) defined as the proportion of patients with confirmed complete 
response (CR) or confirmed partial response (PR) is the key-secondary endpoint. 
At the end of the second stage, the significance level for testing the null hypothesis H0: ORR 
≤ 5% will be calculated as the exact binomial probability i.e.  Prob(X>s| n, p=0.05), where ‘s’ 
is the observed number of patients achieving a confirmed objective response and ‘n’ is the 
total number of patients.  A Wilson 90% confidence interval will be provided also.
Other Secondary Endpoints
Progression-free survival will be analysed by Kaplan-Meier method. Clinical deterioration 
without image-based progression will not be counted towards progression. Detailed censoring 
rule for PFS and sensitivity analysis will be specified in the Trial Statistical Analysis Plan 
(TSAP).
Disease control rate (DCR) defined as the proportion of patients with confirmed CR, PR or
stable disease (SD) will be analysed similarly to ORR.
Duration of objective response is defined as the time from first documented CR or PR to the 
time of progression or death. Duration of objective response will be summarized 
descriptively. 
Kaplan-Meier estimates of overall survival will be provided.
Tumor shrinkage from baseline will be summarized descriptively and by waterfall plot of the 
maximum percentage decrease from baseline of the sum of the longest diameters of target 
lesions will be presented.
 
 
7.3.4
Safety analyses
All patients who receive at least one dose of trial medication will be included in the safety
analysis. Adverse events will be graded according to CTCAE, Version 4.03.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the residual effect period 
(REP), a period of 30 days after the last dose of trial medication, will be assigned to the 
treatment period for evaluation.


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Standard tabulations arranged by MedDRA SOC and PT will include:

The overall incidence and intensity of adverse events,

AE judged to have been related to afatinib

AE leading to dosage reduction

AE leading to permanent treatment discontinuation

SAE

Fatal outcome
These standard tables will be supplemented with tables in which MedDRA SMQ and HLT
(with some modifications) will be used to group MedDRA PT for the following:

rash/acne

stomatitis

paronychia
Tables that describe the frequency, intensity, time to onset, and clinical consequences will be 
produced for the following AEs of special interest:

diarrhea

rash/acne

stomatitis
Listings will be prepared of patients who are identified as having experienced any of the 
following AE. For AE other than dehydration, identification will be based upon modified 
MedDRA SMQ and HLT groupings.

Dehydration

Renal insufficiency

hepatic impairment

ILD-like events

heart failure

Keratitis

Pancreatitis

Severe skin reaction

Gastrointestinal perforation

Hypersensitivity reaction

Developmental toxicity
Primary laboratory tests are defined as:

Low values (-): haemoglobin, total WBC, platelets, neutrophils, lymphocytes, potassium, 
magnesium, sodium, creatinine clearance and GFR

High values (+): AST, ALT, alkaline phosphatase, aPTT, INR, and total bilirubin
The following analyses will be presented for the primary laboratory tests:

descriptive statistics at each planned assessment,

frequency of patients with transitions in CTCAE grade from baseline to worst and last 
values during treatment, and

frequency of patients with possible clinically significant abnormalities.


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Possible clinically significant abnormalities are defined as CTCAE grade of 2 or greater, with
an increase of at least one grade from baseline.
7.3.5
Pharmacokinetic analyses
No pharmacokinetic analyses are planned.
INTERIM ANALYSES
7.4
PFS6 and confirmed ORR will be evaluated for the first 25 treated patients when the last 
patient among them completes the 24-week tumor assessment. If 12 or more patients achieve 
PFS6, or at least 2 have a confirmed response, the study will move on to the full targeted 
accrual  in Stage 2. The primary analysis will be conducted when 70 patients in Cohort A 
complete the 24-week tumor assessment.
If fewer than 12 patients achieve PFS6 and fewer than 2 patients have a confirmed response, 
the trial will be stopped for futility. All patients enrolled will be followed until disease 
progression and a full analysis will be carried out after all patients discontinue the study.
Stages 1 and 2 of the study will be conducted in a seamless fashion with no interruption in 
enrolment after treating 25 patients. Therefore by the time of the futility assessment, more 
than 25 patients might have been treated. The sponsor may however suspend recruitment 
after enrolling the pre-defined 25 patients in Stage 1 in the event of low likelihood to meet 
the criteria to move from Stage 1 to Stage 2. 
HANDLING OF MISSING DATA
7.5
In general, missing data will not be imputed. Missing or incomplete AE onset and end dates 
are imputed according to BI standards (see “Handling of missing and incomplete AE dates”).
Missing of imaging data will be handled with the censoring rules for PFS.
RANDOMISATION
7.6
Not applicable.
DETERMINATION OF SAMPLE SIZE
7.7
Table 7.7: 1 shows that 70 patients would be expected to provide appoximately 90% power 
for PFS6, with PFS6=60% under the alternative hypothesis and PFS6=40% under the null.  
Although the Stage 1 futility criterion will reduce the power, the power after adjustment for 
the futility analysis would likely be between the unadjusted and adjusted power estimates in 
Table 7.7:1, because the futility criterion allows the trial to proceed to Stage 2 with fewer 
than 12 patients with successful PFS6, provided at least two patients have confirmed response. 


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Table 7.7: 1 
Power1 for PFS6 in Cohort A, with PFS6=60% under the alternative 
hypothesis.
N=65
N=70
N=75
Without adjustment for Stage 1
alpha=0.025
87.2%
90.9%
93.6%
alpha=0.050
91.7%
94.3%
96.0%
With adjustment for Stage 1
(N=25, PFS6>12)
alpha=0.025
83.5%
86.3%
88.2%
alpha=0.050
87.1%
88.8%
89.9%
1Based upon simulating one million samples under the alternative hypothesis of PFS6=60%. For each sample a 
significance level was calculated as the binomial probability (X>s| n, p=0.40), where ‘s’ is the observed number 
of patients achieving PFS6 and ‘n’ is the total number of patients.
Table 7.7: 2 shows that 70 patients would be expected to provide approximately 80% power 
for ORR, with ORR=15% under the alternative hypothesis and ORR=5% under the null.
Tables 7.7:1 and 7.7:2 present power for both alpha=0.025 and 0.05 because the Hochberg 
multiplicity procedure would compare the higher of the observed significance levels for PFS6 
and ORR to 0.05.  If the larger significance level is smaller than 0.05, then we can reject null 
hypothese for both PFS6 and ORR. If the larger significance level is greater than 0.05, then 
the smaller significance level would be compared to a more stringent threshold 0.025, in 
order to refrain the family-wise error rate at 0.05.
If the underlying PFS6 rate is 40%, the probability of observing fewer than 12 patients out of 
25 in Stage 1 would be 73%. Under the alternative that PFS6=60%, the chance of observing 
at least 12 patients would be 92%.
For ORR under the null ORR=5%, the probability of observing fewer than 2 confirmed 
responses in Stage 1 would be 64%. Under the alternative that ORR=15%, the chance of 
observing at least 2 responses would be 91%.
For Cohort B the analyses will be exploratory and descriptive in nature and the sample size is 
determined based on feasibility and practical considerations.
Table 7.7: 2
Power1 for ORR in Cohort A, with ORR=15% under the alternative 
hypothesis.
N=65
N=70
N=75
Without adjustment for Stage 1
alpha=0.025
77.8%
84.2%
81.1%
alpha=0.050
87.4%
84.2%
89.2%
With adjustment for Stage 1
(N=25, ORR>2)
alpha=0.025
74.3%
79.6%
76.9%
alpha=0.050
82.4%
79.6%
83.5%


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1Based upon simulating one million samples under the alternative hypothesis of ORR=15%.  For each sample a 
significance level was calculated as the binomial probability (X>s| n, p=0.05), where ‘s’ is the observed number 
of patients achieving a confirmed objective response and ‘n’ is the total number of patients.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), and 
relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract. As a rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’s legally accepted representative) according to ICH/GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”
The Investigator must give a full explanation to trial patients including the items listed below 
in association with the use of the patient information form, which is prepared avoiding the 
use of technical terms and expressions. The patient is given sufficient time to consider 
participation in the trial. The Investigator obtains written consent of the patient’s own free 
will with the informed consent form after confirming that the patient understands the contents. 
The Investigator must sign (or place a seal on) and date the informed consent form. If a trial 
collaborator has given a supplementary explanation, the trial collaborator also signs (or 
places a seal on) and dates the informed consent.


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Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
DATA QUALITY ASSURANCE
8.2
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB/IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
RECORDS
8.3
(e)CRF for individual patients will be provided by the Sponsor. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
All data in eCRFs must be derived from source documents:

Patient identification (gender, year of birth)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results (in validated electronic format, if available)

Completion of Patient’s Participation in the trial”

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records or testing conducted specific for a protocol) to support 
inclusion/exclusion criteria does not make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. 
CRF/eCRF and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the BI’s clinical trial monitor, 


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auditor and inspection by health authorities (e.g. FDA). The Clinical Research Associate 
(CRA)/on site monitor and auditor may review all CRF/eCRF, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For afatinib it is the current version of the Investigator’s Brochure (c01617169-04). 
The current version of this reference document is provided in the ISF. No AEs are classified 
as listed for trial design, or invasive procedures.
8.4.2
Expedited reporting of Adeverse Events
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this protocol.
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities.
TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment of the first patient in the whole
trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Out”, LPO). And LPO is when the last patient has 24 months FU or evaluable 
for PFS6.
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of SUSARs occurring with the trial 
medication until 30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the
sponsor with the intention to resume it.


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Suspension of the trial is defined as an interruption of the trial based on a Health Authority
request.
The IEC / competent authority in each participating EU member state will be notified about
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed
the trial in all countries (EU or non-EU) to incorporate and consider all data in the report. The 
sponsor will submit to the EU database a summary of the final trial results within one year 
from the end of a clinical trial as a whole, regardless of the country of the last patient (EU or 
non-EU).


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9.
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PUBLISHED REFERENCES
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programme francais de medecine personnalisee pour les patients en essais 
precoces: 
le 
principe 
de 
medecine 
personnalisee 
en 
oncologie. 
http://www.dons-gustaveroussy.fr/moscato (access date: 8 October 2014) 
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Massard CA, Auger N, Vielh P, Lacroix L, Lazar V, Ngo-Camus M, Deley 
MC le, Andre F, Baere T de, Soria JC. MOSCATO: preliminary analysis of 
a molecular screening triage trial for patients enrolled in phase I trial. 24th 
EORTC-NCI-AACR Symp on Molecular Targets and Cancer Therapeutics, 
Dublin, 6 - 9 Nov 2012 (Poster) 2012. 
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_Product_Information/ human/002280/WC500152392.pdf (access date: 17 
December 2014); 2014.
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NCCN Clinical Practice Guidelines in Oncology:  Bladder Cancer, v2.2015.  
www.nccn.org : National Comprehensive Cancer Network; 2015.
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Lorusso V, Pollera CF, Antimi M, et al. A phase II Study of Gemcitabine in 
Patients with Transitional Cell Carcinoma of the Urinary Tract Previously 
Treated with Platinum. European Journal of Cancer, Vol. 34, No. 8, pp. 
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Knowles M, and Hurst C. Molecular biology of bladder cancer: new 
insights into pathogenesis and clinical diversity. Nature Reviews Vol 15, 
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Dreicer R, Li S, Manola J, Haas NB, Roth BJ, Wilding G. Phase 2 Trial of 
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of the Urothelium (E3800). Cancer 2007;110:759–63;
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DeGraff DJ, Clark PE, Cates JM, Yamashita H, Robinson VL, et al. (2012) 
Loss of the Urothelial Differentiation Marker FOXA1 Is Associated with 
High Grade, Late Stage Bladder Cancer and Increased Tumor Proliferation. 
PLoS ONE 7(5): e36669. doi:10.1371/journal.pone.0036669
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Bellmunt. J, Theodore C, Denkov T, et al. Phase III Trial of Vinflunine Plus 
Best Supportive Care Compared With Best Supportive Care Alone After a
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Sweeney J, Roth BJ, et al. Phase II Study of Pemetrexed for Second-Line 
Treatment of Transitional Cell Cancer of the Urothelium Clin Oncol 
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Rebouissou S et al. EGFR as a potential therapeutic target for a subset of 
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UNPUBLISHED REFERENCES
9.2
c01617169-04
Investigator´s brochure. Afatinib (BIBW 2992). Version 17, 1200.P1 –
1200.P13. 05 Jul 2016
U07-3128
 A phase I open-label dose escalation study of 
continuous once-daily oral treatment with BIBW 2992 in patients with 
advanced solid tumours.  Trial 1200.4.  30March 2007.  Revised 23 April 
2010.
U08-1023
  phase I open-label dose escalation study of 
continuous once-daily oral treatment with BIBW 2992 in patients with 
advanced solid tumours.  Trial 1200.3.  30 January 2008. Revised 25 
February 2010.


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10.
APPENDICES
APPENDIX 1: PGP INHIBITORS AND INDUCERS
10.1
List of potent inhibitors and inducers of P-glycoprotein (MDR1)
Inhibitors
Inducers
Amiodarone
Carbamazepine
Azithromycin
Phenytoin
Captopril
Rifampicin
Carvedilol
St. John´s Worth
Clarithromycin
Phenobarbital Salt
Cyclosporine
Tipranavir
Diltiazem
Ritonavir
Dronedarone
Erythromycin
Felodipine
Itraconazole
Ketoconazole
Lopinavir
Nelfinavir
Quinidine
Ranolazine
Saquinavir
Tacrolimus
Ticagrelor
Verapamil
As the information on potent inhibitors and inducers of P-glycoprotein may evolve, it is 
important for the investigator to assess such status on concomitant therapies and in case of 
questions contact BI clinical monitor.


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APPENDIX 2: COCKCROFT-GAULT FORMULA
10.2
The following formula may be used for estimated creatinine clearance rate (eCCR) using 
Cockcroft-Gault formula. Other on-line calculators or formulas which are institution 
standards for eCCR and differ slightly may also be used. 
When serum creatinine is measured in mg/dL:
Or when serum creatinine is measured in µmol/L
Where Constant is 1.23 for men and 1.04 for women
APPENDIX 3: ECOG PERFORMANCE STATUS
10.3
ECOG PERFORMANCE STATUS
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours
4
Completerly disabled. Cannot carry on any self-care. Totally confined to bed or 
chair.
5
Dead
R01-0787
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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APPENDIX 4: CLINICAL EVALUATION OF LIVER INJURY
10.4
10.4.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.3.5.1 (Adverse Events of 
Special Interest), are to be further evaluated using the following procedures:
10.4.2
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. Complete blood count and cell morphology
3. Reticulocyte count
4. CK
5. LDH
6. 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”. Any resulting 
diagnoses will be reported via the eCRF:

obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the “DILI checklist” provided in the ISF;

obtain history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets 
according to the “DILI checklist” provided in the ISF;

obtain a history of exposure to environmental chemical agents (consider home and work 
place exposure) according to the “DILI checklist” provided in the ISF;


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
complete the following laboratory tests as detailed in the DILI checklist provided in the 
ISF: 

Clinical chemistry 
alkaline phosphatase, cholinesterase (serum)*, albumin, PT or INR, CK,
CK-MB, coeruloplasmin*, α-1 antitrypsin*, transferrin*, amylase, lipase, 
fasting glucose, cholesterol, triglycerides

Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs,DNA), 
Hepatitis C (Anti-HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-
IgM, Anti-IgG), Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti-
HEV IgM positive), Anti-Smooth Muscle antibody (titer), Antinuclear
antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-
mitochondrial antibody, Epstein Barr Virus (VCA IgG, VCA IgM),
cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, IgM)*, varicella
(IgG, IgM)*, parvovirus (IgG, IgM)*

Hormones, tumormarker
Thyroid-stimulating hormone(TSH)*

Haematology
Thrombocytes, eosinophils
*If clinically indicated (e.g immunocompromised patients) 
Long term follow-up
o
Initiate close observation of subjects by repeat testing of ALT, AST, and bilirubin 
(with fractionation to total and direct) at least weekly until the laboratory ALT and or 
AST abnormalities stabilize or return to normal, then according to the protocol. 
Depending on further laboratory changes, additional parameters identified e.g. by 
reflex testing will be followed up based on medical judgement and Good Clinical 
Practices (GCP).
Report any resulting diagnoses via the eCRF.
APPENDIX 5: RECIST 1.1 CRITERIA
10.5
The criteria below are based on RECIST 1.1 (R09-0262).
The preferred method of assessment is a spiral CT scan with IV and oral contrast, unless IV 
and/or oral contrast are medically contraindicated. CT scans of the chest, abdomen and other 
areas of known or newly suspected disease must be performed. Scans of the abdomen, pelvis 
and other areas of the body, but not chest, may be done with MRI instead of CT. 
Skin lesions followed as target lesions must be documented by colour digital photography 
and must include in the image a ruler with millimetre subdivisions and a label that includes 
the patients ID and date. 
Bone scans (using 99m-technetium polyphosphonate scintigraphy) are recommended at 
baseline if the patient has any signs and symptoms consistent with bone metastasis or a 


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history of bone metastasis. Bone metastasis identified at baseline must be documented and 
assessed according to RECIST 1.1 at the times of the other tumour measurements indicated in 
the flow chart. During the study bone scans should be repeated as clinically indicated in 
patients without bone metastasis at Baseline. 
For the purposes of this study, patients should be re-evaluated for response at weeks 8, 16, 24
and every 8 weeks thereafter. 
In the event of a treatment delay, interruption or 
discontinuation of treatment, tumour assessment should continue to follow the original 
schedule. 
Follow-up tumour assessments must utilize the same CT/MRI/photographic method and 
acquisition technique (including use or non-use of IV contrast) as were used for screening 
assessments to ensure comparability. A chest x-ray or skeletal x-ray which clearly 
demonstrates a new metastatic lesion may be used to document progression in lieu of 
CT/MRI/bone scan.
These patients will have their response classified according to the definitions stated below.
Measurability of the disease
Measurable lesions
Lesions that can be accurately measured in at least one dimension with longest diameter ≥10 
mm (by CT scan, MRI, caliper measurement) or ≥20 mm (by chest X-ray).  Pathological 
lymph nodes, defined as lymph nodes with a short axis >15mm are also measurable.
Measurable disease
Measurable disease requires the presence of at least one measurable lesion. Measurable lesion 
if limited to either small (<2cm) solitary visceral lesion or scant (<5cm) lymph nodes only 
metastasis should be evaluated for additional evidence of malignant nature and discussed 
with BI trial clinical monitor before enrolling.
Non-measurable disease
Non-measurable lesions are all other lesions, including small lesions (longest diameter <10 
mm with CT scan, MRI or caliper measurement or <20 mm with chest X-ray or pathological 
lymph nodes with shortest axis ≥10 and <15 mm) as well as truly non-measurable lesions. 
Lesions considered truly unmeasurable include leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/ abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques.
Lesions with prior local treatment 
Tumour lesions situated in a previously irradiated area, or in an area subjected to other loco -
regional therapy, are usually not considered measurable unless there has been demonstrated 
progression in the lesion
Methods of measurement
All measurements must be recorded in metric notation, using a ruler or calipers. All baseline 
evaluations must be performed as close as possible to the treatment start and never more than 
4 weeks before the beginning of the treatment. If a lesion is considered too small to measure, 


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a default measurement of 5mm should be applied. If the lesion is not visible, a default 
measurement of 0 mm should be applied.
The same method of assessment and the same technique must be used to characterise each 
identified and reported lesion at baseline and during follow-up.
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). In the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is obligatory.
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 5 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to the chest, abdomen and 
pelvis.
Ultrasound, endoscopy and laparoscopy should not be used to measure tumour lesions or
evaluate tumour response. However, these techniques can be useful to supplement 
information from other techniques.
Cytology and histology can be used to differentiate between PR and CR in rare cases (for 
example, residual lesions in tumour types such as germ cell tumours where known residual 
benign tumours can remain).
Baseline Documentation of Target and Non-target Lesions
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs should be identified as target lesions and will be 
recorded, measured (longest diameter = LD) and numbered at baseline. Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their suitability 
for accurate repetitive measurements (either by imaging techniques or clinically). Lymph 
nodes must be ≥15mm in order to be considered as target lesions. 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference to further characterise 
the objective tumour response of the measurable dimension of the disease (see table below):
Table 10.5: 1
Evaluation of target lesions
Complete Response 
(CR)
Disappearance of all target lesions.
Partial Response 
(PR)
At least a 30% decrease in the sum of LD of target lesions taking as 
reference the baseline sum LD.
Progression (PD)
At least a 20% increase in the sum of LD of target lesions taking as 
reference the smallest sum LD recorded since the treatment started, 
together with an absolute increase in the sum of LD of at least 5mm.
OR
The appearance of one or more new lesions.
Stable Disease (SD)
Neither sufficient shrinkage to qualify for PR, taking as reference 
the baseline SoD, nor sufficient increase to qualify for PD taking as 
reference the smallest SoD since the treatment started.


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All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. Measurements are not required and these lesions should be 
followed as “present” or “absent” (see Table 10.5: 2).
Table 10.5: 2
Evaluation of non-target lesions and new lesions
Complete 
Response (CR)
Disappearance of all non-target lesions and normalisation of tumour 
marker level. All lymph nodes must be non-pathological in size 
(<10 mm short axis)
Non-CR/Non-PD 
Persistence of one or more non-target lesions or/and maintenance of 
tumour marker level above normal limits.
Progression (PD) 
Appearance of one or more new lesions and/or unequivocal
progression of existing non-target lesions. Although a clear progression 
of non-target lesions only is exceptional, in such circumstances, the 
opinion of the treating physician should prevail and the progression 
status should be confirmed later by the review panel (or study chair).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it
is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status.
Confirmation
In case of tumour response (CR or PR), confirmation will be performed with a repeat 
assessment no less than 4 weeks after the RECIST criteria for response have been met. In the 
case of SD, measurement must have met the SD criteria at least once after study entry at an 
interval of not less than 6 weeks.
Evaluation of best response to study treatment
The best response to study treatment (Table 10.5: 3) is the best response recorded from the 
start of treatment until disease progression or start of further anti-cancer treatment (taking as 
reference for progressive disease the smallest measurements recorded since the treatment 
started). In general, the patient’s best response assignment will depend on the achievement of 
both measurements and confirmation criteria (Table 10.5: 3).
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment.


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Table 10.5: 3
Algorithm for evaluation of overall response
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/ Non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not 
evaluated
No
PR
SD
Non-PD or not 
evaluated
No
SD
Not evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
APPENDIX 6: NYHA CLASSIFICATION OF HEART FAILURE
10.6
Class
Patient Symptoms
Class I (Mild)
No limitation of physical activity. Ordinary physical activity does 
not cause undue fatigue, palpitation, or dyspnea (shortness of breath)
Class II (Mild)
Slight limitation of physical activity. Comfortable at rest, but 
ordinary physical activity results in fatigue, palpitation, or dyspnea.
Class III 
(Moderate)
Marked limitation of physical activity. Comfortable at rest, but less 
than ordinary activity causes fatigue, palpitation, or dyspnea.
Class IV (Severe)
Unable to carry out any physical activity without discomfort. 
Symptoms of cardiac insufficiency at rest. If any physical activity is 
undertaken, discomfort is increased.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
13 MAR 2017
EudraCT number
2015-005427-10
BI Trial number
1200.261
BI Investigational Product(s)
Afatinib (Giotrif, Gilotrif)
Title of protocol
Phase II open label single arm exploratory trial of 
oral afatinib monotherapy following platinum 
failure for patients with advanced/metastatic 
urothelial tract carcinoma with ERBB receptor
deregulation.
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
Y
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
N
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
N
Section to be changed
Study title
Description of change
Addition of an acronym to the trial (LUX-Bladder 
1), and revision of the wording (change 
“deregulation” by “genetic alterations”)
Rationale for change
The addition of the name to the trial was 
implemented for an easier reference to this trial, 
while the revision of the wording was included to 
have amore accurate definition of the genetic 
characteristics.
Section to be changed
Clinical trial protocol synopsis – Methodology
Description of change
Revision of the wording referring to genetic 
charachteristics (change “deregulation” by “genetic 
alterations”)
Rationale for change
To have a more accurate definition of the ERBB 
alterations
Section to be changed
Clinical trial protocol synopsis – Duration of 


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treatment
Description of change
Addition of the need to confirm disease 
progression by RECIST 1.1, and inclusion of the 
adverse events under a global cathegory of “other
reasons requiring treatment discontinuation”
Rationale for change
To refine the criteria about treatment 
discontinuation and align with project guidelines.
Section to be changed
Clinical trial protocol synopsis – Objectives and 
Safety criteria
Description of change
Revision of the CTCAE version used to 4.03
Rationale for change
To keep consistency throughout the protocol
Section to be changed
Clinical trial protocol synopsis – No. of patients 
each treatment
Description of change
Increase of the number of patients to be included in 
Stage 2
Rationale for change
To keep consistency with Section 7 and new 
statistical assumptions.
Section to be changed
Flow chart
Description of change
Addition of one visit one week after starting second 
course of treatment.
Rationale for change
To add a better follow up and management of 
potential adverse events
Section to be changed
Flow chart
Description of change
Addition of a column on description of visits after 
Course 3
Rationale for change
To have a better and clearer description of trial 
procedures
Section to be changed
Flow chart footnote #2
Description of change
Addition of the window for EoR visit
Rationale for change
To add flexibility to the conduct of this visit, and 
keep consistency with section 6.2.3.2
Section to be changed
Flow chart footnote #4
Description of change
Change the units of timeframe for vital status 
collection (from months to days)
Rationale for change
To keep consistency throughout the protocol and 
have all timeframes in days
Section to be changed
Flow chart footnote #5
Description of change
To clarify that after course 3 of treatment only one 


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visit per cycle is required.
Rationale for change
To keep consistency throughout the protocol as a 
consequence of the addition of the new visit after 
C21V1.
Section to be changed
Flow chart footnote #7
Description of change
Addition of a comment about the need to have one 
more vistit one week after starting course 2
Rationale for change
To add a better follow up and management of 
potential adverse events
Section to be changed
Flow chart footnote #15
Description of change
Clarification regarding previous image assessments 
obtained within 28 days of starting study treatment
Rationale for change
To add clarity on trial procedures
Section to be changed
1. Introduction
Description of change
Change ErbB1 by ERBB1, and rewording of 
specific parts of the text
Rationale for change
To have a more accurate definition on genetic 
alterations and better English wording.
Section to be changed
1.1 Medical Background
Description of change
Expansion of what TCCU stands for, better 
definition of genetic alterations, and updates on 
previous trials.
Rationale for change
To have a more accurate definition of the ERBB 
alterations, better English wording, and updated 
results on previous investigations.
Section to be changed
1.2 Drug Profile
Description of change
Update on Investigators´ Brochure reference 
number and Giotrif approvals
Rationale for change
To update protocol on latest afatinib´s documents 
and labelling.
Section to be changed
2.1 Rationale for performing the trial
Description of change
Update on the results of previous trials 
Rationale for change
To keep protocol updated according to recent 
publications
Section to be changed
2.2 Trial Objectives
Description of change
Addition of a reference and rewording of parts of 
the section.
Rationale for change
To add clarity to this section.


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Section to be changed
2.3 Benefit-risk assessment
Description of change
Revision of the AEs related to afatinib
Rationale for change
To align the protocol with latest updates on 
Afatinib and project requirements.
Section to be changed
3.1 Overall trial design and plan
Description of change
Revision of the wording referring to genetic 
charachteristics and conditions for treatment 
discontinuation
Rationale for change
To keep consistency throughout the trial protocol
Section to be changed
3.1.1 Administrative structure of the trial
Description of change
Increase the number of participating sites
Rationale for change
This is consequence of the expansion of the trial to 
two additional countries in Europe
Section to be changed
3.2 Discussion of trial design, including the choice 
of control groups
Description of change
Revision of the text referring to the statistical 
analysis
Rationale for change
To keep consistency with Section 7.
Section to be changed
3.3.2 Inclusion criteria #4
Description of change
Rewording of the criteria, specifying what could be 
considered as one line of chemotherapy
Rationale for change
To add clarity to the criteria.
Section to be changed
3.3.2 Inclusion criteria #5
Description of change
Revision of the criteria about previous treatments
Rationale for change
To add clarity to the criteria, especially regarding 
the use of previous immunotherapy, which was not 
detailed before.
Section to be changed
3.3.3 Exclusion criteria #4
Description of change
Revision of the wording regarding previous 
radiotherapy
Rationale for change
To add clarity to the criteria and align to RECIST 
1.1
Section to be changed
3.3.3 Exclusion criteria #8
Description of change
Addition of the incidental localized prostate cancer 
to previous or concomitant allowed malignancies
Rationale for change
To allow for this patients to be entered, since 
patients with incidental localized prostate cancer 


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have good prognostic and would not need further 
treatment, which would interfere with treatment of 
urothelial cancer.
Section to be changed
3.3.3 Exclusion criteria #14 and #15
Description of change
Revision of the text referring to women of child-
bearing potential
Rationale for change
To align with project standards and current 
international guidelines (ICH) 
Section to be changed
3.3.4.1 Removal of individual patients
Description of change
Rewording of the removal criteria and addition of a 
text referring to potential treatment with Afatinib 
beyond study
Rationale for change
To add clarity to the removal criteria and align with 
project standards.
Section to be changed
3.3.4.2 Discontinuation of the trial by the sponsor
Description of change
Addition of one reason for trial discontinuation, 
and the possibility to suspend the trial after 
completing recruitment in stage 1.
Rationale for change
To align with project standards, and to include the 
possibility of suspending recruitment (after stage 1 
is completed and before its analysis) when there are 
possibilities that the the drug is not working.
Section to be changed
4.1.4.1 Administration of Afatinib
Description of change
Revision of the duration of treatment with afatinib
Rationale for change
To keep the consistency throughout the protocol 
regarding the treatment duration.
Section to be changed
4.1.4.1.2:1 Dose reduction scheme for Afatinib
Description of change
Revision of the wording of the AE related to renal 
function to specify that only if caused by 
dehydration secondary to diarrhea.
Rationale for change
To update te protocol according to Afatinib safety 
profile and to clarify that afatinib does not cause 
renal failure per se (only diarrhea, that can lead to 
pre-renal failure). Consequently, only renal 
impairment related to dehydration caused by 
diarrhea should lead to dose reduction of Afatinib.
Section to be changed
4.2.2.3 Restrictions regarding women of child-
bearing potential
Description of change
Revision of the text describing women of child-


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bearing potential and methods of birth control
Rationale for change
To align with project standards and current 
international guidelines (ICH)
Section to be changed
Table 4.2.3.2:1 General recommendations for 
prophylaxis while receiving afatinib
Description of change
Change in the table title to specify that the table 
refers to “dermatological AEs” 
Rationale for change
In the previous version of the protocol this mention 
was missing.
Section to be changed
5.1.2 Secondary endpoints
Description of change
Rewording of part of the section and correction of 
typos.
Rationale for change
To add clarity and facilitate reading of the section.
Section to be changed
5.3 Assessment of Safety
5.3.5.1 Definitions of AEs – Intensity of AEs
5.7 Appropiateness of measurements
Description of change
Rationale for change
Section to be changed
5.5 Biomarker assessments
Description of change
Change of the word “biobanking” to “sample 
storage”
Rationale for change
Technically, BI is not intended to build a biobank 
because the samples will only be used for trial 
purposes. Therefore, wording has been adapted
accordingly.
Section to be changed
5.5.1.1 Method of sample collection
Description of change
Revision of the number of required slides from 
tumour samples
Rationale for change
To align the protocol with the lab manual.
Section to be changed
5.5.2.1 Exploratory tumour tissue analyses
Description of change
Removal of the “mRNA expression of the ERBB 
receptors, their ligands and genes of relevance by 
technologies such as nanostring or RT PCR” and 
addition of the “expression of mRNAs by Next 
generation sequencing”
Rationale for change
To update the trial tests according to latest 
investigations on biomarkers in urothelial cancer.


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Section to be changed
5.5.4 Biobanking
Description of change
Addition of the whole section and change of title
Rationale for change
The whole section was missing in the previous 
version of the protocol. 
Section to be changed
6.2.1 Screening period – pre-screening visit
Description of change
Clarification regarding previous image assessments 
obtained within 28 days of starting study treatment
Rationale for change
To add clarity on trial procedures
Section to be changed
6.2.2 Treatment period
Description of change
Addition of a patient contact one week after 
starting second course of treatment
Rationale for change
To add a better follow up and management of 
potential adverse events
Section to be changed
6.2.3.2 End of residual effect period (EoR)
Description of change
Addition of a window for this visit
Rationale for change
To add flexibility to the conduct of this visit.
Section to be changed
6.2.3.3.1 Follow-up for progression
Description of change
Increasing of the window to perform imaging tests 
in this visit, from 2 days to 1 week.
Rationale for change
To add flexibility to the conduct of this visit.
Section to be changed
6.2.3.3.2 Follow-up for Overall survival
Description of change
Change the units on timeframe for vital status 
collection (from months to days), and rewording of 
the follow up visit
Rationale for change
To keep consistency throughout the protocol (to 
and have all timeframes in days, and to correctly 
name the visits according to flowchart).
Section to be changed
7 Statistical Methods and determination of the 
sample size
Description of change
Revision of the whole section
Rationale for change
To refine the statistical model and better describe 
trial hypotheses and analysis.
Section to be changed
7.3.4 Safety analysis
Description of change
Updates on the tables and listing that will be 
provided with these analyses
Rationale for change
To align the protocol with project standards and 
latest updates on Afatinib safety profile.


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Section to be changed
9 References
Description of change
Addition of few publications and removal of 
outdated ones
Rationale for change
To update the protocol on latest published data 
Section to be changed
10.1 Appendix 1
Description of change
Addition of the whole section and title
Rationale for change
The whole section was missing in the previous 
version of the protocol.
Section to be changed
10.2 Appendix 2: Cockcroft-Gault formula
Description of change
Remove the need to add calculation in patient´s 
chart and rewording.
Rationale for change
All variables used for eCcr are already present in 
patient´s chart and do not see the need to detail the 
calculations. 
Section to be changed
10.4 Appendix 4: Clinical Evaluation of liver 
injury 
Description of change
Removal of Haptoglobin from the required 
parameters to be obtained in case of confirmed 
DILI case
Rationale for change
To update the protocol according to BI standard: 
DILI Checklist was revised and this parameter is 
not longer required.
Section to be changed
10.5 Appendix 5: RECIST 1.1 criteria
Description of change
Revision of the text about new lesions in irradiated 
fields
Rationale for change
To adapt the trial protocol to the latest version of 
RECIST 1.1 criteria.


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03510257
2.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c09176328-02
BI Trial No.:
1200.261
Title:
LUX-Bladder 1: Phase II open label single arm exploratory trial of 
oral afatinib monotherapy following platinum failure for patients 
with advanced/metastatic urothelial tract carcinoma with genetic 
alterations in ERBB receptors.
Including protocol amendment version 2.0 [c03510257-02]
Investigational 
Product:
Afatinib (Giotrif, Gilotrif)
Responsible trial 
statistician:
Telephone: 
Fax: 
Email: 
Date of statistical 
analysis plan:
01 Oct 2018 SIGNED
Version:
Final
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.   TABLE OF CONTENTS
TITLE PAGE..........................................................................................................1
1.         TABLE OF CONTENTS..............................................................................2
LIST OF TABLES...................................................................................................3
2.
LIST OF ABBREVIATIONS ......................................................................4
3.
INTRODUCTION ......................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINTS..............................................................................................8
5.1
PRIMARY ENDPOINT ......................................................................................8
5.2
SECONDARY ENDPOINTS..............................................................................8
5.2.1
Key secondary endpoint..................................................................................8
5.2.2
Other secondary endpoints.............................................................................8
6.
GENERAL ANALYSIS DEFINITIONS.....................................................10
6.1
TREATMENTS..................................................................................................10
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................10
6.3
PATIENT SETS ANALYSED..........................................................................12
6.5
POOLING OF CENTRES ................................................................................12
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................12
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................13
7.
PLANNED ANALYSIS.............................................................................14
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........14
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................15
7.3
TREATMENT COMPLIANCE .......................................................................15
7.4
PRIMARY ENDPOINT ....................................................................................15
7.5
SECONDARY ENDPOINTS............................................................................16
7.5.1
Key secondary endpoint................................................................................16
7.5.2
Other Secondary endpoints..........................................................................16
7.7
EXTENT OF EXPOSURE................................................................................19
7.8
SAFETY ANALYSIS.........................................................................................19
7.8.1
Adverse events ...............................................................................................19
7.8.2
Laboratory data.............................................................................................22
7.8.3
Vital signs.......................................................................................................23
8.
REFERENCES.........................................................................................24
10.
HISTORY TABLE ...................................................................................25


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LIST OF TABLES
Table 6.2: 1  Important protocol violations .............................................................................10
Table 7.5.2: 1   Rules to determine events and censoring for sensitivity analyses of PFS......18


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
BRPM
Blinded Report Planning Meeting
CR
Complete Response
CRF
Case Report Form
CTC
Common Terminology Criteria  
CTP
Clinical Trial Protocol
DCR
Disease Control Rate
DOR
ECOG
EGFR
Duration of Response
Eastern Cooperative Oncology Group
Epidermal Growth Factor Receptor, also known as ERBB1
EMEA
ERBB2
ERBB3
European Agency for the Evaluation of Medicinal Products
Second member of the ERBB family of proteins
Third member of the ERBB family of proteins
HLT
High Level Term
ICF
Informed Consent Form
ICH
IPV
International Conference on Harmonisation
Important Protocol Violations
MedDRA
MQRM
Medical Dictionary for Regulatory Activities
Medical Quality Review Meeting
NCI
NE
National Cancer Institute
Not Evaluable
NN
ORR
Non-CR/Non-PD
Objective Response Rate
OS
Overall Survival
PD
Progressive Disease
PDL1
Programmed Death Ligand 1
PFS
Progression Free Survival
PK
Pharmacokinetics
PSTAT
Project Statistician
PR
Partial Response
PT
Preferred Term


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Term
Definition / description
PV
Protocol Violation
RECIST
Response Criteria for Solid Tumours
SD
Stable Disease
SMQ
Standardised MedDRA query
TOC
Table of Contents
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size.
The validated SAS® version will be used that is in place on the BI system at the time of 
analyses.  Currently Version 9.3 is being used.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The protocol was amended to modify the futility analysis criterion to assess ORR as well as 
PFS6. This amendment is reflected in Sections 7.4 and 7.5.1 of this document. 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
This is an open label, uncontrolled, exploratory phase II trial with two patient cohorts. The 
purpose of this trial is to assess the anti-tumour activity and safety of afatinib monotherapy in 
patients with urothelial tract carcinoma carrying ERBB2 or ERBB3 mutations or ERBB2 
amplifications (Cohort A), and EGFR amplification positive tumours (Cohort B), progressing 
despite previous platinum based chemotherapy, and thereby to improve their prognosis.
Cohort A of the study follows a two stage design where an analysis for futility will be 
performed at the end of stage 1 to determine if the stage 2 of cohort A will be carried out. 
Cohort B of the study will include up to 10 patients with EGFR amplification. Analysis will 
be conducted in parallel to, and independent of cohort A.
The primary endpoint of this study is progression-free survival rate at six months (PFS6), as 
assessed at the investigative sites, in the ERBB2/ERBB3 cohort (Cohort A).  Patients who are 
alive and progression-free at the 24-week assessment will be considered successes. 
RECIST 1.1 (2) will be used to determine all response and progression endpoints.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint 

The key secondary endpoint for the ERBB2/ERBB3 cohort (Cohort A) is confirmed 
objective response rate (best overall response of CR or PR) by investigator review.
5.2.2
Other secondary endpoints
Refer to Section 5.1.2 of the CTP.
Other secondary endpoints for the ERBB2/ERBB3 cohort are: 

Progression-free survival (PFS)
o
Defined as the time from the treatment start date to the date of disease 
progression, or to the date of death if a patient died earlier

Overall survival (OS)
o
Defined as the time from the date of treatment start date to the date of death


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
Disease control rate (best overall confirmed response of CR, PR, or SD)

Duration of confirmed objective response  

Tumour shrinkage


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For reporting purposes, patients in the ERBB2/ERBB3 cohort will be presented separately 
from those in the EGFR cohort.
The following study periods based on actual start and stop dates of afatinib administration are 
defined:

Screening: day of informed consent to day prior to starting afatinib.

On-treatment: day of first administration of afatinib to the last administration of afatinib.

Residual effect period: day after last administration of afatinib to the 30th day after last 
administration of afatinib.

Post-study: on or after the 31st day after last administration of afatinib.
Data from the on-treatment and residual effect periods will be included in the safety analyses.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Patients with potentially important protocol violations (IPVs) will be documented.  The 
following list of potentially IPVs will be used; note that this is a working list and may not be 
finalised until the final Blinded Report Planning Meeting (BRPM) prior to database lock.
Table 6.2: 1  Important protocol violations
Category/code
Description
Comment
Manual/ 
Automatic
A
Entrance criteria 
not met
A1
Diagnosis of 
urothelial tract 
carcinoma 
questionable
Refer to IN  2,3
Automatic
A2
Prior treatment for 
urothelial tract 
carcinoma does not 
meet entrance criteria
Refer to IN 4,5, EX 1,2
Should have received one line of prior 
systematic chemotherapy in metastatic set up. 
This needs to be platinum based therapy. 
Check for patients with no prior systematic 
platinum based therapy or more than one line 
of prior systematic therapies as well.
Also check exclusion criterion 1 and 2.
Manual/Automatic
A3
Prior surgery and 
radiotherapy do not 
meet entrance 
criterion
Refer to EX 3, 4. Major Surgery within 4 
weeks before starting study treatment, 
Radiotherapy within 4 weeks prior to start of 
study treatment in non-palliative setting.
Manual/Automatic 
A4
No measurable 
disease according to 
RECIST 1.1 at 
screening
Refer to IN6  
Automatic


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Table 6.2: 1
Important protocol violations (Contd.)
Category/code
Description
Comment
Manual/ 
Automatic
A5
No evaluable biopsy 
obtained at screening
Refer to IN9
Manual
A6
Patients not correctly 
classified according to 
EGFR, ERBB2, and 
ERBB3 status at screening
Refer to IN10
Manual
A7
Abnormal screening values 
Refer to IN11
Automatic
A8
ECOG PS is not 0 or 1
Refer to IN7
Automatic
A9
Other deviation from 
entrance criteria
Refer to in/exclusion criteria
Manual
B
Informed consent
B1
Informed consent not 
available 
Signed informed consent not available
Manual
B2
Inadequate informed 
consent
Informed consent obtained but not 
adequately done (e.g., obtained after 
the study specific activities were done, 
patient signed the wrong version of the 
ICF, and version signed did not receive 
prior IRB/IEC approval).
Manual
C
Trial medication
C1
Incorrect medication dose 
taken
e.g., starting dose is not 40 mg for 
afatinib; dose was not paused, resumed, 
reduced, or discontinued according to 
protocol 
Manual
C2
Non-compliance 
Check MQRM listings for extreme 
non-compliance only
Manual
D
Concomitant medication
D1
Use of prohibited 
concomitant medications  
Review concomitant medications for 
prohibited medication use.
Automatic
E
Trial specific
E1
Week 24 response 
assessment not performed 
according to protocol
Week 24 imaging and response 
assessment expected but  not performed
OR 
Week 24 imaging and response 
assessment performed before Day 140
Automatic
E2
Procedures not performed 
according to protocol
Check applicable data.
Manual
E3
Prohibited  anticancer 
interventions 
Patient received therapeutic radiation or 
another anti-cancer treatment before 
termination of afatinib
Manual


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6.3
PATIENT SETS ANALYSED
Treated set: this includes all patients who received at least one dose of afatinib. 
The treated set will be used for all efficacy and safety analyses.
6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing efficacy data will not be imputed and all reasonable efforts will be taken during the 
study to obtain such data.  Patients with unknown vital status or time to progression will be 
censored for time to event analyses; further details are provided in Section 7.  
Missing or incomplete AE dates are imputed according to BI standards (see “Handling of 
missing and incomplete AE dates”). (3)


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline values will be the measurements taken most recently prior to first dose of afatinib.
Study day will be calculated relative to the date of the first administration of afatinib.  The 
day prior to first administration of afatinib will be ‘Day -1’ and the day of first administration 
of afatinib will be ‘Day 1’; therefore ‘Day 0’ will not exist.
Imaging will be performed at 8, 16 and 24 weeks, and in 12-weekly intervals thereafter; 
images will be slotted to the planned time based on their relative day and using a ±4 week 
window as appropriate (images taken in the first 4 weeks from afatinib initiation will be 
slotted to Week 8).  If two or more images for a patient are assigned to one interval then the 
last assessment will be used to ensure progressive disease is not missed.  


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7.
PLANNED ANALYSIS
In general the display format of the analysis results will follow BI guideline (7, 8) as much as 
possible.
This is an open label, uncontrolled, exploratory phase II trial with two patient cohorts. The 
purpose of this trial is to assess the anti-tumour activity and safety of afatinib monotherapy in 
patients with urothelial tract carcinoma carrying ERBB2 or ERBB3 mutations or ERBB2 
amplifications (Cohort A), and EGFR amplification positive tumours (Cohort B), progressing 
despite previous platinum based chemotherapy, and thereby to improve their prognosis.
Cohort A of the study follows a two stage design where an analysis for futility will be 
performed at the end of stage 1based on first 25 treated patients to determine if the stage 2 of 
cohort A will be carried out. Cohort B of the study will include up to 10 patients with EGFR 
amplification. Analysis will be conducted in parallel to, and independent of cohort A.
If the trial is continued into Stage 2 for the ERBB2/ERBB3 cohort (cohort A), an analysis 
will be prepared to document the efficacy results among the first 25 patients.  This analysis 
will be restricted to the first 25 treated patients in cohort A, and will be conducted after no 
more of these 25 patients are eligible to be assessed for progression at 24-weeks (6 months).
The primary report will be produced after there are no more patients eligible to be assessed 
for progression at 24-weeks.
A final report will be produced when all patients have discontinued afatinib and none remain 
to be assessed for progression at 24-weeks.  The data for this report may be included in the 
primary report, if the gap in time between the last 24-week assessment and the final 
discontinuation is not too long.
If central radiological reviews are performed, differences in PFS6 outcome and response 
between the central and investigator reviews will be tabulated for each patient and 
summarized for all patients.   If there are differences, the analyses of PFS6 and response 
might be repeated using the central assessments. 
Company standard displays will be used whenever possible.
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. Percentages will 
be rounded to one decimal place. The category missing will be displayed only if there are 
actually missing values.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Descriptive statistics using standard summary tables for all treated patients are planned for 
this section of the report.
7.3
TREATMENT COMPLIANCE
Descriptive statistics using standard summary tables for the treated set of patients are planned 
for this section of the report.  A summary of whether patients took afatinib according to the 
protocol and whether they missed any doses will be produced for each planned visit.  In 
addition a summary of overall percentage compliance will be produced using visit dates and 
the total number of doses missed during the study.
7.4
PRIMARY ENDPOINT
The primary endpoint of this study is progression free survival rate at 6 months (PFS6), 
determined as being alive and progression-free at the 24-week assessment.
Patients who are alive and progression-free at the 24-week (168-day) assessment will be 
considered successes for PFS6.  The following rules are required for PFS6 to be considered a 
success:
1) Consider only valid assessments done before starting of any new anticancer therapy. 
Also do not consider any assessments done after EOT date+ 30 days. 
2) Patient has at least one valid assessment demonstrating non-progression on or after 
day 168 with reference to treatment start day.
3) Patient who did not meet the second criterion but has at least one valid non-PD 
assessment on or after day 154 (22 weeks) and has progression documented after day 
182 (26 weeks) is considered as success for PFS6. 
Examples:
i)
With SD at Day 156 followed by PD at Day 183 will be considered as success 
for PFS6.
ii)
With SD at Day 146 followed by PD at Day 170 will not be considered as 
success for PFS6.
iii)
With SD at Day 156 followed by PD at Day 170 will not be considered as 
success for PFS6.
For Cohort A, at the end of stage 2, final goal is to test H: PFS6 ≤40% vs alternative:
H: PFS6 > 40%.  If we observe fewer than 12 PFS6 successes and fewer than 2 objective 
responses among the first 25 patients in Stage 1, enrollment for Cohort A will be 
terminated, and the null hypothesis will be accepted.


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At the end of Stage 2, the significance level for testing the null hypothesis will be calculated 
as the exact binomial probability i.e. Prob(X > s| n, p = 0.40), where ‘s’ is the observed 
number of patients achieving PFS6 and ‘n’ is the total number of patients.  A Wilson 90% 
confidence interval will be provided also.
If trial stops at stage 1, for cohort A, PFS6 will be analysed descriptively and no formal 
statistical testing will be performed.
PFS6 for Cohort B patients will be analysed descriptively when all patients in Cohort B have 
completed the 24-week tumour assessment.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
Each patient will be assigned to one of the following RECIST categories: CR, PR, SD, 
Non-CR/Non-PD (NN), PD or Not Evaluable (NE), irrespective of protocol violations or 
missing data.
Objective response is defined as CR or PR, with confirmation as specified by RECIST 1.1. 
A summary of confirmed objective response rate (ORR) using the investigator assessment of 
best overall response will be produced.  
The null hypothesis for this key secondary endpoint ORR is H0: ORR ≤ 5% and the 
alternative Ha: ORR >5%.
At the end of the second stage, for cohort A, the significance level for testing the null 
hypothesis H0: ORR ≤ 5% will be calculated as the exact binomial probability i.e. Prob(X >
s| n, p = 0.05), where ‘s’ is the observed number of patients achieving a confirmed objective 
response and ‘n’ is the total number of patients.  A Wilson 90% confidence interval will be 
provided also.
A Hochberg multiple adjustment procedure will be used to control the family-wise error rate 
at 0.05 (one-sided) for testing PFS6 and ORR.
7.5.2
Other Secondary endpoints
PFS is determined as the time (months) from the date of first administration of Afatinib to the 
date of disease progression, or date of death (if a patients dies without progressing). The date 
of progression for the primary analyses will be determined based on assessments made by the 
investigators.  All treated patients will be included.
Table 7.5.2: 1 describes rules that can be used for sensitivity analyses to determine whether 
or not patients have had a PFS event (progression or death) along with the date of event or 
date of censoring (for those with no event).  


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These censoring rules will be used as a sensitivity analysis.  Any additional sensitivity 
analyses that relax part of the rules will be determined later and will be mentioned in 
technical SAP.
Kaplan–Meier curve and associated tables will be produced for overall survival.
A summary of disease control rate using the investigator assessment of response will be 
produced. Disease control rate (DCR) is defined as the proportion of patients with best 
overall response as complete response (CR), partial response (PR) or stable disease (SD)
Following analysis for time to response, duration of response, tumor shrinkage will be done 
after completion of stage 2.
Time to objective response (TTR) is the time from first afatinib administration to the date of 
first documented CR or PR. This analysis will be based on treated set.
The duration of objective response (DOR) is the time from first documented CR or PR to the 
time of progression or death. This analysis will be based on responders set only.
Time to response will be summarised by the planned imaging time points. Descriptive 
statistics will be calculated for the duration of objective response and duration of disease 
control, where applicable patients will be censored as for the PFS primary analysis.
Waterfall plots (and associated tables) of the maximum percentage reduction from baseline 
sum of target lesion diameters will be presented for each cohort.


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Table 7.5.2: 1   Rules to determine events and censoring for sensitivity analyses of PFS
Rule #
Situation
Outcome 
(event or 
censored)
Date of PFS event or 
censoring
1
No baseline tumour assessment (no death 
before second scheduled assessment)
censored
Date of the start of afatinib
2
Progressed from  imaging (no missed 
radiologic assessments)
event
Date of PD
3a
Non-PD from  imaging1, death before next 
scheduled assessment
event
Date of death
3b
Non-PD from  imaging1, one missed 
assessment, death or progression after date 
of missed assessment, but before a second 
scheduled assessment
event
Date of PD or death
3c
Non-PD from  imaging1, more than one 
consecutive missed assessment, death or 
progression after date of second missed 
assessment
censored
Date of last imaging before 
missed assessment
3d
Non-PD from  imaging1, more than one 
consecutive missed assessment, non-PD 
according to imaging after missed 
assessments
censored
Date of last non-PD imaging
4
New anti-cancer medication before 
progression or death
censored
Date of last imaging before 
new anti-cancer medication
5
Death before the scheduled date of first 
imaging
event
Date of death
6a
No imaging performed post-baseline, patient 
dies between first and second scheduled 
assessments
event
Date of death
6b
No imaging performed post-baseline, patient 
dies after second scheduled assessment
censored
Date of the start of afatinib
6c
No imaging performed post-baseline, vital 
status is unknown or patient known to be 
alive
censored
Date of the start of afatinib
7
Alive and not progressed from  imaging (no 
missed assessments)
censored
Date of last imaging
  1 From the last assessment at which CR, PR or SD was assessed.


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7.7
EXTENT OF EXPOSURE
Total treatment time (days and number of courses) will be calculated for each patient; 
off-drug periods due to non-compliance or toxicity prior to permanent discontinuation will be 
included as treatment time.  In addition, the total treatment time will be summed over all 
patients and transformed to patient years.  Standard descriptive summaries of these data will 
be provided for the treated set of patients.
Further summaries will also be produced:

Treatment time (days) broken down by each dose level (40 mg, 30 mg and 20 mg for 
afatinib.

Number and proportion of patients on each dose level over time.

Time to first dose reduction and duration (days) of off-drug periods prior to first dose 
reduction.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. 
7.8.1
Adverse events
Unless otherwise specified, the analyses of AEs will be descriptive in nature. All analyses of 
AEs will be based on the number of patients with AEs and NOT on the number of AEs. The 
reporting and analyses of AEs will follow the BI guideline (4). AEs will be coded with the 
most recent version of MedDRA®. The severity of AEs will be scaled according to the 
Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.
Furthermore, for analysis of AE attributes such as duration, severity, etc. multiple AE 
occurrence data on the CRF, will be collapsed into AE episodes provided that all of the 
following applies:
•
The same MedDRA lowest level term was reported for the occurrences


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•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day 
after the end of the first occurrence)
•
Treatment did not change between the onset of the occurrences OR treatment changed 
between the onset of the occurrences, but no deterioration was observed for the later 
occurrence
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 summarization of AE data, please refer to the guideline 
'Handling and summarization of adverse event data for clinical trial reports and integrated 
summaries'. (4)
For further details on summarization of AE data, please refer to (3, 4).
The analysis of AEs will include all events with onset in the on-treatment period (between 
treatment start date and (last date of trial medication + 30 days)) and residual effect period.  
Events occurring before first drug intake will be assigned to ‘screening', and all events 
occurring after the residual effect period will be assigned to ‘Post-study/follow-up’. 

An overall summary of AEs will be presented. 
The frequency of patients with AEs will be summarised by highest CTC grade (grade 3, 4, 5 
and all grades to allow both cohorts to fit on one page), treatment, primary system organ class 
and preferred term (PT). Separate tables will be provided for patients with each of the 
following AE categories:

AEs by treatment, highest CTCAE, using SOC and PT

Drug related AEs, as assessed by investigators, by treatment, highest CTCAE, using SOC 
and PT

AEs leading to dose reduction by treatment, highest CTCAE, using SOC and PT

AEs leading to afatinib discontinuation by treatment, highest CTCAE, using SOC and PT

Serious AEs by treatment, highest CTCAE, using SOC and PT

Drug related serious AEs by treatment, highest CTCAE, using SOC and PT

AEs leading to death by treatment, highest CTCAE, using SOC and PT

other significant AEs using SOC and PT ( see definition below)

AEs of special interest (discussed below)
The system organ classes will be sorted according to the standard sort order specified by 
EMA, preferred terms will be sorted by frequency (within system organ class).
Grouped terms
In order to most accurately characterize those AEs related to different mechanism, MedDRA 
SMQ and HLT (with some modification) will be used to group MedDRA PT for 


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
rash/acne, 

stomatitis, 

paronychia. 
As a first step in the analysis of grouped AE, all constituent PT will be presented in a separate 
table for each grouped AE. Standard tables will be supplemented with tables using the 
grouped AE.
Groupings will follow the project standard and details are defined in the technical TSAP. In 
these tables the grouped AEs will replace the original PTs for all AEs that are included within 
the grouped term.  The grouped AE categories will then be tabulated along with all remaining 
MedDRA PTs, sorted by descending frequency.  A reference table presenting all project 
defined groupings and MedDRA PTs within each grouping will also be produced. The 
following tables with grouping terms will be provided:

AEs by treatment, highest CTCAE, using grouped terms and PT

Drug-related AEs by treatment, highest CTCAE, using grouped terms and PT

AEs leading to dose reduction by treatment, using grouped terms and PT

AEs leading to treatment discontinuation by treatment, using grouped terms and PT

AEs leading to death by treatment, using grouped terms and PT

SAEs by treatment, highest CTCAE, using grouped terms and PT

Drug-related SAEs by treatment, highest CTCAE, using grouped terms and PT
Additional tables will be produced to describe the frequency, intensity, time to onset, and 
clinical consequences for 

diarrhea, 

rash/acne.

stomatitis
Pre-defined adverse events of special interest
Some pre-defined AEs are considered to be of special interest (AESIs).
Separate listings will be prepared for patients who are identified as having experienced any of 
the following AEs.  Identification will be based upon modified MedDRA SMQ and HLT 
groupings. If sufficient events occur within the trial, analyses similar to those for diarrhea 
rash/acne and stomatitis may be performed.  

Diarrhoea

Rash/ acne

stomatitis

Dehydration


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
Renal insufficiency

hepatic impairment

Interstitial Lung Disease (ILD-like events)

heart failure

Keratitis

Pancreatitis

Severe cutaneous adverse reactions (Severe skin reaction)

Gastrointestinal perforation

Hypersensitivity reaction

Developmental toxicity
Other significant AEs
Other significant AEs are defined as serious and non-serious AEs that lead to dose reduction
or permanent discontinuation of study medication. Their incidence will be reported by
severity according to CTCAE grades. A listing of patients who developed ‘other significant’ 
AEs will be provided and a flag for serious and non-serious will be included.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (6). CTCAE version 4.03 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).
Primary laboratory tests are defined as:

Low values (-):Red blood cell count (RBC),haemoglobin, total white blood cell 
(WBC), platelets, neutrophils (only at baseline),
lymphocytes, , sodium, potassium,
calcium, and glomerular filtration rate (GFR)
High values (+): aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline 
phosphatase, activated partial thromboplastin time (aPTT), international normalized ratio 
(INR), creatininetotal bilirubin, LDH, uric acid
The following analyses will be presented for the primary laboratory tests:

Descriptive statistics at each planned assessment 

Frequency of patients with transitions in CTCAE grade from baseline to worst and 
last values during treatment 

Frequency of patients with possible clinically significant abnormalities.
Possible clinically significant abnormalities are defined as CTCAE grade of 2 or greater, with 
an increase of at least one grade from baseline.


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Frequency and time of onset of liver enzyme elevations will be tabulated. Additional, more 
in-depth analyses will be performed as needed. These analyses will examine the influence of 
extent of exposure and time to event onset.
Note: Section 5.3.3 in protocol has detailed list of lab parameters which will be summarized 
beside important lab parameter mentioned above. 
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
R09-0262: Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D et al., New 
response evaluation criteria in solid tumors: revised RECIST guideline (version 1.1). 
Eur J Cancer 2009; 45:228-247 [R09-0262].
3
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
4
001-MCG-156: "Handling and summarisation of adverse event data for clinical trial 
reports and integrated summaries", current version; IDEA for CON.
5
BI Guidance document ‘Conversion of laboratory values to CTCAE grades within 
Boehringer Ingelheim’.
6
001-MCG-157: “Handling, Display and Analysis of Laboratory Data”, current version; 
IDEA for CON.
7
001-MCG-159: “Reporting of Clinical Trials and Project Summaries”, current version; 
IDEA for CON.
8
001-MCG-159_RD-03: “Standard table shells for inferential and descriptive End-of-
Text tables (EoT-Catalogue)”, current version; IDEA for CON.
9
001-MCS-60-113: “Clinical Trial Report”, current version; IDEA for CON.


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Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09176328
2.0