Conditions: Carcinoma, Non-Small-Cell Lung
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 32
Healthy volunteers: no

Brief summary:
Part A: To determine the maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) of Xentuzumab (BI 836845) in combination with afatinib in patients with non-small cell lung cancer with progression following prior treatment (EGFR TKI or platinum-based chemotherapy).

Part B: To evaluate the early anti-tumour activity of Xentuzumab (BI 836845) in combination with afatinib in patients with EGFR mutant non-small cell lung cancer with progression following prior irreversible EGFR TKIs.

Part A and B: To evaluate the safety and pharmacokinetics of BI 836845 in combination with afatinib in patients with non-small cell lung cancer

Detailed description:

Arms:
arm 1: Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Dose confirmation part (Part A). arm 2: Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Dose confirmation part (Part A). arm 3: Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 20 mg film-coated tablet. Expansion part (Part B). arm 4: Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 30 mg film-coated tablet. Expansion part (Part B). arm 5: Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib 40 mg film-coated tablet. Expansion part (Part B).

Interventions: intervention 1: Xentuzumab intervention 2: Afatinib
Intervention descriptions: intervention 1: Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet. intervention 2: Patients received intravenous infusion of Xentuzumab 1000 milligram (mg) delivered over 60 minutes per week for 4 weeks, in combination with once daily oral treatment of Afatinib film-coated tablet.

Protocol document:
Prot_000.pdf: 
TITLE PAGE
Clinical Trial Protocol
Doc. No.: c02190401-06
BI Trial No.:
1280.16
BI Investigational
Product:
Xentuzumab (BI 836845)
Title:
A phase Ib open-label clinical trial of once daily oral treatment of 
afatinib plus weekly intravenous infusion of Xentuzumab (BI 836845)
in patients with EGFR mutant non-small cell lung cancer with 
progression following prior EGFR tyrosine kinase inhibitors
Clinical Phase:
Ib
Trial Clinical 
Monitor:
Telephone: 
Fax: 
Email: 
Co-ordinating 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol based on Global Amendment 3)
Version and Date:
Version: 4.0
         
Date: 02 Nov 2016
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
Trial number:
Revision date:
02 Nov 2016
28 Mar 2014
1280.16
Title of trial:
A phase Ib open-label clinical trial of once daily oral treatment of afatinib plus weekly 
intravenous infusion of Xentuzumab (BI 836845) in patients with EGFR mutant non-
small cell lung cancer with progression following prior EGFR tyrosine kinase 
inhibitors
Co-ordinating 
Investigator :
Phone: 
Fax: 
Trial sites:
Multi-centre trial conducted in 4 countries (Korea, Taiwan, Singapore and Japan)
Approximately 12 sites
Clinical phase:
Ib
Objectives:
Primary objectives

Part A: To determine the Maximum Tolerated Dose (MTD) and/or
Recommended Phase II Dose (RP2D) based on evaluation of safety and 
tolerability of Xentuzumab (BI 836845) when administered in combination with 
afatinib in patients with non-small cell lung cancer with progression following 
prior treatment (EGFR TKI or platinum-based chemotherapy)   

Part B: To evaluate the early anti-tumour activity of Xentuzumab (BI 836845) in 
combination with afatinib in patients with EGFR mutant non-small cell lung 
cancer with progression following prior irreversible EGFR TKIs. 
Secondary objectives Part A and Part B:

To evaluate the safety 
 of Xentuzumab (BI 836845) in
combination with afatinib in patients with non-small cell lung cancer


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
Trial number:
Revision date:
02 Nov 2016
28 Mar 2014
1280.16
Methodology:
Open-label, 3+3 dose escalation (Part A) study of Xentuzumab (BI 836845) in 
combination with afatinib, followed by an expansion phase (Part B)
No. of patients: 
total entered:
Approximately 42 patients
each treatment:
Part A: Approximately 24 patients / Part B: Approximately 18 patients 
Diagnosis :
Part A:Patients with pathologic confirmation of advanced and/or metastatic stage 
IIIb/IV non-small cell carcinoma of lung
Part B: Patients with pathologic confirmation of advanced and/or metastatic stage 
IIIb/IV non-small cell carcinoma of lung who have failed at least one irreversible 
EGFR TKI therapy


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
Trial number:
Revision date:
02 Nov 2016
28 Mar 2014
1280.16
Main criteria
for inclusion:
1.
Patients with pathologic confirmation of advanced and/or metastatic stage 
IIIb/IV non-small cell carcinoma of lung 
2.
Documented activating EGFR mutation (exon 19 deletion, L858R, G719X, 
L861X). Exception: patient with squamous cell predominant histology in 
Part A
3.
Presence of EGFR activating mutation and absence of EGFR T790M 
mutation in the tumour associated with the latest disease progression. Only 
applicable in Part B
4.
Adequate fresh or archival tumour tissue at the latest disease progression
immediately prior to the study entry must be made available for central 
EGFR mutation test and/or resistance analysis
5.
Part A: Progression of disease (RECIST v1.1) while on continuous treatment 
with single agent EGFR TKI (e.g. erlotinib or gefitinib or afatinib) or for 
histology other than adenocarcinoma and without prior EGFR TKI 
treatment: progression of disease (RECIST v1.1) on platinum-based 
chemotherapy.
Part B: Progression of disease (RECIST v1.1) while on continuous treatment 
with single agent of the second generation irreversible EGFR TKI (e.g. 
afatinib or dacomitinib) 
Note: In both parts, patients whose disease progresses only in the central 
nervous system (CNS) are not eligible
6.
No intervening systemic therapy between cessation of EGFR TKI and 
initiation of the treatment in the study. Exception: patient with squamous 
cell predominant histology in Part A
7.
Patients must have measurable disease per RECIST v1.1 (R09-0262 -
Appendix 10.5) presented after tumour biopsy for the latest disease 
progression
8.
Recovered from any previous therapy related toxicity to ≤ Grade 1 at study 
entry (except for stable sensory neuropathy ≤Grade 2 and alopecia)
Test product(s):
Xentuzumab (BI 836845) in combination with afatinib
dose:
Xentuzumab (BI 836845) 1000 mg  with 30 mg afatinib (starting dose level)
mode of admin.:
Xentuzumab (BI 836845): Intravenous infusion over 60 minutes/ afatinib: Once daily 
oral dosing
Comparator products:
NA
dose:
NA
mode of admin.:
NA


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
N.A.
Name of active ingredient:
Xentuzumab (BI 836845)
Protocol date:
Trial number:
Revision date:
02 Nov 2016
28 Mar 2014
1280.16
Duration of treatment: Continuous treatment until disease progression, intolerable adverse events (AEs), 
consent withdrawal or non-compliance with the study protocol
Criteria for efficacy: 
Primary endpoint (for Part B)

Objective response  (OR), defined as complete response (CR) or partial response 
(PR) according to RECIST v1.1
Secondary endpoints (for Part B)

Disease control, defined as complete response (CR), partial response (PR) or 
stable disease (SD) 

Time to objective response, defined as the duration of time from the date of first 
treatment administration until objective response 

Duration of objective response, defined as the duration of time from objective 
response to the date of first objective tumour progression or death due to any 
cause
 
 
 
Criteria for safety:

MTD of Xentuzumab (BI 836845) in combination with afatinib (primary 
endpoint for Part A only)

Dose limiting toxicity (DLT) during the first treatment course (primary endpoint 
for Part A only)

Adverse Events (AEs) according to Common Terminology Criteria (CTCAE 
version 4.03), physical examination, vital signs, ECOG performance score, safety 
laboratory parameters, electrocardiogram (ECG), and Left Ventricular Ejection 
Fraction (LEVF)
Statistical methods:
Descriptive and exploratory analyses


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FLOW CHART 
Refer to Part A and Part B
Study Periods
Scree
ning
Treatment courses**
FU ****
OP 
*****
SCR
*
Course 1
Couse 2 Onwards
Visit
1
2
3
4
1
2
3
4
EOT
***
FU1
FU2
–
FUn
Days
-42    
to -1
1
8
(±2)
15
(±2)
22
(±2)
1
(±2)
8
(±2)
15
(±2)
22
(±2)
Every 
90 
(±15)
Informed consent1
X
Demographics
X
Medical history
X
In- /Exclusion criteria 
(eligibility)
X2
X2
Physical examination3
X
X
X
X
X
Body height
X
ECOG performance score
X
X
X
X
X
Vital signs4
X
X
X
X
X
X
X
X
X
X
X
Body weight
X
X
X
X
X
12 lead –ECG5
X
X
X
X
X
Left ventricular
ejection fraction6
X
Safety lab parameters
7
X
X
X
X
X
X
X
X
X
Urinalysis
8
X
X
Pregnancy test
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X9
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X10
Tumour assessment by 
RECIST v1.1
11
X
X
X
X
Tumour biopsy12
X
X12
 
 
 
 
 
Medication diary card 
dispense18
X
X
X
X
X
Afatinib compliance check
X
X
X
X
X
X
X
X
BI836845 i.v. 
administrationweekly
X
X
X
X
X 
X 
X
X
Afatinib administration 
20daily
Continuous daily administration.


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Study Periods
Scree
ning
Treatment courses**
FU ****
OP 
*****
SCR
*
Course 1
Couse 2 Onwards
Visit
1
2
3
4
1
2
3
4
EOT
***
FU1
FU2
–
FUn
Days
-42    
to -1
1
8
(±2)
15
(±2)
22
(±2)
1
(±2)
8
(±2)
15
(±2)
22
(±2)
Every 
90 
(±15)
Dispense afatinib
X
X
Termination of trial 
medication
X
Conclusion of Patient 
Participation21
X
X
Patient status (Part B)
X22
*Screening visit should be performed within 42 days prior to first drug administration. Safety lab at the screening assessment 
can serve as the C1/V1 assessment if performed within 72 hours before the first treatment and does not need to be repeated.
**A treatment course consists of 28 days and will be repeated until tumour progression (according to RECIST v1.1) 
confirmed by tumour imaging.
*** End Of Treatment (EOT) visit must be performed within 14 days of the last administration of study drug, i.e. both 
Xentuzumab (BI 836845) and afatinib. If last administration of the study drug occurs during a scheduled visit, examinations 
as defined for EOT should be performed instead of examinations for the scheduled visit.
****First Follow-up (FU) visit 42 calendar days (up to +7 days) after the last administration of study drug for all patients (part 
A and part B). Additional FU visits (only for patients who discontinue not due to progressive disease) at 8-week intervals 
until progression, lost to follow-up or initiation of other anti-cancer treatment.
*****Observation period only for part B. For details see Section 6.2.3.3.
1Written informed consent must be obtained before any trial specific screening assessments are performed.
2In/Exclusion criteria must be checked at screening and ensured before study medication has been firstly administered.
3 Physical examination: includes cardiopulmonary examination, examination of the regional lymph nodes, and examination 
of the abdomen and an assessment of the mental and neurological status.
4Vital signs: include pulse, temperature and blood pressure.
5 ECG to be performed at Screening/ pre-infusion, during infusion (after 30±5 mins) and immediately prior to the end of the 
infusion (-10 mins) on Day 1 of Course 1/ a single ECG to be taken on Day 15 of Course 1/ thereafter a single ECG to be 
taken pre-infusion at the start of every course on Day 1, and also at EOTV.
6MUGA scan or echocardiogram not older than 28 days prior to start of treatment. Further scans may be performed post 
treatment if clinically indicated
7Haematology, biochemistry and coagulation parameters. Safety labs may be collected up to two days prior to the scheduled 
time points. Safety lab result at course 1 visit 1 should be reviewed by investigator before first administration of study 
medications. From course 2 onwards, safety lab assessment will be done at visit 1 and 3 of each course. For details see 
Section 5.2.3.
8Urinalysis (Dipstick).
9 For observation period (after the patient completed last follow-up and when progression occurred or when new anti-cancer 
therapy started), the investigator may report SAE if she/he becomes aware of and considers relevant. 
10During Follow-up, concomitant therapy only needs to be recorded if indicated for the treatment of an AE.
11Tumour assessment will be performed every 4 weeks after start of treatment with Xentuzumab (BI 836845) and afatinib for 
first 8 weeks (prior to courses 2 and 3 ), in 8-week intervals thereafter (e.g. prior to courses 5, 7, 9, etc.) and in 12-week 
interval after course 16 until PD or start of further anti-cancer treatment. It should include CT scans or MRI. CT images not 
older than 30 days at start of treatment will suffice as screening images and don’t have to be repeated. The EOT tumour 
assessment is optional if performed in the previous 4 weeks. Imaging may be performed within 7 days of scheduled time 
point. Additional imaging follow up will be required for patients who discontinued not due to progressive disease at 8-week 
intervals until progression, lost to follow-up or initiation of other anti-cancer treatment.
12Tissue biopsies to determine EGFR mutations and other relevant pathways at study entry and following progression may 
be obtained after obtaining informed consent. (Optional at the time of progression) In case there is a documented result of 
EGFR mutations available before study entry for Part A, local result is acceptable. For Part B, tumour sample provision to 
central laboratory is mandatory for confirmation of the result. Prior to any biopsy, patients must have controlled hematology 
parameters (INR and PTT within normal range) and platelet count (≥100,000 /μL). See Section 4.2.2 for restriction of 


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antiplatelet and anticoagulant medications. For tissue biopsy at the time of progression after study treatments, separate 
informed consent must be obtained.
 
 
 
 
18Part A: afatinib intake starting from Course 1 Day 8 up to Course 2 Day 1 and Course 3 Day 1 must be recorded in the 
patient diary and it should be dispensed to the patient on Day 1, 8, 15 and  22 of Course 1and Day 22 of Course 2.            
Part B: afatinib intake from Course 2 Day 1 and Course 3 Day 1 must be recorded in the patient diary and the diary card 
should be dispensed to patient on Day 22 of Course 1 and Day 22 of Course 2. 
Completed diary card should be returned from the patient at next visit. 
Afatinib treatment oral continuous daily administration. Patients should take the study medication at the same time every 
day to ensure a dose interval of approximately 24 hours. 
21Refer to Section 6.2.3.
22 All patients in Part B will be followed-up for overall survival at 3 monthly intervals (90±15 days) after the last follow-up 
visit. For details see Section 6.2.3.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................6
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS.......................................................................................... 14
1.
INTRODUCTION.................................................................................... 16
1.1
MEDICAL BACKGROUND............................................................................16
1.2
DRUG PROFILE...............................................................................................18
1.2.1
Xentuzumab (BI 836845)......................................................................18
1.2.2
Afatinib ..................................................................................................21
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 23
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................23
2.2
TRIAL OBJECTIVES.......................................................................................25
2.2.1
Primary objectives ................................................................................25
2.2.2
Secondary objectives.............................................................................25
2.3
BENEFIT - RISK ASSESSMENT ...................................................................25
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 27
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................27
3.1.1
Administrative structure of the trial...................................................28
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................29
3.3
SELECTION OF TRIAL POPULATION ......................................................30
3.3.1
Main diagnosis for study entry............................................................30
3.3.2
Inclusion criteria...................................................................................30
3.3.3
Exclusion criteria ..................................................................................32
3.3.4
Removal of patients from therapy or assessments.............................33
3.3.4.1
Removal of individual patients................................................33
3.3.4.2
Discontinuation of the trial by the sponsor..............................34
3.3.4.3
Replacement of patients...........................................................35
4.
TREATMENTS........................................................................................ 36
4.1
TREATMENTS TO BE ADMINISTERED....................................................36
4.1.1
Identity of BI investigational product and comparator product......36
4.1.1.1
Xentuzumab (BI 836845) (investigational product)................36
4.1.1.2
Afatinib (investigational product)............................................36
4.1.2
Method of assigning patients to treatment groups ............................37
4.1.2.1
The dose confirmation Part A..................................................37


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4.1.2.2
The expansion Part B...............................................................37
4.1.3
Selection of doses in the trial................................................................37
4.1.3.1
Planned dose levels in the Part A.............................................37
4.1.3.2
Part B – dosing schedule..........................................................39
4.1.4
Drug assignment and administration of doses for each patient .......39
4.1.4.1
Initial study drug assignment and administration....................39
4.1.4.1.1 Xentuzumab (BI 836845)........................................................40
4.1.4.1.2 Afatinib....................................................................................40
4.1.4.2
Additional course of treatment.................................................41
4.1.4.3
Temporary treatment interruption and dose reduction.............41
4.1.5
Blinding and procedures for unblinding ............................................44
4.1.5.1
Blinding....................................................................................44
4.1.5.2
Procedures for emergency unblinding .....................................44
4.1.6
Packaging, labelling, and re-supply ....................................................44
4.1.7
Storage conditions.................................................................................45
4.1.7.1
Afatinib ....................................................................................45
4.1.7.2
Xentuzumab (BI 836845) ........................................................45
4.1.8
Drug accountability ..............................................................................45
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................46
4.2.1
Rescue medication, emergency procedures, and additional 
treatment................................................................................................46
4.2.2
Restrictions............................................................................................48
4.2.2.1
Restrictions regarding concomitant treatment .........................48
4.2.2.2
Restrictions on diet and life style.............................................48
4.2.2.3
Women of Child-Bearing Potential and Pregnancy Prevention
..................................................................................................48
4.2.3
Management of expected adverse events ............................................49
4.2.3.1
Management of diarrhoea and hydration status.......................49
4.2.3.2
Management recommendations for dermatological AEs.........50
4.2.3.3
Management of mucositis/stomatitis .......................................54
4.2.3.4
Management and grading of infusion reactions.......................55
4.2.3.5
Management of hyperglycemia................................................56
4.3
TREATMENT COMPLIANCE.......................................................................56
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 57
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................57
5.1.1
Endpoints  of efficacy (anti-tumour activity) .....................................57
5.1.1.1
Dose confirmation Part A ........................................................57
5.1.1.2
Expansion Part B......................................................................57
5.1.2
Assessment of efficacy...........................................................................57
5.2
SAFETY..............................................................................................................58
5.2.1
Endpoints of safety................................................................................58
5.2.1.1
Dose confirmation Part A ........................................................58


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5.2.1.2
Expansion Part B......................................................................58
5.2.2
Assessment of adverse events...............................................................58
5.2.2.1
Definitions of adverse events...................................................58
5.2.2.2
Adverse event and serious adverse event reporting.................60
5.2.3
Assessment of safety laboratory parameters......................................62
5.2.4
Electrocardiogram................................................................................63
5.2.5
Assessment of other safety parameters...............................................64
5.2.5.1
Physical examination, vital signs, height and weight ..............64
5.2.5.2
Left ventricular fraction...........................................................64
5.2.6
Dose Limiting Toxicity .........................................................................64
5.2.7
Maximum Tolerated Dose and recommended phase II dose............65
5.3
OTHER...............................................................................................................66
5.3.4
Demographics and medical history.....................................................67
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................68
 
6.
INVESTIGATIONAL PLAN.................................................................. 72
6.1
VISIT SCHEDULE............................................................................................72
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................72
6.2.1
Screening period....................................................................................72
6.2.2
Treatment period ..................................................................................73
6.2.3
End of trial and follow-up period........................................................73
6.2.3.1
End of treatment visit...............................................................73
6.2.3.2
Follow-up.................................................................................74
6.2.3.3  Observation period ....................................................................74
6.2.3.4
Patient completion ...................................................................75
6.2.3.5  End of whole Trial.....................................................................75


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 76
7.1
STATISTICAL DESIGN – MODEL ...............................................................76
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................76
7.3
PLANNED ANALYSES....................................................................................76
7.3.1
Primary analyses...................................................................................76
7.3.1.1
Part A .......................................................................................76
7.3.1.2
Part B .......................................................................................77
7.3.2
Secondary analyses ...............................................................................77
7.3.3
Safety analyses.......................................................................................77
7.3.4
Interim analyses ....................................................................................77
7.4
HANDLING OF MISSING DATA ..................................................................79
7.5
RANDOMISATION ..........................................................................................80
7.6
DETERMINATION OF SAMPLE SIZE ........................................................80
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 81
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................81
8.2
DATA QUALITY ASSURANCE .....................................................................81
8.3
RECORDS..........................................................................................................82
8.3.1
Source documents .................................................................................82
8.3.2
Direct access to source data and documents.......................................82
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................82
8.4.1
Listedness...............................................................................................82
8.4.2
Expedited reporting to health authorities and IECs/IRBs................82
8.5
STATEMENT OF CONFIDENTIALITY.......................................................83
9.
REFERENCES......................................................................................... 84
9.1
PUBLISHED REFERENCES...........................................................................84
9.2
UNPUBLISHED REFERENCES.....................................................................89
10. APPENDICES .......................................................................................... 90
10.1
LIST OF POTENT INHIBITORS AND INDUCERS OF P-
GLYCOPROTEIN.............................................................................................90
10.2
COCKCROFT-GAULT FORMULA ..............................................................91
10.3
NYHA CLASSIFICATION OF HEART FAILURE......................................92
10.4
ECOG PERFORMANCE STATUS.................................................................92


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10.5
RECIST (VERSION 1.1)...................................................................................93
10.6
CLINICAL EVALUATION OF LIVER INJURY .........................................96
10.6.1 Introduction...........................................................................................96
10.6.2 Procedures .............................................................................................97
11. DESCRIPTION OF GLOBAL AMENDMENTS............................... 103


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ABBREVIATIONS
AE
AESI
ALT (SGPT)
AST (SGOT)
Adverse Event
Adverse Event of Special Interest
Alanine amino Transferase (Serum Glutamate Pyruvate Transaminase)
Aspartate amino Transferase (Serum Glutamic Oxaloacetic Transaminase)
BI
Boehringer Ingelheim
CI
CM
Confidence Interval
Clinical Monitor
CML
CR
Local Clinical Monitor 
Complete Response
CRA
Clinical Research Associate
CRF
CRO
Case Report Form
Contract Research Organization
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
DILI
DLT
Clinical Trial Report
Drug-Induced Liver Injury
Dose Limiting Toxicity
DMC
Data Monitoring Committee
eCRF
Electronic Case Report Form
ECG
EDC
ECHO
ECOG
EGFR
EOTV
Electrocardiogram
Echocardiogram
Electronic Data Capture
Eastern Cooperative Oncology Group
Epidermal Growth Factor Receptor
End of Treatment Visit
EudraCT
HER2
European Clinical Trials Database
Human Epidermal growth factor Receptor 2
FAS
FDA
Full Analysis Set
Food and Drug Administration
GCP
Good Clinical Practice
HPC
Human Pharmacology Centre
IB
Investigator’s Brochure
IEC
ILD
Independent Ethics Committee
Interstitial Lung Disease
IRB
Institutional Review Board
IGF
IGF-1R
IGF-1
IGF-2
IGFBP
INR
Insulin-like Growth Factor
Insulin-like Growth Factor -1 Receptor
Insulin-like Growth Factor 1
Insulin-like Growth Factor 2
Insulin Growth Factor Binding Protein
International Normalized Ratio


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IRB
IRT
ISF
Institutional Review Board
Interactive Response Technologies
Investigator Site File
i.v.
LVEF
mAb
Intravenous
Left Ventricular Ejection Fraction
Monoclonal Antibody
MedDRA
Medical Dictionary for Drug Regulatory Activities
MST
MTD
MUGA
NSCLC
Medical Subteam
Maximum Tolerated Dose
Multiple Gated Acquisition
Non Small Cell Lung Cancer
OPU
OS
Operative Unit
Overall Survival
p.o.
per os (oral)
PCC
P-gp
PR
Protocol Challenge Committee
P-glycoprotein
Partical Response
q.d.
RDC
RECIST
RP2D
quaque die (once a day)
Remote Data Capture
Response Evaluation Criteria in Solid Tumours
Recommended Phase II Dose
SAE
Serious Adverse Event
s.c.
SD
SOPs
Subcutaneous
Stable Disease
Standard Operating Procedures
SPC
Summary of Product Characteristics
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
t.i.d.
TK
TKI
TMF
ter in die (3 times a day)
Tyrosine Kinase
Tyrosine Kinase Inhibitor
Trial Master File
TMM
Team Member Medicine
TMW
Trial Medical Writer
TSAP
ULN
Trial Statistical Analysis Plan
Upper Limit of Normal


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
The epidermal growth factor receptor (EGFR) is a membrane-bound receptor tyrosine kinase 
that belongs to a subfamily of four closely related receptors: HER1/EGFR/ERBB1, HER2/ 
ERBB2, HER3/ERBB3, and HER4/ERBB4. EGFR tyrosine kinase (TK) mutations can be 
found in about 10% of Caucasian patients with non-small cell lung cancer (NSCLC) and 
about 40–50% in East Asian patients with NSCLC. EGFR mutant NSCLC is a special type of 
lung cancer with distinct biology (P11-11496). EGFR mutation is a “driver” mutation 
because mutation of EGFR TK results in constitutional kinase activation and is oncogenic 
(R14-1169). It has been suggested that transformed lung cancer cells are dependent on EGFR 
activation and its downstream signalling related to proliferation and survival, a phenomenon 
called oncogene addiction (R14-1169). As a consequence, apoptosis is inhibited. Application 
of selective EGFR tyrosine kinase inhibitor (TKI) to EGFR mutant tumours abruptly breaks
this balance and makes tumours regress through apoptosis, a phenomenon called oncogenic 
shock (R14-1169).
Exon 19 deletion (LREA deletion) and exon 21 L858R substitution are the two most common 
EGFR mutations in NSCLC. These two so-called common mutations attribute to more than 
85% of EGFR mutations and are sensitive to selective EGFR TKIs (P13-03214). There are 
other less common EGFR mutations, such as G719X, L861X, T790M, and exon 20 insertion. 
Among these uncommon mutations G719X and L861X are sensitive to EGFR TKIs (P11-
11496, P13-03214, R13-4230, R10-0095).
With almost one decade of intensive clinical investigations, mono therapy with EGFR TKIs 
has been established as standard first-line treatment for advanced EGFR mutant NSCLC. As 
of 2013, there are three EGFR TKIs approved for the first-line treatment of EGFR mutant 
NSCLC (R09-4437, R12-1015, P13-07382). Compared to chemotherapy, first-line EGFR 
TKI treatment provides a marked clinical benefit with response rates of about 60–70% and a 
progression-free survival of about 9–13 months in patients with common EGFR mutations 
(R09-4437, R12-1015, P13-07382).
Despite an initial response or disease stabilization to first-line EGFR TKIs, patients will 
invariably develop acquired resistance (P11-11496). It is crucial to understand the 
mechanisms of resistance in order to prolong the clinical benefit in patients with EGFR 
mutant lung cancer. Several mechanisms have been identified in clinical or non-clinical 
studies (R12-5206, P13-03214, P14-00839, P14-04205). After exclusion of factors such as 
drug-drug interactions and suboptimal drug exposure (pharmacokinetic reasons or the blood-
brain barrier), the most common mechanism for acquired resistance is the development of 
secondary mutations in EGFR. EGFR T790M alone is responsible for 50–60% of acquired 
resistance (P14-00839, P13-03214, R12-5206). Other mechanisms of resistance include 
alternative pathway activation (e.g. c-MET in 5–10%, PIK3CA in ~5%, ~1% BRAF) and 
histological transformation. The molecular basis of about 30–40% of acquired resistance 
cases is still unknown. Caution should be exercised because most of the aforemtioned data 
were obtained from patients treated with first generation reversible TKIs (erlotinib and 


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gefitinib). Mechanisms of acquired resistance to irreversible EGFR TKIs (e.g. afatinib, 
dacomitinib, AZD 9291) are poorly characterized thus far.
Therefore, the current strategy to overcome acquired resistance to EGFR inhibitors may be 
divided to T790M-directed and non-T790M-directed. To effectively develop treatments for 
acquired resistance, the importance of tumour biopsies cannot be overestimated (R12-5206, 
P14-00839). Two EGFR wild-type sparing and T790M-specific irreversible TKIs, i.e. AZD 
9291 and CO-1686, are currently under clinical investigations. According to preliminary 
phase I results of AZD 9291, there were 7 partial responses out of 12 patients with EGFR 
T790M (R14-1166). In contrast, so far there is no such promising molecular-targeted therapy 
for non-T790M acquired resistance. Indeed, many targeted therapies are under investigation, 
e.g. heat shock protein inhibitor, mTOR inhibitor, c-MET inhibitor, and dual targeting of the 
EGFR by combining an antibody and a TKI. Although chemotherapy added to an EGFR TKI 
could provide benefit to patients with acquired resistance (R14-1167), it is desirable to 
develop mechanism-based therapies with a favourable safety profile. 
The insulin-like growth factor (IGF) pathway holds a crucial role in cell growth, 
differentiation and proliferation. The insulin-like growth factor family encompasses three 
ligands, IGF-1, IGF-2, insulin; their corresponding receptors IGF-1 receptor (IGF-1R), IGF-2 
receptor (IGF-2R), Insulin-Receptor (InsR) (two isoforms: InsR-A and InsR-B); as well as 
six, IGF-binding proteins (IGFBP1-6) and IGFBP degrading enzymes known as proteases 
(R13-2052, P13-05658). Activation of IGF-1R triggers a cascade of reactions involving two 
main signal transduction pathways: the Ras–Raf–mitogen-activated protein kinase (MAPK) 
network and the phosphatidylinositol 3-kinase (PI3K)–Akt–mTOR pathway.
Among various non-T790M mechanisms, IGF signalling pathway has been implicated in the 
acquired resistance to EGFR TKIs (R12-5206, P14-00839, R14-1168). However, thus far, 
there is no clear evidence derived from a clinical study. Cortot et al. established a resistant 
cell line by incubating PC9 cells, which harbor exon 19 deletions, in high concentration of 
irreversible EGFR TKI or T790M selective TKI. IGF-1R activation was noted in this 
resistant cell line though T790M was not identified. The growth of the IGF-1R activated 
resistant cells can be effectively inhibited by treatment with an IGF-1R blocker. Interestingly, 
the preemptive combination of an EGFR TKI and an IGF-1R blocker prevented the 
emergence of resistant cells (R14-1168). 
Taken collectively, it is conceivable that there is a subset of patients with non-T790M 
acquired resistance who could potentially be identified with a predictive biomarker and 
whose disease may be controlled by the administration of an IGF pathway inhibitor such as 
Xentuzumab (BI 836845). This clinical trial is therefore aiming to investigate the safety and 
efficacy of an IGF ligand antibody (Xentuzumab (BI 836845)) in combination with an EGFR 
TKI (afatinib) in patients previously treated with reversible or irreversible EGFR TKIs. The 
mechanism of acquired resistance to irreversible TKI will be explored in this study as well.


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1.2
DRUG PROFILE
1.2.1
Xentuzumab (BI 836845)
Xentuzumab (BI 836845) is a fully human monoclonal antibody of the IgG1 isotype that 
binds to human insulin-like growth factor-1 and insulin-like growth factor-2 and thereby 
neutralizes the growth-promoting activities of IGF-1 and IGF-2.
 
 
 
 
Xentuzumab (BI 836845) binds with high affinity to IGF-1 and IGF-2, and potently 
neutralizes proliferative and prosurvival cellular signalling triggered by both proteins. The 
mode of action of Xentuzumab (BI 836845) is different from IGF-1 receptor targeted mAbs. 
In particular, Xentuzumab (BI 836845) can inhibit IGF-2 stimulated Insulin Receptor-A 
(InsR-A) activation, which is an additional proliferative and prosurvival pathway not blocked 
by IGF-1R targeted mAbs (U10-2830). In addition, by sparing InsR-B and its hybrid 
receptors, Xentuzumab (BI 836845) may achieve anti-tumour activity without perturbing 
glucose homeostasis. 
Preclinical studies showed that Xentuzumab (BI 836845) treatment inhibited the rapamycin-
induced feedback phosphorylation of AKT in PI3K-AKT-mTOR pathway. Similarly, 
rapamycin resulted in an increase in the IGF bioactivity (IGF-1R phosphorylation potential) 
of mouse serum, which could be inhibited by Xentuzumab (BI 836845) (P13-16103).
 
 
 
 
 
 
 


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Expansion cohorts in two phase I studies with Xentuzumab (BI 836845) monotherapy given 
weekly or every three weeks are currently ongoing in patients with advanced solid tumours. 
These studies are intended to determine the safety, maximum tolerated dose and/ or relevant 
biological dose, pharmacokinetics (PK) and PK/pharmacodynamic (PD) correlation. 
Preliminary interim data from these trials indicate that maximum plasma concentrations of 
Xentuzumab (BI 836845) are reached at the end of the infusion or shortly thereafter. After 
reaching the peak, plasma concentrations showed an at least biphasic decay with a terminal 
half-life of about 6 days. The estimated volume of distribution was about 5.8 L (approx. two 
times the plasma volume) and the total plasma clearance was about 0.5 mL/min. 
 
 
No deviations from dose-proportional pharmacokinetics have been observed in the dose 
range analyzed (10-1050 mg q1w in 1280.1 and 10-3600 mg q3w in 1280.2). Steady state 
plasma concentrations of Xentuzumab (BI 836845) were achieved after 5-7 weeks. Repeated 
weekly dosing resulted in about 1.5 fold accumulation of Xentuzumab (BI 836845) plasma 
concentration at steady state, while only limited accumulation was observed after repeated 
infusions every three weeks. 


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It is known that human IgGs like Xentuzumab (BI 836845) are mainly cleared by catabolism. 
This mechanism of clearance is not shared or overlapping with the clearance mechanism for 
small molecules. Thus, Xentuzumab (BI 836845) is not predicted to directly affect the 
hepatic, renal, or biliary elimination of small molecules. Furthermore, Xentuzumab (BI 
836845) is not targeting cytokines, and mAbs targeting upstream IGFs have not been related 
to modulation of CYP450 isozymes or drug transporters (P13-02270). Hence, the potential of 
Xentuzumab (BI 836845) to alter the pharmacokinetics of co-medication is considered low. 
Xentuzumab (BI 836845) has been formulated for i.v. infusion and will be provided as a 
liquid formulation. The appropriate dose of Xentuzumab (BI 836845) should be diluted in 
physiological sodium chloride solution (0.9%) prior to intravenous administration. 
As of Jul 10, 2013, 48 and 33 patients have been dosed in 1280.1 and 1280.2 trial using 
weekly and every three-week schedule, respectively. Among these two trials, only one dose 
limiting toxicity (DLT), a pulmonary haemorrhage, was observed at 450 mg (in the trial using 
weekly schedule), which was considered drug-related by the investigator. Consequently, 3 
additional patients were dosed at this level for a total of 6 patients, no additional DLT was 
observed. Four subjects in study 1280.1 discontinued treatment due to non drug-related AEs. 
A CTCAE grade 3 hyponatraemia (syndrome of inappropriate antidiuretic hormone secretion 
– SIADH) occurred in a single patient in the 3600 mg q3w cohort. As there is no connection 
to the mechanism of action of Xentuzumab (BI 836845), an alternative explanation may have 
been an underlying paraneoplastic syndrome. However, consequently, investigator should 
carefully monitor electroytes and excretion under treatment with Xentuzumab (BI 836845).
Dose escalation to 1800 mg weekly or 3600 mg q3w did not identify a maximum-tolerated 
dose (MTD).
Based on toxicity studies the side effects expected with Xentuzumab (BI 836845) are 
possibly abnormal liver function test and changes in haematological parameters (reduced 
white and red blood cells). However, abnormal liver function tests as well as anaemia and 
decreased white blood cells were only infrequently observed in the 81 patients treated thus far 
in Phase I and generally of low grade (Grade 1 and 2). 
Infusion reactions have not been observed. Metabolic AEs involving perturbed glucose 
homeostasis, among the most common toxicities documented for IGF-1R-targeting mAbs and 
small molecule TKIs, were observed at low frequencies: Two out of 81 subjects reported 
transient hyperglycemia; 1 patient (Grade 2) in 1280.1 and 1 patient (Grade 3) in 1280.2.
Of note, two confirmed partial responses (PR) have been reported in the weekly schedule 
trial; firstly, in a 
-year old 
 with a recurrent nasopharyngeal carcinoma (NPC) and 
multiple lung metastases after concurrent chemoradiotherapy; secondly, in a 
-year old 
 with a peripheral primitive neuroectodermal tumour (pPNET). In addition, 12 (25%) 
and 4 (12.1%) patients with confirmed stable diseases were reported in study 1280.1 and 
1280.2, respectively.


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Full details of the clinical pharmacology, toxicology, clinical pharmacokinetics and safety 
data can be found in the current Investigator Brochure for Xentuzumab (BI 836845) (U10-
2830).
1.2.2
Afatinib
For the latest information on the drug profile of afatinib, please refer to the current 
Investigator’s Brochure (IB) (U03-3218).  All references in this protocol concerning afatinib 
refer to the free base compound afatinib BI which is used as the oral formulation.  
Afatinib (BIBW2992) is a small molecule, selective and irreversible ErbB family blocker. In 
preclinical models it effectively inhibits EGFR (ErbB1), HER2 (ErbB2) and HER4 (ErbB4) 
phosphorylation resulting in tumour growth inhibition and regression of established 
subcutaneous tumours derived from four human cell-lines known to co-express ErbB 
receptors. Afatinib is under regulatory review for treatment of patients with EGFR mutation-
positive NSCLC and has already been approved for first-line use in the USA, the EU, 
Taiwan, Korea, Singapore and other countries. Afatinib is also in clinical development as a 
therapy for several other ErbB-driven cancers.
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. 
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. 


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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 
(U03-3218 and P12-14433). Adverse events (AE) observed with afatinib are consistent with 
those reported for other EGFR and dual EGFR/HER2 inhibitors. The most frequent 
investigator defined drug-related AEs were associated with gastrointestinal disorders 
(including diarrhoea, and stomatitis), skin and subcutaneous tissue disorders (rash, dry skin, 
pruritus, acneiform rash, acne), nail effects, epistaxis, fatigue and decreased appetite. Early 
and proactive management of diarrhoea, mucositis/stomatitis and skin rash together with 
treatment interruptions and dose reductions is recommended in line with recent guidelines in 
the management of common toxicities of EGFR and EGFR/HER2 TKIs and monoclonal 
antibodies (R07-4077, P07-11507, R07-4078, P13-03658 and P13-03659).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Somatic mutations in exons encoding the tyrosine kinase (TK) domain of the epidermal 
growth factor receptor (EGFR) are positively associated with increased sensitivity of non-
small cell lung cancer (NSCLC) patients to the selective EGFR TK inhibitors (TKIs), 
gefitinib (IressaTM) and erlotinib (TarcevaTM) (R04-4507, R04-4508, R06-1259). Prospective 
trials have demonstrated an impressive ~75% response rate for patients whose tumours 
harbor these mutations (R06-1403, R09-4439), which occur as either multinucleotide in-
frame deletions in exon 19 (e.g., delE746-A750) or as single missense mutations (e.g., 
L858R). Unfortunately, the EGFR TKI-driven improvement in patient outcome is only 
limited because virtually all NSCLC patients with erlotinib/gefitinib-sensitizing EGFR 
mutations eventually acquire resistance after a median of 6–12 months of EGFR TKI therapy 
and eventually succumb to their disease (R06-1403, R06-1311). In approximately half of 
cases, the tumour cells present after disease progression contain second-site mutations that 
alter drug binding to the EGFR TK domain. The most common lesion (>90%) is the so-called 
“gatekeeper mutation”, which involves a substitution of methionine for threonine at position 
790 (T790M).
More recently, in addition to other second-site mutations associated with acquired resistance 
to EGFR TKIs (e.g., L747S and D761Y in exon 19 or T854A in exon 21), novel EGFR-
independent mechanisms have been discovered that contribute to EGFR TKI resistance, 
either in the absence or presence of the EGFR T790M mutation (R11-4674, P09-09950).
Another such mechanism of gefitinib/erlotinib resistance is the MET receptor tyrosine kinase 
(RTK) gene amplification: “oncogene kinase switch”. EGFR T790M and MET amplification, 
which can be detected in up to 20% of EGFR NSCLCs with acquired resistance to EGFR 
TKIs, account for approximately 60–70% of all known causes of acquired resistance to 
gefitinib/erlotinib. Consequently, ongoing research is attempting to identify the mechanisms 
that may account for the 30–40% of EGFR TKI-resistant, EGFR-mutated tumours that do not 
carry EGFR mutations or MET amplification. Another possible kinase switch mechanism 
could involve hyperactivity of the IGF/IGF-1R system. Although increased activation of 
insulin-like growth factor-1 receptor (IGF-1R) through IGF overexpression, the loss of IGF-
binding proteins and loss or reduction of the tumour suppressor PTEN have been associated 
with acquired resistance to EGFR TKIs in laboratory models (R09-1568, R14-1339, R14-
1338), this hypothesis has not yet been tested in a clinical trial with EGFR TKI-resistant 
patients.
IGF pathway signalling is important in many physiological functions and also in 
carcinogenesis. IGF pathway signalling shares some downstream effector pathways and 
biological functions with EGFR signalling. Several evidences show there is a signalling
cross-talk between IGF-1R and EGFR; this cross-talk may be involved in a compensatory 
mechanism. Along this line, several non-clinical reports have shown that the IGF pathway is 
involved in the resistance to EGFR targeted therapy in EGFR mutant NSCLC (P09-09950, 
R14-1173, R14-1172, R14-1168, R14-1171). For instance, as described in Section 1.1, IGF 


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pathway activation has been reported to be responsible for acquired resistance to irreversible 
EGFR TKIs in an EGFR mutant cell line (R14-1168). It is therefore conceivable that the 
addition of an IGF signalling inhibitor to an EGFR TKI can overcome drug resistance to an 
EGFR TKI alone. So far, there is no evidence that IGF signalling plays an important role in 
the development of resistance in the presence of EGFR T790M. This subset of patients may 
rather fall in the category of acquired resistance without T790M. Nevertheless, no clinical 
trial has tested this concept until now. 
To test this hypothesis, an EGFR TKI, afatinib, will be continued in this resistant setting. It is
assumed that once IGF-mediated resistance is controlled by the IGF antibody Xentuzumab 
(BI 836845), afatinib will still inhibit EGFR-addicted cells in the absence of T790M
mediated drug resistance. This strategy is supported by the results of Cortot et al., showing 
that the combination of an IGF-1R TKI and an EGFR TKI achieved better inhibition of 
downstream phospho-Akt and phospho-ERK (R14-1168). 
To date, several studies using an IGF-1R antibody (R-1507 or cixutumumab) in combination 
with an EGFR TKI (erlotinib) reported disappointing results in patients with NSCLC. The 
main reasons were a lack of a predictive biomarker for patient selection and an unfavourable
safety profile stemming from the receptor-targeting approach (R13-0059, R12-5650, R16-
4930). At present, there is no IGF ligand antibody, with a potentially more favourable safety
profile, under clinical investigation in EGFR mutant NSCLC. 
Afatinib has been studied in an EGFR-TKI pretreated setting and shown encouraging efficacy
results. In patients who met Jackman’s criteria of acquired resistance, the PFS was 4.5 
months in afatinib group and 1.0 month in the placebo group (P12-03682). 
Xentuzumab (BI 836845) has been investigated in two phase I studies, with expansion 
cohorts till ongoing. A favourable safety profile without the typical class side-effects of IGF-
1R-targeted agents (antibodies or TKIs) has been observed. Moreover, a preliminary efficacy 
signal was noted with two partial responders and several disease stabilizations (U10-2830). 
Taken collectively, these studies suggest that co-targeting the IGF and EGFR pathways with 
Xentuzumab (BI 836845) and afatinib may offer synergistic therapeutic benefits for EGFR 
mutant NSCLC.
Since the mechanism of acquired resistance to irreversible EGFR TKI is largely unknown, a 
better molecular characterization could improve the selection of treatment for individual 
patients. Consequently, in addition to tumour biopsies, circulating free DNA (so-called liquid 
biopsies) will be collected to support the investigation of unknown resistance pathways and 
to identify candidate predictive biomarkers for future patient enrichment.
This clinical trial is intended as a pilot study before a larger, randomized proof-of-clinical-
concept study. The purpose is 1) to establish an acceptable safety profile as well as a 
recommended Phase II dose for the combination of Xentuzumab (BI 836845) and afatinib 
and 2) to identify an initial efficacy signal before embarking on a larger and broader clinical 
development in other EGFR mutant cancer indications.


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2.2
TRIAL OBJECTIVES
The overall objective of this trial is to evaluate the safety and anti-tumour activity of 
Xentuzumab (BI 836845) combined with afatinib in patients with EGFR mutant lung cancer.
2.2.1
Primary objectives
Part A – Dose confirmation:

To determine the Maximum Tolerated Dose (MTD) and/or Recommended Phase II Dose 
(RP2D) of Xentuzumab (BI 836845) in combination with afatinib in patients with non-
small cell lung cancer with progression following prior treatment (EGFR TKIs or 
platinum-based chemotherapy)
Part B – Expansion cohorts:

To evaluate the early anti-tumour activity of Xentuzumab (BI 836845) in combination 
with afatinib in patients with EGFR mutant non-small cell lung cancer with progression
following prior irreversible EGFR TKIs
2.2.2
Secondary objectives
Part A and Part B:

To evaluate the safety 
 of Xentuzumab (BI 836845) in combination 
with afatinib in patients with non-small cell lung cancer
For details on endpoints and their assessments, see Section 5.
2.3
BENEFIT - RISK ASSESSMENT
Most patients with EGFR mutant NSCLC will develop acquired resistance to EGFR TKI 
despite initial benefit. Consequently, most patients with locally advanced or metastatic 
tumours will succumb to their disease. Thus, there is a substantial need for novel therapeutic 
strategies to improve the outcome for patients with advanced or metastatic EGFR mutant 
NSCLC.
Aberrant ErbB (HER) family expression and signalling contribute to the malignant phenotype 
in many tumour types including squamous cell carcinoma of lung. It is therefore expected 
that treatment with an ErbB family blocker may result in tumour control. Afatinib is a potent, 
irreversible, orally available ErbB family blocker studied in more than 3000 patients to date. 
The combination of afatinib with Xentuzumab (BI 836845) may further improve 
EGFR/ErbB1 target inhibition and overcome acquired resistance to EGFR TKIs.


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Based on toxicological findings and the experience with other EGFR (ErbB1) and HER2
(ErbB2) inhibitors, as well as results from Phase I studies, the risks of anti-EGFR/HER2 
therapy with afatinib primarily consist of gastrointestinal (GI) AEs (including diarrhoea, 
nausea, and vomiting), and skin AEs. Skin and subcutaneous tissue disorders primarily 
consist of erythematous, maculo-papular and papular skin rashes, pruritus, acne, eczema, 
folliculitis, and pustular rash. 
Xentuzumab (BI 836845) has been tested in two separate Phase I clinical trials. As of the 
database cut-off date of July 10, 2013, 81 patients received Xentuzumab (BI 836845)
monotherapy. The AE profile observed has generally been consistent with the underlying 
neoplastic conditions with most AEs being CTCAE grade 1 or 2. As the clinical experience 
with Xentuzumab (BI 836845) is limited, safety will be carefully monitored throughout the 
duration of treatment with Xentuzumab (BI 836845); supportive treatments, and/or dose 
modification/discontinuation of Xentuzumab (BI 836845) will be mandated as necessary.
Although Xentuzumab (BI 836845) is a fully humanised antibody given intravenously, there 
may be a potential for infusion-related reactions and immune responses to occur. Such 
infusion reactions will be graded and treated following standard of care or local guidance.
Out of 81 patients who received Xentuzumab (BI 836845), no infusion reaction has been 
observed (U10-2830). The immune responses to Xentuzumab (BI 836845) mAb will be 
assessed through measurement of anti-drug antibodies in the study.
Because IGF-1R signalling could be a compensatory pathway to EGFR inhibition, and IGF-
1R shares a similar downstream effector pathway, AEs, e.g. cutaneous side effects and 
diarrhoea due to afatinib might be augmented by combining afatinib and Xentuzumab (BI 
836845). Nevertheless, these side effects are not expected to become life-threatening as they 
can be identified early and treated appropriately with comprehensive supportive treatment
and/or interruption or dose adaptation of the study treatment. In this study, detailed 
recommendations on management of expected side effects of afatinib will be provided to 
minimize the intensity and duration of side effects.
Weight loss should be monitored closely. Nutritional consultation may be recommended
early and nutrition support including tube feeding or total parenteral nutrition should be
provided if indicated.
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this study requires timely detection, evaluation, and 
follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients 
safety.
Given the high unmet medical need in NSCLC, the potential benefits to be expected from 
afatinib in combination with Xentuzumab (BI 836845) are likely to outweigh its risks in this
study population.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multi-centre, open-label, phase Ib clinical trial to evaluate the safety, tolerability and 
anti-tumour activity of the combination of Xentuzumab (BI 836845) and afatinib. This trial 
will consist of a dose confirmation part (Part A) and an expansion part (Part B). Part A and 
Part B will be conducted sequentially.
Initially, recruitment in Part A will follow an escalation/de-escalation “3+3” design (R07-
0220) to determine the Maximum Tolerated Dose (MTD) and/or recommended dose for Part 
B of Xentuzumab (BI 836845) in combination with afatinib in patients with NSCLC who 
have had progression following prior treatment (EGFR TKIs or platinum-based 
chemotherapy). The starting dose of afatinib will be one level below the registered dose and 
for Xentuzumab (BI 836845) the current monotherapy RP2D will be used. The safety of the 
RP2D of Xentuzumab (BI 836845) in combination with afatinib will be confirmed in a total 
of 12 patients across. Thus, 6 additional patients will be treated at the MTD/RP2D dose level. 
After conclusion of Part A (determination of RP2D), Part B of the trial will commence in one
expansion cohort to evaluate the safety, tolerability and preliminary anti-tumour activity in 
patients with EGFR mutant non-small cell lung cancer who have progressed on irreversible
EGFR TKIs (e.g. afatinib, dacomitinib). In the expansion cohort,18 additional patients will be
treated.
Patients are enrolled in the study once the informed consent form is signed. The screening 
period will be up to 6 weeks (42 days) during which time the eligibility will be confirmed. In 
order to meet the eligibility criteria regarding EGFR genotypes and/or to characterize 
resistance mechanisms, all patients need to provide archived tumour sample which is 
associated with EGFR TKI (or other treatment in EGFR wild type) resistance or undergo a 
fresh tumour biopsy. In the Part B, the EGFR genotypes must be confirmed by the authorized 
central laboratory. The eligibility criteria will be reconfirmed prior to the first administration 
of study medications. Eligible patients will be treated continuously with the study regimen in 
the absence of disease progression, intolerable adverse events, or other reason necessitating 
withdrawal (refer to Section 3.3.4). The treatment will be administered as courses of 28 days. 
Continued treatment beyond disease progression will not be allowed in the study.
All patients will have regular assessment of safety parameters as detailed in the Flow Chart.
 
Tumour assessment by imaging according to RECIST version 1.1 will be conducted at 
baseline and at fixed time points as specified in the Flow Chart. 
 
 
An End of Treatment (EOT) visit is to be completed when a patient permanently discontinues 
both study drugs, for any reason listed in Section 3.3.4.
 


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The assessments required are listed in the Flow Chart. Patients who permanently discontinue 
both study drugs due to other reason than progressive disease will continue to have tumour 
assessments according to the Flow Chart until disease progression, lost to follow-up or 
initiation of other anti-tumour therapy, whichever occurs first.
A Follow-up visit (FU1) will be completed 42 (+ 7) days after the last administration of study 
drug. Refer to the Flow Chart and Figure 3.1: 1 below for details. FU1 will be defined as the
end of on-treatment period for this trial. After disease progression, patients will be monitored 
for vital status in the observation period (for Part B only). 
* Part B only: For patients who had disease progression while on afatinib less than 40 mg/day, the starting dose is the last dose of afatinib.
Alternative starting dose of afatinib must be discussed and agreed by Sponsor.
Figure 3.1: 1
Study design
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim.
Anti-tumour activity and safety
Part A- Dose confirmation
Screening:
Up to 28 days before treatment 
start (30 days for tumour 
imaging)
- EGFR mutant 
adenocarcinoma of lung 
with progression following 
prior EGFR TKIs 
- Squamous cell carcinoma of 
lung with progression 
following prior platinum-
based chemotherapy
                     Part A
3+3 dose escalation
Treatment starting dose in the 1st
dose escalation cohort: 
Afatinib: 30 mg daily
                    +
BI 836845: iv.q1w 1000mg
                        Part B 
Treatment starting dose: 
MTD/RP2D*
18 treated patients 
Part B-expansion cohorts
Screening:
Up to 42 days before treatment 
start (30 days for tumour 
imaging)
- EGFR mutant (without 
T790M) NSCLC immediate 
post irreversible EGFR TKIs 
Determination of MTD/RP2D
End of 
Treatment
EOT visit
within 14 
days of the 
last 
administration 
of study drug
Follow up
FU1
First follow up 
visit 42 days 
after 
administration 
of study drug
(BI836845 
/Afatinib).
Additional 
imaging FU
Until PD or 
further 
treatment
Observation 
period 
(Only for 
Part B)
Every 90 
days after 
last follow-
up visit


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The coordinating investigator is an oncologist with experience in this type of trial and 
investigations. The coordinating investigator has been designated by Boehringer Ingelheim 
and will sign the clinical trial report. The investigators participating in the trial must have 
experience in diagnosing and treating patients with locally advanced or metastatic non-small 
cell lung cancer. Each decision on dose escalation or de-escalation steps will be taken in 
agreement between the Sponsor and the principal investigators at each site and safety will be 
closely monitored by a BI monitor or a Contract Research Organisation (CRO) appointed by 
BI. There will be no steering committee or data monitoring committee for this trial.
Regular teleconferences (or online meeting) will be held for decision of dose escalation, 
discussion of ongoing patients, discussion and determination of MTD/RP2D, and discussion 
of operational aspects. The participants are the investigators and BI study team. Relevant 
safety, laboratory, and efficacy data should be checked by on-site monitoring or review of 
eCRF before the teleconference. During the regular teleconferences with the investigators and 
study team, the next higher dose level will be determined from the progress of existing 
patients at the current dose level and in consideration of available AE and PK-PD data. Any 
potential patients for the trial will also be discussed. Conclusion of dose escalation decision 
should be agreed by the investigators and BI study team. All teleconference details will be 
documented accordingly.
BI will appoint CROs and independent service providers for special services such as central 
laboratory services for biomarker testing and part of bioanalytical testing, biosample 
collection and logistics, and Interactive Response Technologies (IRT) for trial medication 
assignment/logistics. The analysis of biomarker and PK will be performed by BI or a CRO 
appointed by BI.
On-site monitoring will be performed by BI or a Contract Research Organisation (CRO) 
appointed by BI.
All trial relevant documentation will be stored in the Trial master file (TMF) at BI. In 
addition each site will have an Investigator Site File (ISF) containing all trial documents 
relevant for the site.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
The ‘3+3’ dose finding design (R07-0220) for phase I clinical studies in oncology with 
escalating/de-escalating steps will be used to determine the MTD of Xentuzumab (BI 836845)
combined with daily dosing of afatinib. No control group is needed.
As no data regarding the optimal dose for Xentuzumab (BI 836845) combined with a daily 
dose of afatinib exist so far, the assessment of MTD will be performed in part A prior to 
further exploring the anti-tumour activity of the combination regimen in Part B. In part B, for 
patients who had disease progression while on afatinib less than 40 mg/day, the starting dose 
is the last dose of afatinib. Alternative starting dose of afatinib must be discussed and agreed 
by Sponsor. (P16-10813).


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Patients will continue trial treatment until any reason listed in Section 3.3.4 is met.
3.3
SELECTION OF TRIAL POPULATION
Since the objective is to evaluate the tolerability of Xentuzumab (BI 836845) plus afatinib for 
patients with NSCLC who have failed previous treatment (EGFR TKI or platinum based 
chemotherapy), it is important to conduct the dose confirmation part (Part A) in a closely
related patient population and to conduct the expansion part (Part B) for the exploration of a 
preliminary efficacy signal in a well-defined group of patients with resistance to EGFR TKIs. 
Squamous cell carcinoma, a subtype of NSCLC, will be also eligible in Part A because 
emerging data shows that afatinib provides clinical benefit in this patient group (P15-06906). 
Both EGFR mutant NSCLC and SCC of lung are more likely expected to obtain benefit from 
afatinib-based therapy. The safety and tolerability profiles of afatinib between EGFR mutant 
NSCLC and SCC are similar. Ideally, a clear signal whether the experimental treatment can 
work in truly resistant disease will be obtained; a false positive signal has a very low 
likelihood as no response is to be expected from resistant clones.
Part A
An estimated total of about 9 to 18 patients will be necessary to establish the MTD for the
combination of Xentuzumab (BI 836845) plus afatinib. If 6 evaluable patients have been 
treated at the MTD dose level, an additional 6 patients will be recruited to determine the 
RP2D, i.e., a total of 12 patients with resistance to EGFR TKIs will be treated at the MTD 
level. If the RP2D is different from the MTD dose, a total of 12 patients should be treated at 
the RP2D dose prior to commencing the Part B of the study.
Part B
Once the RP2D has been determined, 18 additional patients will be treated in the expansion 
cohort of Part B. In part B, for patients who had disease progression while on afatinib less 
than 40 mg/day, the starting dose is the last dose of afatinib. Alternative starting dose of 
afatinib must be discussed and agreed by Sponsor(P16-10813).
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not. 
3.3.1
Main diagnosis for study entry
3.3.2
Inclusion criteria
1. Male or female patients aged 18 years or older
2. Patients with pathologic confirmation of advanced and/or metastatic stage IIIb/IV 
non-small cell carcinoma of lung 
Note: In Part A and B, diagnosis is not necessarily based on the latest tumour
sample. Small cell lung cancer transformation must be excluded.


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3. Documented activating EGFR mutation (exon 19 deletion, L858R, G719X, 
L861X). Exception: patient with squamous cell predominant histology in Part A
4. Presence of EGFR activating mutation and absence of EGFR T790M mutation in 
the tumour associated with the latest disease progression. Only applicable in Part 
B
5. Adequate fresh or archival tumour tissue at the latest disease progression
immediately prior to the study entry must be made available for central EGFR 
mutation test and/or resistance analysis
6. Part A: Progression of disease (RECIST v1.1) while on continuous treatment 
with single agent EGFR TKI (e.g. erlotinib or gefitinib or afatinib) or for 
histology other than adenocarcinoma and without prior EGFR TKI treatment: 
progression of disease (RECIST v1.1) on platinum-based chemotherapy. 
Part B: Progression of disease (RECIST v1.1) while on continuous treatment with 
single agent of the second generation irreversible EGFR TKI (e.g. afatinib or 
dacomitinib).
Note: In both parts, patients whose disease progresses only in the central nervous 
system (CNS) are not eligible
7. No intervening systemic therapy between cessation of EGFR TKI and initiation 
of the treatment in the study. Exception: patient with squamous cell predominant 
histology in Part A
8. Patients must have measurable disease per RECIST v1.1 (R09-0262 - Appendix 
10.5) presented after tumour biopsy for the latest disease progression
9. Eastern Cooperative Oncology Group (ECOG) performance score 0 or 1 (Refer 
to Appendix 10.4)
10. Life expectancy of ≥3 months in the opinion of the investigator
11. Fasting plasma glucose < 8.9 mmol/L (< 160mg/dL) and HbA1C < 8%
12. Adequate organ function as defined by the following criteria:
•
LVEF >50% or within institutional values
•
Absolute neutrophil count (ANC) ≥1,500/ mm3
•
Platelet count ≥100,000/ mm3
•
Estimated creatinine clearance > 45ml/ min Appendix 10.2.
•
Total bilirubin ≤1.5 times upper limit of institutional normal.
•
Aspartate amino transferase (AST) and alanine amino transferase (ALT)
≤3 x upper limit of institutional normal (ULN) (if related to liver 
metastases ≤5xULN)
13. Recovered from any previous therapy related toxicity to ≤Grade 1 at study entry 
(except for stable sensory neuropathy ≤Grade 2 and alopecia)
14. Written informed consent that is consistent with ICH-GCP guidelines and local 
regulation.


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15. No known potentially targetable mutation other than IGF signalling pathway or 
EGFR or no available treatment for potentially targetable mutation
3.3.3
Exclusion criteria
1. Part A only: For patient who has been treated with afatinib,last treatment at reduced 
dose below the assigned dose level 
2. Patient whose disease progressed on insufficient dose of EGFR TKI immediately 
prior to study in the opinion of the investigator
3. Part B only: More than 2 prior EGFR TKI treatment regimens for relapsed or 
metastatic NSCLC
4. Chemotherapy, biological therapy or investigational agents (except EGFR TKIs)
within 4 weeks prior to the start of study treatment.  
5. Use of previous EGFR TKIs except afatinib within 3 days of treatment administered. 
6. Radiotherapy within 4 weeks prior to the start of study treatment, except as follows:
(a) Palliative radiation to target organs other than chest may be allowed up to 
2 weeks prior to the start of study treatment, and 
(b) Single dose palliative treatment for symptomatic metastasis outside above 
allowance to be discussed with sponsor prior to enrolling.
7. Patients with active brain or subdural metastases are not eligible, unless they have 
completed local therapy and have discontinued the use of corticosteroids or have 
been on stable dose of corticosteroids for at least 4 weeks before starting study 
treatment. Any symptoms attributed to brain metastases must be stable for at least 4 
weeks before starting study treatment. 
8. Meningeal carcinomatosis.
9. Major surgery (as judged by the investigator) within 4 weeks before starting study 
treatment or scheduled for surgery during the projected course of the study.
10. Known hypersensitivity to afatinib, monoclonal antibody or the excipients of any of 
the trial drugs.
11. Prior severe infusion-related reaction to a monoclonal antibody
12. History or presence of clinically relevant cardiovascular abnormalities such as 
uncontrolled hypertension, congestive heart failure NYHA classification of 3 (Refer 
to Appendix 10.3), unstable angina or poorly controlled arrhythmia as determined by 
the investigator. Myocardial infarction within 6 months prior start treatment.
13. Female patients of childbearing potential (see Section 4.2.2.3) and male who are able 
to father a child who:
(a) are nursing or
(b) are pregnant or


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(c) are not using an acceptable method of birth control (see Section 4.2.2.3) or do 
not plan to continue using this method throughout the study and/or do not agree 
to submit to pregnancy testing required by this protocol.
14. 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.
15. Previous or concomitant malignancies at other sites, except effectively treated non-
melanoma skin cancers, carcinoma in situ of the cervix, ductal carcinoma in situ or 
effectively treated malignancy that has been in remission for more than 3 years and is 
considered to be cured.
16. Disease that is considered by the investigator to be rapidly progressing or life 
threatening such as extensive symptomatic visceral disease including hepatic 
involvement and pulmonary lymphangitic spread of tumour (subjects who are 
intended for urgent chemotherapy)
17. Requiring treatment with any of the prohibited concomitant medications listed in 
Section 4.2.2 that cannot be stopped for the duration of trial participation.
18. Known pre-existing interstitial lung disease (ILD).
19. Any history or presence of poorly controlled gastrointestinal disorders that could 
affect the absorption of the study drug (e.g. Crohn’s disease, ulcerative colitis, 
chronic diarrhoea, malabsorption).
20. Active hepatitis B infection active hepatitis C infection and/or known HIV carrier.
21. Use of alcohol or drugs incompatible with patient participation in the study in the 
investigator’s opinion.
22. Previous treatment with agents targeting the IGF signalling pathway.
23. Patients unwilling or unable to comply with protocol in the opinion of the 
investigator
24. Previous treatment with EGFR TKI which can’t be documented as either reversible 
or irreversible (Part B only)
25. Part B only: Prior treatment with third generation irreversible EGFR TKI (e.g. 
AZD9291 or CO-1686)
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
A patient has to be removed from the trial in case any of the following criteria applies:

A patient denies further trial participation (patients are free to discontinue their 
participation in this study at any time without the need to justify this decision).


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In this event, the patient will be asked to have their end of treatment assessments and the data 
collected until the point in time when withdrawal occurred will be included in the final 
analysis of the trial data. No further follow-up will be performed in case the patient does not 
agree to follow-up.
A patient has to be discontinued from study treatment in case any of the following applies: 
1. A patient requests discontinuation of active treatment but agrees to be followed-up.
2. Documented progressive disease (Section 5.1.2)
3. The patient is no longer able to participate in the study (e.g., AE, pregnancy, surgery, 
concomitant diagnoses, concomitant therapies or administrative reasons). The 
investigator may also stop a patient’s treatment, if the patient is no longer able to 
attend study visits e.g. due to worsening of disease; in such a case the Investigator’s 
reason for a patient’s removal must be recorded on the appropriate page of the 
Electronic Case Report Form (eCRF).
4. Significant deviation from the protocol. The decision to continue or withdraw 
treatment will be made after discussion between the sponsor and the investigator.
5. Diagnosis of ILD.
6. Further dose reductions considered necessary but not allowed according to the 
protocol for both study drugs (Section 4.1.4.3).
7. An interruption of both drugs for more than 14 days as counted from the next planned 
treatment administration. If an interruption of more than 14 days is necessary and 
clinically justified, the patient may continue study treatment after discussion and 
agreement between the investigator and the BI Clinical Monitor.
Patient withdrawal will be documented and the reason for withdrawal recorded and discussed 
in the final study report.
As soon as a patient has withdrawn from the trial, the EOT visit should be performed where 
feasible. Every effort should be made to follow up patients in case an adverse event is still 
ongoing at the time of withdrawal.
All patients who are included into the trial (i.e. having given informed consent) will have 
their data entered into the trial database. This includes patients who are considered screen 
failures i.e. do not commence study drug treatment.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1.
Failure to meet expected enrolment goals overall or at a particular trial site, 
2.
Emergence of any efficacy/safety information that could significantly affect 
continuation of the trial. 


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3.
Violation of GCP, the CTP, or the contract by a trial site or investigator, affecting the 
appropriate conduct of the trial. 
4.
Discontinuation of the clinical development programme with Xentuzumab (BI 836845)
or the combination of Xentuzumab (BI 836845) with afatinib. 
5.
Any other administrative reason
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.4.3
Replacement of patients
Replacement of entered patients is only applicable in part A before the determination of 
MTD.
Patients will be replaced for the assessment of Dose Limiting Toxicities in case of:
1) Patient’s withdrawal during the first course of treatment for reasons other than DLT, 
e.g. patient no longer wishes to participate, or lost to follow up during first course
2) Patients who do not experience DLT, but miss more than one visit during the first 
course of treatment
3) Patients who do not experience DLT but miss ≥ one Xentuzumab (BI 836845)
administration or ≥ 5 doses of afatinib in first treatment course
4) Patients who miss one complete course at any time beyond the first course of 
treatment may be replaced after discussion between the sponsor and the investigator
5) Patients who are non-evaluable with respect to DLT
Patients that have been replaced might continue treatment in the trial upon agreement 
between investigator and sponsor however these patients will not be considered for the 
evaluation of MTD.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
Patients will receive Xentuzumab (BI 836845) weekly in combination with afatinib once 
daily. The manufacturers for each of the products are listed in Section 4.1.1. 
4.1.1
Identity of BI investigational product and comparator product
4.1.1.1
Xentuzumab (BI 836845) (investigational product)
Substance:
Xentuzumab (BI 836845) human monoclonal antibody
Pharmaceutical form:
Liquid formulation
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
10 mg/ml of Xentuzumab (BI 836845) supplied in 20 ml vials 
(200 mg/vial)
Weekly dose:
1000 mg (starting dose), 750 mg 
Posology:
Once weekly administrated through one hour intravenous 
infusion. Infusion duration may be extended to over one hour 
and up to a maximum of three hours in cases of grade ≥ 2 
infusion reactions. See Section 4.1.3 for dose selection
Route of 
administration:
Intravenous infusion. Appropriate dose of Xentuzumab (BI 
836845) will be diluted in isotonic sodium chloride solution 
(0.9%)
Duration of use:
Continuous weekly dosing (days 1, 8, 15 and 22 in a 28-day 
course) in the absence of disease progression, intolerable AEs 
or other reason necessitating withdrawal
4.1.1.2
Afatinib (investigational product)
Substance:
Afatinib
Brand name:
Giotrif
Pharmaceutical form:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
20 mg, 30 mg or 40 mg (the dose of afatinib in tablets is 
related to the free base equivalent of afatinib)


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Route of 
administration: 
Oral
Posology:
Once daily. Take afatinib at least 1 hour before or 3 hours
after a meal. See Section 4.1.3 for dose selection
Duration of use:
Continuous daily dosing until criterion in Section 3.3.4.1 is 
met
4.1.2
Method of assigning patients to treatment groups
4.1.2.1
The dose confirmation Part A
Treatment slots are assigned by the BI Clinical Monitor (CM) in close communication 
(email/phone/FAX) with the recruiting sites and will be assigned on a competitive basis. 
After the BI Clinical Monitor has been notified by a site about a potential patient, the slot will 
be reserved to this site for a maximum of seven calendar days. If the informed consent form 
(ICF) has not been signed by the potential patient within this time window, the slot will be 
opened up again for all recruiting sites.
Patients that meet the eligibility criteria and who have given their written informed consent 
will be entered into the study.
Before entering patients at the next dose level it will be ensured that all patients at an ongoing 
cohort have completed the first course. Prior to inclusion of a new patient, the investigator 
should confirm the respective dose with the BI clinical monitor.
4.1.2.2
The expansion Part B
The enrolment in Part B is competitive. In order to reach an adequate number, eligible 
patients need to be communicated to the BI Clinical Monitor (CM). These communications 
may be done by FAX/e-mail and will be documented. Patients that meet the eligibility criteria 
and who have given their written informed consent will be entered into the Part B of the 
study. Investigators will be notified by the sponsor when the appropriate number of patients 
have been screened and screening is complete, thereafter additional patients will not be 
allowed to recruit for this study. Patients who have signed an informed consent form and are 
eligible prior to notification of the termination of recruitment will be allowed to participate in 
the study.
4.1.3
Selection of doses in the trial
4.1.3.1
Planned dose levels in the Part A
The Part A will follow an escalation/de-escalation “3+3” design. The starting dose level 
consists of 1000 mg weekly Xentuzumab (BI 836845) in combination with 30mg/day of 
afatinib.


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The approved dose of afatinib in first-line monotherapy treatment of EGFR mutant NSCLC 
is 40 mg daily. Afatinib has also been studied in NSCLC with settings of EGFR TKI failure. 
In the LUX-Lung 1 study, afatinib was administered as monotherapy with a daily dose of 50 
mg (P12-03682). Afatinib at 40 mg daily in combination with bi-weekly cetuximab of 500 
mg/m2 has been established as recommended dose for patients who failed prior EGFR TKI 
(P12-11350). In the current trial, an afatinib dose of 30 mg daily, a dose lower than the 
registered dose, has been chosen as a starting dose level. Given the cross-talk between IGF-
1R and EGFR, it is conceivable that side-effects as well as efficacy of EGFR TKIs might be 
potentiated when an IGF pathway inhibitor is added (R16-4930, R12-5650). Hence, to 
mitigate this risk, a lower than labeled dose is chosen for the first dose cohort.
The starting dose level of Xentuzumab (BI 836845) has been determined as 1000 mg every 
week. Based on data from two phase I studies, the recommended monotherapy dose of 
Xentuzumab (BI 836845) is 1000 mg every week. In these two studies, a formal MTD was 
not established in the absence of DLT from 1000 mg per week up to 1800 mg per week. 
About 90% neutralization of IGF-1 can be achieved with dose of 1000 mg every week. 
Tolerability and safety are considered favourable even at dose levels above 1000 mg every 
week. Therefore, a dose of 1000 mg Xentuzumab (BI 836845) every week is chosen as 
starting dose to combine with 30 mg QD of afatinib.
Table 4.1.3.1: 1
Planned dose levels
Dose level
Xentuzumab 
(BI 836845)
(mg/week)
Afatinib
(mg /day)
Dose level -1
750
30
Dose level 1
Starting dose
1000
30
Dose level 2
Intended RP2D
1000
40
Study treatment will be administered in 4-week (28 days) courses. 
To determine the maximum tolerated dose (MTD), patients will be entered sequentially into 
escalating/de-escalating dosage tiers of BI836845 and afatinib (see Table 4.1.3.1: 1). Three 
patients will be treated at the starting dose level (dose level 1). If 1 out of 3 patients at that
dose level experiences a dose limiting toxicity (DLT), then 3 additional patients will be 
treated at that dose level. If more than 1 out of 3 or more than 1 out of 6 patients at dose level 
1 have a DLT, then the MTD has been exceeded and the dose is de-escalated to dose level -1.
If 1 out of 3 patients experience a DLT at any dose level, then 3 additional patients will be 
treated at that dose level. If at dose level 1, 0 out of 3 patients or 1 out of 6 experiences a 
DLT, the dose will be escalated to dose level 2. If 0 or 1 out of 3 patients experience a DLT 
and dose level 2, then 3 additional patients will be treated at that dose level. If more than 1 
out of up to 6 patients experiences a DLT at the lowest dose level -1, the trial will be 
discontinued, and no MTD could be established. Intra-patient dose escalation is not permitted. 
For decision on dose escalation, please see Section 3.1.1. During the dose confirmation stage 
(Part A) of the study, the safety profile as well as DLTs will be discussed with the 


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investigator as well as a coordinating investigator. The decision on the next dose level or 
determination of the MTD will be documented.
Table 4.1.3.1: 2
Rules for dose escalation/de-escalation
4.1.3.2
Part B – dosing schedule
The decision on dose escalation/de-escalation, MTD and RP2D will be determined in 
discussion with a group of BI Trial Clinical Monitor, BI project physician (TMM) and
investigators including Coordinating Investigator and taking into account patient safety. This 
decision will be documented and patients will be treated at the MTD/RP2D determined from 
Part A. For decision on MTD/RP2D determination, please see Section 3.1.1.
MTD/RP2D has been determined as Xentuzumab (BI 836845) 1000 mg/week plus afatinib 
40 mg/day and it will be used as starting dose in Part B. However, in part B, for patients who 
had disease progression while on afatinib less than 40 mg/day, the starting dose is the last 
dose of afatinib. Alternative starting dose of afatinib must be discussed and agreed by
Sponsor.
4.1.4
Drug assignment and administration of doses for each patient
The treatment medication assignment for Xentuzumab (BI 836845) and afatinib will be 
managed through an IRT system. In addition, patient’s screening, dose assignment, all drug 
dispensation visits and EOTV will be collected in the IRT system.
4.1.4.1
Initial study drug assignment and administration
General information that applies to this study regardless of the IRT is described in below 
sections of each individual study drug. The medication kit as well as the treatment will be 
assigned with the support of the IRT system. The detailed information regarding handling of 
medication number will be described in ISF. 
Number of Patients with DLT at a 
Given Dose Level
Escalation/de-escalation Decision Rule
0 out of 3
Enter 3 patients at the next dose level.
>2 out of 3
Dose de-escalation will commence. Three (3) 
additional patients will be entered at the lower 
dose level.
1 out of 3
Enter up to 3 more patients at this dose level.
If 0 of these 3 additional patients experience 
DLT, proceed to next dose level.
If 1 or more of these 3 additional patients 
experience DLT, then dose de-escalation will 
commence. 
≤ 1 out of 6 at the highest dose level 
This is the MTD (or maximal administered dose)
to be considered as RP2D


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Before entering patients at the next dose level of Part A, it will be ensured that all patients at 
the current ongoing dose level have completed at least one course of treatment.
4.1.4.1.1 Xentuzumab (BI 836845)
Patients will start treatment with their assigned dose tier (see Section 4.1.3) or RP2D of 
Xentuzumab (BI 836845) from course 1 day 1. Xentuzumab (BI 836845) will be 
administered at the investigator site intravenously over one hour with a constant infusion rate 
on the treatment day as specified in the Flow Chart. No prophylaxis for infusion-related 
reaction is recommended at Course 1 Visit 1. Mannitol is used in the formulation of 
Xentuzumab (BI 836845), so an infusion duration of less than one hour must be avoided. The 
infusion time may be extended to over one hour and up to a maximum of three hours in cases 
of CTCAE grade ≥ 2 infusion reactions (see Section 4.2.3.4) for grading and management of 
infusion reactions). Further information on infusion equipment and procedure is described in 
the ISF. In case of a delay or an interruption of infusion, the reason and the exact time of 
deviation must be recorded in the eCRF. The accuracy of this information is crucial for the 
proper evaluation and appraisal of the pharmacokinetics and other data.
Detailed information of dispensation, preparation, and handling of Xentuzumab (BI 836845)
will be described in ISF.
4.1.4.1.2 Afatinib
Patients will take a single oral dose of afatinib each day starting at their assigned dose-level 
(Part A) or RP2D (Part B), continuously during each treatment course. The medication 
should be taken at the same time each day (± 2 hours) without food (at least one hour before 
or at least three hours after a meal) to ensure a dose interval of approximately 24 hours.
If a dose is missed, it should be taken within the same day as soon as the patient remembers. 
However, if the next scheduled dose is due within 8 hours then the missed dose must be 
skipped and the next scheduled dose at the usual time should be taken. Patients with emesis 
must not take a replacement dose.
The tablet should be swallowed with a glass of water (approximately 250 mL). Afatinib 
tablets should not be chewed or crushed, but may be administered after dispersing the afatinib 
tablets according to the following procedure: If dosing of whole tablets is not possible, 
afatinib tablets can also be dispersed in approximately 100 ml of non-carbonated drinking 
water. No other liquids should be used. The tablet should be dropped in the water, without 
crushing it, and occasionally stirred for up to 15 min until the tablet is broken up into very 
small particles. The dispersion should be drunk immediately. The glass should be rinsed with 
approximately 100 ml of water which should also be drunk. The dispersion can also be 
administered through a naso-gastric tube. 
Medication will be dispensed in bottles containing 30 tablets at the beginning of each 
treatment course. Treatment will start when the patient is taking the first dose of medication 
at course 1 Day1. Study drug will be prescribed by the investigator and may be dispensed 
either by the investigator, site staff or affiliated pharmacy.


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4.1.4.2
Additional course of treatment 
The doses of Xentuzumab (BI 836845) and afatinib assigned upon entry to this trial will be 
used on all scheduled administrations described in the Flow Chart unless the patient 
experiences DLTs or treatment related adverse events which require dose modification. 
Intra-patient dose escalation of either afatinib or BI 836345 is not allowed in this trial.
Patients demonstrating a clinical benefit (i.e., with either an objective tumour response or the 
absence of disease progression) with the trial drug, and who have recovered from any 
clinically relevant drug-related AE, are eligible for further treatment courses as per the Flow 
Chart until any of the conditions in Section 3.3.4.1 is met.
4.1.4.3
Temporary treatment interruption and dose reduction 
DLTs or those AEs requiring dose adjustment as indicated within the prescribing 
information, should be managed by treatment interruptions and subsequent dose reductions of 
the presumed causal study drug(s) according to the schedule described in Table 4.1.4.3: 1. 
Please also refer to Section 4.2.3 for additional recommendations. In Part A, both 
Xentuzumab (BI 836845) and afatinib must be paused when a DLT occurs during the first 
treatment course. Dose reductions will apply to individual patients only and dose of 
Xentuzumab (BI 836845) and/or afatinib may be reduced independent of one another. Once 
the dose has been reduced, it cannot be increased later. 
To prevent the development of more severe adverse events, treatment related AEs should be 
closely monitored and managed early and proactively as described in Section 4.2.3.
Treatment should be paused until a patient has recovered from a drug-related AE to grade ≤1 
or baseline. Baseline is defined as the CTCAE grade at the start of treatment. For patients 
who develop a DLT, treatment may be resumed at reduced dose according to the dose 
reduction scheme of the patient’s starting dosage (Table 4.1.4.3: 1). If a patient has not 
recovered to Grade ≤1 or baseline within 14 days, study treatment must be permanently 
discontinued. In the event that the patient is deriving obvious clinical benefit according to the 
investigator’s judgment, further treatment with study drug(s) will be decided in agreement 
between the sponsor and the investigator.
Diarrhoea and skin-related AEs are common side-effects of afatinib listed within the 
prescribing information. Please refer to the current afatinib prescribing information/SmPC for 
dose adjustment recommendations (except for the Course 1 of Part A if a DLT occurs, in 
which case both drugs need to be interrupted until AE recovery, refer to Section 5.2.6). When 
these AEs occur and are considered related to study treatment, the first dose modification is 
recommended to be made preferentially for afatinib.
In the event of any unrelated AEs or related non-DLT AEs, the investigator may choose to 
interrupt the medication (Xentuzumab (BI 836845) and/or afatinib) for up to 14 days, but no 
dose reduction should occur unless indicated in the current drug label/SmPC of afatinib. If 
the medication is interrupted for more than 14 days, the decision to continue with 


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Xentuzumab (BI 836845) and/or afatinib will be made by the BI clinical monitor in 
agreement with the investigator.
Applicable dose levels for weekly Xentuzumab (BI 836845) are 1000 mg and 750 mg. For 
afatinib, the applicable dose levels are 40 mg, 30 mg, and 20 mg. No dose reduction is 
allowed below 750 mg for Xentuzumab (BI 836845) or below 20 mg for afatinib. Patients 
who need further dose reduction which is not allowed according to protocol should be 
discontinued from that drug treatment. An exception to this rule can be considered upon 
discussion with BI’s Clinical Monitor in patients who derive obvious clinical benefit 
according to the investigator’s judgement. Alternative dose modification scheme can only be 
considered after discussion and agreement between the investigator and the BI clinical 
monitor.
Management of afatinib related adverse reaction and dose adjustment should be based on the 
European SPC or current prescribing information for afatinib of the respective country or 
institutional standard if not specified by protocol.
During temporary treatment interruption of Xentuzumab (BI 836845), the scheduled drug 
infusion will be skipped and will not be retrospectively administered. 


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Table 4.1.4.3: 1
Dose reduction scheme by AE type and CTCAE Grade (Part A and 
Part B)
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
- Nausea and/or Vomiting  Grade 2 
persisting for 7 or more consecutive days 
despite anti-emetic treatment/hydration
- Reduced renal function to  ≥ Grade 2 as 
measured by serum creatinine, proteinuria 
or decrease in glomerular filtration rate of 
more than 50% from baseline
- Drug-related skin AE Grade ≥3
Pause afatinib treatment until 
patient has recovered to Grade 
≤1 or baseline1. Xentuzumab 
(BI 836845) may be paused at 
the discretion of the 
investigator
Resume treatment at reduced 
dose according to schedule 
opposite.
If patient has not recovered to 
Grade ≤1 or baseline within 14 
days study treatment must be 
permanently discontinued2.
Afatinib
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.
Xentuzumab (BI 836845)
Reduce Xentuzumab (BI 
836845) at investigator’s 
discretion after interruption, 
but by no more than one level 
at a time. (1000mg (starting 
dose)->750mg (-1 dose 
level))
If patient need further dose 
reduction below 750 mg, 
discontinue BI836845.
Drug-related DLTs (see Section 5.2.6) or 
any other drug-related AE ≥ 33
Pause afatinib and/or 
Xentuzumab (BI 836845)
treatment until patient has 
recovered to Grade ≤1 or 
baseline1. In Part A, both 
afatinib and Xentuzumab (BI 
836845) must be paused when 
DLT occurs in the first course.
Resume treatment at reduced 
dose according to schedule 
opposite. Drug without 
interruption will maintain dose 
level.
If patient has not recovered to 
Grade ≤1 or baseline within 14 
days study treatment must be 
permanently discontinued2.
Afatinib (if interrupted)
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.
Xentuzumab (BI 836845) (if 
interrupted)
Reduce Xentuzumab (BI 
836845) by not more than 
one level at a time. (1000mg 
(starting dose)->750mg (-1 
dose level))      
If patient need further dose 
reduction below 750 mg, 
discontinue BI836845.


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Table 4.1.4.3: 1
Dose reduction scheme by AE type and CTCAE Grade (Part A and 
Part B) (Cont’d)
AE type and CTCAE Grade
Action
Dose reduction scheme
Acute onset and/or unexplained 
worsening of pulmonary systems 
(dyspnoea, cough, fever)
Pause afatinib and 
Xentuzumab (BI 836845)
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 drug-related, resume 
afatinib and Xentuzumab (BI 
836845) at current dose.  If 
AEs are drug-related, follow 
directions in row above.
If ILD is confirmed, 
discontinue afatinib and 
Xentuzumab (BI 836845). 
Xentuzumab (BI 836845) induced 
CTCAE grade ≥3 infusion-related 
reaction 
No action on afatinib
Pause BI836845
See specific guideline in 
Section 4.2.3.4
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 and/or Xentuzumab (BI 836845) will be decided in agreement between the BI clinical monitor and the 
investigator.
In the event of any unrelated adverse events, the investigator may choose to interrupt the medication (afatinib and/or
Xentuzumab (BI 836845)) 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 and/or Xentuzumab (BI 836845) will be made by the BI clinical monitor 
in agreement with the investigator.
3 except alopecia, infusion reaction and allergic reaction
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Not applicable. This is an open-label trial.
4.1.5.2
Procedures for emergency unblinding
Not applicable.
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF.
For details of drug supply, refer to Section 4.1.1.
Boxes and vials of Xentuzumab (BI 836845) and boxes of afatinib will be labelled according 
to local regulations and will include the following as a minimum:

The study number (1280.16)


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
Product name

Contents of the bottle/carton box

Strength

Batch number

Use-by date

Storage information

Instructions for use

Sponsor name and address

A statement indicating that the medication is for clinical trial use only

A caution statement
Examples of the labels will be filed in the ISF.
The Xentuzumab (BI 836845) and afatinib drug supply will be managed through Interactive 
Response Technologies (IRT) by the study sites and BI personnel. Refer to the ISF for details 
of packaging and the description of the label as well as the process for resupply of study drug. 
4.1.7
Storage conditions
Trial medication (afatinib and Xentuzumab (BI 836845)), which will be provided by the 
sponsor and/or a CRO appointed by the sponsor, must be kept in a secure, limited access 
storage area under the storage conditions defined below until supplied/administered to 
patient. Temperature logs must be maintained to make certain that the drug supplies are 
stored at the correct temperature. In case temperature would be out of range, this has to be 
reported in the ISF and the sponsor be notified.
4.1.7.1
Afatinib 
Afatinib must be stored in the original package in order to protect from light. Film-coated 
tablets are humidity-sensitive; therefore, bottles must be kept tightly closed to protect from 
moisture. Tablets must be stored according to label instructions.
4.1.7.2
Xentuzumab (BI 836845)
Investigational drug supply of Xentuzumab (BI 836845) must be stored in the original 
packaging and will be stored in accordance with the instructions on the label. 
A temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature.
4.1.8
Drug accountability
Drug supplies, which will be provided by the sponsor and/or a CRO appointed by the 
sponsor, must be kept in a secure, limited access storage area under the storage conditions 
defined by the sponsor. Where necessary, a temperature log must be maintained to make 
certain that the drug supplies are stored at the correct temperature.


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The investigator (e.g. pharmacist or study drug storage manager) will receive the study 
drug(s) delivered by the sponsor when the following requirements are fulfilled:

approval of the study protocol by the IRB / ethics committee,

availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre,

approval/notification of the regulatory authority, e.g. competent authority,

availability of the curriculum vitae of the principal investigator,

availability of a signed and dated clinical trial protocol or immediately imminent 
signing of the clinical trial protocol,

if applicable: availability of the proof of a medical licence for the principal 
investigator.
The investigator or delegate must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each patient, and the return to the sponsor or alternative 
disposition of unused product(s). 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) and trial patients. The 
investigator or delegate will maintain records that document adequately that the patients were 
provided the doses specified by the CTP and reconcile all investigational product(s) received 
from the sponsor. At the time of return to the sponsor and/or appointed CRO, the investigator 
or delegate must verify that all unused or partially used drug supplies have been returned by 
the clinical trial patient and that no remaining supplies are in the investigator’s possession.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment
Rescue medications to reverse the action of afatinib or Xentuzumab (BI 836845) are not 
available. Potential side effects of afatinib and/or Xentuzumab (BI 836845) have to be treated
symptomatically.
Patients should receive full supportive care including transfusions of blood and blood 
products, antibiotics, analgesia etc., according to local practice/guidelines where appropriate. 
Anti-emetic medication should be prescribed according to local practice.
Precaution should be taken to avoid extravasation of Xentuzumab (BI 836845). Patients 
should be asked to report any pain or burning at the site of injection immediately. If 
extravasation is suspected the infusion should be stopped immediately. Treatment should be 
initiated according to local practice
Common adverse events of treatment with afatinib or Xentuzumab (BI 836845) with 
specified management recommendations and/or requirements include diarrhoea, and 
rash/acne. To improve tolerability and the probability of clinical benefit, patients should 


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receive prompt and appropriate supportive care at the first signs of symptoms. Suggested 
treatments for AEs are described in Section 4.2.3.
Symptomatic treatments of side effects or tumour-associated symptoms are allowed.
Concomitant treatments
Concomitant medications or therapy to provide adequate care may be given as clinically 
necessary.
After study enrolment, 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 
tumour response assessment. During palliative radiotherapy, study treatment should be 
delayed and may be resumed once the patient has recovered from any radiation associated 
AE. 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 >14
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/Xentuzumab (BI 836845) around one week prior to the surgery, and to restart 
treatment after complete wound healing. If afatinib/Xentuzumab (BI 836845) is interrupted 
for more than 14 days, the decision to continue will be made by the BI Clinical Monitor in 
agreement with the investigator.
Emergency procedures
Careful assessment of all patients with an acute onset and/or unexplained worsening of 
pulmonary symptoms (dyspnoea, cough, fever) should be performed to exclude interstitial 
lung disease (ILD). 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.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Concomitant medications, or therapy to provide adequate supportive care, may be given as 
clinically necessary.
Palliative radiotherapy may be given as described in Section 4.2.1.
Additional experimental anti-cancer treatment and/or standard chemo-, immunotherapy, 
hormone treatment (with the exception of megestrol acetate for decreased appetite), or 
radiotherapy (other than palliative radiotherapy for symptom control) is not allowed 
concomitantly with the administration of study treatment. 
Any concomitant medication should be reduced to the clinically necessary minimum on the 
days of Xentuzumab (BI 836845) infusion.
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 (refer to 
Appendix 10.1).
Antiplatelet medications (e.g. acetylsalicylic acid) should be discontinued 7 days prior to 
tumour biopsy. Anticoagulant medications should be discontinued prior to tumour biopsy. 
Warfarin should generally be discontinued at least 5 days prior to tumour biopsy. In all 
patients, the risk of discontinuing antiplatelet and/or anticoagulant medications must be 
weighed against the (potential) risk of bleeding during/after biopsy. Antiplatelet and 
anticoagulant may be restarted after tumour biopsy by the judgment of the investigators.
4.2.2.2
Restrictions on diet and life style
Patients should be advised to avoid lactose-containing products or any foods known to 
aggravate diarrhoea see Section 4.2.3.1.
To prevent skin related AEs, intense irradiation with UV light should be avoided, see also 
Section 4.2.3.2.
Patient has to show up in fasting condition at the site for analysis of specific blood parameters 
when safety lab is required.
4.2.2.3
Women of Child-Bearing Potential and Pregnancy Prevention
Patients who are not of childbearing potential due to being postmenopausal (1 year without 
menstruations and at least 2 years without menstruation following chemotherapy) or surgical 
sterilisation (oophorectomy and/or hysterectomy) do not need to use contraception to be 
eligible for the trial.


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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 months 
after last dose of trial medication, whichever is later). 
Acceptable methods of contraception include surgical sterilisation and double barrier method, 
and must be in accordance with local regulations where applicable. Double barrier method of 
contraception is defined as two barrier methods used simultaneously each time the patient has 
intercourse. Accepted barrier methods include diaphragm, female condom, cervical cap, male 
condom and intrauterine device (UID) (the diaphragm and cervical cap must be used in 
conjunction with spermicidal jelly/cream). Those using hormonal contraceptives, or with 
partners using hormonal contraceptives, must also be using an additional approved method of 
contraception (as described above). Partner vasectomy, natural "rhythm" and spermicidal 
jelly/cream are not acceptable methods of contraception.
Women who become pregnant while participating in the study must discontinue study 
medication immediately. The pregnancy must be reported following procedures detailed in 
Section 5.2.2.2.
4.2.3
Management of expected adverse events
Dermatologic AEs and diarrhoea are the most common side effects associated with treatment 
with afatinib. Treatment of these side effects should be proactive and should be started as 
early as possible after onset of symptoms, and recommendations for management are 
described below. 
4.2.3.1
Management of diarrhoea and hydration status 
Diarrhoea occurs at a high frequency and generally begins within 2 weeks of exposure to 
study treatment with 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 and 
Xentuzumab (BI 836845), patients should be given a supply of loperamide to keep with them 
at all times; and patients should be counselled on the appropriate use. In addition to diarrhoea 
management described in Table 4.2.3.1: 1, upon onset of diarrhoea CTCAE grade >1, patient 
should take racecadotril (Tiorfan 100 mg), if available, 1 tablet twice daily (morning and 
evening) to be continued until recovery at the investigator’s discretion. 
For the use of anti-diarrhoeal medication, please refer to latest version of local drug label.
Patients must be advised to drink an adequate amount of fluids to make up for the fluid lost 
through diarrhoea. 


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Table 4.2.3.1: 1
Grade specific treatment recommendations for diarrhoea
Severity 
(CTCAE 
grade)
Description**
Intervention concerning 
afatinib 
Specific intervention
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
Grade 2
Increase of 4-6 stools per day over 
baseline
i.v. fluids indicated <24 hours
Moderate increase in ostomy 
output compared with baseline
Not interfering with activity of 
daily life (ADL)
Continue same dose unless 
grade 2 diarrhoea 
continues for ≥ 2 days (48 
hours) in which case 
afatinib must be 
interrupted until recovered 
to grade ≤1 followed by 
dose reduction
Continue loperamide
Assess for dehydration 
and electrolyte 
imbalance
Consider i.v. fluids and 
electrolyte replacement
Grade 3 
Increase of ≥7 stools per day over 
baseline
Incontinence
i.v. fluids >24 hours
Hospitalisation
Severe increase in ostomy output 
compared with baseline
Interfering with ADL
Also see Section 4.1.4.3.
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 i.v. fluid 
replacement ≥24 hours
Hospitalisation to 
monitor progress
Consider prophylactic 
antibiotics if patient is 
also neutropenic
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 and/or Xentuzumab (BI 836845) 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 and/or
Xentuzumab (BI 836845) will be decided in agreement between the sponsor and the investigator.
** May refer to CTCAE version 4.03 for updated description of grading
4.2.3.2
Management recommendations for dermatological AEs 
Dermatologic AEs include rash, acneiform, dermatitis and dry skin. A proactive and early 
approach to management is crucial, and depending on the investigator’s own clinical 
experience, early involvement of a dermatologist and/or prompt institution of therapy such as


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a topical (e.g. clindamycin) and /or oral (e.g. minocycline) antibiotic amongst other measures 
(Table 4.2.3.2:1 & Table 4.2.3.2:2) should be considered at onset of a rash CTCAE grade >1.
Dermatological events can be managed by a variety of treatment options to relieve symptoms 
and reduce skin reaction. 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.
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 
Potthoff et al., R11-0826).
Table 4.2.3.2: 1
General recommendation for skin reactions prophylaxis 
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
Prevention of 
paronychia
Patients should keep their hands dry and out of water if ever possible
They should avoid friction and pressure on the nail fold as well as picking or 
manipulating the nail
Topical application of petrolatum is recommended around the nails due to its 
lubricant and smoothing effect on the skin


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Table 4.2.3.2: 2
Grade specific treatment recommendations of skin reactions 
Severity
(CTCAE grade)
Description1)
Specific intervention
ACNEIFORM RASH
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
Grade 2
Macular or papular eruptions with 
pruritus or other associated 
symptoms; localized desquamation 
or other lesions covering <50% of 
body surface area (BSA)
Topical treatment as for grade 1, plus
short term topical steroids, e.g. prednicarbate 
cream 0.02%, plus
an oral antibiotic (for at least 2 weeks) e.g. 
Doxycycline 100mg b.i.d. or Minocycline 
hydrochloride 100mg b.i.d.
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
See Section 4.1.4.3 for dose modification
Grade 4
Generalized exfoliative, ulcerative, 
or bullous dermatitis
See grade 3
Systemic steroids are recommended
EARLY AND LATE XEROTIC SKIN REACTIONS – PRURITUS
Grade 1
Mild or localized
Topical polidocanol cream
Consider oral antihistamines, e.g. 
diphenhydramine, dimethindene, cetirizine, 
levocetirizine, desloratidine, fexofenadine or 
clemastine)
Grade 2
Intense or widespread
See grade 1, plus
oral antihistamines
Consider topical steroids, e.g. topical 
hydrocortisone
Grade 3
Intense or widespread and interfering 
with ADL
See grade 2
See Section 4.1.4.3 for dose modification
XEROSIS (DRY SKIN)
Grade 1
Asymptomatic
Soap-free shower gel and/or bath oil
Avoid alcoholic solutions and soaps
Urea- or glycerine-based moisturizer
In inflammatory lesions consider topical 
steroids (e.g. hydrocortisone cream)
Grade 2
Symptomatic, not interfering with 
ADL
See grade 1
In inflammatory lesions consider topical 
steroids (e.g. hydrocortisone cream)
Grade 3
Symptomatic,
interfering with ADL
See grade 2
Topical steroids of higher potency (e.g. 
prednicarbate, mometasone furoate)
Consider oral antibiotics
See Section 4.1.4.3 for dose modification


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Table 4.2.3.2: 2
Grade specific treatment recommendations of skin reactions (con'd)
Severity
(CTCAE grade)
Description1)
Specific intervention
FISSURES
Grade 1
Asymptomatic
Petroleum jelly, Vaseline® or Aquaphor for 
30 minutes under plastic occlusion every 
night, followed by application of 
hydrocolloid dressing; antiseptic baths (e.g. 
potassium permanganate therapeutic baths, 
final concentration of 1:10,000, or povidone-
iodine baths)
Topical application of aqueous silver nitrate 
solutions to fissures
Grade 2
Symptomatic, not interfering with ADL
See grade 1
Consider oral antibiotics.
Afatinib and/or Xentuzumab (BI 836845)
treatment interruption
Grade 3
Symptomatic,
Interfering with ADL
See grade 2
1) May refer to CTCAE version 4.03 for updated description of grading
* If grade 2 rash persists for ≥7 days despite treatment and is poorly tolerated by the patient, the investigator 
may choose to pause afatinib and/or Xentuzumab (BI 836845) treatment up to 14 days followed by a 
reduction in the dose of afatinib and/or Xentuzumab (BI 836845) according to the dose reduction scheme in 
Table 4.1.4.3: 1.
If despite optimal supportive care and a treatment pause, grade 2 rash does not resolve to CTCAE Grade ≤ 1 
within 14 days, treatment with afatinib and/or Xentuzumab (BI 836845) 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 and/or Xentuzumab (BI 836845) will be decided in agreement between the 
sponsor and the investigator.
**CTCAE grade 3 (or greater) rash: may be treated in a manner similar to CTCAE grade 2 rash. In the event 
of CTCAE grade ≥3 rash, treatment with afatinib and/or Xentuzumab (BI 836845) should be paused until 
recovery to CTCAE grade ≤1. Treatment should be resumed at a reduced dose (Table 4.1.4.3: 1). If CTCAE 
grade ≥3 rash does not resolve to CTCAE grade ≤1 within 14 days of stopping afatinib and/or Xentuzumab 
(BI 836845) treatment and despite optimal supportive care, the patient should not receive any further 
treatment with afatinib and/or Xentuzumab (BI 836845) and the End of Treatment visit should be 
performed.


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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 and for restrictions on concomitant therapies refer to 
Sections 4.2.2 and Appendix 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 –
viscous lidocaine 2%; mucosal coating agents - topical kaolin/pectin; oral antacids, 
maltodextrin, sucralfate; topical antifungals – nystatin suspension. (Adapted from P11-
09424)
Mouth washed with steroids (not to be swallowed) should be considered for oral ulcers as 
soon as they appear for CTCAE grade >1 until recovery at the investigator’s discretion. 
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
Grade 1
Minimal 
symptoms; 
normal diet 
Oral rinses with agents such as non-
alcoholic mouth wash with steroids (not 
to be swallowed), normal saline, diluted 
salt and baking soda solution .
No change .
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.
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
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
* May refer to CTCAE version 4.03 for updated description of grading


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4.2.3.4
Management and grading of infusion reactions
The study drug infusions should always be administered in a hospital environment and under 
close supervision of the medically qualified staff member with immediate availability of 
appropriate resuscitation facilities.
Infusion reactions may occur during infusion with Xentuzumab (BI 836845) and include 
pyrexia, chills, rigors, dyspnoea, urticaria, bronchospasm, hypotension and hypertension. A 
one hour observation period is recommended following each infusion. Mild to moderate 
infusion reactions may be managed with a slower infusion rate and prophylactic 
antihistamines for subsequent dosing. Severe reactions require immediate and permanent 
discontinuation of infusion. The grading of hypersensitivity reactions will be according to the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03 (R10-4848).
Table 4.2.3.4: 1
Infusion reaction management
Infusion Reaction Grade
Management
CTCAE Grade 1 or 2
In the event of a mild to moderate CTCAE grade 1 or 2 non-
allergic infusion event, the infusion rate should be reduced by 
50%. Once the event has resolved the investigator should wait 
and deliver the infusion at the reduced rate for another 30 
minutes. If tolerated, the infusion rate may then be increased to 
the next close rate on the patient’s infusion schedule. In case of 
a Grade 2 event that requires therapy (e.g., antihistamines, 
NSAIDs, steroids, narcotics, IV fluids) or infusion interruption 
and resolves promptly the infusion may also be re-started at 
half of the infusion rate at the time of onset of the reaction.
CTCAE Grade 3
For patients experiencing CTCAE grade 3 infusion related 
event, infusion should be interrupted immediately and patients 
should receive aggressive symptomatic treatment. Only after all 
the symptoms have disappeared the infusion should be started. 
The infusion rate at restart should be half of the infusion rate at 
the time of onset of the reaction.
CTCAE Grade 4
Patients experiencing CTCAE grade 4 such as anaphylaxis 
during an infusion should have infusion immediately stopped 
and receive appropriate treatment including use of resuscitation 
medications and equipment that must be available. Such 
patients should be withdrawn from treatment and should be 
followed up.
The infusion duration may be extended to over one hour and up to a maximum of three hours, 
see Section 4.1.4.1.1.


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The infusion reactions should be treated symptomatically as judged clinically relevant by the 
investigator. For symptomatic treatment of infusion reactions: hydrocortisone, antihistamines 
such as chlorphenamine accompanied by an antipyretic/analgesic and/or a bronchodilator is 
recommended.
4.2.3.5
Management of hyperglycemia
In case of hyperglycaemia, treatment should follow standard and/or local guidelines and may 
include oral antidiabetics such as metformin 1g to 2.5 g/d. The appropriate expert advice 
should be considered in the management of hyperglycemia. 
In case of a grade 3 or higher hyperglycemic event, the patient should have immediate access 
to consultation with an endocrinologist or specialist. When treatment with the study drug is 
discontinued, the need for further antidiabetic treatment has to be evaluated depending on the 
blood glucose levels of the patient.
4.3
TREATMENT COMPLIANCE
Xentuzumab (BI 836845) will only be administered by trained staff in participating sites. 
Date and time of start and end of infusion, the exact amount of drug administered at each 
infusion will be documented in the eCRF/ study medication form.
Afatinib will be given in accordance with the protocol and the instructions of a site 
investigator.
The appropriate number of afatinib tablets for 4-week treatment course 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 4-week course 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 4-week 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. For afatinib, a maximum of 6 consecutive doses or 7 
non-consecutive doses may be missed for other reasons than drug-related AEs. Patients who
miss afatinib treatment more frequently are considered non-compliant. 
Afatinib should not be taken more than once a day. Patient experiencing emesis should not 
take a replacement dose.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY 
5.1.1
Endpoints of efficacy (anti-tumour activity) 
5.1.1.1
Dose confirmation Part A
There are no formal efficacy endpoints for the dose confirmation part, as this is mainly 
concerned with the determination of the MTD/RP2D of Xentuzumab (BI 836845) in 
combination with afatinib. However, anti-tumour activity will also be assessed by tumour
measurement and evaluation.
5.1.1.2
Expansion Part B
Primary endpoint
The primary endpoint for Part B is the objective response (OR), defined as complete response 
(CR) or partial response (PR).
Secondary endpoints

Disease control (DC), defined as complete response (CR), partial response (PR) or stable 
disease (SD). 

Time to objective response, defined as the duration of time from the date of first treatment 
administration until objective response.

Duration of objective response, defined as the duration of time from first objective 
response to the date of first objective tumour progression or death due to any cause.
 
 
Patients with measurable and evaluable disease should have assessment according to RECIST 
version 1.1.
5.1.2
Assessment of efficacy
The assessment by the investigator and the local radiologist will be the basis for continuation 
or discontinuation of the trial in an individual patient (in addition to safety).
Tumour assessment will be performed every 4 weeks after start of treatment with 
Xentuzumab (BI 836845) and afatinib for first 8 weeks (prior to courses 2 and 3),in 8-week 
intervals thereafter (e.g. prior to courses 5, 7, 9, etc.) and in 12-week interval after course 16 


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until PD or start of further anti-cancer treatment . Imaging may be performed within 7 days of 
scheduled time point. 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.
CT/MRI images not older than 30 days at start of treatment will suffice as screening images 
and don’t have to be repeated. The EOT tumour assessment is optional if performed within 
the previous 4 weeks. At baseline, the investigator along with the radiologist will record the 
target (five target lesions maximum and maximum two per organ) and non-target lesions at 
baseline in the eCRF before the start of treatment. The same method of assessment and the 
same technique should be used to characterise each reported lesion at baseline and during 
follow up. Measurable lesion should be available after tumour biopsy. Lesions in previously 
irradiated areas may not be considered measurable at baseline unless the lesions occurred 
after irradiation. Response will be evaluated according to the response evaluation criteria in 
solid tumours (RECIST version 1.1, R09-0262 – Appendix 10.5). In the event of a delay, 
interruption or discontinuation of treatment, tumour assessment should continue to follow the 
original schedule. The schedule should be followed until progression is observed or until the 
patient commences further treatment for disease, whichever occurs first.
5.2
SAFETY
5.2.1
Endpoints of safety
5.2.1.1
Dose confirmation Part A
The determination of the MTD/RP2D is the primary objective of Part A of this study and it 
will be based in occurrence of DLTs during the first treatment course. The MTD, together 
with the safety profile (if required, pharmacokinetic- and pharmacodynamic parameters) will 
serve to define the recommended phase II dose (RP2D) to be used for further trials in the 
development of Xentuzumab (BI 836845) in combination with afatinib.
Primary endpoints:

Maximum tolerated dose (MTD) of Xentuzumab (BI 836845) in combination with 
afatinib

Dose limiting toxicity (DLT) during the first treatment course
5.2.1.2
Expansion Part B
There are no formal safety endpoints for the expansion cohort in Part B of this trial. However, 
evaluation of safety data will be performed and presented separately for the expansion cohort.
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event


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An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions.
Patients may be hospitalized for administrative reasons during the trial (e.g. days on which 
pharmacokinetics sampling takes place). These and other hospitalizations planned at the 
beginning of the trial will not be considered as SAE if they have been reported at the 
screening visit in the source documents and performed as planned. Pre-existing conditions at 
baseline other than the disease will not be recorded as Adverse Events if they remain 
unchanged during the trial.
Intensity of adverse event
The intensity of adverse events should be classified and recorded according to the Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03 in the eCRF.
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms. 
Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
Worsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the (e)CRF.
If progressive disease occurs and is associated with symptoms , the term “Progressive 
Disease” should not be reported as AE, however, signs and symptoms of progressive disease 
will be reported as an (S)AE (if applicable). In this case Progressive Disease should be 


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documented on the CRF referencing also the AEs documented in the AE module of the CRF. 
Exception to this: Death due to progressive disease and where no signs or symptoms are 
available should be reported as “malignant neoplasm progression (grade 5, outcome fatal).”
Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the (e)CRF , if they are judged clinically relevant by the investigator.
Protocol-specified Adverse Events of Special Interest (AESI)
The following are considered as Protocol-specified Adverse Events of Special Interest:

Hepatic injury defined by the following alterations of liver parameters: 
o
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. Patients 
showing these lab abnormalities need to be followed up according to 
Appendices 10.6 this clinical trial protocol and the “DILI checklist” provided 
in ISF.
o
For patients with abnormal liver function tests at baseline (AST and/or 
ALT>ULN):
an elevation of transaminase ≥(baseline + 4 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. Patients 
with abnormal liver function tests must have their abnormalities and the
etiology documented in detail as baseline conditions. Every effort should be 
made to exclude the worsening of liver function due to underlying diseases.
Although rare, drug-induces liver injury is under constant surveillance by sponsors and 
regulators and is considered a protocol-specified significant adverse event. Timely 
detection, evaluation, and follow-up of laboratory alterations of selected liver laboratory 
parameters to distinguish an effect of the underlying malignancy on liver function from 
other causes are important for patient safety 

DLT occurs in the Part A. Please refer to Section 5.2.6 for definition of DLTs.
Protocol-specified AESI are to be reported in an expedited manner similar to Serious Adverse 
Events, even if they do not meet any of the seriousness criteria – for details please see section
5.2.2.2.
5.2.2.2
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through the end of the follow-up period) 


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will be collected, documented and reported to the sponsor by the investigator on the 
appropriate CRF(s) / eCRFs / SAE reporting forms. Reporting will be done according to the 
specific definitions and instructions detailed in the ‘Adverse Event Reporting’ section of the 
Investigator Site File. 
For each adverse event, the investigator will provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in 
Section 5.2.2.1. 
The residual effect period (REP) for Xentuzumab (BI 836845) is 42 days. Therefore all 
events reported within 42 days after the last trial medication will be considered on treatment. 
All adverse events will be reported up until last follow up visit. The investigator does not 
need to actively monitor patients for adverse events during the observation period or once the 
clinical trial has ended. However, if the investigator becomes aware of an SAE(s) that 
occurred during the observation period or after the patient has completed the clinical trial, it 
should be reported by the investigator to the sponsor if considered relevant by the investigator, 
see Table 5.2.2.2:1.
Table 5.2.2.2: 1
AE/SAE reporting requirements 
Time period
Reporting requirements
From signing of informed consent until 
last follow up visit (including 42 days 
after last trial drug administration and 
beyond if required)
Report all AEs and SAEs regardless of 
relatedness or whether the trial drug was 
administered. This includes all deaths.
Observation period (after the patient 
completed last follow-up and when 
progression occurred or when new anti-
cancer therapy started)
The investigator may report SAE if s/he 
becomes aware of and considers relevant.
Death should not be reported as an SAE 
except when it is considered related to 
trial treatment or trial design (because 
death is an outcome endpoint and will be 
followed up separately).
If not stipulated differently in the ISF, the investigator must report the following events via 
telephone/fax or if available for the trial, using the electronic submission process (RDC) 
immediately (within 24 hours) to the sponsor: SAEs and non-serious AEs relevant to the 
SAE(s), and protocol-specified AESI.   
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non-serious 
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the event.  If the event description is correct, the 


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item “serious” needs to be ticked and an SAE has to be reported in expedited fashion 
following the same procedure as above.
The list of these adverse events can be found via the RDC-system.
With receipt of any further information to the adverse events, a follow-up SAE report has to 
be provided. SAEs and non-serious AEs must include a causal relationship assessment made 
by the investigator.
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the Investigator Site File) or by using the 
electronic submission process. This immediate report is required irrespective of whether the 
investigational product has been administered or not and irrespective of causal relationship. It 
also applies if new information to existing SAEs or protocol-specified AESI becomes 
available. 
AEs which are not yet recovered at the End of Treatment (EOT) visit will be followed up 
until recovery or, in case of persistence, sufficient characterization of the AEs has been 
achieved and the investigator and the BI Clinical Monitor agree not to pursue them further.
Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female subject has been 
enrolled into the clinical trial, after having taken study medication, the investigator must 
report immediately any drug exposure during pregnancy to the sponsor. Drug exposure 
during pregnancy has to be reported immediately (within 24 hours or next business day 
whichever is shorter) to the defined unique entry point for SAE forms of the respective BI 
OPU (country-specific contact details will be provided in the Investigator Site File). The 
outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up. In the absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical 
Trials and not the SAE form is to be completed. The ISF will contain the Pregnancy 
Monitoring Form for Clinical Trials (Part A and Part B).
5.2.3
Assessment of safety laboratory parameters
Blood samples, including fasting serum samples (fasting state for at least 12 hours) will be 
collected up to two days prior to the scheduled time points as specified in the Flow Chart and 
analysed in a laboratory facility at (or close to) the investigational site. Safety laboratory 
examinations include hematology, coagulation, biochemistry and urine examination. See 
Table 5.2.3: 1 for details. In case of abnormal findings such as neutropenia or 
thrombocytopenia, blood will be examined as clinically indicated at the discretion of the 
investigator. All analyses are to be performed by the local clinical laboratory.  Unscheduled 
safety laboratory examinations will be documented in the eCRF along with the results. 
Safety laboratory assessment may be performed according to local practice but must include 
at least the following parameters:


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Table 5.2.3: 1 Clinical laboratory tests
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)
Chemistry
Blood urea/blood urea nitrogen (BUN), creatinine, 
alkaline phosphatase, aspartate aminotransferase (AST), 
alanine aminotransferase (ALT), γ-glutamyltransferase 
(GGT), bilirubin (total and direct), albumin, total protein, 
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
Electrolytes
Sodium, potassium, calcium, magnesium
Other (fasting)
Glucose and HbA1C
Urinalysis
pH, protein, glucose, erythrocytes, leucocytes, ketones 
and nitrite will be analyzed by dipstick (semi-quantitative 
measurements: -, +, ++, +++); in case of pathological 
finding further evaluation should be performed and results 
documented
5.2.4
Electrocardiogram
A standard 12-lead resting ECG will be performed locally at the time points specified in the 
Flow Chart. 
•
Screening
•
Pre-infusion, during infusion (after 30±5 min) and immediately prior to the end of 
the infusion (-10 min) on Day 1 of Course 1 
•
A single ECG to be taken pre-infusion on Day 15 of Course 1, pre-infusion at the 
start of every course on Day 1
•
EOT visit


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5.2.5
Assessment of other safety parameters
5.2.5.1
Physical examination, vital signs, height and weight
The physical examination must include cardiopulmonary examination, examination of the 
regional lymph nodes, and examination of the abdomen and an assessment of the mental and 
neurological status. Additional symptoms which have not been reported during a previous 
examination must be clarified. Wherever possible the same investigator should perform this 
examination.
The physical examination will be done at screening visit and at the time points specified in 
the Flow Chart. A symptom-directed examination is to be performed on all other visits. 
Vital sign measurements of blood pressure (systolic blood pressure, diastolic blood pressure), 
pulse rate, temperature and measurement of height (in cm, at screening) and body weight (in 
kg) and the evaluation of the ECOG performance status will be performed at the times 
specified in the Flow Chart.  
5.2.5.2
Left ventricular fraction
Left ventricular ejection fraction (LVEF) as measured by echocardiography or multiple gated
acquisition (MUGA) will be assessed at time points specified in the Flow Chart. LVEF 
assessment after start of study treatment may be performed if clinically indicated. The same 
method of measurement should be used throughout the study.
5.2.6
Dose Limiting Toxicity
The primary endpoint of Part A of this trial is the occurrence of Dose Limiting Toxicity 
(DLT).
For definition of DLT, it is essential that patients are treated sufficiently according to 
supportive care standards. DLT is assessed throughout the Part A. A study drug-related 
adverse event constitutes a DLT, if one of the following applies:

CTCAE Grade 4 neutropenia (< 0.5 x109/L) lasting ≥ 7 days

Febrile neutropenia ANC< 1.0 x109/L with a single temperature of > 38.3°C or a 
sustained temperature of ≥ 38°C for more than one hour.

Documented infection with ANC < 1.0 x109/L

CTCAE Grade 4 thrombocytopenia (< 25.0 x109/L) or CTCAE Grade 3 
thrombocytopenia associated with bleeding requiring platelet transfusion. 

CTCAE Grade 2 or higher decrease in cardiac left ventricular function

CTCAE Grade 2 diarrhoea lasting for 7 days or more, despite appropriate use of
standard anti-diarrhoeal therapy

CTCAE Grade ≥3 diarrhoea despite appropriate use of standard anti-diarrhoeal 
therapy for at least two days


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
CTCAE Grade ≥3 nausea and/or vomiting despite appropriate use of standard anti-
emetics for at least three days

CTCAE Grade ≥3 skin rash despite standard medical management as outlined in 
Section 4.2.3.2

AST or ALT > 5x ULN (for baseline AST/ALT ≤ ULN) or > (baseline value + 4x 
ULN) (for baseline AST/ALT > ULN)

CTCAE Grade ≥3 fatigue/asthenia lasting for more than seven days

CTCAE Grade ≥3 hyperglycemia lasting > 48 hours

All other non-hematologic adverse events of CTCAE Grade ≥3 (except alopecia, 
infusion reaction, and allergic reaction) leading to an interruption of afatinib and/or 
Xentuzumab (BI 836845) for more than 14 days until recovery to baseline or Grade 1, 
whichever is higher

Any other study drug related toxicity considered significant enough to be qualified as 
DLT in the opinion of the investigators (e.g. AE which not defined as DLT but 
requires dose reduction according to afatinib label) and confirmed by the safety 
review with the BI clinical monitor and BI project physician (TMM), will be reported 
as a DLT.
For the purposes of MTD determination, only DLT events that occur during the first 
treatment course of 28 days will be considered. Decisions regarding dose escalation/de-
escalation steps will be made only after discussion between the sponsor and the investigators 
at all sites, and in consideration of the available AE data. DLTs occurring after first treatment 
course and all unusual/unexpected AE during the whole treatment will be considered for the 
purpose of recommending the dose for Part B.
5.2.7
Maximum Tolerated Dose and recommended phase II dose
The Maximum Tolerated Dose (MTD) is defined as the highest dose level studied for which 
the incidence of DLT is no more than one out of 6 patients during the first course. DLTs 
occurring after the start of the second treatment course will be analyzed separately. DLTs will 
only be investigated in Part A of the study.
For the definition of DLT and determination of MTD refer to Sections 5.2.6 and 4.1.3.1.
The MTD will be defined on the basis of DLT observed during the first treatment course 
only. However, also DLTs after that time period will be considered for the purpose of 
determination of recommended phase II dose (RP2D). The MTD, maximal administered dose,
or a lower dose level will be chosen as the RP2D based on the totality of the safety data 
available. The discussion and agreement on dose selection between the investigator and the 
sponsor will be documented and communicated to all participating sites. 


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5.3
OTHER
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5.3.4
Demographics and medical history
The following patient demographic, baseline characteristics and medical history will be 
collected on the eCRF:

Demographics including sex, date of birth, ethnicity, race if allowed by local law, 
information on smoking and alcohol history.

Medical history and baseline conditions will be collected during the screening visit. 
Relevant concomitant diagnoses and/or therapies present at study entry and/or during 
screening and relevant to the patient’s safety during the study as judged by the 
investigator will be recorded in the eCRF.

History of lung cancer will also be obtained. The histological subtype, the date of the first 
histological diagnosis (month and year may be sufficient), tumour Stage according to the 


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TNM-classification at diagnosis, and the primary tumour site will be reported on the 
eCRF. The differentiation grade (not specified, undifferentiated, poorly differentiated, 
moderately differentiated, well differentiated), the number and location of metastatic sites 
(bone, liver, lung, pleural effusion, brain, other) at study entry will be provided. 

Previous surgeries and radiotherapy will be reported. Previously administered 
chemotherapy, tyrosine kinase inhibitors treatment, vaccine-therapy, antibodies therapy, 
immuno-therapy, and hormone-therapy will be reported including start and end dates 
(month and year may be sufficient) as well as the number of courses (when applicable), 
the best response obtained (complete response, partial response, stable disease, 
progressive disease, unknown), the reason leading to treatment discontinuation 
(completion, PD, AE) as well as the therapy mode (neoadjuvant, adjuvant or palliative). 
The date of tumour progression after previous line(s) of therapy for advanced or 
metastatic disease will be documented. 

Previous EGFR mutation status of the original tumour will be recorded if available.
5.4
APPROPRIATENESS OF MEASUREMENTS
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. 
The CTCAE criteria are used in the assessment of adverse events in cancer patients. In the 
present trial CTCAE version 4.03 (R10-4848) will be used.
 
 
 
 
 
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients must provide written informed consent (ICF) before any study related screening 
procedures can be performed.  A diagram of the stages of a patient’s participation in this trial 
is included in Section 3.1, and allowable time windows for visits are included in the Flow 
Chart.
Investigational drugs Xentuzumab (BI 836845) and afatinib will be dispensed at visit 
according to the Flow Chart. Patients will receive a new medication kit through the IRT 
system on each occasion for medications supplied by the sponsor.
Tumour assessments at screening must be completed within 30 days of start of treatment. 
However, upon clinical assessment if a patient presents with clinical symptoms of 
progressive disease, the investigator may use clinical judgement to determine whether to have 
the patient undergo another scan prior to starting treatment. All other screening assessment 
must be completed within 42 days of start of treatment. 
All patients are to adhere to the visit schedule as specified in the Flow Chart. If any visit has 
to be rescheduled, subsequent visits should follow the original visit date schedule. The date 
and reason for the rescheduled visit should be noted in the source documentation. In the event 
of any study drug interruption or delay of treatment, the tumour assessment schedule should 
not be changed. Scheduled visit which coincides holiday and can’t be adjusted within time 
window may be skipped after discussion with BI Clinical Monitor.
Blood samples for pharmacokinetics, biomarkers and pharmacogenetics will be collected 
from all patients. Tissue and blood samples will be collected for biomarkers from both 
treatment arms; For specific PK, biomarker and pharmacogenetics sampling schedule refer to 
Section 5.3, 5.5 and Appendix 10.7. Actual clock time for study drug administration and for 
each blood draw needs to be documented in the eCRF.
On visit days when PK sampling is scheduled, afatinib should be administrated during the
clinical visit. On visit days when safety lab is scheduled, patients should show up in fasting 
condition.
Adverse events and concomitant medication must be collected starting from the date of ICF 
being obtained until the last follow-up visit. 
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
Refer to the Flow Chart for procedure details. Please review Sections 3.3.2 and 3.3.3 for 
specific eligibility criteria for Part A and Part B.


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Screening procedures must be performed within 42 days of start of treatment. Patients who 
failed screening may repeat the screening after discussion between investigator and sponsor 
providing that reasons for screening failure were reversible and have resolved.
The provision of tumour tissue is mandatory. An archival tumour tissue must be collected at 
screening visit for biomarker analysis. If an archival tumour sample is not available, tumour
biopsy must be performed during screening period.
In case there is a documented result of EGFR mutations available before study entry, local 
result will be accepted in Part A. In the Part B, the eligibility criteria of EGFR mutations 
must be based on the results of the authorized central laboratory.
6.2.2
Treatment period
Every treatment course is 28 days. In case a patient misses the scheduled study visit but 
reports to the investigative site before the next scheduled study visit, the missed visit will be 
performed. The current date and reason for the delayed visit will be noted in the source 
documentation. All subsequent study visits should take place at the next scheduled visit the 
Flow Chart. In the event of any study drug interruption or delay of treatment, the tumour 
assessment scheduled will not be changed. The missed scheduled Xentuzumab (BI 836845)
administration will be skipped if the patient reports to the investigator outside the time 
window specified in Flow Chart.
In this trial, patients may be hospitalized for the day of treatment and PK sampling at the 
discretion of the investigator; patients may be discharged if tolerated the treatment well and 
no safety concerns are present as judged by the investigator.
Refer to the Flow Chart for procedure details. 
6.2.3
End of trial and follow-up period
6.2.3.1
End of treatment visit
The End of Treatment (EOT) visit should be performed within14 days after permanent 
discontinuation of study drug (Xentuzumab (BI 836845) and afatinib). If the last 
administration of study drug occurs during a scheduled visit, examinations as defined for 
EOTV should be performed instead of the examination for the scheduled visit.
The patient must return all study drugs, and the site must document why the patient is 
discontinuing the treatment.
Blood samples for soluble biomarkers, PK and immunogenicity must be obtained.
In patients who are experiencing disease progression at EOTV, an optional fresh tumour
biopsy might be performed from those with appropriate informed consent in case patient 
agrees to provide tumour samples after progression.
Refer to Flow Chart for details.


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6.2.3.2
Follow-up
The residual effect period (REP) for Xentuzumab (BI 836845) is 42 days. Therefore all 
events reported within 42 days after permanent discontinuation of trial medication will be 
considered as ‘on treatment’. At the end of REP, the first follow-up visit (FU1) is to be 
performed. 
All patients should have a follow-up visit 42 days (+ 7 days) after permanent discontinuation 
of study drugs. At this follow-up visit, an end of trial assessment will be performed and 
documented in the e-CRF. 
Additional follow-up visits at 8-week intervals should be performed for patients who are not 
progressed or new anti-cancer treatment has not been started according to the Flow Chart.
Follow-up period for every patient will end at the earliest of the following events:

Lost to follow-up

Disease progression

Initiation of a new anti-cancer therapy

Death

End of whole trial as specified in Section 6.2.3.5
The following will be obtained and/or performed during the follow-up visits.

Record any new AEs or SAEs and follow-up of ongoing adverse events

Concomitant medications for treatment of an adverse event including trade name, 
indication and dates of administration

Tumour assessment and imaging will be performed if applicable.  

Treatment and date with any other anti-cancer drug and/or best supportive care including 
the name and type of the anti-cancer drug

Outcome (date of and reason for death, in case the patient had PD the actual date of PD 
will be recorded)
Follow-up of patients with AEs which have not recovered at the last planned follow-up visit, 
please refer to Section 5.2.2.2.
6.2.3.3 Observation period
There is no observation period in Part A.
All patients in Part B will be followed-up for overall survival every 90 days (± 15 days) after 
the last follow-up visit (as specified in Section 6.2.3.2) until death, lost to follow-up or 
completion of the whole trial (as specified in Section 6.2.3.5) whatever occurs earlier.


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For patients who progressed on treatment, this period starts after the FU1 visit. For patients 
who have not progressed on treatment, this period starts after the last follow up visit. 
No further AE/SAE collection is needed unless considered relevant by the investigator.
Follow-up of AEs not yet recovered at the last follow up visit will continue. 
These visits may also be performed by telephone interview in case the patient is unable to 
visit the investigator.
The following information will be collected during the observation period:

Date and method of contact

Further anti-cancer treatment : regimen and drugs name, start and stop dates, reason 
for stopping this treatment

Information on death

Follow-up of adverse events in case they were not yet recovered at last follow up 
visit
6.2.3.4
Patient completion
A patient has to be considered to have completed the trial if no further information is 
collected, i.e. in case any of the following applies:

Completion of planned observation period

Lost to follow-up

Death
6.2.3.5  End of whole Trial
The end of the trial (both parts) will be when the last patient has completed the first follow-up 
visit (FU1) as defined in Section 6.2.3.2.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The trial will be performed as an open label study. The primary objective of the dose 
confirmation part of the trial is to determine the MTD/RP2D of Xentuzumab (BI 836845) in 
combination with afatinib in patients with NSCLC with progression following prior treatment
(EGFR TKI or platinum based chemotherapy). To do so, patients are entered sequentially 
into escalating/de-escalating dose tiers. Patients will be included into the study following 
a3+3 design with escalating/de-escalating steps (Edler and Burkholder in Crowley R07-0220, 
see also Section 4.1.3). After the determination of MTD for Xentuzumab (BI 836845) in 
combination with afatinib, 6 additional patients will be included at this dose level for the 
evaluation of the RP2D. 
In the expansion cohort of Part B, 18 additional patients will be entered. These patients must 
be diagnosed with EGFR mutant NSCLC and must have been progressed following prior 
TKIs. They will be treated with Xentuzumab (BI 836845) in combination with afatinib at the 
RP2D found in the dose confirmation part of the study. For patients who had disease 
progression while on afatinib less than 40 mg/day, the starting dose is the last dose of afatinib.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The analyses in this trial are descriptive and exploratory. No formal statistical tests will be
performed.
7.3
PLANNED ANALYSES
All patients who are treated with at least one single dose of Xentuzumab (BI 836845) or
afatinib will be included in all efficacy and safety analyses.
During Part A, cohorts of patients treated with Xentuzumab (BI 836845) in combination with 
afatinib will be evaluated continuously based on the totality of the safety data in order to 
determine the MTD and the RP2D.
Summary outputs of efficacy analyses will include all patients entered in Part B of the trial
and patients entered in RP2D level in Part A. All endpoints defined in Section 5.1.1 will be 
summarized descriptively. 
Safety analysis will be summarized separately for patients treated in Part A and Part B. 
7.3.1
Primary analyses
7.3.1.1
Part A
The primary objective of the dose confirmation part is to determine the MTD of Xentuzumab 
(BI 836845) in combination with afatinib. The analysis will be based in occurrence of DLT 
during the first treatment course. 


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Section 5.2.6 specifies adverse events that qualify for DLT, and Section 7.3.3 below gives
further information about the safety analyses.
7.3.1.2
Part B
Early efficacy signals of Xentuzumab (BI 836845) in combination with afatinib will be 
explored in the second part of this trial, and objective response rate will be used as primary 
endpoint. Tumour assessments will be performed according to RECIST v1.1.
Descriptive statistics for objective response rate (CR or PR) will be provided for all treated 
patients. The primary analysis will be performed when the last patient in Part B completes the 
first follow-up visit (FU1) as specified in Section 6.2.3.2.
7.3.2
Secondary analyses
Disease control (CR, PR or SD), time to objective response, duration of objective response, 
 will be summarized using descriptive statistics. 
Kaplan-Meier curves will be plotted to graphically display the progression-free survival and 
overall survival for the expansion cohort in Part B.
7.3.3
Safety analyses
The occurrence of dose limiting toxicity (DLT) as well as the incidence, intensity, duration
and causality of adverse events graded according to CTCAE Version 4.03 (R10-4848), 
laboratory parameters and vital signs will be evaluated in both parts of the study.
AEs will be evaluated using the CTCAE grading scheme. The overall incidence and intensity 
of adverse events, as well as their relatedness to the study medication will be reported for all 
treatment arms and combinations. Serious adverse events and events leading to dose
reduction or treatment discontinuation will be tabulated. Descriptive statistics will be used to 
describe changes in laboratory parameters over time. In addition, all abnormalities of 
potential clinical relevance will be reported. 
AEs that started within the period starting with first administration of the trial drug and 
ending 42 days after permanent discontinuation of study drugs (both Xentuzumab (BI 836845)
and afatinib) will be considered as having occurred during ‘on treatment’. Later events will 
be attributed to the post-treatment period and and events occurring between IC date and first 
drug intake will be presented separately.
7.3.4
Interim analyses
No formal interim analysis is planned. 
The data will be evaluated as they accumulate. DLTs and other AEs will be reviewed by the 
sponsor before each dose escalation/de-escalation. In addition, although no formal interim 
clinical trial report will be produced, a limited set of tables and listings will be provided to 
document the MTD/RP2D of Xentuzumab (BI 836845) in combination with afatinib.
Snapshots of the database (e.g., as a basis for presentation of preliminary study results at 


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conferences, or for safety reasons, or for regulatory documents) may be taken at any time 
during the study conduct.
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.4
HANDLING OF MISSING DATA
Every effort will be made to obtain complete information in this phase I study, especially on
all adverse events with particular emphasis on dose limiting toxicities. No imputation will be
performed on missing data unless otherwise specified.
Missing baseline laboratory values will be imputed by the respective values from the
screening visit. Missing or incomplete AE dates will be imputed according to BI guidelines.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.5
RANDOMISATION
In this open-label, Phase Ib study, randomisation is not applicable. Patients will be assigned,
not randomised, independently and sequentially to each dose level in both parts of the study.
7.6
DETERMINATION OF SAMPLE SIZE
Part A follows a 3+3 design with escalating/de-escalating steps (R07-0220) for the 
determination of the MTD of Xentuzumab (BI 836845) in combination with afatinib. 
According to this design as described in Section 4.1.3, up to 18 evaluable patients may be 
needed to identify the MTD. Six additional patients will be treated at the RP2D level before 
commencing Part B. 
The patients in Part B will be treated at the RP2D. In the expansion cohort, 18 additional 
patients will be treated. Assuming a true response rate of 20% a sample size of 18 patients 
leads to a probability of 73% of observing at least 3 objective responses (CR or PR). If the 
true response rate is higher i.e. 25%, then the probability to observe at least 3 objective 
responses is 86%. The probability of a false positive signal is <0.1%.   
True Response Rate
# Patients 
per cohort
Probability to observe at least
1 event
2 events
3 events
4 events
5 events
0.15
16
0.92575
0.71610
0.43862
0.21011
0.07905
0.15
18
0.94635
0.77595
0.52034
0.27976
0.12056
0.15
20
0.96124
0.82444
0.59510
0.35227
0.17015
0.20
16
0.97185
0.85926
0.64816
0.40187
0.20175
0.20
18
0.98199
0.90092
0.72866
0.49897
0.28365
0.20
20
0.98847
0.93082
0.79392
0.58855
0.37035
0.25
16
0.98998
0.93652
0.80289
0.59501
0.36981
0.25
18
0.99436
0.96054
0.86470
0.69431
0.48133
0.25
20
0.99683
0.97569
0.90874
0.77484
0.58516
0.01
16
0.14854
0.01093
0.00051
0.00002
0.00000
0.01
18
0.16549
0.01376
0.00073
0.00003
0.00000
0.01
20
0.18209
0.01686
0.00100
0.00004
0.00000
Altogether the total sample size is anticipated to be approximately 42 entered patients. 
Naturally this represents only a rough estimation since the number of patients needed is 
induced by the “3+3” design and is subject to different influencing factors. Assuming a 60% 
of screen fail rate, 105 patients are anticipated to be enrolled in the trial.


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


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auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
8.3
RECORDS
eCRFs for individual patients will be provided by the sponsor via RDC. For drug
accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRFs/eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRFs/eCRFs, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents
described in Section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not.
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For Xentuzumab (BI 836845), this is the current version of the Investigator’s Brochure (U10-
2830). For afatinib, this is the current version of the Company Core Data Sheet (CCDS). The 
current versions of these reference documents are to be provided in the ISF. No AEs are 
classified as listed for study design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.


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8.5
STATEMENT OF CONFIDENTIALITY
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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growth factor receptor tyrosine kinase inhibitors in non-small-cell lung 
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Porta C, Osanto S, Ravaud A, Climent MA, Vaishampayan U, White DA et.al.
Management of adverse events associated with the use of everolimus in 
patients with advanced renal cell carcinoma. Eur J Cancer 2011. 47: 1287 -
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Pao W, Chmielecki J. Rational, biologically based treatment of EGFR mutant 
non-small-cell lung cancer. Nat Rev Cancer. 2010. 10: 760 - 774 
P12-03682
Miller VA, Hirsh V, Cadranel J, Chen YM, Park K, Kim SW et.al. Afatinib 
versus placebo for patients with advanced, metastatic non-small-cell lung 
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2045(12)70087-6 Lancet Oncol 2012. 13(5):528-538.
P12-11350
Janjigian YY, Smit EF, Horn L, Groen HJM, Camidge DR, Gettinger S et.al. 
Activity of afatinib/cetuximab in patients with EGFR mutant non-small cell 
lung cancer and acquired resistance to EGFR inhibitors. 37th Ann Cong of the 
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Gordon MS, Mendelson DS, Gross M, Uttenreuther-Fischer M, Ould-Kaci M, 
Zhao Y, Stopfer P, Agus DB. A phase I, open-label, dose-escalation study of 
continuous once-daily oral treatment with afatinib in patients with advanced 
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P13-02270
Zhou H, Mascelli MA. Mechanisms of monoclonal antibody-drug interactions. 
Annu Rev Pharmacol Toxicol. 2011. 51: 359-72
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tyrosine kinase inhibitor-resistant disease. J Clin Oncol. 2013. 31 (8): 1070 -
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Lacouture M, Schadendorf D, Chu CY, Uttenreuther-Fischer M, Stammberger 
U, O'Brien D et.al. Dermatologic adverse events associated with afatinib: an 
oral ErbB family blocker. Expert Review of Anticancer Therapy, Epub ahead 


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of print, Posted online on March 18, 2013, doi: 10.1586/era.13.30 Expert Rev 
Anticancer Ther 2013. 13(6)(Suppl): 721-728.  
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Yang JCH, Reguart N, Barinoff J, Koehler J, Uttenreuther-Fischer M, 
Stammberger U et.al. Diarrhea associated with afatinib: an oral ErbB family 
blocker. Expert Review of Anticancer Therapy, Epub ahead of print, Posted 
online on March 18, 2013, doi: 10.1586/era.13.31 Expert Rev Anticancer Ther 
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Zardavas, D, Basalga J and Piccart M. Emerging targeted agents in metastatic 
breast cancer. Nat Rev Clin Oncol. 2013 Apr;10(4):191-210.
P13-07382
Sequist LV, Yang JCH, Yamamoto N, O'Byrne K, Hirsh V, Mok T et.al.
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metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013. 31 
(27): 3327 - 3334 
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Friedbichler K, Hofmann MH, Kroez M, Ostermann E, Lamche HR, Koessl C
et.al. Pharmacodynamic and antineoplastic activity of BI 836845, a fully 
human IGF ligand neutralizing antibody, and mechanistic rationale for 
combination with rapamycin. Mol Cancer Ther. 2014. 13 (2): 399 - 409 
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Chong CR, Janne PA. The quest to overcome resistance to EGFR-targeted 
therapies in cancer. Nature Med. 2013. 19(11): 1389 - 1400 
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Soria JC, Felip E, Cobo M, Lu S, Syrigos K, Lee KH, Goker E, Georgoulias V, 
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Wang B, Chand VK, Goss GD, LUX-Lung 8 Investigators. Afatinib versus 
erlotinib as second-line treatment of patients with advanced squamous cell 
carcinoma of the lung (LUX-Lung 8): an open-label randomised controlled 
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Yang JC, Sequist LV, Zhou C, Schuler M, Geater SL, Mok T, Hu CP, 
Yamamoto N, Feng J, O'Byrne K, Lu S, Hirsh V, Huang Y, Sebastian M, 
Okamoto I, Dickgreber N, Shah R, Märten A, Massey D, Wind S, Wu YL. 
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mutation-positive lung adenocarcinoma: post hoc analyses of the randomized 
LUX-Lung 3 and 6 trials. Ann Oncol. 2016 Sep 6. pii: mdw322. 
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Lynch TJ, Bell DW, Sordella R, Gurubhagavatula S, Okimoto RA, Brannigan 
BW et.al. Activating mutations in the epidermal growth factor receptor 


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underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J 
Med 2004. 350(21):2129-2139.
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Paez JG, Janne PA, Lee JC, Tracy S, Greulich H, Gabriel S et.al. EGFR 
mutations in lung cancer: correlation with clinical response to gefitinib 
therapy. Science 2004. 304:1497-1500.
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Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I et.al. EGF 
receptor gene mutations are common in lung cancers from 'never smokers' and 
are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl 
Acad Sci USA 2004. 101(36):13306-13311.
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Jackman DM, Yeap BY, Sequist LV, Lindeman N, Holmes AJ, Joshi VA et.al. 
Exon 19 deletion mutations of epidermal growth factor receptor are associated 
with prolonged survival in non-small cell lung cancer patients treated with 
gefitinib or erlotinib. Clin Cancer Res 2006. 12(13):3908-3914.
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Riely GJ, Pao W, Pham D, Li AR, Rizvi N, Venkatraman ES et.al. Clinical 
course of patients with non-small cell lung cancer and epidermal growth factor 
receptor exon 19 and exon 21 mutations treated with gefitinib or erlotinib. 
Clin Cancer Res 2006. 12(3):839-844.
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Crowley J, Ankerst DP, Handbook of statistics in clinical oncology. Second 
Edition, Boca Raton, Chapman & Hall/CRC Press, 2006 2006 
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Giaccone G, Melosky B, Reck M. Epidermal growth factor receptor inhibitor 
(EGFRI)-associated rash: a suggested novel management paradigm.A 
consensus position from the EGFRI dermatologic toxicity forum. ECCO 14, 
14th Eur Cancer Conf, Barcelona, 23 - 27 Sep 2007 (Poster) 2007
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Lynch TJ, Kim ES, Eaby B, Garey J, West DP, Lacouture ME. Epidermal 
growth factor receptor inhibitor-associated cutaneous toxicities: an evolving 
paradigm in clinical management. Oncologist 2007. 12(5):610-621.
R09-0262
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R,
Dancey J et.al. New response evaluation criteria in solid tumours: revised 
RECIST guideline (version 1.1). Eur J Cancer 2009;45: 228-247
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Guix M, Faber AC, Wang SE, Olivares MG, Song Y, Qu S et.al. Acquired 
resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by 
loss of IGF-binding proteins. J Clin Invest 2008. 118(7):2609-2619.
R09-4437
Mok TS, Wu YL, Thongprasert S, Yang CH, Chu DT, Saijo N, 
Sunpaweravong P et.al. Gefitinib or carboplatin-paclitaxel in pulmonary 
adenocarcinoma. N Engl J Med 2009. 361(10):947 - 957 
R09-4439
Rosell R et al, Spanish Lung Cancer Group. Screening for epidermal growth 
factor receptor mutations in lung cancer. New England Journal of Medicine, 


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published on August 19, 2009, doi: 10.1056/NEJMoa0904554 N Engl J Med 
2009. 361(10):958-967.
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Jackman DM, Pao W, Riely GJ, Engelman JA, Kris MG, Janne PA et.al.
Clinical definition of acquired resistance to epidermal growth factor receptor 
tyrosine kinase inhibitors in non-small-cell lung cancer. J Clin Oncol. 2010. 28 
(2): 357 - 360 
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Common terminology criteria for adverse events (CTCAE): version 4.0 (NIH 
publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 2010), 
revised June 2010, reprinted June 2010). 
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Potthoff K, Hofheinz R, Hassel JC, Volkenandt M, Lordick F, Hartmann JT
et.al. Interdisciplinary management of EGFR-inhibitor-induced skin reactions: 
a German expert opinion. Ann Oncol 2011. 22(3): 524-535.
R11-4674
Morgillo F, Kim WY, Kim ES, Ciardiello F, Hong WK, Lee HY. Implication 
of the insulin-like growth factor-IR pathway in the resistance of non-small cell 
lung cancer cells to treatment with gefitinib. Clin Cancer Res 2007. 
13(9):2795-2803.
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Cancerologie, Associazone Italiana Oncologia Toracica Erlotinib versus 
standard chemotherapy as first-line treatment for European patients with 
advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a 
multicentre, open-label, randomised phase 3 trial. Lancet Oncol 2012. 13: 239 
- 246 
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Sequist LV et.al. Genotypic and histological evolution of lung cancers 
acquiring resistance to EGFR inhibitors.Sci Transl Med. 2011. 3(75): 75ra26 
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Weickhardt A, Doebele R, Oton A, Lettieri J, Maxson D, Reynolds M et.al. A 
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cancer: the current and future in breast cancer therapy. Recent Patents 
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Wu JY, Yu CJ, Chang YC, Shih JY, Yang PC. Effectiveness of tyrosine 
kinase inhibitors on 'uncommon' epidermal growth factor receptor mutations 
of unknown clinical significance in non-small cell lung cancer. Clin Cancer 
Res. 2011. 17 (11): 3812 - 3821 
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results from a phase I study with AZD9291: an irreversible inhibitor of 
epidermal growth factor receptor (EGFR) activating and resistance mutations
in non-small-cell lung cancer (NSCLC). Eur Cancer Cong, Amsterdam, 27 
Sep - 1 Oct 2013. 2013. Abstr 33
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Goldberg SB, Oxnard GR, Digumarthy S, Muzikansky A, Jackman DM, 
Lennes IT et.al. Chemotherapy with erlotinib or chemotherapy alone in 
advanced non-small cell lung cancer with acquired resistance to EGFR 
tyrosine kinase inhibitors. Oncologist 2013. 18(11): 1214-1220.
R14-1168
Cortot AB, Repellin CE, Shimamura T, Capelletti M, Zejnullahu K, Ercan D
et.al. Resistance to irreversible EGF receptor tyrosine kinase inhibitors 
through a multistep mechanism involving the IGF1R pathway. Cancer Res.
2013. 73(2): 834-843
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Sharma SV, Settleman J. Oncogene addiction: setting the stage for 
molecularly targeted cancer therapy. Genes Dev 2007. 21(24): 3214-3231.
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Choi YJ, Rho JK, Jeon B, Choi SJ, Park SC, Lee SS et.al. Combined 
inhibition of IGFR enhances the effects of gefitinib in H1650: a lung cancer 
cell line with EGFR mutation and primary resistance to EGFR-TK inhibitors. 
Cancer Chemother Pharmacol 2010. 66: 381-388.
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Qi HW, Shen Z, Fan LH. Combined inhibition of insulin-like growth factor-1 
receptor enhances the effects of gefitinib in a human non-small cell lung 
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Peled N, Wynes MW, Ikeda N, Ohira T, Yoshida K, Qian J et.al. Insulin-like 
growth factor-1 receptor (IGF-1R) as a biomarker for resistance to the tyrosine 
kinase inhibitor gefitinib in non-small cell lung cancer. Cell Oncol. 2013. 
36(4): 277-288.
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Vazquez-Martin A, Cufi S, Oliveiras-Ferraros C, Torres-Garcia VZ, 
Corominas-Faja B, Cuyas E et.al. IGF-1R/epithelial-to-mesenchymal 
transition (EMT) crosstalk suppresses the erlotinib-sensitizing effect of EGFR 
exon 19 deletion mutations. Sci Rep 2013. 3:2560
R14-1339
Yamasaki F, Johansen MJ, Zhang D, Krishnamurthy S, Felix E, 
Bartholomeusz C et.al. Acquired resistance to erlotinib in A-431 epidermoid 
cancer cells requires down-regulation of MMAC1/PTEN and up-regulation of 
phosphorylated Akt. Cancer Res 2007. 67(12):5779-5788.


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R16-4930
Calvo E, Soria JC, Ma WW, Wang T, Bahleda R, Tolcher AW, et al A phase I 
clinical trial and independent patient-derived xenograft study of combined 
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9.2
UNPUBLISHED REFERENCES
U03-3218
Investigator’s Brochure. BIBW2992 Version 17, 5 July 2016.
U10-2830
Investigator’s Brochure: BI 836845, Version 7.0, 30 May 2016.


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10.
APPENDICES
10.1
LIST OF POTENT INHIBITORS AND INDUCERS OF P-GLYCOPROTEIN 
Inhibitors
Inducers
Amiodarone
Azithromycin
Captopril
Carvedilol
Clarithromycin 
Conivaptan
Cyclosporine 
Diltiazem
Dronedarone
Erythromycin
Felodipine
Itraconazole
Ketoconazole
Lopinavir
Nelfinavir
Ritonavir
Quinidine
Ranolazine
Saquinavir
Tacrolimus
Ticagrelor
Verapamil
Carbamazepine
Phenytoin
Rifampicin
St John’s Wort
Phenobarbital Salt
Tipranavir
Ritonavir
As the information on potent inhibitors and inducers of P-glycoprotein may evolve, it is
important for the investigator to assess the status of each concomittant therapies and in case 
of questions contact BI clinical monitor.
While caution needs to continue to be exercised in concomitant use of P-gp 
inhibitors/inducers with afatinib, based on new data from two drug-drug interaction (DDI) 
trials (U03-3218) investigating the effect of ritonavir and rifampicin, respectively, on 40 mg 
afatinib, their use in patients needing such therapies is no longer prohibited. It cannot be 
excluded that the plasma exposure to afatinib may increase under concomitant treatment with 
strong P-gp inhibitors. Conversely, strong P-gp inducers may decrease the plasma 
concentrations of afatinib. However, maximum observed effects are rather mild to moderate 
and could even be avoided for the potent inhibitor ritonavir when given simultaneously or 6 h 
after afatinib. Therefore caution has to be exercised when combining afatinib with potent P-
gp modulators.


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10.2
COCKCROFT-GAULT FORMULA
Estimated creatinine clearance rate (eCCR) using Cockcroft-Gault formula
Or when serum creatinine is measured in µmol/L
Where Constant is 1.23 for men and 1.04 for women
eCCR =
(140-Age)X Mass (in kilograms) X (0.85 if Female)
72 X Serum Creatinine (in mg/dL)
(140-Age)X Mass (in kilograms) X Constant
eCCR =
Serum Creatinine (in µmol/L)


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10.3
NYHA CLASSIFICATION OF HEART FAILURE 
Class
Patient Symptoms
Class I (Mild)
No intention 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.
10.4
ECOG PERFORMANCE STATUS
ECOG PERFORMANCE STATUS*
Grade
ECOG
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all selfcare but unable to carry out any work 
activities. Up and about more than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of 
waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or 
chair
5
Dead
* As published in Am. J. Clin. R01-0787


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10.5
RECIST (VERSION 1.1)
The criteria below are based on RECIST 1.1 (R09-0262).
The preferred method of assessment is a spiral CT scan with IV and oral contrast, unless IV 
and/or oral contrast are medically contraindicated. CT scans of the chest, abdomen and other 
areas of known or newly suspected disease must be performed. Scans of the abdomen, pelvis 
and other areas of the body, but not chest, may be done with MRI instead of CT. 
Skin lesions followed as target lesions must be documented by colour digital photography 
and must include in the image a ruler with millimetre subdivisions and a label that includes 
the patients ID and date. 
Bone scans (using 99m-technetium polyphosphonate scintigraphy) are recommended at 
baseline if the patient has any signs and symptoms consistent with bone metastasis or a 
history of bone metastasis. Bone metastasis identified at baseline must be documented and 
assessed according to RECIST 1.1 at the times of the other tumour measurements indicated in 
the flow chart. During the study bone scans should be repeated as clinically indicated in 
patients without bone metastasis at Baseline. 
Tumour assessment will be performed every 4 weeks after start of treatment with 
Xentuzumab (BI 836845) and afatinib for first 8 weeks (prior to courses 2 and 3), in 8-week 
intervals thereafter (e.g. prior to courses 5, 7, 9, etc.) and in 12-week interval after course 16
until PD or start of further anti-cancer treatment. 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.   
Measurability of tumour at baseline
Measurable lesions
Lesions that can be accurately measured in at least one dimension with longest diameter ≥10 
mm (by CT scan, MRI, caliper measurement) or ≥20 mm (by chest X-ray).  Pathological 
lymph nodes, defined as lymph nodes with a short axis >15mm are also measurable.
Measurable disease
Measurable disease requires the presence of at least one measurable lesion. Measurable lesion 
if limited to either small (<2cm) solitary visceral lesion or scant (<5cm) lymph nodes only 


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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.
New lesions in irradiated fields
Previously irradiated lesions should not be used as indicator lesions unless there has been 
demonstrated progression in the lesion. However, new lesions occurring in previously 
irradiated fields can be used to assess the anti-tumour response.
Methods of measurement
All measurements must be recorded in metric notation, using a ruler or calipers. All baseline 
evaluations must be performed as close as possible to the treatment start and never more than 
4 weeks before the beginning of the treatment. If a lesion is considered too small to measure, 
a default measurement of 5mm should be applied. If the lesion is not visible, a default 
measurement of 0mm should be applied.
The same method of assessment and the same technique must be used to characterise each 
identified and reported lesion at baseline and during follow-up.
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). In the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is obligatory.
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 5 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to the chest, abdomen and 
pelvis.
Ultrasound, endoscopy and laparoscopy should not be used to measure tumour lesions or 
evaluate tumour response. However, these techniques can be useful to supplement 
information from other techniques.
Cytology and histology can be used to differentiate between PR and CR in rare cases (for 
example, residual lesions in tumour types such as germ cell tumours where known residual 
benign tumours can remain).


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Baseline Documentation of Target and Non-target Lesions
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs should be identified as target lesions and will be 
recorded, measured (longest diameter = LD) and numbered at baseline. Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their suitability 
for accurate repetitive measurements (either by imaging techniques or clinically). Lymph 
nodes must be ≥15mm in order to be considered as target lesions. 
A sum of the longest diameter (LD) for all target lesions will be calculated and reported as 
the baseline sum LD. The baseline sum LD will be used as reference to further characterise 
the objective tumour response of the measurable dimension of the disease (see Table 10.5:1).
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.
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).


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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.
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
10.6
CLINICAL EVALUATION OF LIVER INJURY
10.6.1
Introduction
Alterations of liver parameters, as described in Section 5.2.2.1 (Protocol-Specified Adverse 
Events of Special Interest), are to be further evaluated using the following procedures:


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10.6.2
Procedures
Any elevation of ALT/AST and bilirubin qualifying as laboratory alert should be confirmed 
using the initial sample if possible.
If the alert is confirmed on initial sample, or it is not possible to repeat testing using initial 
sample, the following must be completed:
1)
Evaluate patient within 48 hours and
2)
Perform the following laboratory tests: 
1.
Repeat of AST, ALT, bilirubin (with fractionation to total and direct) 
2.
Haptoglobin
3.
Complete blood count and cell morphology
4.
Reticulocyte count
5.
Creatine Kinase (CK)
6.
Lactate dehydrogenase (LDH)
7.
Alkaline Phosphatase
The results of these laboratory tests must be reported to BI as soon as possible.
If the initial alert values (ie AST,ALT, and bilirubin) are confirmed on the second sample 
described as above, then an abdominal ultrasound or clinically appropriate alternate imaging  
(to rule out biliary tract, pancreatic or intrahepatic pathology, e.g. bile duct stones or 
neoplasm) must be completed within 48 hours. 
The findings from the hepatic imaging (including comparison to prior imaging if available) 
must be made available as soon as possible as part of the adverse event reporting process. In 
the event the etiology of the abnormal liver tests results is not identified based on the imaging 
(e.g. biliary tract, pancreatic or intrahepatic pathology), then the “DILI checklist” must be 
completed.  Details of the “DILI checklist” are provided in the ISF.  The following 
assessments need to be performed in order to complete the “DILI checklist” and results will 
be reported via the eCRF:

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), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-
mitochondrial antibody, Epstein Barr Virus (VCA IgG, VCA IgM), cytomegalovirus (IgG, 
IgM), herpes simplex virus (IgG, IgM)*, varicella (IgG, IgM)*, parvovirus (IgG, IgM)*
Hormones, tumour marker
Thyroid-stimulating hormone(TSH)*
Haematology
Thrombocytes, eosinophils
*If clinically indicated (e.g. immunocompromised patients)
Long term follow-up
Initiate close observation of subjects by repeat testing of ALT, AST, and bilirubin (with 
fractionation to total and direct) at least weekly until the laboratory ALT and or AST 
abnormalities 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).


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1
Date of CTP revision
15 Jul 2015
EudraCT number
Not applicable
BI Trial number
1280.16
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
A phase Ib open-label clinical trial of once daily 
oral treatment of afatinib plus weekly intravenous 
infusion of Xentuzumab (BI 836845) in patients 
with EGFR mutant non-small cell lung cancer 
with progression following prior EGFR tyrosine 
kinase inhibitors
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Change 1: Cover page
Change 2: Clinical Trial Protocol Synopsis- Trial 
sites
Change 3: Clinical Trial Protocol Synopsis-
Objective, Diagnosis and Main criteria
for inclusion
Change 4: Flow Chart and 6.2.1 Screening period
Change 5: 2.2.1 Primary objectives, 2.2.2
Secondary objectives, 3.1 Overall Trial Design 
and Plan, Figure 3.1: 1 Study design , 3.3
Selection of Trial Population and 7.1 Statistical 
Design – Model
Change 6: 2.3 Benefit-Risk Assessment, 3.3 


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Number of global amendment
1
Selection of Trial Population, 3.3.2 Inclusion 
criteria, criteria no. 2, 3, 5, 6 and 7 and 5.3.2
Pharmacogenomic evaluation
Change 7: 3.3.2 Inclusion criteria, criteria no. 2
Change 8: 3.3.2 Inclusion criteria, criteria no. 4
Change 9: 3.3.2 Inclusion criteria, criteria no. 6
Change 10: 3.3.2 Inclusion criteria, criteria no. 12
Change 11: 3.3.2 Inclusion criteria, criteria no. 15
Change 12: 3.3.3 Exclusion criteria, criteria no.3
Change 13: 3.3.3 Exclusion criteria, criteria no.25
Change 14: 4.1.4.3 Temporary treatment 
interruption and dose reduction
 
Change 17: 9.1 Published references and 9.2 
Unpublished references
Description of change
Change 1: Change of TCM
Change 2: Addition of Japan as a participating
country and update of number of participating 
sites
Change 3: Change in statement of objective, 
diagnosis and main inclusion criteria
Change 4: Clarification on allowance of local 
result of EGFR mutation in Part A
Change 5: Change in statement of primary 
objective and target population in Part A
Change 6: Inclusion of squamous cell carcinoma 
of lung in Part A and its related changes and 
justification
Change 7: Clarification on histology and need of 
diagnosis based on the latest tumour sample, 
Exclusion of small cell lung cancer 
transformation
Change 8: Removal of T790M status in Part A
Change 9: Removal of 30 days interval between 
progression of disease and initiation of study 
treatment and  addition of limitation of TKI free 
period in Part B
Change 10: Clarification of ALT and AST criteria
Change 11: Addition of inclusion criteria on 
patients with known potentially targetable 
mutation
Change 12: Removal of limitation of number of 


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Number of global amendment
1
prior TKI in Part A and change of limitation of 
number of prior TKI in Part B
Change 13: Addition of exclusion criteria on prior 
treatment with third generation irreversible EGFR
TKI in Part B
Change 14: Correction of typo on section to be 
referred
Change 15: Rephrasing
 
 
Change 17: Addition of new and missing
references/ rearrangement of reference in 
alphabetic and numeric order
Rationale for change
Change 1 and 17: Administrative change 
Change 2: Japan to be participated in Part B
Change 3: To align the texts to the information in 
section 2.2.1 and  3.3.2
Change 4: To clarify that T790M result at 
baseline will be collected in Part A even though
patients can be enrolled in Part A regardless of 
T790M status
Change 5, 6 and 8: To investigate safety of this 
combination in broader spectrum of NSCLC for 
part A as a dose escalation cohort
Change 7: To make a clarification for the patients 
with mixed histology of cancer
Change 9: To reflect the clinical practice
Change 10: To make a clarification on ALT and 
AST criteria for eligibility
Change 11: To make a clarification for known 
potentially targetable mutation other than IGF 
signalling pathway or EGFR 
Change 12: To reflect the clinical practice and 
treatment guideline
Change 13: To make a clarification for prior 
treatment with third generation irreversible EGFR 
TKI in Part B
Change 14: To correct typo error
Change 15: To make it more clear
 
 


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Number of global amendment
2
Date of CTP revision
17 May 2016
EudraCT number
Not applicable
BI Trial number
1280.16
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
A phase Ib open-label clinical trial of once daily 
oral treatment of afatinib plus weekly intravenous 
infusion of Xentuzumab (BI 836845) in patients 
with EGFR mutant non-small cell lung cancer 
with progression following prior EGFR tyrosine 
kinase inhibitors
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
-
Change 1: Clinical Trial Protocol Synopsis-
Objective, No. of patients, Diagnosis and
Main criteria for inclusion, 2.2.1 Primary 
objectives, 3.1 Overall Trial Design and Plan, 
Figure 3.1: 1 Study design , 3.3 Selection of 
Trial Population, 3.3.2 Inclusion criteria, 
criteria no. 6, 4.1.2.2 The expansion Part B, 
5.1.2.2 The expansion Part B, 7.1 Statistical 
Design – Model, 7.3.1.2 Part B and 7.3.2 
Secondary analyses 
-
Change 2: 7.6 Determination of sample size
-
Change 3: Flow chart foot note 12 and 6.2.1 
Screening period
-
Change 4: Flow chart foot note 15
-
Change 5: 2.3 Benefit-risk assessment
-
Change 6: Figure 3.1: 1 Study design
-
Change 7: 3.3.4.3 Replacement of patients


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Number of global amendment
2
-
Change 8: Table 4.1.4.3: 1 Dose reduction 
scheme by AE type and CTCAE Grade (Part 
A and Part B)
-
Change 9: Table 4.2.3.1: 1 Grade specific 
treatment recommendations for diarrhea, 
Table 4.2.3.2: 2 Grade specific treatment 
recommendations of skin reactions and Table 
4.2.3.3: 1 Grade specific treatment 
recommendations of study-drug related 
mucositis/stomatitis
-
Change 10: Table 4.2.3.2: 1 General
recommendation for skin reactions
prophylaxis
-
Change 11: 5.2.1.1 Dose confirmation Part A
-
Change 12: 5.2.2.1 Definitions of adverse 
events
-
Change 13:
 
-
Change 14: 6.2.3.4 Patient completion
-
Change 15:
 
 
Description of change
-
Change 1 and 2: Group 2 in Part B has been 
removed and no. of target patient has been 
adjusted accordingly.
-
Change 3: Requirement on the separate
informed consents for tissue biopsy has been 
clarified. 
-
Change 4:
 
-
Change 5: Recommendation to monitor 
weight loss has been added.
-
Change 6: Allowable time frame for baseline 
imaging at screening has been corrected as 
described in flowchart, footnote 11.
-
Change 7, 10 and 12: Typo errors have been 
corrected. 
-
Change 8: Clarification on dose reduction 
scheme for any drug-related AEs ≥CTCAE 
grade 3 has been added.
-
Change 9: Reference for AE descriptions by 
CTCAE grade has been added. 
-
Change 11: Supporting data in determination 


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Number of global amendment
2
of RP2D has been clarified. 
-
Change 13: I
 
-
Change 14: Incorrect information has been 
deleted. No PC page in eCRF
-
Change 15:
 
Rationale for change
-
Change 1: Decision in the consideration of 
scientific merits based on the evolving 
treatment options in EGFR mutated NSCLC, 
Change 2: To correct and adjust the number 
of patients anticipated to be enrolled in the 
trial according to modification on expansion 
cohort.
-
Change 3:
 
-
Change 4: To align the information in section 
5.3.2
-
Change 5: Patients well-being
-
Change 6: To align the information in 
flowchart, footnote 11
-
Change 7, 10 and 12: Correction of typo 
errors
-
Change 8: To clarify that dose reduction is 
required only for drug-related AEs described 
in table 4.1.4.3: 1.
-
Change 9: Clarification on AE descriptions 
and CTCAE reference version
-
Change 11: Clarification on supporting data 
in determination of RP2D
-
Change 13:
 
-
Change 14: Deletion of incorrect
information, No PC page in eCRF
-
Change 15:
 
 


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Number of global amendment
3
Date of CTP revision
02 Nov 2016
EudraCT number
Not applicable
BI Trial number
1280.16
BI Investigational Product(s)
Xentuzumab (BI 836845)
Title of protocol
A phase Ib open-label clinical trial of once daily 
oral treatment of afatinib plus weekly intravenous 
infusion of Xentuzumab (BI 836845) in patients 
with EGFR mutant non-small cell lung cancer 
with progression following prior EGFR tyrosine 
kinase inhibitors
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
-
Change 1: Throughout document
-
Change 2: Flowchart, footnote 7 in 
flowchart, 3.1 Overall trial design and plan, 
Figure 3.1: 1 Study design, 3.3.2 Exclusion 
criteria, exclusion no. 1 and 6.1 visit schedule
-
Change 3: Figure 3.1: 1 Study design, 3.2
Discussion of trial design, including the 
choice of control group, 3.3 Selection of trial 
population, 4.1.3.2 Part B – dosing schedule
and 7.1 Statistical desing-model
-
Change 4: 3.3.2 Inclusion criteria, inclusion
no. 6
-
Change 5: Women of Child-Bearing 
Potential and Pregnancy Prevention
-
Change 6: 9.1 Published references
-
Change 7: 1.2.2 afatinib, 2.1 Rationale for 
performing the trial, 3.3 Selection of trial 


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Number of global amendment
3
population, 4.1.3.1 planned dose levels in Part 
A, 9.1 published references and 9.2 
unpublished references
Description of change
-
Change 1: addition of xentuzumab to the 
name of BI investigational product
-
Change 2: extension of screening period
from 28 days to 42 days and addition of the 
statement that safety lab result should be 
reviewed before first administration of study 
treatment
-
Change 3: allowance of lower dose of 
afatinib as a starting dose in part B for the 
patients who have progressed on afatinib less 
than 40mg after discussion and agreement by
sponsor 
-
Change 4: deletion of TKI-free period 
-
Change 5: deletion of tubal from a method of 
permanent sterilization
-
Change 6: addition of new publication
-
Change 7: replacement with updated 
publication/reference
Rationale for change
-
Change 1: new name added for completeness
-
Change 2: 28 days of screening period is too 
short to complete re-biopsy procedures at in 
some circumstances. For safety confirmation 
before initiating study treatments, the safety 
laboratory result at course 1 visit 1 should be 
reviewed by investigators before first study 
medications.
-
Change 3: To reflect the clinical practice of 
afatinib use. 
-
Change 4: To reflect the clinical practice
-
Change 5: The recommendation related to 
contraception and pregnancy testing in 
clinical trials by Clinical Trial Facilitation 
group (CTFG) has been updated.  
-
Change 6: The publication supports afatinib
30mg as a starting dose for the patients who 
have progressed on reduced dose of afatinib 
30mg due to adverse events of afatinib
-
Change 7: To reflect the updated 
publication/reference


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02190401
6.0
clinical-trial-protocol-revision-03
A phase Ib open-label clinical trial of once daily oral treatment of afatinib plus
weekly intravenous infusion of Xentuzumab (BI 836845) in patients with EGFR
mutant non-small cell lung cancer with progression following prior EGFR tyrosine
kinase inhibitors
Author-Trial Clinical Monitor
08 Nov 2016 10:04 CET
Approval-Clinical Program 
08 Nov 2016 10:04 CET
Approval-Team Member Medicine
08 Nov 2016 10:31 CET
Approval-Therapeutic Area 
08 Nov 2016 13:04 CET
Approval-Dept 
 or 
 or
08 Nov 2016 15:43 CET
Approval-Biostatistics
09 Nov 2016 09:17 CET
Author-Trial Clinical
Pharmacokineticist
10 Nov 2016 01:43 CET
Verification-Paper Signature
Completion
10 Nov 2016 06:27 CET


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(Continued) Signatures (obtained electronically) 
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02190401
6.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan 
c02542327 -02
BI Trial No.:
1280.16
Title:
A phase Ib open-label clinical trial of once daily oral treatment of 
afatinib plus weekly intravenous infusion of Xentuzumab(BI 
836845) in patients with EGFR mutant non-small cell lung cancer 
with progression following prior EGFR tyrosine kinase inhibitors.
Including Protocol Amendment 03 [c02190401-06]
Investigational
Product(s):
Xentuzumab (BI 836845)
Responsible trial 
statistician(s):
Tel.:
Fax:
Tel.
Fax:
Date of statistical 
analysis plan:
27 SEP 2017 SIGNED
Version:
Final
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1
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................4
2
LIST OF ABBREVIATIONS ...............................................................5
3
INTRODUCTION..................................................................................9
4
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY.......10
4.3
CLARIFICATIONS...........................................................................................10
5
ENDPOINTS ........................................................................................11
5.1
PRIMARY ENDPOINTS..................................................................................11
5.1.1
First part ........................................................................................................11
5.1.2
Second part ....................................................................................................11
5.2
SECONDARY ENDPOINTS............................................................................11
5.2.1
Key secondary endpoints..............................................................................11
5.2.2
Other secondary endpoints...........................................................................11
5.2.2.1
First part......................................................................................................11
5.2.2.2
Second part .................................................................................................12
5.4.2
Treatment exposure ......................................................................................18
6
GENERAL ANALYSIS DEFINITIONS...........................................22
6.1
TREATMENTS..................................................................................................22
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................22
6.3
PATIENTS SETS ANALYSED........................................................................25
.....................................................................................................26
6.5
POOLING OF CENTRES ................................................................................26
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................27
6.6.1
Adverse events ...............................................................................................27
6.6.2
Laboratory values at baseline ......................................................................28
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS .................28
6.7.1
Baseline...........................................................................................................28
6.7.2
Time windows for every RECIST assessment ............................................28
7
PLANNED ANALYSES......................................................................30
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........31


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7.1.1
Disposition of patients...................................................................................31
7.1.2
Important protocol violations ......................................................................31
7.1.3
Demographic and other baseline characteristics........................................31
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................31
7.3
TREATMENT COMPLIANCE .......................................................................32
7.4
PRIMARY ENDPOINTS..................................................................................32
7.4.1
First part ........................................................................................................32
7.4.2
Second part ....................................................................................................32
7.5
SECONDARY ENDPOINTS............................................................................32
7.5.1
Key secondary endpoints..............................................................................32
7.5.2
Other secondary endpoints...........................................................................32
7.5.2.1
First part......................................................................................................32
7.5.2.2
Second part .................................................................................................33
................................................................................33
................................................................................33
................................................................................33
7.7
EXTENT OF EXPOSURE................................................................................33
7.8
SAFETY ANALYSES........................................................................................34
7.8.1
Adverse events ...............................................................................................34
7.8.2
Laboratory data.............................................................................................36
7.8.2.1
Laboratory data...........................................................................................36
7.8.2.2
Laboratory values of special interest..........................................................36
7.8.3
Vital signs.......................................................................................................36
7.8.4
ECG ................................................................................................................37
8
REFERENCES.....................................................................................38
9
ADDITIONAL SECTIONS ................................................................39
9.1
SAFETY ANALYSIS.........................................................................................39
10
HISTORY TABLE...............................................................................40


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LIST OF TABLES
Table 5.2.2.2: 1
Derivation rules for Duration of Objective Response................................12
........................................................................15
........................................................................17
Table 6.2:1    Important protocol violations ............................................................................22
Table 6.6:1     Rules for imputations of missing or incomplete dates ......................................27
Table 6.7.2:1    Nominal time-points and windows for imaging.............................................28
Table 10: 1     History table ......................................................................................................40


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2
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALKP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AST
Aspartate Transaminase
ATC
Anatomical, Therapeutic, Chemical (classification system)
ANOVA
Analysis of Variance
 
BI
Boehringer Ingelheim
BIRDS
Boehringer Ingelheim Regulatory Documents for Submission
BMI
Body Mass Index
BRPM
Blinded Report Planning Meeting
BSA
Body Surface Area
CR
Complete Response
CRF
Case Report Form
CT
Concomitant Therapy
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DC
Disease Control
DILI
Drug-Induced Liver Injury
DLT
Dose Limiting Toxicity
DMG
Dictionary Maintenance Group


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Term
Definition / description
DMS
Data Management and Statistics
ECG
Electrocardiogram
ECGS
ECG set
eCRF
Electronic Case Report Form
ENR
Enrolled Set
EOTV
End of Treatment Visit
FDA
Food and Drug Administration
FU
Follow Up
ICH
International Conference on Harmonisation
IGF
Insuline-Like Growth Factor
 
 
IPV
Important Protocol Violation
IRT
Interactive Response Technology
ITT
Intent-to-Treat
LLT
Lowest Level Term
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical Quality Review Meeting
MRI
Magnetic Resonance Imaging
MTD
Maximum Tolerated Dose
MS
MTD Set
NE
Not Evaluable
OR
Objective Response
OS
Overall Survival
PD
Progressive Disease
PFS
Progression Free Survival


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Term
Definition / description
PPS
Per Protocol Set
PR
Partial Response
PR interval
ECG interval from the onset of the P wave to the beginning of the QRS 
complex
PT
Preferred Term
PV
Protocol Violation
Q1
25th percentile
Q3
75th percentile
QRS
Combination of the Q, R and S waves
QT
ECG interval from the beginning of the QRS complex to the end of the 
T wave
QTc
Generic term for QTcF and QTcB intervals
QTcB
QT interval, corrected by Bazett’s formula
QTcF
QT interval, corrected by Fridericia’s formula
RECIST
Response Evaluation Criteria In Solid Tumors
REP
Residual Effect Period
RP2D
Recommended Phase II Dose
RS
Randomised Set
SAE
Serious Adverse Event
SD
Stable Disease
SDL
Subject Data Listings
SIR
Synoptic Interim Report
SOC
System Organ Class
SOP
Standard Operating Procedure
TCM
Trial Clinical Monitor
TMCP
Translational Medicine and Clinical Pharmacology
TSAP
Trial Statistical Analysis Plan
TTP
Time to Progression
TS
Treated Set


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Term
Definition / description
ULN
Upper Limit of Normal
WHO-DD
World Health Organisation - Drug Dictionary


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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 (see in section “Statistical Methods and Determination of Sample Size”). 
Therefore, TSAP readers may consult the CTP for more background information on the 
study, e.g., on study objectives, study design and population, treatments, definition of 
measurements and variables, planning of sample size, randomisation. This TSAP follows 
Boehringer Ingelheims (BI) internal reference (1).
The trial consists of two parts, the first part is the dose confirmation part (Part A) and second 
part is an expansion cohort (Part B).
The TSAP describes the analysis for both parts of the trial. After the first part, safety analyses 
outputs were performed and documented.(see Section 9.1).
In general, study or trial medication refers to the combination of xentuzumab with afatinib.
SAS Version 9.4 or later version will be used for all analyses unless otherwise specified.


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4
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY
 
 
 
4.3
CLARIFICATIONS
The following points warrant further clarification:

If not stated otherwise, date of randomisation will be replaced by first treatment 
administration of any study medication in the outputs  .

The terms “progression”, “progressive disease” (PD) and “disease progression” will be 
used interchangeably within this document.

The terms “treatment cycle” or “treatment course” will be used interchangeably 
throughout this document.

The terms “study medication” and “trial medication” will be used interchangeably 
throughout this document. These terms may be used for the combination of xentuzumab 
and afatinib, or any of these medications alone. Clarification is given when necessary.

The terms “Part A” and “first part” will be used interchangeably throughout this 
document. The terms “Part B” or “second part” will be used interchangeably throughout 
this document.


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5
ENDPOINTS
5.1
PRIMARY ENDPOINTS
5.1.1
First part
The primary endpoints are the maximum tolerated dose (MTD) of trial medication based on 
the occurrence of dose limiting toxicity (DLT) during the first treatment course. The planned 
treatment course consists of 28 days.
MTD:
MTD is defined as the highest dose level examined of trial medication, at which no more than 
1 out of 6 patients experienced a DLT during the MTD evaluation period. The MTD 
evaluation period is defined as the time from the first administration of xentuzumab up to 
start of cycle 2. That means that the exact duration of this period will be derived for each 
patient. If the patient does not start cycle 2, a fixed duration of 28 days will be used.
The MTD and the safety profile (including DLTs occurring after first treatment course), 
pharmacokinetic and pharmacodynamics parameters will be the basis to define the 
recommended phase II dose (RP2D) to be used for further trials in the development of 
xentuzumab in combination with afatinib.
5.1.2
Second part
Objective response (OR)
The primary endpoint for the second part of the study is objective response (OR).
OR is defined as best overall response of complete response (CR) or partial response (PR). 
Best overall response to trial medication will be determined according to Response 
Evaluation Criteria In Solid Tumours (RECIST) version 1.1 (see Appendix 10.5 of the CTP) 
recorded from first administration of trial medication until the earliest of disease progression, 
death or last adequate tumour assessment before start of subsequent anti-cancer therapy. 
Note that an adequate tumour assessment includes an assessment of target lesions, as well as 
radiological tests to evaluate non-target lesions and to search for new lesions, i.e. a RECIST 
tumour evaluation. If no RECIST tumour evaluation has been performed, the assessment will 
be set to missing.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Other secondary endpoints
5.2.2.1
First part
There are no secondary endpoints.


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5.2.2.2
Second part
Time to OR
Time to objective response is defined as the time from first treatment administration until first 
documented CR or PR.
Time to objective response will only be calculated for patients with an objective response:

Time to OR [days] = date of first documented CR or PR - date of first treatment 
administration +1.
Duration of OR
Duration of objective response is defined as the time from first documented CR or PR until 
the earliest of disease progression or death among patients with objective response.
Duration of objective response will only be calculated for patients with an objective response. 
For patients with disease progression or death:

Duration of objective response [days] = date of outcome – date of first assessment 
indicating OR + 1.
For patients without disease progression or death:

Duration of objective response (censored) [days] = date of outcome – date of first 
assessment indicating objective response + 1
The censoring rules for duration of OR are given in Table 5.2.2.2: 1.
Table 5.2.2.2: 1
Derivation rules for Duration of Objective Response
Situation
Outcome (event or 
censored)
Date of outcome
No other anti-cancer therapy
Alive and not progressed, no 
more than one consecutively 
missed radiological 
assessments 
Censored
Date of last radiological assessment
Alive and not progressed, two 
or more consecutively missed 
radiological assessments 
Censored
Date of last radiological assessment prior to 
missed radiological assessments
Progressed, zero or one missed 
radiological assessment prior 
to progression 
Event
Date of radiological assessment of 
progression
Progressed, but two or more 
consecutively missed 
radiological assessments prior 
to progression
Censored
Date of last radiological assessment prior to 
missed assessments


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Table 5.2.2.2: 1 
Derivation rules for Duration of Objective Response (cont.)
Situation
Outcome (event or
censored)
Date of outcome
Death but no progression, zero 
or one missed radiological 
assessment prior to death
Event
Date of death
Death without progression, but 
two or more consecutively 
missed radiological 
assessments prior to death
Censored
Date of last radiological assessment prior to 
missed assessments
Initiation of subsequent anti-cancer therapy
Subsequent anti-cancer 
therapy started before 
progression or death, no more 
than one consecutively missed 
radiological assessments prior 
to start of subsequent anti-
cancer therapy 
Censored
Date of last radiological assessment before 
initiation of subsequent anti-cancer therapy
Only radiological assessments after first assessment indicating objective response will be 
taken into consideration.
Disease control (DC)
DC is defined as best overall response of CR or PR or SD where best overall response is 
defined according to RECIST version 1.1 (see Appendix 10.5 of the CTP) from first 
administration of trial medication until the earliest of disease progression, death or last 
evaluable tumour assessment before start of subsequent anti-cancer therapy. 
Note that an adequate tumour assessment includes an assessment of target lesions, as well as 
radiological tests to evaluate non-target lesions and to search for new lesions, i.e. a RECIST 
tumour evaluation. If no RECIST tumour evaluation has been performed, the assessment will 
be set to missing.


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5.4.2
Treatment exposure
Total treatment duration [days]:
Date of last administration of any trial medication – date of first administration of any trial 
medication + 1.
Total treatment duration therefore includes time when treatment was temporarily 
discontinued and subsequently reintroduced. 
Duration of specific medication exposure [days]:
Date of last administration of specific medication – date of first administration of specific 
medication + 1.
Duration of specific medication exposure will be calculated separately for xentuzumab and 
afatinib.
Number of courses initiated [N]:
Course initiated means that the patient received at least one administration of trial medication 
in the initiated course.
Total number of xentuzumab infusions [N]:
Sum of xentuzumab infusions calculated across all courses.
It will be calculated for each patient who received at least one infusion of xentuzumab.
Number of patients with at least one dose reduction [N]
Number of patients with at least one dose reduction will be counted.


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The number of patients with at least one dose reduction will first be calculated for any 
medication and then separately for each specific medication for which dose reduction is 
allowed. This means that it will be calculated separately for xentuzumab and afatinib.
Time to first dose reduction of specific medication [days]:
Date of first administration of the first reduced dose of specific medication – date of first 
administration of specific medication + 1.
Time to first dose reduction will be calculated only for patients who had a dose reduction.
This will also be calculated separately for patients with a dose reduction of xentuzumab or 
afatinib.
Total dose of specific trial medication [mg]:
Total dose of trial medication will be calculated separately for xentuzumab and afatinib.
For xentuzumab, this is the sum of the administered doses calculated across all courses. This 
takes into account the dose reductions.
For afatinib, this is calculated as the total duration of treatment with this medication in days 
multiplied by the actual dose taken (using the actual dose recorded on the Case Report Form 
(CRF)) for the days the medication was taken. This takes into account the dose reductions of 
afatinib. This calculation is only an approximation of the total dose taken, since the way the 
data are collected do not allow a more precise calculation.
Dose intensity of specific trial medication during all treatment duration (%):
Dose intensity of trial medication will be calculated separately for xentuzumab and afatinib.
100*(Total dose of specific trial medication actually received by a patient / Planned total dose 
of specific trial medication during the entire duration of treatment).
The planned total dose is calculated as the total dose of the medication a patient should have 
received from the date of first administration of the medication to the date of last 
administration.
The planned total dose of xentuzumab for each patient is calculated using the following 
formula: planned dose per infusion (e.g. 1000 mg) multiplied by number of visits with 
administration of xentuzumab. 
For afatinib, the planned total dose for each patient is calculated using the following formula: 
total duration of treatment with this medication in days multiplied by the planned daily dose 
(e.g. 40 mg, using the dose the patient was initially assigned to).
This is done assuming that the initial dose was taken throughout, and dose reduction as 
specified in the protocol will not be considered in the calculation. This means that if a patient 
had protocol-defined dose reduction due to an Adverse Event (AE), the reduced dose will not 
be used in the calculation of the denominator.
For afatinib, this calculation is only an approximation of the dose intensity, since the way the 
data are collected does not allow a more precise calculation.


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6
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
Part A and part B: Patients will be analysed according to the cohort initially assigned. All 
planned analysis will be presented by this cohort, unless specified otherwise. Handling of 
patients where cohort assignment has not been followed will be handled on a case-by-case 
basis, to be agreed at report planning meetings or DBL meeting (but prior to database lock).
For safety summaries data recorded during the Residual Effect Period (REP) will be 
considered as on-treatment. For this trial, the length of the REP is 42 days.
The actual study periods and treatment codes are defined in a document entitled “8-07-other-
sdtm-trial-arms-trial-elements”, which can be found in Data Management and Statistics 
(DMS) folder, Section 8, within BIRDS.
6.2
IMPORTANT PROTOCOL VIOLATIONS
No per protocol set (PPS) analysis will be performed for this study, hence, no patient will be 
excluded from the analyses (except those with missing informed consent or not adhering to 
age limit). However patients with potentially important protocol violations (IPVs) will be 
documented. The following list of potentially IPVs in Table 6.2: 1 will be used; note that this 
is a working list and may not be finalised until the final Blinded Report Planning Meeting 
(BRPM) or DBL meeting (but prior to database lock for the primary analysis). Potentially 
important protocol violations will be handled according to BI standards (6).
During the study conduct, protocol deviation should be monitored and guidance for 
improving / teaching the respective sites should be discussed during the study Medical 
Quality Review Meetings (MQRMs).
Table 6.2:1 Important protocol violations
Category/
Code
Description
Requirements
Excluded 
from
A 
[1]
Entrance criteria not met
A1
Diagnosis of trial disease 
questionable
Inclusion criteria IN2-IN4 not met.
or
Indicated by medical review of 
oncological history and baseline 
tumour assessment details from 
investigator.
None


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Table 6.2:1 Important protocol violations (cont.)
Category/
Code
Description
Requirements
Excluded 
from
A2
Prohibited baseline 
condition, diagnosis or 
treatment
At least one of inclusion criteria IN6-
IN9 or IN13 is not met
or
At least one of exclusion criteria EX3, 
EX7-EX8, EX10-EX12, EX14-EX16, 
or EX18-EX20 is met.
or
Indicated by medical review of 
baseline conditions.
or
Prohibited medication use (or surgery) 
before the treatment period of the trial, 
that is,
At least one of exclusion criteria EX1, 
EX2, EX4-EX6, EX9, EX22, or EX24 
is met
or
Indicated by medical review of 
concomitant therapy use before start 
of study treatment.
None
A3
Laboratory result indicating 
inadequate organ function at 
screening
Inclusion criteria IN11 or IN12 not 
met
or
Both screening and baseline (defined 
in Section 6.7 of this document) 
laboratory results are missing.
None
A4
Adequate archival tumour 
tissue not available
IN5 not met.
None
B 
[1]
Legal Criteria
B1
Informed consent not 
available / not done
Inclusion criterion IN14 is not met.
or
Date of informed consent is missing.
All


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Table 6.2:1 Important protocol violations (cont.)
Category/
Code
Description
Requirements
Excluded 
from
B2
Informed consent too late
Informed consent date was after 
Screening Visit date
None
B3
Age limit for patient 
inclusion not adhered to
Patient’s age < 18 as in IN1
All
C 
[2]
Trial medication and 
randomisation
C1
Time window violation for 
procedures performed at 
screening
Baseline disease assessment not 
within 30 days prior to first treatment.
Create listing, decision at MQRM / 
RPM.
None
C2
Trial medication not given 
according to protocol
Dose reduction scheme not followed 
(see CTP section 4.1.4.3); 
Administration of trial medication(s) 
not compliant. 
Indicated by medical review (i.e. 
where Administration of xentuzumab 
according to the protocol = ‘No’ and 
associated comments, or compliance 
data from afatinib with associated 
comments)
Please note: This excludes the 
investigational treatment given outside 
the boundaries specified in the CTP 
(covered in Category C3).
None
C3
Infusion time for the 
investigational treatment 
outside of CTP specific 
boundaries
Infusion duration of xentuzumab 
given < 50 minutes or > 200 minutes 
(Infusion time should be from 60 to 
180 minutes, but the thresholds above 
are accepted). 
The exact duration of the infusion 
should be calculated taking 
interruptions into account.
In case of missing administration 
times, the violation will not be 
considered important if administration 
according to protocol = ‘Yes’.
None


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Table 6.2:1 Important protocol violations (cont.)
Category/
Code
Description
Requirements
Excluded 
from
C4
Patient assignment not 
followed
Patients do not receive the initial 
treatment they were allocated to.
None
D 
[2]
Concomitant medication
D1
Prohibited treatment during 
trial conduct phase
Exclusion criterion EX17 met
or
Indicated by medical review of 
concomitant therapy use during study 
treatment.
None
E 
[2]
Missing Data
E1
Imaging assessments not 
done according to CTP 
instructions
Imaging assessment should be 
performed at screening and several 
time points thereafter (see TSAP 
Section 6.7.2).
None
E2
Pregnancy test not done 
according to CTP 
instructions
Only for studies where pregnancy tests 
are required.
None
F 
[2]
Trial Specific protocol 
violations
F1
Other protocol violations 
affecting patient rights or 
safety
Manual PVs will be collectively 
captured.
None
[1] IPV will be derived automatically .
[2] IPV will be identified via individual review at MQRM/RPM/DBL.
6.3
PATIENTS SETS ANALYSED
The following analysis sets will be defined for this trial:

Enrolled set (ENR)
This patient set includes all patients with informed consent given. The enrolled set will be 
used for patient disposition tables.

Treated set (TS)
This patient set includes all patients who are documented to have received and taken at least 
one dose of any study medication during the treatment cycles (from day 1).


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The TS will be used for all planned safety and efficacy analyses. 

MTD Set (MS)
The MTD set defines the set of patients in the first part of the trial that are fully evaluable for 
determination of the MTD in the first treatment course. The MTD set will be used for some 
safety analyses in the first part, this is specified in the technical TSAP.
Patients in the TS who were replaced within the MTD evaluation period in the first part of the 
trial will be excluded from the determination of the MTD. Replacement of patients in the first 
part of the study is defined in Section 3.3.4.3 of the CTP. The final list of replaced patients is 
supplied by the Trial Clinical Monitor (TCM) no later than the last report planning meeting 
before the database lock for the safety analysis.
 
 
 
 
 
 
 
 
 
6.5
POOLING OF CENTRES
This section is not applicable because there are no inferential statistics, and therefore there is 
no statistical model in which centre/country can be included.


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6.6
HANDLING OF MISSING DATA AND OUTLIERS
In general, missing data will not be imputed, unless required for the following analyses and 
definitions. Then the rules as described below apply.
Missing dates that affect the evaluation of endpoints specified in previous sections of this 
TSAP will be imputed utilising a “worst case” approach, which will be applied on a case-by-
case basis (depending on the affected endpoint) and agreed to by the trial team members at 
the final BRPM before database lock at the latest.
The rules in the table 6.6: 1 below have been agreed by the trial and project teams, and will 
be used in this trial, if applicable.
Table 5.3.2.2:1
Rules for imputations of missing or incomplete dates
Date
Imputation rule
Date of birth
In case only the year is given: 1st of January 
Date of death
Date last known to be alive.
If only year and month are given: this will be imputed with 1st  
of the month for the analysis of OS
Date of first histological 
diagnosis
1st of month if day is missing
1st of January if month also missing
Date of start of concomitant 
medication
No imputation required
Date of end of concomitant 
medication
No imputation required
Date of start of subsequent 
anti-cancer therapy 
(imputation required only 
for censoring of PFS)
If the day (respectively day and month) of the start date of 
subsequent anti-cancer therapy is missing, then the first of the 
month (respectively 1st January) will be imputed unless this 
date leads to a date before the stop date of study medications. 
In this case, the study medications stop date + 1 day will be 
imputed.   Additionally, all imputed start dates of subsequent 
anti-cancer therapy should be before death date if available.
Date of stop of subsequent 
anti-cancer therapy
No imputation required
Date of end of treatment 
(only for patients still 
ongoing at time of 
snapshot/DBL)
Date of snapshot
If date of death before this date, use date of death
6.6.1
Adverse events
Missing or incomplete AE dates are imputed according to BI standards (2).


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6.6.2
Laboratory values at baseline
For missing laboratory data at Cycle 1 Visit 1 (before the very first administration of study 
medication) data from preceding visits will be used.
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS
6.7.1
Baseline
The last measurement observed prior to start of trial medication will be assigned to baseline. 
Note that for some trial procedures (for example body weight, vital signs, laboratory tests) 
this may be the value measured on the same day trial medication was started. In these cases it 
will be assumed that the measurements were taken prior to the intake of any study 
medication. For tumour assessment, baseline evaluations must be based on Magnetic 
Resonance Imaging (MRI) or Computed Tomography scans performed no more than 30 days 
prior to start of trial medication.
Study days and visits will be labelled according to the flow chart of the CTP.
Unless otherwise specified, baseline is defined as the latest time-point before the very first 
administration of any study medication. If this criterion is not fulfilled then no baseline will 
be derived .
Laboratory values:
Baseline is defined as the latest time-point before the very first administration of any study 
medication.
If any of these times are missing and the date of laboratory value is equal to the date of first 
study drug administration, then the laboratory assessment will be considered as according to 
protocol, i.e. as prior to first study medication.
6.7.2
Time windows for every RECIST assessment
In order to identify whether consecutive imaging time-points are missing for a given patient, 
a nominal time point [4, 8, 16, 24, 32, 40, 48, 56, 68 weeks and every 12 weeks thereafter] 
will be assigned to each and every image. This is achieved by creating windows for every 
RECIST assessment. The windows are defined in Table 6.7.2: 1 below. Day 1 corresponds to 
the date of first drug intake of xentuzumab or afatinib.
Table 6.7.2:1 Nominal time-points and windows for imaging
Nominal time-point [weeks 
from start of therapy]
Due date of scans [days]
Window [days]
4
29
1 to =< 43


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8
57
44 to =< 85
16
113
86 to =< 141
24
169
142 to =< 197
32
225
198 to =< 253
40
281
254 to =<309
48
337
310 to =<365
56
393
366 to =<435
68
477
436 to =<519
every 12 week interval
etc (1)
etc (1)
(1) Due date of imaging = (nominal time point * 7) + 1. To calculate the lower bound of the 
window, use the middle point between the due date of the previous time point and the current 
due date + 1. To calculate the upper bound of the window, use the middle point between the 
due date of the next time point and the current due date.
If a patient does not have an image in one of the windows described above, he/she will be 
said to have 'missed an assessment' for that time-point. In case a patient has more than one 
assessment in one window, the assessment with the latest outcome will be used for the 
analysis unless a PD has been recorded earlier then PD will be used.


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7
PLANNED ANALYSES
The labelling and display format of statistical parameters will follow BI standards (7).
Unless otherwise specified, outputs will be displayed separately for each part of the trial.
With protocol amendment 4, starting doses of xentuzamab 1000mg + afatinib 30mg and 
xentuzamab 1000mg + afatinib 20mg are also allowed in part B. For part B, sections for trial 
subjects and safety analyses will be displayed by starting dose and total. Efficacy analyses 
will be done for part B patients, and RP2D patients (defined as pooled patients of all the 
patients in part B and the patients starting with xentuzumab 1000mg + afatinib 40mg in part 
A excluding squamous carcinoma patients).
Descriptive statistics for continuous variables will generally contain N (number of patients in 
that patient set with non-missing values), Mean, Standard Deviation, Minimum (Min), Q1 
(25th percentile), Median, Q3 (75th percentile), Maximum (Max). In general, means, standard 
deviations, medians, Q1 and Q3 will be presented to one more decimal place than the raw 
data. Minima and maxima will be presented to the same number of decimal places as the raw 
data.
For time-to-event analysis tables, the set of statistics is: number of patients [N (%)], Number 
of patients with event [N (%)], Number of patients censored [N (%)], <Time to event> 
[months] followed by P25 (25th percentile), Median, P75 (75th percentile). If not specified 
otherwise, the duration as well as time to event will be displayed in months.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group total. Percentages will be rounded to one decimal place.
In general a category “missing” will be displayed, if there are missing data for the 
corresponding variable. Percentages will also generally be based on all patients in the 
respective patient set whether they have non-missing values or not.
Sort order for general categorical variables: If categories correspond to the collected 
categories on the eCRF and the table shells do not explicitly specify the ordering, the “default 
ordering” defined by the eCRF is to be used in such cases. If categories are derived the 
ordering as specified in the table shell document should be used; in general ordinal data (e.g. 
categorised continuous data) are to be displayed in ascending order.
The denominator of the main categories is defined by the number of patients in the used 
patient set. The main categories define the denominators of the subcategories. Subcategories 
should be indented and “[N (%)]” to be displayed only for the main category.
If a table includes only categorical data, “[N (%)]” is to be displayed in the column header.
In general, a “Total” column will not be displayed for post-baseline displays. Tables that 
display the status of patients for a primary or secondary endpoint with number of events and 
number censored will contain a total column.


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Abbreviations (e.g., Wors.) or acronyms (e.g., PD) should not be displayed in tables and 
patients data listings without any explanation. They will be either spelled out in the table or 
explained in footnotes (whatever is more reasonable from the programming point of view).
If applicable, conversion from days to weeks, months and years will be as follows:

Weeks = days ÷ 7

Months = days × 12 ÷ 365.25

Years = days ÷ 365.25
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.1.1
Disposition of patients
For patient disposition the standard descriptive table from the EOT catalogue will be 
populated. Additionally, patients with discontinuations by initial treatment and the reasons 
will be listed and tabulated, overall and and for each treatment separately. The same output 
will also contain an overview of discontinued and non-discontinued, as well as completed and 
non-completed patients.
7.1.2
Important protocol violations
A table and a listing of patients with important protocol violations based on Table 6.2: 1 will 
be created in Section 15.1.3 and Appendices 16.2.3 and 16.1.9.2.3 (if needed) respectively, of 
the CTR.
7.1.3
Demographic and other baseline characteristics
Standard descriptive analysis and summary tables for all patients treated by initial treatment 
will be created for demographic data, oncological history and baseline conditions.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. Concomitant diseases will 
be coded similarly as adverse events based on the most current Medical Dictionary for 
Regulatory Activities (MedDRA) version. Concomitant therapies will be coded according to 
World Health Organisation - Drug Dictionary (WHO-DD). Concomitant therapies (CT) will 
be classified according to the Anatomical, Therapeutic, Chemical (ATC) classification 
system. The third ATC level will be used to categorise CTs by therapy type. In situations 
where a medical product may be used for more than one equally important indication, there 
are often several classification alternatives. As appropriate, patients receiving CTs with more 
than one possible ATC level-three category will be counted more than once; footnotes will 
clarify this possible double counting in tables.
Concomitant medications will be presented according to whether they are concomitant with 
the reception of study medication, or whether they were given prior to study medication. In 
case start and stop dates of the medications are completely missing, they are assigned as 
given prior to study medication.


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7.3
TREATMENT COMPLIANCE
Compliance was not analysed separately, but assessed in terms of exposure (including dose 
intensity). Refer to Section 7.7 for further details on exposure analysis.
7.4
PRIMARY ENDPOINTS
7.4.1
First part
The primary endpoints are the MTD and the occurrence of DLT. The MTD is determined 
from the occurrences of DLTs during the MTD evaluation period (this period is defined in 
Section 5.1.1). An overall summary of the DLTs (see CTP Section 5.2.6 for definitions of 
DLT) which occurred during the MTD evaluation period and the on-treatment period will be 
provided for each dose cohort.
Patients that were treated but replaced for the MTD evaluation (see CTP Section 3.3.4.3) will 
be excluded from the MTD determination. Replacement of patients will be determined on a 
case by case basis; exclusion of these patients from the MTD evaluation will be confirmed by 
the trial team at the report planning meeting prior to database lock.
A listing of patients with DLTs by initial treatment will be performed.
At the end of the dose escalation phase, a safety analysis will be performed to determine the 
RP2D. The results will be documented for internal use and communication with the 
participating investigators. (see also in Section 9.1)
7.4.2
Second part
Objective response (OR)
OR as assessed by investigators is defined as a best overall response of CR or PR and will be 
analysed. Descriptive statistics including number of treated patients, number of patients with 
objective response as best overall response and the corresponding percentages will be 
presented and evaluated.
The same analysis will also be done for RP2D patients (defined as pooled patients of all the 
patients in part B and the patients starting with xentuzumab 1000mg + afatinib 40mg in part 
A excluding squamous carcinoma patients).
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Other secondary endpoints
7.5.2.1
First part
This section is not applicable as no secondary endpoint has been specified in the protocol.


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7.5.2.2
Second part
Disease control
Disease control (DC) is defined as best overall response of complete response (CR) or partial 
response (PR) or stable disease (SD) (defined in Section 5.2.2.2). Only descriptive statistics 
are planned for this section of the report.
Time to OR
For patients with objective response, time to objective response will be shown on patient 
level. If applicable a set of summary statistics for time to objective response on cohort level 
will also be produced.
Duration of OR
For patients with objective response, duration of objective response will be shown on patient 
level. If applicable a set of summary statistics for duration of objective response on cohort 
level will also be produced.
The same analysis will also be done for RP2D patients (defined as pooled patients of all the 
patients in part B and the patients starting with xentuzumab 1000mg + afatinib 40mg in part 
A excluding squamous carcinoma patients).
7.7
EXTENT OF EXPOSURE
The variables defined in Section 5.4.2 will be summarised descriptively for each dose cohort.


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7.8
SAFETY ANALYSES
All safety analyses will be performed on the TS (unless otherwise specified; for example, the 
MTD Set will be used for some safety outputs). Patients in the first part of the trial who were 
replaced within or before the first treatment cycle will be excluded from the determination of 
the MTD. 
7.8.1
Adverse events
The analyses of AEs will be descriptive in nature. All analyses will be based on the number 
of patients with AEs (not the number of AEs).
For analysis multiple AE occurrence data on the CRF will be collapsed into an AE event 
provided that all of the following applies: 

All AE attributes are identical (Lowest Level Term (LLT), Common Terminology 
Criteria for Adverse Events (CTCAE) grade, action taken with trial medication, therapy 
required, seriousness, reason for seriousness, relationship, outcome, AE of special 
interest)

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)
For further details on summarisation of AE data, please refer to (2) and (4).
Adverse events will be coded with the most recent version of MedDRA. The severity of AEs 
will be scaled according to CTCAE (CTCAE version 4.03 (10)).
The analyses of adverse events will be based on the concept of treatment-emergent adverse 
events. That means that all adverse events with an onset between first treatment 
administration until end of the REP will be assigned as ‘on treatment’. All adverse events 
occurring before first drug intake will be assigned to ‘screening’ and all adverse events 
occurring after the residual effect period will be assigned to ‘post-treatment’; these AEs will 
be displayed in listings only. Adverse events will be displayed by the initial dose of study 
medication administered on the first day of treatment .
An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarised by treatment, primary system organ class and preferred 
term.
Separate tables will be provided for patients with drug-related adverse events, adverse events 
leading to dose reduction, adverse events leading to discontinuation, serious adverse events, 
serious drug-related serious adverse events, adverse events leading to death, other significant 
adverse events, adverse events of special interest, and adverse events fulfilling the DLT 
definition (for part A only), and drug-related adverse events leading to discontinuation.
Sorting order:
In tables presenting System Organ Classes (SOCs) and Preferred Terms (PTs), SOCs will be 
sorted alphabetically and PTs (within SOC) by descending frequency.
Reporting of CTCAE grades in tables:


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In tables showing AEs by worst CTCAE grade, AEs with missing CTCAE grade will only be 
displayed under the category "All grades", but no category "Missing grade" will be displayed. 
Therefore the categories "Grade 1" to "Grade 5" might not add up to the category "All 
grades"; a footnote will explain this handling.
Displaying of CTCAE grades in AE tables (Section 15) will be “All grades”, “Grade 1”, 
“Grade 2”, “Grade 3”, “Grade 4”, and “Grade 5” separately. 
Listings of adverse events
Adverse events will be reported with start and end day as calculated from the first day of 
treatment with study medication.
Incidence and severity of adverse events
The incidence of AEs overall (irrespective of relatedness to study medication), related AEs, 
and serious AEs (SAE) will be reported by severity according to CTCAE grades.
Other significant adverse events
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.
AEs leading to dose reduction or permanent discontinuation will include:

AEs leading to dose reduction of xentuzumab

AEs leading to dose reduction of afatinib

AEs leading to permanent discontinuation of xentuzumab

AEs leading to permanent discontinuation of afatinib
AEs leading to death
AEs leading to death during the on-treatment period will be tabulated in a separate table. In 
this table no CTCAE grades will be shown. For fatal AEs without CTCAE grade 5 or missing 
grade, the grade will be imputed as CTCAE grade 5. Reported fatal AEs that occurred in the 
follow-up period will be listed.
Protocol-specified Adverse Events of Special Interest (AESI)
Protocol-specified AESIs are specified in the CTP Section 5.2.2.1. Their incidence will also 
be reported.
Adverse events by user defined AE categories (UDAEC)
User defined adverse events categories (UDAEC) as defined on project level by the 
pharmacovigilance working group will be derived and the latest version will be used for the 
analysis.The most recent version of the categories is defined in a document entitled "8-02-
sap-safety-core", which can be found in the Project Data Management and Statistics folder, 
section 8 (project level), within BIRDS. The incidence of AE by UDAEC will be analysed.


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7.8.2
Laboratory data
7.8.2.1
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (5). The same on-treatment periods as considered for the analysis of adverse events 
will be applied for laboratory values except for that the baseline laboratory value will be 
included in the 'on-treatment' period. Patients having at least one post-baseline laboratory 
value will be displayed in the descriptive analyses.
Descriptive statistics, including change from baseline and frequency of patients with 
transitions relative to the reference range, will be provided. CTCAE grades for applicable 
laboratory parameters will be calculated according to CTCAE version 4.03 (10). The 
following outputs will be presented:

Worst CTCAE grade experienced during the on-treatment phase.

Transitions of CTCAE grade from baseline to worst laboratory value, from worst to last 
laboratory value during the on-treatment phase, and from baseline to last laboratory 
value.
Patients with missing CTCAE grade at baseline or no baseline value but post baseline values 
will be displayed in the category “Missing CTCAE grade at baseline”. Laboratory values 
without CTCAE grading will be compared to their reference ranges and frequency tables will 
be provided for the number of patients within and outside the reference range at baseline and 
the last measurement on treatment.
Analysis of potentially clinically significant abnormal laboratory values, and handling of 
CTCAE grade -1 and -9 laboratory parameters, are described in the SOP for "Display and 
analysis of laboratory data" (5), Reference Document 9.
7.8.2.2
Laboratory values of special interest
Hepatic enzyme elevations (potential Hy’s law cases):
These are defined as those cases where a combination of all of the following events occurred: 
any on-treatment value of ALT and/or AST > 3ULN with total bilirubin ≥2ULN and ALKP 
< 2 ULN. The events can occur in any order, but must occur within 14 days of the previous 
event, i.e. the second event must occur within 14 days of the first event, and the third event 
must occur within 14 days of the second event, etc.
Patients with missing laboratory values for liver enzymes will be excluded from these 
analyses but will be presented separately in a listing. Tabulations of hepatic enzyme 
elevations and liver laboratory values (see Section 5.2.2.1 of the CTP), including flags of true 
DILI cases, are created in accordance with the Food and Drug Administration (FDA) DILI 
guidance (8).
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.


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7.8.4
ECG
ECGs are done throughout the trial, and changes in analysis results will be recorded as an 
(S)AE in the eCRF, if they are judged clinically relevant by the investigator.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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8
REFERENCES
1
001-MCG-160_RD-06: "Trial Statistical Analysis Plan - Template", current 
version; IDEA for CON.
2
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
3
001-MCS-36-472: "Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics", 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
001-MCG-157: "Display and Analysis of Laboratory Data", current version, 
IDEA for CON.
6
001-MCS-50-413: “Handling of Protocol Violations in Clinical Trials and 
Projects”, current version; IDEA for CON.
7
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current 
version; IDEA for CON.
8
Guidance for industry: drug-induced liver injury: premarketing clinical 
evaluation U.S. Departement of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER), Center for 
Biologics Evaluation and Research (CBER), 2009.[ P09-12413]
9
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey 
J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan 
R, Lacombe D, Verweij J. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45: 228-247 [R09-
0262]
10
Common terminology criteria for adverse events (CTCAE): version 4.0 (NIH 
publication no. 09-5410, published: May 28, 2009 (v4.03: June 14, 2010), revised 
June 2010, reprinted June 2010).  
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_8.5x11.pdf (2010) [R10-4848]
11
Shankar G, Arkin S, Cocea L, Devanarayan V, Kirshner S, Kromminga A, 
Quarmby V, Richards S, Schneider CK, Subramanyam M, Swanson S, Vethelyi 
D, Yim S. 
Assessment and reporting of the clinical immunogenicity of therapeutic proteins 
and peptides-harmonized terminology and tactical recommendations. AAPS J 16 
(4), 658 - 673 (2014) [R15-1067]


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9
ADDITIONAL SECTIONS
9.1
SAFETY ANALYSIS
After 12 evaluable patients treated at the designated MTD dose have completed at least the 
first course of treatment in part A,  a safety analysis will be performed. For this purpose a 
database snapshot will be performed. The safety analysis will summarise results regarding 
safety and will be used for recommendation of the dose of trial medication to be taken 
forward as recommended phase II dose. The selection of the RP2D will consider overall 
safety observed during available treatment cycles for all treated patients, including the ones 
that were replaced for the determination of the MTD.
Disposition of patients, demographic characteristics and oncological history, previous 
therapies (listing), concomitant therapies (listing), exposure (total duration of treatment, 
patients with dose reduction), adverse events and laboratory parameters (listing of laboratory 
values, table of frequency of patients with transitions of CTCAE grades at baseline and worst 
grade on treatment) will be shown in the safety analysis.


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10 HISTORY TABLE
Table 7.8.2.2: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
27-Sep-17
None
This is the final TSAP without any 
modification