Clinical trial NCT02668393
Conditions: Carcinoma, Non-Small-Cell Lung
Sponsor: Boehringer Ingelheim
Start date: 2016-03-07; Completion date: 2019-11-27
Enrollment: 14 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase I study. To determine the MTD (Maximum Tolerated Dose) of nintedanib + weekly Docetaxel in patients with locally advanced or metastatic lung adenocarcinoma after failure of platinum-based first line chemotherapy.

Detailed description:

Arms: arm 1: Nintedanib low dose with docetaxel arm 2: Nintedanib medium dose with docetaxel arm 3: Nintedanib high dose with docetaxel arm 4: Nintedanib continuous high dose with docetaxel
Interventions: intervention 1: Docetaxel intervention 2: Nintedanib intervention 3: Nintedanib intervention 4: Nintedanib intervention 5: Nintedanib
Intervention descriptions: intervention 1: None intervention 2: Low Dose intervention 3: Medium dose intervention 4: High dose intervention 5: Continuous high dose

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
TITLE PAGE
Document Number:
c03239885-01
EudraCT No.:
2015-000317-52
BI Trial No.:
1199.224
BI Investigational 
Product(s):
nintedanib, BIBF 1120
Title:
An open label Phase I of oral nintedanib plus weekly docetaxel
therapy in patients with locally advanced or metastatic lung 
adenocarcinoma after failure of platinum-based first line 
chemotherapy
Brief Title:
Phase I nintedanib and weekly docetaxel in lung adenocarcinoma.
Clinical Phase:
Phase I
Trial Clinical 
Monitor:
Phone : 
Mobile
Coordinating 
Investigator:
Tel: 
Status:
Final Protocol
Version and Date:
Version:
Date:
Version 1.0
04 Nov 2015
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Proprietary confidential information.
2015 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
Vargatef
Name of active ingredient:
Nintedanib, BIBF1120
Protocol date:
04 Nov 2015
Trial number:
1199.224
Revision date:
Title of trial:
An open label Phase I of oral nintedanib plus weekly docetaxel therapy 
in patients with locally advanced or metastatic lung adenocarcinoma 
after failure of platinum-based first line chemotherapy
Coordinating
Investigator:
Tel : 
Trial site(s):
Multi-centre trial conducted in 2 countries (2 sites in France and 2 in Germany)
Clinical phase:
I
Objective(s):
To determine the MTD of nintedanib twice daily (b.i.d.) plus weekly docetaxel 35 
mg/m2 (day1, day8, day15 following a 28 days cycle) in patients with locally 
advanced or metastatic lung adenocarcinoma after failure of platinum-based first line 
chemotherapy
Methodology:
Open - label
No. of patients: 
35
total entered: Up to 30 patients  (24 evaluable patients)
each treatment: NA
Diagnosis :
Patients with locally advanced or metastatic lung adenocarcinoma after failure of 
platinum-based first line chemotherapy
Main criteria
for inclusion:
1.
Patient aged 18 or older at the date of informed consent
2.
Patients with histologically/cytologically  confirmed locally advanced or 
metastatic lung adenocarcinoma after failure of first line platinum-based 
chemotherapy (patients with non-target lesions only are eligible)
First line chemotherapy may include continuation or switch maintenance 
therapy. One prior adjuvant and/or neoadjuvant chemotherapy is accepted. 
Prior immunotherapy is allowed.
3.
Patients who have a life expectancy of at least 3 months
4.
Patients who are Eastern Cooperative Oncology Group (ECOG) 
performance status (PS) of 0 or 1 at screening 
5.
Patient must have given written informed consent in accordance with ICH-
GCP
Test product(s):
Nintedanib with weekly docetaxel in second line chemotherapy.


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Vargatef
Name of active ingredient:
Nintedanib, BIBF1120
Protocol date:
04 Nov 2015
Trial number:
1199.224
Revision date:
dose:
100 mg b.i.d (dose level – 1, de-escalation dose), 150 mg b.i.d (dose level 1, starting 
dose), 200 mg b.i.d (dose level 2, escalation dose) continuously except on the days of 
docetaxel infusion.
Continuous administration of nintedanib 200 mg b.i.d without interruption on 
docetaxel infusion days (dose level 3) 
If the MTD reaches the nintedanib dose of 200 mg b.i.d (with or without interruption 
on the docetaxel infusion days), 6 additional patients will be included in the 
expansion cohort at the MTD level.
mode of 
administration:
Oral
Backbone chemotherapy
Docetaxel
dose:
35 mg/m² at Day 1, at Day 8, at Day 15 every 28 days cycle.
mode of 
administration:
i.v.
Duration of treatment:
Twenty-eight days per treatment cycle (docetaxel administration on day 1, day 8 and 
day 15 and nintedanib every day except the days of docetaxel infusion and 
continuously even during docetaxel infusion in the dose-level 3 cohort). Treatment 
cycles may be repeated until disease progression, development of intolerable toxicity, 
withdrawal of consent or until other discontinuation criteria are met.
In case patients have to discontinue docetaxel or nintedanib for reasons other than 
progression, patients can continue therapy with remaining drug as monotherapy.
Endpoints
Primary endpoints : 
1. MTD of nintedanib in combination with weekly docetaxel. 
2. Number of patients with Dose Limiting Toxicity (DLT) for nintedanib in 
combination with docetaxel during Cycle 1
Secondary endpoints :
There are no formal secondary safety endpoints.
There is no primary or secondary endpoint for efficacy.
Safety criteria:
The safety evaluation is based on the occurrence of DLTs during cycle 1 to 
determine the MTD, frequency and severity of adverse events according to CTCAE 
version 4.0, on safety laboratory parameters, ECOG status and electrocardiogram 
(ECG)


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Name of company:
Boehringer Ingelheim 
Name of finished product:
Vargatef
Name of active ingredient:
Nintedanib, BIBF1120
Protocol date:
04 Nov 2015
Trial number:
1199.224
Revision date:
Statistical methods:
Descriptive statistics.


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FLOW CHART
Combination therapy with nintedanib plus docetaxel. Also to be used for docetaxel monotherapy in case nintedanib is
discontinued
Trial period
Screening
Treatment period (28 days per cycle)
Cycle 1
Cycle 2
Cycle n onwards
Visit
C1D13
C1D83
C1D153
C2D13
C2D83
C2D153
CnD13
CnD83
CnD153
EOT１
± 7
EOR2+
7
Day
-14 -1
1
8±2
15±2
1±2
8±2
15±2
1± 2
8 ± 2
15 ± 2 
Informed consent:
X
Demographics 
X
Medical history
X
Inclusion/exclusion criteria
X
Patient registration 4
X
Eligibility for further courses
X
X
X
X
X
X
X
X
Physical examination
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
Vital signs5 (blood pressure, heart rate, body temperature)
X
X5
X5
X5
X5
X5
X5
X5
X5
X5
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
ECG (resting)6
X7
X6
X6
X6
Safety laboratory test : Haematology and biochemistry7-8
X7
X8
X8
X8
X8
X8
X8
X8
X8
X8
X8
Coagulation parameters7-9
X7
X9
X9
X9
X9
Urine examination7-9
X7
X9
X9
X9
X9
Pregnancy test10
X10
X10
X10
X10
Premedication for docetaxel treatment11
X11
X11
X11
X11
X11
X11
X11
X11
X11
Docetaxel treatment
X
X
X
X
X
X
X
X
X
Dispensing of nintedanib12
X
X12
X12
Nintedanib treatment13
X13
X13-14
X13-14
X13-14
X13-14
X13-14
X13
X13
X13
Compliance check15
X15
X15
X
Concomitant therapy
X
X
X
X
X
X
X
X
X
X
X
X
Tumour assessment  (CT/MRI)16-17-18
X16
X17
X18
Blood sampling for PK analysis19
X19
X19
X19
X19
X19
AEs/SAEs
X
X
X
X
X
X
X
X
X
X
X
X
Other subsequent anti-cancer therapy
X


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1
End of treatment (EOT) visit is to be performed within 7 days after permanent discontinuation of last trial medication. If the patient permanently discontinues the trial medication 
during treatment interruption, see Section 6.2.3.1. 
2
EOR: End of residual effect period (REP) visit is to be performed at 28 days or later after permanent discontinuation of last trial medication.
3
Day 1, Day 8 and Day 15 of each cycle may be postponed for up to 2 days.
4
Registration will be performed following RDC. The IRT system will assign nintedanib and docetaxel kit numbers.
5
Vital signs at Day 1, Day 8 and Day 15 of each cycle at pre and post-dose of docetaxel infusion.
6
Resting electrocardiogram (ECG) to be performed on day 1 of every odd number of treatment cycles (can be performed within 2 days prior to docetaxel administration) and at EOT.
7
If ECG and safety laboratory data (Heamatology, biochemistry, coagulation parameters and urine examination) were obtained within 7 days prior to registration including before 
obtaining informed consent, that data may be used for registration at screening.
8
Safety laboratory test (haematology and biochemistry) to be performed within 2 days prior to docetaxel administration (CnDay 1, CnDay 8 and Cn Day 15) and at EOT.
9
Coagulation parameters and urinalysis (see Section 5.3.3) to be performed on day 1 of each cycle (can be performed within 2 days prior to docetaxel infusion) and at EOT
10
In women of childbearing potential (i.e. women who have not had a hysterectomy, premenopausal, or have been amenorrhoeic for less than 12 months), a pregnancy test will be 
performed by urinalysis or serum β-human chorionic gonadotropin (β-hCG) at screening, pre-dose on Day 1 of Cycle 1 (if the test at screening has been performed beyond 72 hours on 
Day 1 of Cycle 1, it may be skipped), every odd number of treatment cycle (3, 5, and so on) within 2 days before administration of docetaxel, and at the EOT.
11
All patients should be pre-medicated prior to docetaxel treatment (see Section 4.1.4).
12
If Day 1 of the next treatment cycle is planned later than 28 days from Day 1 of current cycle, one more medication kit of nintedanib can be dispensed.
13
Nintedanib will be administered from Day 2 to Day 7, from Day 9 to Day 14 and from Day 16 to Day 27 on each treatment cycle but not on the days of docetaxel infusion.
For the cohort of patients, nintedanib 200 mg b.i.d (dose level 3) will be administered continuously from Day 1 to Day 28 without interruption during docetaxel infusion.
14
The patients of the cohort dose level 3 (nintedanib 200 mg b.i.d) will take the morning dose of nintedanib at the hospital at days of PK blood sample.
15
Check nintedanib actual drug intake and collect unused nintedanib capsules at the next dispense of nintedanib. 
16
Tumour assessment (CT / MRI) taken within 28 days prior to start of Cycle 1 may be used as the baseline scan.
17
Tumour assessments according to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 have to be performed on Day 1 of every odd number of treatment cycles from 
Cycle 3 (within 7 days prior to planned date) until tumour progression. Imaging can be performed outside of scheduled visit if progression is suspected.
18
If a patient discontinues from the study without progression, tumour assessment should be performed if not done in the past 21 days.
19
Blood samples for PK analysis (nintedanib) will be drawn in patients treated with nintedanib at 200 mg b.i.d continuously (dose level 3). Just before nintedanib and docetaxel 
administration, PK samples will be withdrawn at C1D8, C1D15, at C2D1, C2D8 and C2D15. Detailed schedule of PK blood sampling is provided in Appendix 10.2.


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Monotherapy with nintedanib (after permanent discontinuation of docetaxel treatment)
Trial period
Treatment period 
(28 days per cycle)
EOT1
EOR2
Cycle n
Visit
Cn Day1
Day
1 3
Eligibility for the next cycle
X
Physical examination
X
X
ECOG PS
X
X
X
Vital sign (blood pressure, heart rate, body temperature)
X
X
Weight
X4 
X
ECG (resting)
X4
X
Safety laboratory test (Haematology and biochemistry) 
and coagulation parameters.4
X4
X
Urine examination 4
X4
X
Pregnancy test5
(X)5
X
Dispensing of nintedanib6
X6
X
Nintedanib treatment7
X
X
Compliance check8
X
X
Concomitant therapy
X
X
X
Tumour assessment (CT/MRI)
(X)9 
X10
AEs/SAEs
X
X
X
Other subsequent anti-cancer therapy
X
1.
EOT visit is to be performed within 7 days after permanent discontinuation of trial medication. If the patient 
permanently discontinues the trial medication during treatment interruption, see Section 6.2.3.
2.
EOR visit is to be performed at 28 days or later after permanent discontinuation of trial medication.
3.
Day 1 of each cycle may be postponed for administrative reasons for up to 7 days.
4.
Examinations such as weight, ECG, safety laboratory test, and urinalysis (see Sections 5.3.3 and 5.3.4) can be 
performed within 2 days before the scheduled visit.
5.
In women of childbearing potential (i.e. women who have not had a hysterectomy, premenopausal, or have been 
amenorrhoeic for less than 12 months), a pregnancy test will be performed by urinalysis or serum β-hCG every odd 
number of treatment cycle (3, 5, and so on) within 2 days before treatment and at the EOT.
6.
If Day 1 of the next treatment cycle is planned later than 28 days from Day 1 of current cycle, one more medication kit 
of nintedanib can be dispensed.
7.
Nintedanib will be administered from Day 1 to Day 28 on each treatment cycle.
8.
Check nintedanib actual drug intake and collect unused nintedanib capsules at the next dispense of nintedanib. 
9.
Tumor assessments according to RECIST version 1.1 have to be performed on Day 1 of every odd number of 
treatment cycles from Cycle 3 (within 14 days prior to planned date) until tumour progression. Imaging can be 
performed outside of scheduled visit if progression is suspected.
10.
If a patient discontinues from the study without progression, tumour assessment should be performed if not done in the 
past 21 days


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................5
TABLE OF CONTENTS ........................................................................................................8
ABBREVIATIONS................................................................................................................12
1.
INTRODUCTION...............................................................................................16
1.1
MEDICAL BACKGROUND.............................................................................16
1.2
DRUG PROFILE................................................................................................18
1.2.1
Nintedanib............................................................................................................18
1.2.2
Docetaxel..............................................................................................................20
1.2.3
Combination of nintedanib and docetaxel........................................................21
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....22
2.1
RATIONALE FOR PERFORMING THE TRIAL.........................................22
2.2
TRIAL OBJECTIVES........................................................................................22
2.3
BENEFIT - RISK ASSESSMENT.....................................................................22
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................24
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................24
3.1.1
Administrative structure of the trial .................................................................25
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................26
3.3
SELECTION OF TRIAL POPULATION .......................................................26
3.3.1
Main diagnosis for study entry ..........................................................................27
3.3.2
Inclusion criteria .................................................................................................27
3.3.3
Exclusion criteria ................................................................................................27
3.3.4
Removal of patients from therapy or assessments...........................................30
3.3.4.1
Removal of individual patients:.........................................................................30
3.3.4.2
Discontinuation of the trial by the sponsor.......................................................30
3.3.4.3
Patient replacement ............................................................................................31
4.
TREATMENTS...................................................................................................32
4.1
TREATMENTS TO BE ADMINISTERED.....................................................32
4.1.1
Identity of BI investigational product(s) and  combination product(s) .........32
4.1.1.1
Nintedanib (investigational medical product)..................................................32
4.1.2
Method of assigning patients to treatment groups...........................................33
4.1.3
Selection of doses in the trial..............................................................................35
4.1.3.1
General recommendations for dose selection in the present trial ..................35
4.1.3.1.1
Nintedanib............................................................................................................35
4.1.3.1.2
Docetaxel..............................................................................................................35
4.1.4
Drug assignment and administration of doses for each patient......................36


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4.1.4.1
Treatment cycle intervals...................................................................................36
4.1.4.1.1
Treatment criteria for docetaxel therapy .........................................................37
4.1.4.1.2
Stopping criteria for docetaxel therapy ............................................................37
4.1.4.1.3
Temporary treatment interruption of nintedanib treatment .........................37
4.1.4.1.4
Retreatment criteria for nintedanib..................................................................38
4.1.4.2
Dose reduction scheme of nintedanib (given in combination or as 
monotherapy) ......................................................................................................38
4.1.5
Blinding and procedures for unblinding...........................................................40
4.1.6
Packaging, labelling, and re-supply...................................................................41
4.1.7
Storage conditions...............................................................................................41
4.1.8
Drug accountability.............................................................................................42
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
TREATMENT.....................................................................................................43
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....43
4.2.2
Restrictions ..........................................................................................................43
4.2.2.1
Restrictions regarding concomitant treatment ................................................43
4.2.2.2
Restrictions on diet and life style.......................................................................44
4.3
TREATMENT COMPLIANCE........................................................................44
5.
VARIABLES AND THEIR ASSESSMENT ....................................................46
5.1
TRIAL ENDPOINTS..........................................................................................46
5.1.1
Primary Endpoint(s)...........................................................................................46
5.1.2
Secondary Endpoint(s) .......................................................................................47
5.1.3
Further Endpoint(s)............................................................................................47
5.1.3.1
Pharmacokinetics................................................................................................47
5.1.3.2
Endpoint(s) of efficacy........................................................................................47
5.2
ASSESSMENT OF EFFICACY........................................................................48
5.2.1
Assessment of efficacy following RECIST criteria (version 1.1) (Appendix 
10.3). .....................................................................................................................48
5.2.2
Progression of disease.........................................................................................48
5.3
ASSESSMENT OF SAFETY.............................................................................49
5.3.1
Physical examination ..........................................................................................49
5.3.2
Vital Signs............................................................................................................49
5.3.3
Safety laboratory parameters ............................................................................49
5.3.4
Electrocardiogram ..............................................................................................50
5.3.5
Other safety parameters:....................................................................................50
5.3.6
Assessment of adverse events.............................................................................50
5.3.7
Adverse event collection and reporting.............................................................54
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................56
5.4.1
Assessment of Pharmacokinetics.......................................................................56
5.4.2
Methods of sample collection .............................................................................56
5.4.3
Analytical determinations ..................................................................................56
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship: .....................................56
5.5
ASSESSMENT OF EXPLORATORY BIOMARKERS.................................57
5.5.1
Biobanking...........................................................................................................57


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5.6
OTHER ASSESSMENTS...................................................................................57
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................57
6.
INVESTIGATIONAL PLAN.............................................................................58
6.1
VISIT SCHEDULE.............................................................................................58
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................58
6.2.1
Screening and treatment period(s)....................................................................58
6.2.2
Treatment cycles .................................................................................................59
6.2.2.1
Cycle 1 Day 1 (C1D1)..........................................................................................59
6.2.2.2
Cycle 1 Day 8 (C1D8) and Cycle 1 Day 15 (C1D15) ........................................59
6.2.2.3
Cn Day 1 ± 2 days of every treatment onwards ...............................................60
6.2.2.4
Cn Day 8 and Cn Day 15 of treatment cycle 2 onwards :................................61
6.2.2.5
Cn (Day 1) of a treatment cycle with monotherapy nintedanib .....................62
6.2.2.6
Optional visits between scheduled visits ...........................................................62
6.2.3
End of treatment (EOT) and EOR ( End of Residual Effect Period (REP) ..63
6.2.3.1
End of treatment .................................................................................................63
6.2.3.2
EOR (End of Residual Effect Period (REP).....................................................63
6.2.3.3
Trial completion for an individual patient .......................................................64
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................65
7.1
STATISTICAL DESIGN - MODEL.................................................................65
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................65
7.3
PLANNED ANALYSES.....................................................................................65
7.3.1
Primary endpoint analyses.................................................................................65
7.3.2
Secondary endpoint analyses .............................................................................65
7.3.3
Further endpoint analyses..................................................................................65
7.3.4
Safety analyses.....................................................................................................66
7.3.5
Pharmacokinetic analyses ..................................................................................66
7.4
INTERIM ANALYSES ......................................................................................67
7.5
HANDLING OF MISSING DATA ...................................................................67
7.5.1
Plasma drug concentration - time profiles........................................................67
7.6
RANDOMISATION ...........................................................................................67
7.7
DETERMINATION OF SAMPLE SIZE .........................................................67
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........68
8.1
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ...........................................................................................................68
8.2
DATA QUALITY ASSURANCE ......................................................................69
8.3
RECORDS...........................................................................................................69
8.3.1
Source documents ...............................................................................................69
8.3.2
Direct access to source data and documents.....................................................70
8.3.3
Storage period of records ...................................................................................70
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS70
8.4.1
Listedness.............................................................................................................70
8.4.2
Expedited reporting to health authorities and IEC / IRB...............................71


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8.5
STATEMENT OF CONFIDENTIALITY........................................................71
8.6
END OF TRIAL..................................................................................................71
8.7
PROTOCOL VIOLATIONS .............................................................................71
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
TRIAL RELATED INJURY..............................................................................71
9.
REFERENCES....................................................................................................72
9.1
PUBLISHED REFERENCES............................................................................72
9.2
UNPUBLISHED REFERENCES......................................................................75
10.
APPENDICES.....................................................................................................77
10.1
CLINICAL EVALUATION OF LIVER INJURY ..........................................77
10.1.1
Introduction.........................................................................................................77
10.1.2
Procedures ...........................................................................................................77
10.2
PHARMACOKINETIC ANALYSES...............................................................79
10.2.1
Handling procedure of blood samples for plasma concentration-time 
measurements......................................................................................................79
10.2.2
Time schedule for Pharmacokinetic (PK) blood sampling..............................79
10.3
RECIST CRITERIA (VERSION 1.1)...............................................................80
10.4
STATISTICAL APPENDIX..............................................................................85
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................87


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ABBREVIATIONS
AE
adverse event
AESI
adverse event of special interest
ALK
anaplastic lymphoma kinase
ALP
alkaline phosphatase
ALT
alanine amino transferase
ANC
absolute neutrophil count
aPTT
activated partial thromboplastin time
AST
aspartate aminotransferase
ATP
adenosine triphosphate
AUC
area under the curve
BI
Boehringer Ingelheim
b.i.d.
twice daily
β-hCG
BLQ
β-human chorionic gonadotropin
below the lower limit of quantification
BSA
CA
body surface area
competent authority
CK
creatine kinase
CI
confidence interval
CML
Local Clinical Monitor 
Cmax
maximum measured concentration of the analyte in plasma
Cpre(,ss)
Pre-dose concentration of the analyte in plasma (at steady-state)
CR
complete response
CRA
clinical research associate
CRO
contract research organization
CT
computerized tomography
CTCAE
Common Terminology Criteria for Adverse Events – Version 4.
CTP
clinical trial protocol
CTR
clinical trial report
CYP
cytochrome p
D35
D75
docetaxel 35 mg/m2
docetaxel 75 mg/m2
DCR
DEDP
disease control rate
drug exposure during pregnancy
DILI
drug induced liver injury
DLT
DMC
dose limiting toxicity
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic case report form
ECOG PS
Eastern Cooperative Oncology Group performance status
EDTA
ethylenediaminetetraacetic acid
EGFR
EMA
epidermal growth factor receptor
European Medicines Agency
EML4-
echinoderm microtubule-associated protein-like 4 anaplastic lymphoma 


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ALK
kinase
EOT
end of treatment
EOR
EU
end of residual effect period
European Union
FDA
Food and Drug Administration
FGF
fibroblast growth factor
FGFR
fibroblast growth factor receptor
mFOLFOX modified FOLFOX (Folinic acid, 
leucoverin, 5 FU and oxaliplatin)
G-CSF
granulocyte colony stimulating factor
GCP
Good Clinical Practice
γ-GT
gamma glutamyl transferase
GI
gastrointestinal
h
hour
HBV
hepatitis B virus
HCV
HDV
hepatitis C virus
hepatitis D virus
HIV
human immunodeficiency virus
HR
hazard ratio
IC50
half maximal (50%) inhibitory concentration
ICH
IEC
IMP
International Conference on Harmonisation
Independent Ethics Committee
Investigational product
INN
international approved names for pharmacopoeial substances
INR
international normalised ratio
IPF
idiopathic pulmonary fibrosis
IRB
institutional review board
IRT
interactive response technology
ISF
Investigator Site File
IWRS
interactive web-based response system
LC-
L
LD
LDH
m2
liquid chromatography-tandem mass spectrometry
litre
longest diameter
lactate dehydrogenase
squaral meter
MAPK
mitogen-activated protein kinase
MedDRA
mg
ml
Medical Dictionary for Drug Regulatory Activities
Milligram
millilitre
MRI
MRT
magnetic resonance imaging
mean residence time
MTD
maximum tolerated dose
N100
nintedanib 100 mg b.i.d.
N150
nintedanib 150 mg b.i.d.
N200
nintedanib 200 mg b.i.d.
NC
not calculated


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NE
not evaluable
NIMP
non investigational product
nM
nano molar
NOA
not analysed
NOR
no valid result
NOS
no sample available
NSCLC
non-small cell lung cancer
NYHA
New York Heart Association
OC
ovarian cancer
OPU
OR
operative unit
objective response
ORR
objective response rate
OS
overall survival
PD
PD-1
progressive disease
programmed death 1 receptor
PK/PD
PD-L ½  
Pharmacokinetics/Pharmacodynamics,
Ligand of programmed death 1 receptor
PDGF
platelet derived growth factor
PDGFR
platelet derived growth factor receptor
PFS
progression free survival
PGx
pharmacogenomics
P-gp
P-glycoprotein
PK
pharmacokinetics
PMDA
Pharmaceuticals and Medical Devices Agency
PR
partial response
PS
performance status
PT
prothrombin time
RDC
remote data capture
RECIST
Response Evaluation Criteria in Solid Tumours
REP
residual effect period
SAE
serious adverse event
SD
stable disease
SOP
SPC
standard operating procedures
summary of product characteristics
SRC
safety review committee
SUSAR
suspected unexpected serious adverse reactions
TCM
Trial Clinical Monitor
TCPK
Trial Clinical Pharmacokineticist
TDM
Trial Data Manager
TDMAP
trial data management and analysis plan
TKI
tyrosine kinase inhibitor
TSH
thyroid-stimulating hormone
TSTAT
trial statistician
TMF
TTP
Trial Master File
Time to tumour progression
ULN
upper limit of normal


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US
United States
VEGF
vascular endothelial growth factor
VEGFR
vascular endothelial growth factor receptor
WBC
white blood count
WHO-DD
World Health Organisation Drug dictionary


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Lung cancer is one of the leading causes of cancer death. In 2012, 1.8 million people were 
newly diagnosed with lung cancer worldwide, and 1.6 million deaths were caused by lung 
cancer i.e. 19.4% of the overall cancer mortality [R14-2236]. Non-small cell lung cancer 
(NSCLC) accounts for approximately 85% of lung cancer cases [R08-2617]. Histological 
subtypes of adenocarcinoma and squamous cell carcinoma each account for about 30 to 50% 
of NSCLC cases [P11-08063]. The majority of patients with lung cancer are diagnosed after 
the disease has progressed to a more advanced stage. The prognosis for the majority of 
patients with advanced stage disease has not changed significantly in the past decade. With 
an overall 5-year survival rate of 9 to 13%, the treatment of NSCLC remains a major clinical 
challenge [R11-0052]. 
Several treatment options are available for NSCLC patients in the first-line setting. These 
include platinum-combination regimens and, as a more recent addition to the treatment 
option, targeted therapies such as epidermal growth factor receptor tyrosine kinase inhibitors 
(EGFR TKIs) or echinoderm microtubule-associated protein-like 4 anaplastic lymphoma 
kinase (ALK) inhibitors in patients carrying EGFR mutation and ALK translocation positive, 
respectively. In the second line setting, the development of treatment options has significantly 
lagged behind developments in the first-line setting, and there is a high unmet medical need 
to improve the treatment options for patients with advanced NSCLC in the second line 
setting.
The understanding of NSCLC has evolved tremendously over recent years. Today, NSCLC is 
viewed as a cluster of different disease variants that can be identified by histological 
subtyping or genetic characterisation of tumours harboring specific mutations. These 
different variants and subtypes have been shown to respond differently to different therapies. 
Examples include pemetrexed that shows benefit in one histological subtype and not the 
other; differentiation by genetic alterations such as EGFR mutations where agents including 
afatinib, erlotinib and gefitinib show the greatest improvement in outcomes; and 
differentiation by molecular rearrangements such as EML4-ALK where crizotinib has 
recently demonstrated dramatic prolongation in progression free survival (PFS) [R04-4507, 
R07-1199, R13-0232]. There is growing evidence that differences in tumour biology make it 
necessary to develop specific treatment approaches for patients with different tumour 
histologies, and that the further clinical development in NSCLC needs to focus on 
specifically defined patient populations and histological subtypes [R13-3173]. 
Angiogenesis is involved in tumour growth and development of metastases. Vascular 
endothelial growth factor (VEGF) and its high affinity receptor VEGFR-2 are crucial for the 
formation of new tumour vessels. In addition, there is preclinical evidence that fibroblast 
growth factor (FGF) and platelet-derived growth factor (PDGF) and their associated receptor 
tyrosine kinases substantially contribute to tumour angiogenesis. The VEGF–VEGFR-2 axis, 
besides promoting angiogenesis, may also be involved in stimulating growth of tumour cells 


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themselves via autocrine or paracrine interactions [R13-4194, R13-4197]. Increased 
expression of VEGF, found in most solid tumours including NSCLC, has been associated 
with an increased risk of recurrence, metastases and death [R13-4198]. In addition to their 
roles in angiogenesis, these pathways are also expressed in tumour cells and can play a role in 
tumour growth, metastatic spread, and therapeutic resistance. For example, copy number 
gains in the VEGFR-2 gene, have been observed in 20-30% of NSCLC tumours and is 
associated with recurrence after adjuvant therapy and chemo-resistance [R13-4198]. 
Likewise, the FGFR1 gene is also amplified in NSCLC and has been identified as a potential 
therapeutic target [R11-1327]. 
First line use of bevacizumab, an approved anti-VEGF monoclonal antibody in combination 
with platinum based chemotherapy, has been shown to improve overall survival (OS) beyond 
1 year for patients with advanced non-squamous pathology of NSCLC compared with 
chemotherapy alone [R07-1161]. 
Despite the efficacy of a number of first-line treatments, including targeted therapies, the vast 
majority of patients with advanced-stage NSCLC will inevitably experience disease 
progression. Since a decade only few advances were made in the management after first-line 
progression for patients with NSCLC who are not candidates for specific targeted therapies. 
Recently, two anti-angiogenic agents have been approved in patients with advanced NSCLC 
after first-line chemotherapy in combination with docetaxel. The results of the LUME-Lung 1 
trial (NCT00805194; study 1199.13) led to the EU approval of nintedanib, in combination 
with docetaxel, for the treatment of patients with locally advanced, metastatic or locally 
recurrent NSCLC of adenocarcinoma tumour histology after first-line chemotherapy (current 
SmPC). Subsequently, results of the REVEL trial (NCT01168973; study 13852) led to the 
US approval of ramucirumab in combination with docetaxel for patients with metastatic 
NSCLC with disease progression on or after platinum-based chemotherapy (current SmPC).
Immunotherapy, a novel therapeutic approach to treating NSCLC, was evaluated. Circulating 
immune cells may have the ability to recognize inﬁltrate and eliminate some incipient cancer 
cells, but some evade immune surveillance and immune system-mediated cell death [R12-
2552]. Recent studies have improved the understanding of the molecular basis for this 
phenomenon, and aided in the identiﬁcation of anticancer approaches that act by modulating 
the immune system directly. 
Immune checkpoint inhibition, involving the programmed death 1(PD-1) receptor and its 
ligands (PD-L1/2) has clarified the role of these approaches in tumor-induced immune 
suppression and has been a critical advancement in immunotherapeutic drug development.
This new treatment approach is undergoing extensive investigation in NSCLC and other 
malignancies. They indicate important response rates and high quality responses or prolonged 
duration. Unlike standard chemotherapy or targeted agents, which act directly on the tumor 
cells, immune checkpoint inhibitors work by restoring the immune system's capacity to 
eradicate tumors. 
Nivolumab, is a fully human, high affinity, immunoglobulin (Ig) G4 monoclonal antibody to


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PD-L1. Phase III trials for nivolumab versus docetaxel in patients with squamous 
(CheckMate-017; NCT01642004) and non-squamous (CheckMate-057; NCT01673867) 
histology after failure of platinum-based doublet chemotherapy have both been stopped early 
following planned interim analyses and a DMC assessment, which concluded that both 
studies met their primary endpoint, demonstrating superior OS in patients receiving 
nivolumab, when compared to the control arm [R15-3058 and R15-3057] . 
With the advent of these new drugs, more therapeutic options are needed since patients 
eventually relapse. New treatments or treatment combinations are needed to improve 
outcomes for these patients.
1.2
DRUG PROFILE
1.2.1
Nintedanib
Nintedanib is approved in the EU in 2014 for use in combination with docetaxel to treat 
locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma histology, in 
patients who have progressed on first-line chemotherapy. It is an oral triple angiokinase 
inhibitor. It is an indolinone derivative that blocks the kinase activity of VEGFR 1-3, PDGFR 
α and β, and FGFR 1-3 by occupying the adenosine triphosphate (ATP) binding pocket [U02-
1482; U11-1947-01]. VEGFR-2 is considered to be the crucial receptor involved in the 
formation as well as the maintenance of tumour vasculature. Nintedanib inhibits VEGFR 1-3 
kinases with IC50 values of 34, 21, and 13 nM, respectively; PDGFR α and β with IC50 
values of 59 nM and 65 nM; and FGFR 1 to 4 with IC50 values of 69, 37, 137, and 604 nM, 
respectively [P08-08684]. Additional kinases (Flt3, Lck, Src kinases) are inhibited by 
nintedanib with similar potency [P08-08684, R13-3128].
In vitro within cells, nintedanib has a sustained duration of action. Pulse-chase experiments 
with VEGFR 2-transfected NIH3T3 fibroblasts demonstrated that after 1-h exposure to 50 
nM nintedanib, the auto-phosphorylation of VEGFR-2 was blocked for at least 32 h [U02-
1109]. This sustained receptor blockade indicates the potential for a long-lasting anti-
angiogenic effect. Nintedanib was shown to interfere with the mitogen-activated protein 
kinase (MAPK) and Akt signalling pathways downstream of the receptor tyrosine kinases in 
endothelial cells, pericytes, and smooth muscle cells, resulting in down-regulation of 
mitogenic signals and induction of apoptosis [U08-1946].
The clinical development programme for nintedanib includes several cancer indications: 
NSCLC, ovarian cancer (OC), colorectal cancer, renal cell carcinoma, and hepatocellular 
carcinoma. Nintedanib has been studied as well in non-cancer indication idiopathic 
pulmonary fibrosis (IPF) and has been approved as monotherapy by both US-FDA and EMA
in 2014.
A wide range of nintedanib monotherapy doses was investigated in Phase I and II trials, by 
using the doses from 50 to 450 mg once daily and from 150 to 300 mg twice daily (b.i.d). In 
Phase I dose escalation trials the predominant dose limiting toxicities (DLTs) were 


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gastrointestinal adverse events (AEs) and fully reversible increases of liver enzymes (ALT, 
AST, gamma glutamyl transferase [γ-GT] ) not accompanied by relevant bilirubin increases, 
and the maximum tolerated dose (MTD) was determined as 250 mg b.i.d. in Caucasian 
patients [U10-1846-01]. 
In Phase I trials combining nintedanib with docetaxel, pemetrexed, paclitaxel/carboplatin or 
mFOLFOX6, the recommended dose of nintedanib was established to be 200 mg b.i.d. in 
Caucasians [U02-1482]. The pattern of AEs was comparable to the AE profile observed in 
Phase I monotherapy trials except for the chemotherapy-related AEs. Based on the overall 
safety profile from all Phase I and Phase II trials, a nintedanib dose of 200 mg b.i.d. was 
selected for further Phase III trials.
Of over 3300 cancer patients included in 3 Phase III trials in NSCLC or OC, approximately 
1900 patients have received nintedanib in combination with the cytotoxic chemotherapy that 
is standard for the respective indication, namely, docetaxel, pemetrexed or 
paclitaxel/carboplatin.
After administration as a soft gelatin capsule, nintedanib is absorbed quickly; maximum
plasma concentrations are reached within 2 to 4 h. Nintedanib follows at least bi-phasic 
disposition kinetics. After intravenous administration, it showed a volume of distribution of 
1050 L. Non-clinical data suggest a homogenous distribution of the drug, with the exception 
of the central nervous system, and no marked affinity or retention in any tissue. Nintedanib
undergoes a high first-pass metabolism and is primarily metabolised by hydrolytic cleavage 
by esterases, resulting in the free acid moiety BIBF 1202. Subsequently, BIBF 1202 is 
glucuronidated by various UGT enzymes, forming BIBF 1202 glucuronide. Metabolisation 
via CYP enzymes plays a minor role. After intravenous administration, nintedanib showed a 
high total plasma clearance (gMean: 1390 mL/min). Nintedanib is predominantly eliminated 
via metabolism and biliary/faecal excretion (about 94%). Renal excretion is a minor 
elimination pathway, both after intravenous and oral administration. The gMean terminal 
half-life of nintedanib was10 to 15h. Dose-proportional behaviour of Cmax and AUC was 
concluded based on several studies in cancer patients investigating doses from 50 to 450 mg 
qd and from 150 to 300 mg b.i.d.
Based on in vitro investigations, relevant interactions of nintedanib with other drugs via the 
CYP enzyme system or via glucuronidation reactions are not expected. Transporter profiling 
was performed for nintedanib and its 2 main metabolites. In general, any interactions with 
transporter substrates were considered unlikely. Nintedanib is a P-gp substrate. In the drug-
drug interaction trial 1199.161, exposure to nintedanib in healthy volunteers increased by 
about 1.6- to 1.7-fold for AUC and by about 1.8-fold for Cmax following concomitant 
administration with the potent P-gp inhibitor ketoconazole. Thus, if administered 
concomitantly with nintedanib, potent P-gp inhibitors (e.g. ketoconazole, erythromycin) may 
increase nintedanib exposure. After concomitant administration with the potent P-gp inducer 
rifampicin, exposure to nintedanib decreased to approximately 50% based on AUC and to 
approximately 60% based on Cmax. Thus, as potent P-gp inducers (e.g. rifampicin,
carbamazepine, phenytoin, St. John’s Wort) may decrease the exposure to nintedanib.


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Additional data on the PK of nintedanib in patients with hepatic impairment are available
from a dedicated single dose trial in patient volunteers with hepatic impairment (Child Pugh 
category A and B) but otherwise healthy plus matched healthy controls. Exposure in study 
1199.200 increased by approximately 2-fold in subjects with mild liver impairment defined 
as Child Pugh category A and by approximately 8-fold in subjects with moderate liver 
impairment defined as Child Pugh category B [c03149997].
For more details please refer to the investigator drug brochure and to the product information 
for nintedanib [c01632700-18 and current SmPC Nintedanib].
1.2.2
Docetaxel
Docetaxel is an approved drug for a number of malignant cancer diseases including 
monotherapy of locally advanced and/or metastatic NSCLC after first line therapy. Docetaxel
acts by disrupting the microtubular network in cells that is essential for mitotic and interphase 
cellular functions. Docetaxel binds to tubulin and promotes the assembly of tubulin into 
stable microtubules while simultaneously inhibiting their disassembly. This leads to 
microtubule bundles without normal function and to the stabilisation of microtubules causing 
inhibition of mitosis in cells [R04-2230, R07-4086]. According to the SPC, treatment with 
docetaxel may be associated with neutrophil count decreased, febrile neutropenia, anaemia,
thrombocytopenia, hypersensitivity reactions, anorexia, localised erythema of the extremities, 
fluid retention, pain, peripheral motor neuropathy and neurosensory symptoms (such as 
paresthesia, dysesthesia), asthenia, gastrointestinal AEs (such as nausea, stomatitis, vomiting, 
diarrhoea), constipation, hypotension, nail disorders, alopecia, myalgia, cardiovascular side 
effects (arrhythmia: no severe) and infusion site reactions. Elevated liver enzyme values are 
associated with an increased treatment-related mortality [R04-2230, R07-4086]. When 
docetaxel is administered at a standard dosage (75 mg/m² every 3 weeks), the majority of 
patients develop grade 3-4 neutropenia. Myelosuppression and its complications can be 
particularly problematic for older patients and for patients receiving palliative treatment, such 
as those with advanced NSCLC. Attempts to reduce the incidence of toxicity, particularly of 
febrile neutropenia, have resulted in the evaluation of weekly docetaxel regimens, which 
maintain dose intensity while altering the tolerability profile. Three phase III studies have 
compared 3-weekly to weekly dosing in relapsed NSCLC setting. None of the three studies 
showed significant changes in response or survival, although two trended toward favouring
the 3-weekly [R08-2280; R08-2275] dosing while one showed a trend in favour of weekly 
dosing [R15-1184]. All three, however, showed decreased grade 3 and 4 neutropenia with the 
weekly schedule. Results from these three studies and two additional randomized phase II 
studies were compiled in a meta-analysis, which analysed data from 865 patients in total and 
found overall a non-significant difference in median survival (27.4 weeks in the 3-week 
dosing versus 26.1 weeks in the weekly dosing, P = 0.245), and a reduction of grade 3 and 4 
neutropenia (18% versus 5%) and febrile neutropenia (6% versus <1%), (both P < 0.001)
[R15-5085]. These results suggest that weekly dosing is an acceptable alternative, 
particularly in a patient at greater baseline risk for neutropenia. Indeed, results from 
numerous clinical trials demonstrate that weekly dosing of docetaxel dramatically reduces the 
incidence of myelosuppression. In fact, there are fewer acute toxicities and the dose-limiting 


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toxicities, namely fatigue and asthenia, appear to be cumulative. Therefore weekly docetaxel
could be recommended as a feasible alternative second-line treatment option for patients with 
advanced non-small cell lung cancer. [R08-2275, R08-2280; R15-1184].
1.2.3
Combination of nintedanib and docetaxel
A phase I trial of nintedanib plus docetaxel (75 mg/m2) in Caucasian patients with hormone 
refractory prostate cancer established a MTD of 200 mg b.i.d. for nintedanib [U08-1273-02].
A multicentre, randomised, double-blind, phase III trial (1199.13 trial) to investigate the 
efficacy and safety of oral nintedanib plus docetaxel therapy compared to placebo plus 
docetaxel therapy in patients with locally advanced or metastatic NSCLC after failure of first 
line platinum-based chemotherapy showed that the combination of docetaxel and nintedanib
can be safely administrated and demonstrated significant benefit in patients with NSCLC of 
adenocarcinoma histology [P13-13353, P13-13346]. 
Overall survival (OS) was increased in patients with adenocarcinoma histology who were 
treated with nintedanib + docetaxel (median overall survival 12.6 months [95% CI 10.6–15.1] 
vs. 10.3 months [95% CI 8.6–12.2]; HR 0.83 [95% CI 0.70–0.99], p=0.0359).
Nintedanib in combination with docetaxel is an effective second-line option for patients with 
advanced NSCLC previously treated with one line of platinum-based therapy, especially for 
patients with adenocarcinoma [P14-00479].
The safety profile of nintedanib plus docetaxel in the 1199.13 trial was generally manageable 
with dose reductions and supportive care. The most common AEs by preferred term (any 
CTCAE grade) reported for the adenocarcinoma patient population with an incidence of 
>20% and with imbalances of more than 10% between treatment arms were diarrhoea (43.4% 
nintedanib vs. 24.6% placebo); ALT increased (37.8% vs. 9.3%), AST increased (30.3% vs. 
7.2%), and nausea (28.4% vs. 17.7%). Severe AEs by preferred term (CTCAE grade 3 or 
greater) reported in the adenocarcinoma patient population with an incidence of >1% were 
ALT increased (11.6% nintedanib vs. 0.9% placebo), AST increased (4.1% vs. 0.6%), 
decreased neutrophil count (36.3% vs. 34.8%), decreased white blood cell (WBC) count 
(19.7% vs. 18.3%), febrile neutropenia (7.2% vs. 4.5%), diarrhoea (6.3% vs. 3.6%), and 
asthenia (3.1% vs. 0.9%).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
As described in Section 1.2.3, the pivotal trial 1199.13 showed that the combination of 
nintedanib given continuously at the dose of 200 mg b.i.d. and docetaxel administered at the 
dose of 75 mg/m² every 3 weeks demonstrated significant OS benefit in patients with NSCLC 
of adenocarcinoma. In this specific histological pathology, nintedanib is the first drug, which 
prolongs the overall survival (OS) statistically and clinically significantly with 1-year 
survival rate over 50% (nintedanib: 52.7%, placebo: 44.7%) in combination with second line 
standard therapy in the last 10 years. 
There is a high frequency of myelosuppression occurring with docetaxel administered at 75 
mg/m2 every 3 weeks in combination with nintedanib and its complications can be 
problematic for some NSCLC patients. Weekly docetaxel administration, as shown in several 
studies, is associated with a significant lower rate of febrile neutropenia and of grade 3-4
hematologic toxicities. Therefore weekly docetaxel + nintedanib could be an alternative 
treatment option for patients with adenocarcinoma of the lung who failed a platinum based-
chemotherapy to reduce the frequency of myelosuppression.
This Phase I, 3+3 design, open label dose escalation study will explore the feasibility of the 
combination of nintedanib and the weekly administration of docetaxel on day 1, 8 and 15 
every 28 days at the dose of 35 mg/m² with the goal to reduce the incidence of toxicity, 
particularly of febrile neutropenia, with keeping at least the same efficacy.
The differences found in the incidence and severity of neutropenia and febrile neutropenia 
would also imply a possible reduction of the cost of supportive care.
2.2
TRIAL OBJECTIVES
The primary trial objective is to determine the MTD of nintedanib twice daily (b.i.d.) plus 
weekly docetaxel 35 mg/m2 (day 1, day 8, day 15 of a 28-day cycle) in patients with locally 
advanced or metastatic lung adenocarcinoma after failure of platinum-based first line 
chemotherapy
The further objectives concern the safety of nintedanib at each dose level in association with 
weekly docetaxel, as well as the PK data of nintedanib when administered continuously with 
docetaxel treatment. In addition, the efficacy of this combination will be assessed.
2.3
BENEFIT - RISK ASSESSMENT
The pivotal trial 1199.13 showed that the combination of nintedanib and docetaxel
demonstrated statistically significant prolongation of centrally assessed progression free
survival (PFS) and showed a statistically significant improvement of OS in NSCLC patients 


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with adenocarcinoma histology. The safety profile of nintedanib in combination with 
docetaxel in the 1199.13 trial was generally manageable with dose reductions and supportive 
care. No new or unexpected risks have been identified by the combination of nintedanib and 
docetaxel beyond what is known for docetaxel and what has been documented for nintedanib. 
Most common adverse events (AEs) with imbalance of incidence (>10%) in nintedanib arm 
were gastrointestinal (GI) tract (such as nausea and diarrhoea) and liver enzymes (AST, ALT) 
increase, and the safety profile was generally manageable with dose reductions and 
supportive care. 
The weekly docetaxel administration demonstrated a better tolerability which translated in 
less haematological toxicities as compared to the 3-weekly regimen [R08-2275].
The aim of this Phase I study is to determine the MTD of nintedanib given in combination
with weekly docetaxel and to evaluate the safety profile of this association in the lung 
adenocarcinoma.
Although rare, a potential for drug-induced liver injury is under constant surveillance by 
sponsors and regulators. Therefore, if necessary, this study requires timely detection, 
evaluation, and follow-up of laboratory alterations of selected liver laboratory parameters to 
ensure patients safety.
The potential benefit of nintedanib in this combination therapy is anticipated to outweigh the 
risks.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a phase I, open-label safety trial to determine the MTD of nintedanib plus docetaxel
35 mg/m2 given at Day1, Day8 and Day15 (28-day cycle) in patients with locally advanced 
or metastatic lung adenocarcinoma after failure of first line platinum-based chemotherapy.
Recruitment into this Phase I trial will follow a 3 + 3 design [R07-0220]. Four trial sites (two 
trial sites in France and two trial sites in Germany) with Phase I experience will be included 
to establish the MTD for nintedanib with docetaxel following a weekly schedule. In this trial, 
approximately 30 patients will be included. A maximum of 6 evaluable patients per cohort 
are required to determine the MTD of nintedanib in combination with weekly docetaxel.
Patients who meet the inclusion criteria and none of the exclusion criteria and who have 
given their informed consent will be entered to the trial.
Inclusion of a new patient and the actual dose level will be agreed upon between the 
investigator and BI as the sponsor, in close interaction with the investigators. 
The starting dose level of nintedanib administered continuously except the days of docetaxel
infusion (see Section 3.2) will be 150 mg b.i.d, and, provided tolerability is acceptable, will 
increase to 200 mg b.i.d. Dose-escalation of nintedanib will be performed after discussion 
and agreement of the sponsor (BI) and the investigators of the trial. In case of unacceptable 
toxicity of the starting dose level, the dose of nintedanib will be de-escalated to 100 mg b.i.d
to determine whether this dose is the MTD. 
If the dose of nintedanib of 200 mg b.i.d administered continuously except the days of 
docetaxel infusion is tolerable an additional cohort will explore the administration of 
nintedanib 200 mg b.i.d continuously without interruption on the days of docetaxel infusion. 
Only if the nintedanib dose reaches 200 mg b.i.d (with or without interruption on the days of 
docetaxel administration), it is planned to enrol an expansion cohort of 6 patients to better 
characterize the safety at the 200 mg b.i.d (MTD dose).
Patients will be treated with a combination therapy of docetaxel at the dose of 35 mg/m² on 
days 1, 8 and 15 followed by 2 weeks of rest every 28 days, and with nintedanib as long as 
they do not meet one of the treatment discontinuation criteria, e.g. progressive disease (PD), 
withdrawal of informed consent and undue toxicity (see Section 3.3.4.1).The trial will end 
once the last patient has completed the EOR visit foreseen 28 days (+ 7 days) after 
termination of treatment, or, once the last patient has been withdrawn from the trial and no 
further EOR visit is expected. 
The database lock of this trial would be triggered by the date when the last patient reaches the 
end of trial participation.


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Details of statistical considerations are given in section 7.
Pharmacokinetics (PK) of nintedanib will be evaluated only in patients treated with 
nintedanib 200 mg b.i.d given continuously without interruption on the days of docetaxel
infusion. The pharmacokinetics in patients treated with nintedanib continuously except the 
days of docetaxel infusion will not be done.
Nintedanib and Docetaxel will be provided by the Sponsor directly. The trial drugs have to be 
stored according to the storage conditions.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim 
Boehringer Ingelheim will appoint a Trial Clinical Monitor, responsible for coordinating the 
activities required in order to manage the trial in accordance with applicable regulations and 
internal SOPs, directing the clinical trial team in the preparation, conduct, and reporting of 
the trial, ordering the materials as needed for the trial, ensuring appropriate training and 
information of Local Clinical Monitors (CML), Clinical Research Associate (CRA), and 
investigators.
Data management, statistical and PK evaluations will be done by BI and a CRO according to 
BI SOPs. For these activities, a Trial Data Manager (TDM), a Trial Statistician (TSTAT) and 
a Trial Clinical Pharmacokineticist (TCPK) will be appointed. Tasks and functions assigned 
in order to organise, manage, and evaluate the trial will be defined according to BI SOPs. A 
list of responsible persons and relevant local information can be found in the Investigator Site 
File (ISF) and Trial Master File (TMF).
Investigators of participating sites and BI study clinical monitor and representatives will be 
appointed to evaluate DLT, overall safety and other available data (e.g. PK data, if available) 
and confirm dose escalation steps. 
The organisation and on-site monitoring of the trial will be performed by Boehringer 
Ingelheim.
All trial relevant documentation will be stored in BI’s TMF. Trial relevant documentation 
which has to be at the trial site will be filed in the ISF at the investigator site.
A co-ordinating investigator will be nominated by BI to coordinate investigators at different 
sites participating in this trial, and will sign the clinical trial report of this trial, and has 
experience in this type of trial and investigations. Tasks and responsibilities for the co-
ordinating investigator will be defined in a contract filed before initiation of the trial. 
This trial will be conducted by expert investigators in oncology Phase I and also 
chemotherapy of NSCLC at appropriate study sites where a very cautious safety control 
procedure has been established. There will be no steering committee or data monitoring 
committee for this trial.


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Data management, statistical and pharmacokinetic analyses will be performed by Boehringer 
Ingelheim or a CRO authorized by Boehringer Ingelheim. 
The safety laboratory investigations (haematology, biochemistry, coagulation parameters, 
urine analysis) will be performed locally at the sites. The certification for each local 
laboratory must be provided and filed at the sponsor and the local ISF of the site.
Interactive response technology (IRT) will be provided by a CRO/vendor. Details will be 
provided in the IRT manual available in the ISF.
An ISF containing all relevant study related documentation will be maintained according to 
European regulations and BI SOPs at each study site. A copy of the ISF documents will also 
be kept as an electronic TMF at BI according to BI SOPs. Documents related to participating 
investigators and other important participants, especially their curricula vitae, will be filed in 
the TMF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE 
CHOICE OF CONTROL GROUP(S)
In this open label Phase I trial, the dose escalation will follow a 3 + 3 design to evaluate the 
MTD of nintedanib in combination with weekly docetaxel  (Day 1, Day 8 and Day 15 in  28-
day cycles). The safety profile of the patients will be evaluated at each dose level of 
Nintedanib in combination with weekly docetaxel.
The dose levels of nintedanib will be as follows:
o
Nintedanib will be administered continuously except the days of docetaxel infusion: 

Level -1 (de-escalation dose): nintedanib 100 mg b.i.d in combination with docetaxel.

Level 1 (starting dose): nintedanib 150 mg b.i.d in combination with docetaxel

Level 2 (escalation dose): nintedanib 200 mg b.i.d in combination with docetaxel
o
Nintedanib will be administered continuously without interruption on the days of 
docetaxel infusion: 

Level 3 nintedanib 200 mg b.i.d in combination with docetaxel.
3.3
SELECTION OF TRIAL POPULATION
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site.
Approximately 30 entered patients will participate to this trial which will be conducted in 2 
sites in France and in 2 sites in Germany.


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3.3.1
Main diagnosis for study entry 
Patients with locally advanced or metastatic lung adenocarcinoma after failure of first line 
platinum based chemotherapy.
3.3.2
Inclusion criteria
1.
Patients aged 18 or older at the date of informed consent
2.
Patients with histologically/cytologically locally advanced (Stage IIIB) or metastatic
(Stage IV) lung adenocarcinoma after failure of first line platinum-based chemotherapy 
(patients with non-target lesion only are eligible)
First line chemotherapy may include continuation or switch maintenance therapy. 
One prior adjuvant and/or neoadjuvant chemotherapy line is accepted. Prior 
immunotherapy is allowed.
3.
Patients who have life expectancy of at least 3 months
4.
Patients who are Eastern Cooperative Oncology Group (ECOG) performance status 
(PS) ≤1 at screening
5.
Written informed consent that is consistent with ICH-GCP guidelines and local 
legislation.
3.3.3
Exclusion criteria
1.
Patients who have received more than one prior line of chemotherapy (i.e., second or 
third line chemotherapy) for advanced or metastatic NSCLC.
2.
Patients known to be positive for activating Epidermal Growth Factor Receptor (EGFR) 
mutation or patients known to be positive for ALK translocation.
3. 
Patients who have received previous therapy with other vascular endothelial growth 
factor (VEGF) or vascular endothelial growth factor receptor (VEGFR) inhibitors 
(other than bevacizumab) for the treatment of NSCLC at any time.
4.
Patients who have received following treatments within 4 weeks prior to start of study 
therapy: 
a)
Other investigational drugs
b)
Chemo-, hormone-, immunotherapy, or monoclonal antibody. 
5.
Patients who have received radiotherapy within the 4 weeks (in the case of limited -
field [e.g. brain or bone metastasis]), radiotherapy with palliative intent, within 2 
weeks) prior to start of study therapy
6.
Persistence at screening of clinically relevant therapy related toxicities from previous 
chemotherapy and/or radiotherapy (AE from previous treatment ≥ Grade 2)
7.
Patients with one or more of the following laboratory values at screening: 


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a)
Serum creatinine>1.5 x upper limit of normal (ULN)
b)
Proteinuria ≥CTCAE grade 2
c)
Total bilirubin>1.0 x ULN
d)
ALT and/or AST ≥ 1.5 x ULN for patients without liver metastases. ALT and/or 
AST ≥ 2.5 x ULN for patients with liver metastases.
e)
Alkaline phosphatase (ALP)>2.5x ULN
f)
Prothrombin time and/or partial thromboplastin time>50% deviation from normal 
limits
g)
International normalised prothrombin ratio (INR)> 3
h)
Absolute neutrophil count (ANC) < 1500/mm3
i
Platelets<100000/mm3
j)
Haemoglobin< 9 g/dL
8.
Patients with any of the following conditions at screening:
a)
Ascites and/or uncontrolled pleural effusion
b)
Significant weight loss (>10%) within the past 4 weeks prior to registration
c)
Current peripheral neuropathy ≥CTCAE grade 2 except due to trauma
d)
Major injuries and/or surgery within the past 4 weeks prior to start of study 
therapy 
e)
Diabetes mellitus not controlled by medical therapy
f)
Contraindication to high dose corticosteroid therapy
g)
Active or chronic hepatitis C (HCV) and/or B (HBV) infection and/or known 
human immunodeficiency virus (HIV) infection
h)
Known or suspected active alcohol or drug abuse
i)
Serious illness or concomitant non-oncological disease such as neurologic, 
psychiatric, infectious disease or active ulcers (gastrointestinal malabsorption 
or other conditions, skin), or history of hollow-organ perforation
j)
History of laboratory abnormality that may increase the risk associated with 
study participation or study drug administration
k)
Other malignancy within the past 3 years other than basal cell skin cancer, or 
carcinoma in situ of the cervix
l)
Active brain metastases or leptomeningeal disease stable for <4 weeks (e.g. no 
previous adequate treatment with radiotherapy, symptomatic, requiring 
treatment with anti-convulsants). If brain metastases have been treated, they 
must be stable for ≥4 weeks. Dexamethasone therapy will be allowed if 
administered at a stable dose for at least 4 weeks prior to registration. Patients 
with newly diagnosed brain metastases will be excluded from the study 
until/unless treated as described above


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m)
Radiographic evidence (CT or MRI) of cavitary or necrotic tumours or
centrally located tumours with local invasion of major blood vessels
n)
Clinically significant haemoptysis within the past 3 months (more than five 
ml)
o)
Bleeding or thrombotic disorders requiring oral anticoagulant therapy 
(treatment with low molecular weight heparin and/or heparin flush as needed 
for maintenance of an indwelling intravenous device is allowed) or anti-
platelet therapy (except for chronic low-dose therapy with acetylsalicylic acid 
≤325 mg per day). 
p)
History of major thrombotic event or known inherited predisposition to 
thrombosis, or clinically relevant major bleeding event in the past 6 months
q)
Significant cardiovascular diseases (i.e. hypertension not controlled by 
medical therapy, unstable angina, history of myocardial infarction within the 
past 6 months, congestive heart failure New York Heart Association 
(NYHA)>II, serious cardiac arrhythmia, pericardial effusion
9.
Male or female patients of childbearing potential who are sexually active and unwilling 
to use a highly effective method of contraception (e.g. contraceptive implants, 
injectables, combined oral contraceptives, some intrauterine devices or vasectomised 
partner for participating females, a double barrier method such as condom plus 
diaphragm with spermicide for participating males) during the trial and for at least 3 
months after the end of the treatment with nintedanib and for at least 6 months after the 
end of the therapy with docetaxel. Patients will be considered to be of childbearing 
potential unless surgically sterilised by hysterectomy or bilateral tubal 
ligation/salpingectomy, or post-menopausal for at least 1 year
10.
Patients who are pregnant or breast feeding at screening
11.
Any contraindications for therapy with docetaxel or history of severe hypersensitivity 
reactions to docetaxel or other drugs formulated with polysorbate 80 (Tween 80).
12
Hypersensitivity to nintedanib and/or the excipients of the trial drugs. 
13.
Known allergy to soya and/or peanut proteins. Dietary soya products are known to 
cause allergic reactions including severe anaphylaxis in persons with soya allergy. 
Patients with known allergy to peanut proteins carry an enhanced risk for severe 
reactions to soya preparations.
14.
Patients unable to comply with the study protocol for any reason
15
Patients judged inappropriate for entry into the study by the investigator


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3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients:
A patient will discontinue study treatment (nintedanib +/- docetaxel) if any one of the 
following applies: 
•
Progressive disease.
If a patient experiences a radiological progression according to RECIST 1.1 but derive an 
obvious clinical benefit from the treatment according to the investigator’s judgement, the 
patient may remain on study after discussion with the sponsor. The first date of 
progression will be documented as the date of the progression of the disease in the eCRF.
•
Withdrawal of informed consent for active treatment.
•
Patient’s request.
•
The patient is no longer able to participate in the study (e.g. AE, major surgery, 
pregnancy, concomitant diagnoses, concomitant therapies; if the patient is no 
longer able to attend study visits due to worsening of disease, or for administrative 
reasons).
•
Significant deviation from the protocol or eligibility criteria; the patient receives 
prohibited concomitant medication (see Section 4.2.2).
•
The patient cannot complete the docetaxel infusion in treatment Cycle 1 due to 
hypersensitivity reactions etc.
Patients who discontinue only one drug of the combination (e.g., either docetaxel or 
nintedanib) but qualify to receive monotherapy with the remaining drug are not considered to 
have ended active treatment.
Reasons for discontinuation will be documented in the electronic case report form (eCRF).
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 invalidating the earlier positive benefit-
risk assessment that could significantly affect continuation of the trial.
3 Violation of GCP, the CTP, or the contract by a trial site or investigator, disturbing 
the appropriate conduct of the trial. 
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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3.3.4.3
Patient replacement
Patients who meet one of following in Cycle 1 have to be replaced for the DLT evaluation: 
1.
Patient cannot complete the docetaxel infusion due to hypersensitivity 
reactions.
2.
Patient cannot complete treatment cycle due to other reasons than AEs related 
to study treatment (i.e. nintedanib and/or docetaxel) such as progressive 
disease, withdrawn informed consent, non-related AE with CTCAE grade 3 or 
greater or administrative reason.
3.
Missed dose of nintedanib for more than 14 doses (non-compliance) during 
treatment cycle 1 because of the reasons other than drug related AEs.
4.
Patient missed the 2 subsequent docetaxel infusions (Day 8 and Day 15) 
during cycle 1.
  
Replacement of patients will be determined individually after discussion between the 
investigator and the sponsor.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
Patients will be treated in cycles of 28 days duration. During a combination treatment cycle, 
docetaxel will be administered on Day 1, on Day 8, on Day 15 followed by 2 weeks of rest
and nintedanib will be administered twice daily. If patients discontinue docetaxel and meet 
the retreatment criteria for nintedanib (see Section 4.1.4.1.4) and do not meet one of the 
discontinuation criteria (see Section 3.3.4.1), patients on nintedanib monotherapy will start 
therapy on Day 1 of each cycle until Day 28.
4.1.1
Identity of BI investigational product(s) and combination product(s)
4.1.1.1
Nintedanib (investigational medical product)
Table 4.1.1.1: 1
Nintedanib
Substance (INN):
Nintedanib
Pharmaceutical formulation:
Soft gelatine capsule
Pharmaceutical code
BIBF 1120
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
100 mg and 150 mg capsules
Route of administration:
Oral
Posology:
See Section 3.2 (100 mg b.i.d or 150 mg b.i.d or 200 
mg b.i.d).
Twice daily (to be swallowed unchewed with a glass 
of water of about 250 mL with a dose interval of 12 
hours at the same time every day, usually in the 
morning and the evening after food intake).
See Dose reduction according to Section 4.1.4.2.


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Table 4.1.1.1: 2
Docetaxel (investigational medicinal product)
Substance: 
Docetaxel
Pharmaceutical form: 
Injection concentrate
Source: 
Unit strength: 
Docetaxel 160 mg / 8 ml and 80 mg/4ml
Posology:
At Day 1, at Day 8 and at Day 15 every 28 
days cycle
Premedication
Corticosteroid, such as dexamethasone 
(8mg twice daily orally the day before and 
after docetaxel infusion; 8 mg intravenously 
30 minutes before docetaxel). Antiemetics 
are recommended before docetaxel infusion.
Route of administration:
Intravenous infusion over 60 minutes
Infusion dose
35 mg/m²
Duration of use: 
Weekly until discontinuation criteria (see 
Sections 3.3.4.1 and 4.1.4.1.2 are fulfilled).
4.1.2
Method of assigning patients to treatment groups
As the 1199.224 study is designed to determine the MTD of nintedanib in combination with 
weekly docetaxel, it is planned to initially start with 150 mg nintedanib b.i.d.
Patients who meet the eligibility criteria and who have given their written informed consent 
will be entered into the study.
Registration of the patients will be performed following RDC. As there are no predefined 
cohorts, the IRT system can assign nintedanib and docetaxel kit numbers.
Details are described in the IRT manual available in the Investigator Site File (ISF).
The decision regarding the opening of another cohort of 3 patients (e.g. for escalation/de-
escalation of the starting dose) will only be made after discussion between the BI Clinical 
Monitor and the Investigators of the trial. Depending on the occurrence of drug-related DLT 
within treatment course 1 in a three or six patient cohort, the Investigators and the BI Clinical 
Monitor will decide the next dose cohort after discussion of the safety data available at that 
time (including safety data available also for repeated treatment courses).


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Table 4.1.2: 1 
Rules for dose escalation
Number of Patients with DLT at a Given 
Dose Level
Escalation Decision Rule
0 out of 3 or 1 out of 6
Enter 3 patients at the next higher dose level
≥ 2 out of 3
Dose escalation will be stopped. Three (3) 
additional patients will be entered at the 
next lowest dose level if only 3 patients 
were treated previously at that dose level.
If 6 patients were already treated at that next 
lowest dose level, no more patients will be 
entered and this dose will be considered the 
MTD.
1 out of 3
Enter 3 more patients at this dose level.
If 0 of these 3 patients experience DLT, 
proceed to the next dose level (if highest 
dose, this dose will be considered as the 
MTD).
If 1 or more of this group suffer DLT, then 
dose escalation is stopped. Three (3) 
additional patients will be entered at the 
next lowest dose level (see above).
≤ 1 out of 6 at highest dose level 
This is the MTD and recommended dose.
The MTD nintedanib in combination with weekly docetaxel 35 mg/m² will be defined as the 
highest dose of nintedanib at which no more than 1 out of 6 patients have a DLT within 
treatment course 1. The highest dose is capped to 200 mg bid given without interruption even 
on days of docetaxel infusion; if there is no DLT at this dose level then this would be 
considered as the MTD.
Expansion cohort:
Only if the nintedanib dose reaches 200 mg b.i.d (with or without interruption on the day of 
docetaxel administration), it is planned to enrol an expansion cohort of 6 patients to better 
characterize the safety at the 200 mg b.i.d (MTD dose).


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4.1.3
Selection of doses in the trial
4.1.3.1
General recommendations for dose selection in the present trial 
4.1.3.1.1
Nintedanib
The registered dose of nintedanib in combination with 75 mg/m2 of docetaxel is 200 mg 
b.i.d.in Caucasians [U08-1273-02]. 
The purpose of this study is to assess the MTD of nintedanib following a 3+3 design (orally, 
100 mg b.i.d, 150 mg b.i.d or 200 mg b.i.d) in combination with weekly docetaxel
(intravenously, 35 mg/m² at day 1, at day 8 and at Day 15, a 28 day cycle) in lung 
adenocarcinoma. The combination of nintedanib at the MTD with weekly docetaxel should 
have the same efficacy with a better tolerability than nintedanib with standard 3-weekly 
docetaxel 75 mg/m².
4.1.3.1.2
Docetaxel
Docetaxel monotherapy is approved for the treatment of patients with NSCLC previously 
treated with one prior platinum-based chemotherapy. The recommended dose of docetaxel for 
the second line treatment of patients with NSCLC is 75 mg/m2 in global as an intravenous 
infusion every 3 weeks.
Weekly scheduling of docetaxel (35 mg/m² Day 1, Day 8 and Day 15, following a 28 day 
cycle) has been tested and compared to the 3 weekly schedule of docetaxel which showed 
comparable efficacy and less myelotoxicity in pretreated NSCLC patients. In particular, there 
were significantly lower rates of grade 3 to 4 anaemia, leukopenia and neutropenia. Febrile 
neutropenia was observed at a significantly lower rate as well. With less myelotoxicity, the 
weekly schedule of docetaxel seems to be a good alternative for patients at risk of severe 
neutropenia.
A weekly dose of 35 mg/m2 will be used as the fixed dose for all patients enrolled in this 
trial. No dose adjustments will be made and if necessary, docetaxel will not be administered
as defined in Section 4.1.4.1. Docetaxel could be stopped after 8 cycles if there is no further 
clinical benefit is expected in the opinion of the investigator.
As indicated, all patients will receive premedication for docetaxel (such as dexamethasone
and antiemetics) prior to the docetaxel infusion. Premedication for docetaxel will be captured 
in the electronic case report form (eCRF [e.g. trade name or substance name, dose and 
treatment duration]).
Patients should be observed closely for hypersensitivity reactions especially during the first 
and second infusion of docetaxel. Hypersensitivity reactions may occur within a few minutes 
following the initiation of the infusion of docetaxel. Thus, facilities for the treatment of 
hypotension and bronchospasm should be available. If hypersensitivity reactions occur, minor 
symptoms such as flushing or localised cutaneous reactions do not require interruption of 


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therapy. However, severe reactions, such as severe hypotension, bronchospasm or generalised 
rash/erythema require immediate discontinuation of docetaxel and appropriate therapy. 
Patients who have developed severe hypersensitivity reactions should not be re-challenged 
with docetaxel (see Section 4.1.4.1.2).
4.1.4
Drug assignment and administration of doses for each patient
Docetaxel will be administered by intravenous infusion approximately over 60 minutes on 
Day 1, on Day 8, on Day 15 of each 28 days treatment cycle. 
The investigator or his/her assignee will dispense nintedanib trial medication to patients, as 
described in Section 4.1.6.
Nintedanib will be taken (swallowed) whole, unchewed twice daily after a meal every 12 
hours, at approximately the same time e.g. in the morning and in the evening, starting with
the morning dose on the day following the day of docetaxel administration (from Day 2 to 
Day 7, from Day 9 to Day 14; from Day 16 to Day 28 for each cycle). Nintedanib will not be 
taken on the days of docetaxel administration in dose levels 1; 2 and -1. Nintedanib will be 
taken without interruption in dose level 3, even on days of docetaxel administration. 
Patients who are treated with continuous nintedanib in association with docetaxel (cohort 
level 3) are also required to visit the study site without taking the study drug for morning 
dose on the visit day when pharmacokinetic blood samples are planned at Cycle 1 Day 8 and 
Day 15 and at Cycle 2 Day 1, Day 8 and Day 15.
If a patient misses one or more doses of nintedanib, he/she should not replace the missing
dose but take the subsequent doses according to protocol.
If a patient experiences adverse events (AEs) that would require temporary interruption of 
study treatment (nintedanib and / or docetaxel) as follows (see Section 4.1.4.1 and 4.1.4.2): 
- No administration followed by dose reduction of nintedanib.
and/or
- No administration of docetaxel until the next infusion.
The treatment may be resumed when the retreatment criteria are met.
4.1.4.1
Treatment cycle intervals
Treatment cycles should be repeated every 28 days. In case of retreatment criteria with 
docetaxel are not met, docetaxel should be administered at the same dosage at the next 
planned administration. If docetaxel administration was missed due to related AE for two or 
more consecutive infusions, docetaxel treatment should be discontinued. Docetaxel could be 
stopped after 8 cycles if there is no further clinical benefit is expected in the opinion of the 
investigator.


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4.1.4.1.1
Treatment criteria for docetaxel therapy
Treatment criteria for docetaxel are as follows:
1.
Absolute neutrophil count (ANC) ≥ 1500/mm3 before Day 1 of docetaxel
administration and ANC ≥ 1000 / mm3 before Day 8 and Day 15 of docetaxel
administration.
2.
Thrombocyte count ≥ 100000/mm3 before each day of docetaxel administration
3.
Total bilirubin values within normal ranges
4.
ALT and/or AST ≤ 1.5xULN and concomitant with alkaline phosphatases ≤ 2.5 x 
ULN
5.
No severe hypersensitivity reaction to docetaxel in a previous treatment cycle
6.
Peripheral neuropathy CTCAE grade ≤ 1.
7.
Non-hematologic toxicity has recovered to baseline or to CTCAE grade 1 or less 
(excluding CTCAE grade 2 alopecia)
8.
Recovery of docetaxel related AEs to Grade ≤ 1.
In case patients do not meet the treatment criteria for docetaxel therapy, please skip docetaxel
infusion and postpone the administration to the next planned administration. During this 
period, therapy with nintedanib shall continue if none of the discontinuation criteria related to 
nintedanib is met.
In case of discontinuation of nintedanib for other reasons than progressive disease (e.g. 
toxicity), the treatment with docetaxel monotherapy is allowed. 
4.1.4.1.2
Stopping criteria for docetaxel therapy
In case one of the following criteria would apply, docetaxel therapy has to be stopped:
1.
CTCAE grade 3 or greater peripheral neuropathy
2.
Severe hypersensitivity to docetaxel
3.
Omission of 2 or more consecutive docetaxel infusions.
In this event patients may continue monotherapy with nintedanib as long as none of the 
discontinuation criteria related to nintedanib treatment are met (see Section 3.3.4.1 and
Section 4.1.4.2).
4.1.4.1.3
Temporary treatment interruption of nintedanib treatment
Treatment with nintedanib will be temporarily discontinued and adequate therapy be initiated
if one of the following drug related AEs would occur:
1.
CTCAE grade 3 or greater non haematological drug related AEs.
2.
CTCAE grade 3 or greater diarrhoea.
3.
CTCAE grade 2 diarrhoea for more than 7 days despite of supportive care.
4.
CTCAE grade 3 or greater nausea despite supportive care.


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5.
CTCAE grade 2 nausea for more than 7 days despite of supportive therapy
6.
CTCAE grade 2 or greater vomiting despite of supportive care.
7.
An increase of ALT and/or AST to CTCAE grade 3 or greater.
8.
An increase of ALT and/or AST to CTCAE grade 2 or greater in conjunction with 
CTCAE grade 1 or greater total bilirubin increase.
Treatment with nintedanib can be temporarily discontinued because of reasons other than 
above by investigator’s judgement.
4.1.4.1.4
Retreatment criteria for nintedanib
Treatment with nintedanib may be resumed at a dose level described in Section 4.1.4.2 as 
long as the events causing temporary treatment interruption have recovered to baseline, or to 
CTCAE grade 1 (except CTCAE grade 2 alopecia). If the AE is not related to nintedanib
following the investigator judgement, dose reduction is not needed.
In case of interruption of retreatment for more than 21 days would be required by the 
investigator or the patient this needs to be discussed and agreed between the investigator and 
the sponsor.
4.1.4.2
Dose reduction scheme of nintedanib (given in combination or as monotherapy)
In case of nintedanib related AEs as outlined in this section, the dose of nintedanib will be 
reduced after a pause. 

For the patients treated with 200 mg b.i.d of nintedanib: nintedanib will be reduced 
from 200 mg b.i.d. to 150 mg b.i.d. for the first dose reduction and from 150 mg b.i.d. 
to 100 mg b.i.d. for the second dose reduction when a dose reduction is considered 
necessary.

For the patients treated with 150 mg b.i.d of nintedanib: nintedanib will be reduced 
from 150 mg b.i.d to 100 mg b.i.d for the first reduction dose. No dose reduction is 
allowed below 100 mg b.i.d. 
After a pause followed by a dose reduction if the AE is drug related for nintedanib, it is not 
allowed to increase the dosage of nintedanib.
Dose reduction and administration schemes according to the occurrence of drug related AEs 
are presented in the following. (Tables 4.1.4.2.1-4)


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Table 4.1.4.2: 1
Dose reduction (nintedanib) for non-haematological AEs except for 
diarrhoea, nausea, vomiting, isolated gamma-glutamyl transferase, 
AST and/or ALT increases
AE
Nintedanib
CTCAE grade 3 or greater 
non haematological AEs
Interruption of the treatment until Recovery 
(CTCAE grade ≤ 1 or baseline).
If drug related, restart with reduced dose.
Table 4.1.4.2: 2
Dose reduction (nintedanib) for CTCAE grade 3 or greater AST 
and/or ALT increases, or for CTCAE Grade 2 or greater AST and/or 
ALT increases in conjunction with CTCAE grade 1 or greater total 
bilirubin
AE
Nintedanib
1st episode
Interruption of the treatment 
until Recovery (CTCAE 
grade ≤ 1 or baseline).
If drug related, restart with 
reduced dose.
2nd episode
Interruption of the treatment 
until Recovery (CTCAE 
grade ≤ 1 or baseline).
If drug related, restart with 
reduced dose.
3rd episode
Permanent discontinuation


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Table 4.1.4.2: 3
Dose reduction (nintedanib) for CTCAE grade 2 or greater vomiting
or CTCAE grade 3 or greater nausea despite supportive care1.
AE
Nintedanib
1st episode
Interruption of the treatment 
until Recovery (CTCAE 
grade ≤ 1 or baseline).
If drug related, restart with 
reduced dose.
2nd episode
Interruption of the treatment 
until Recovery (CTCAE 
grade ≤ 1 or baseline).
If drug related, restart with 
reduced dose.
3rd episode
Permanent discontinuation
1 Prophylactic anti-emetic therapy is mandatory for the subsequent treatment cycles. See 
Section 4.2.1 for recommended therapies.
Table 4.1.4.2: 4
CTCAE grade 2 diarrhoea for more than 7 consecutive days despite 
supportive care1 or CTCAE grade 3 diarrhoea.
AE
Nintedanib
1st episode
Interruption of the treatment 
until Recovery (CTCAE 
grade ≤ 1 or baseline).
If drug related, restart with 
reduced dose.
2nd episode
Interruption of the treatment 
until Recovery (CTCAE  
grade ≤ 1 or baseline).
If drug related, restart with 
reduced dose.
3rd episode
Permanent discontinuation
1 See Section 4.2.1 for recommended therapies.
4.1.5
Blinding and procedures for unblinding
Not applicable.


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4.1.6
Packaging, labelling, and re-supply
Nintedanib and Docetaxel will be provided by BI.
Nintedanib soft gelatine capsules will be packaged in aluminium-blister sheets. 
Nintedanib will be delivered in medication kits. Kits will be labelled according to French and 
German requirements.
Docetaxel will be also labelled according to French and German requirements.
The IRT system ensures that sufficient medication is allocated to a respective patient for daily 
treatment.
Patients will be handed out the nintedanib trial medication for the upcoming treatment cycle 
during the planned and/or regular visit on Day 1 of each treatment cycle. In case that a patient 
is expected to visit the study site more than 28 days after the Day 1, additional medication 
should be handed out during previous visit. The unused trial drug with the previous cycle has 
to be collected at the Day 1 of each cycle.
In case a patient interrupts intake of nintedanib during a treatment cycle and meets the criteria 
for retreatment within the same treatment cycle with reduced dose, the reduced dose should 
be handed out during the visit by the investigator or a deputy. Nintedanib with the previous 
dose not used until then has to be collected.
See Section 4.1.8 for drug accountability.
For details of packaging and the description of the label, see ISF.
4.1.7
Storage conditions
Nintedanib has to be stored in the original package according to the storage instructions as 
provided on the label and in the ISF at a location with limited access to authorised people.
Docetaxel has to be stored according to the manufacturer’s storage instructions. Docetaxel 
160 mg or 80 mg concentrate for solution i.v. should not be stored at a temperature above 25 
°C. It should be stored in the original container to protect from light. The vials are for single 
use and must be used immediately after their opening. If not used immediately, in-use storage 
times and conditions are the responsibility of the use and would normally not be longer than 6 
hours below 25°C including the one hour infusion.
Docetaxel 160 mg or 80 mg infusion solution is supersaturated therefore may crystallize over 
time. If crystals appear the solution must no longer be used and shall be discarded.
Nintedanib and docetaxel may only be dispensed to trial patients according to the protocol by 
authorised personnel as documented in the form “Investigator’s Trial Staff”.


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Temperature logs must be kept. In case temperature would be out of range, this would have to 
be reported in the ISF and the sponsor be notified.
4.1.8
Drug accountability
Nintedanib and Docetaxel will be provided by the sponsor.
The pharmacist will receive the investigational drugs delivered by the sponsor when the 
following requirements are fulfilled:
•
Approval of the study protocol by the institutional review board (IRB).
•
Availability of a signed and dated clinical trial contract between the sponsor and 
the site.
•
Approval/notification of the regulatory authority, e.g. competent authority.
•
Availability of the curriculum vitae of the principal investigator.
•
Availability of a signed and dated clinical trial protocol (in exceptional cases, 
medication could already be sent to the site, before its activation via IWRS).
The pharmacist must maintain records of the product’s delivery to the trial site, the inventory 
at the site, the use by each patient, and the return to the sponsor or alternative disposition of 
unused product(s). 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) and trial patients. The 
pharmacist will maintain records that document adequately that the patients were provided 
the doses specified by the CTP and reconcile all investigational product(s) i.e., nintedanib
received from the sponsor.
At the time of return to the sponsor and/or appointed CRO, the pharmacist must verify that all 
unused or partially used nintedanib supplies have been returned by the clinical trial patient 
and that no remaining supplies are in the investigator’s possession. Unused or used 
nintedanib medication will be sent back to the sponsor or to an appointed CRO and will be 
destroyed. A destruction certificate will be required. The used or unused docetaxel 
medication will be destroyed at each site with a destruction certificate. 


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
An antidote against nintedanib is not available. Potential side effects of nintedanib and/or 
docetaxel have to be treated symptomatically. Treatment of symptomatic side effects or 
tumour-associated symptoms is allowed (except for therapies listed in Section 4.2.2).
Nausea and/or vomiting should be treated according to the international guidelines and 
recommendations (Multinational Association of Supportive Care in Cancer [R06-0986]). 
Anti-emetic therapy with e.g. glucocorticoids, metoclopramide or dimenhydrinat may be 
initiated as clinically indicated (CTCAE grade 2 or greater nausea and CTCAE grade 1 or 
greater vomiting), with adequate hydration. If other anti-emetic therapy is not effective 
(CTCAE grade 2 or greater vomiting and for CTCAE grade 3 or greater nausea), short-term 
treatment with a 5-HT3 antagonist (e.g. granisetron) and concomitant steroid (e.g. 
dexamethasone) may be indicated. Patients known to suffer from anticipatory vomiting and 
patients who experienced nausea and/or vomiting should receive prophylactic anti-emetic 
therapy prior to any further treatment cycle with docetaxel. In the event of dehydration 
administration of electrolytes and fluids is required. Plasma levels of electrolytes should be 
monitored, if moderate or severe (CTCAE grade 2 or greater) gastrointestinal AEs occur.
Diarrhoea (CTCAE grade 2 or greater) should be treated at first signs with adequate 
hydration and anti-diarrhoeal medicinal products, e.g. loperamide should be administered 
according to the recommended dose schedule: i.e., 4 mg of loperamide at onset followed by 2 
mg after every stool until diarrhoea has abated for 12 hours (maximal daily dosage 12-16 
mg). 
All patients will receive oral corticosteroids as pre- and concomitant medication for docetaxel 
(such as dexamethasone) for three days starting one day prior to the docetaxel infusion.
Patients experiencing neutrophil count decreased may receive granulocyte colony stimulating 
factor (G-CSF) at investigator’s discretion.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Additional chemo-, immuno-, hormone- or radiotherapy is not allowed during the active 
treatment period of this trial. 
Concomitant medications, or therapy to provide adequate care, may be given as clinically 
necessary. 
The use of bisphosphonates for treatment of bone metastases is allowed and Concomitant 
treatment with growth factors (e.g. filgrastim, pegfilgrastim) are allowed 


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For symptom control palliative radiotherapy may be permitted for bone metastases in 
extremities, hip or vertebrae after discussion with the BI clinical monitor, provided that 
radiotherapy does not affect the target lesions, and the reason for the radiotherapy does not 
reflect progressive disease (PD). 
The oral anticoagulant therapy is not allowed (anticoagulant therapy with low molecular 
weight heparin and / or heparin flush may be allowed if clinically required for a patient to 
treat AEs). These patients will be supervised at close intervals until they reach stable 
anticoagulation situation.
Anti-platelets are forbidden except for chronic low-dose therapy with acetylsalicyclic acid ≤ 
325 mg per day.
In vitro studies have shown that the metabolism of docetaxel may be modified by the
concomitant administration of compounds that induce, inhibit, or are metabolised by 
cytochrome P450 (CYP) 3A4, such as cyclosporine, terfenadine, ketoconazole,
erythromycin, nifedipine and troleandomycin. Based on in vitro findings caution should be 
exercised with these drugs when treating patients receiving docetaxel as there is a potential 
for a significant interaction (e.g. substantial increases or decrease in docetaxel blood 
concentrations, see product information).
In contrast, based on in vitro data, only a minor extent of biotransformation of nintedanib
consisted of CYP pathways; nintedanib or its metabolites did not inhibit or induce CYP 
enzymes. Therefore, the likelihood of drug-drug interactions based on CYP metabolism with 
nintedanib is considered to be low.
P-glycoprotein (P-gp): nintedanib is a substrate of P-gp. If co-administered with nintedanib, 
potent P-gp inhibitors (e.g. ketoconazole or erythromycin) may increase exposure to 
nintedanib. In such cases, patients should be monitored closely for tolerability of nintedanib. 
Management of side effects may require interruption, dose reduction, or discontinuation of 
therapy with nintedanib. Potent P-gp inducers (e.g. rifampicin, carbamazepine, phenytoin, 
and St. John’s Wort) may decrease exposure to nintedanib. Co-administration with nintedanib
should be carefully considered.
Treatment with other investigational drugs or treatment under another clinical trial is not 
allowed during the active treatment period.
4.2.2.2
Restrictions on diet and life style
Not applicable
4.3
TREATMENT COMPLIANCE
Docetaxel will be administered as an intravenous infusion in the hospital setting at the 
investigating sites under supervision of authorized personnel. Date of administration as well 
as a statement whether infusion was done according to protocol and/or whether infusion was 
interrupted will be recorded in the e-CRF.


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Patients are requested to bring all remaining nintedanib medication including package 
material with them when attending visits.
Based on capsules counts, treatment compliance of nintedanib will be calculated as the 
number of capsules, divided by the number of capsules which should have been taken 
according to the scheduled period, multiplied by 100. 
Treatment compliance (%) = Number of nintedanib capsules actually taken x 100 / Number 
of nintedanib capsules which should have been taken.
If the number of doses taken is not between 80-120%, site staff will explain to the patient the 
importance of treatment compliance.


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5.
VARIABLES AND THEIR ASSESSMENT 
5.1
TRIAL ENDPOINTS
5.1.1
Primary Endpoint(s)
Determination of the maximum tolerated dose (MTD) of nintedanib in combination with 
docetaxel given in a weekly schedule and the number of patients with DLTs during the first 
treatment cycle is the primary endpoint. The MTD will be defined in view of dose-limiting 
toxicity (DLT) during the first course only. The MTD together with the safety profile will 
serve to determine the dose to be used in further development.
The MTD is defined as:
The Maximum Tolerated Dose (MTD) is defined as the highest dose studied at which not 
more than 1 out of 6 patients in a cohort experiences a DLT during the first treatment course
(Cycle 1) i.e. the incidence of dose-limiting toxicity is no more than 17% (i.e. 1/6 patients).
The safety evaluation of the dose level 2: continuous administration of nintedanib at 200 mg 
b.i.d except the days of docetaxel infusion will be followed by the tolerance evaluation of the 
dose level 3: continuous administration of nintedanib 200 mg b.i.d. This evaluation will be 
done following the same rules i.e. number of DLT during the first cycle.
However, all DLTs occurring in the trial will be considered for selection of a dose for further 
development of nintedanib in combination with weekly docetaxel. 
For the purpose of escalation, only DLT events that occur during the first treatment cycle of 
28 days will be considered. However decisions regarding dose escalation steps will be made 
only after discussion between the sponsor and the clinical investigators at all sites, and in 
consideration of the available toxicity. The pharmacokinetic analysis will be done only when 
nintedanib administration will be done continuously without interruption during docetaxel
infusions (dose level 3).
With the agreement of the clinical monitor and the coordinating investigator, patients with a 
Clinical Benefit may continue to receive treatment for as long as there is a Clinical Benefit. 
Clinical Benefit can include significant symptom control of originally symptomatic tumours
and can be considered even a radiological progression exist. The date of progressive disease 
will always be documented.
DLT events in individual patients occurring during the first treatment course have to be 
reported immediately to the Sponsor Clinical Monitor through a DLT form (see Section 
5.3.6).


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5.1.2
Secondary Endpoint(s)
There are no formal secondary endpoints.
5.1.3
Further Endpoint(s)
5.1.3.1
Pharmacokinetics
The pharmacokinetics of nintedanib and its two metabolites (BIBF 1202 and BIBF 1202 
glucuronide) will also be assessed for dose level 3 only. PK parameters evaluated are 
summarized in section 5.4.1.
5.1.3.2
Endpoint(s) of efficacy
There is no primary or secondary endpoint for efficacy.
Further efficacy endpoints are as follows:
•
Objective response (OR) is defined as best overall response of complete 
response (CR) or partial response (PR) where best overall response is determined 
according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1 
recorded from date of first treatment administration until the earliest of disease 
progression, death or last adequate tumour assessment before new anti-cancer therapy.
Objective response will be analysed in terms of objective response rate (ORR), 
defined as the proportion of patients with complete response (CR) or partial response 
(PR).
The objective response (i.e. complete response (CR) or partial response (PR)) will be 
confirmed by imaging 4 weeks or later after the first occurrence of the response.
•
Duration of objective response is defined as the time from first documented 
complete response (CR) or partial response (PR) until the earliest of disease 
progression or death.
•
Progression free survival (PFS) is defined as the time from first treatment 
administration until tumour progression according to RECIST 1.1 or death from any 
cause, whichever occurs earlier. Patients who stopped active treatment will be 
followed-up as described in Section 6.2.3.


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5.2
ASSESSMENT OF EFFICACY
5.2.1
Assessment of efficacy following RECIST criteria (version 1.1) (Appendix
10.3).
One to 5 target lesions (up to a maximum of 2 per organ) should be identified at baseline and 
recorded in the electronic case report form (eCRF) by the investigator. Lesions in areas 
irradiated within the past 3 months are not considered measurable at baseline. However, new 
lesions occurring in previously irradiated areas have to be considered for assessment of 
tumour response. At baseline a full examination has to be done including chest, abdominal, 
and pelvic CT or MRI to fully assess the extent of the tumour and metastases in an individual 
patient. MRI/CT of other body parts including brain should be performed as indicated by 
clinical needs.
The baseline scan must be performed within 28 days prior to administration of first dose of 
docetaxel. Imaging will be performed at Day 1 of every odd cycle after first administration of 
docetaxel (within 7 days). Imaging can be performed outside of scheduled visit if progression 
is suspected. The same method of assessment and the same technique should be used to 
characterise each reported lesion at baseline and during follow-up (except for brain 
metastases where CT and/or MRI can be used). Patients with stable brain metastases (for 
definition please see the exclusion criteria in Section 3.3.3) at trial entry have to be evaluated 
at each imaging time point for assessment of their brain metastases. Bone scans at baseline 
need to be performed in patients with known bone metastases and in case of clinical 
suspicion of previously unknown bone metastasis (i.e. bone or joint pain associated with 
relevant increases of calcium and alkaline phosphatase [ALP]). In case of a positive bone 
scan a correlative conventional image should be done of the respective lesion(s). These 
images should be performed at every imaging time point. Bone scans need to be repeated 
only at the time when response confirmation imaging is done or when medically indicated 
i.e., in case of suspected new bone metastases. 
Tumour assessment will be evaluated according to the RECIST 1.1 [R09-0262]
(Appendix 10.3)
The investigators will assess the tumour images during the trial at the time points specified. 
Their assessment will be the basis for continuation or discontinuation of treatment in an 
individual patient (see Section 3.3.4.1).
5.2.2
Progression of disease
Date and reason of progressive disease (PD) based upon RECIST 1.1 imaging evaluation or 
upon clinical evaluation will be recorded in the eCRF.  


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5.3
ASSESSMENT OF SAFETY
The safety evaluation is based on the occurrence of DLTs, overall safety and on safety 
laboratory parameters and will be done following CTCAE version 4.0.
5.3.1
Physical examination
A general physical examination will be performed at screening and at the time points 
specified in the Flow chart. Whenever possible, the same investigator should perform this 
examination. 
Measurement of height (in cm), body weight (in kg) and the evaluation of the ECOG 
performance status (PS) will be performed at the time points specified in the Flow chart,  
which should be recorded with date in the eCRF.
5.3.2
Vital Signs
Vital signs will be performed at screening and at the time points specified in the Flow chart.
5.3.3
Safety laboratory parameters
Blood and urine samples must be collected at the time points specified in the Flow chart. 
Safety laboratory examinations include haematology, biochemistry, coagulation and 
urinalysis, which should be recorded with date and time of taken blood sample in the eCRF.
In the event of neutrophil count decreased or white blood cell count (WBC) decreased of 
CTCAE grade 4, blood has to be collected at intervals deemed necessary by the investigator 
until recovery to a CTCAE grade level that would allow further therapy.
The following parameters will be investigated: 
Haematology 
Haemoglobin, white blood cells count (WBC), absolute neutrophil count (ANC), and 
platelets.
Biochemistry 
Glucose, sodium, potassium, calcium, phosphorus, magnesium, serum creatinine, clearance 
creatinine, aspartate amino transferase (AST), alanine amino transferase (ALT), alkaline 
phosphatase (ALP),γ-GT, lactate dehydrogenase, albumin, , total bilirubin (in case of 
bilirubin increase to CTCAE Grade 1 or higher, the direct and indirect bilirubin levels have to 
be determined), urea , total protein, uric acid.
Coagulation parameters
Prothrombin time (PT) and international normalised ratio (INR) or activated partial 
thromboplastin time (aPTT).


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Urine
Proteins, pH, glucose, erythrocytes, leukocytes, nitrite (analysed by quantitative or semi 
quantitative [dipstick] measurement) 
In case of pathological findings, further evaluation should be performed and the findings 
documented. Urine dipstick for patients with proteinuria ≥2+ at the screening, a 24-hour urine 
collection for total protein will be obtained within 72 hours to verify the grade of proteinuria 
for judgment of exclusion criteria.
If laboratory investigations have been performed within 7 days prior to registration, the 
results may be used for screening. During the treatment period, if the lab investigations have 
been performed within 2 days prior to a visit and complete results are available, they do not 
have to be repeated. However, the reference ranges must be provided to the sponsor in case a 
different laboratory was used.
A laboratory abnormality may meet the criteria to qualify as an AE as described in this 
protocol. In these instances, the AE corresponding to the laboratory abnormality will be 
recorded in the eCRF.  
5.3.4
Electrocardiogram
A 12-lead resting ECG will be performed at the time points specified in the Flow chart. If the 
ECG has been performed within 2 days prior to Day 1 of every odd number of treatment 
cycles and complete results are available, they do not have to be repeated. The investigator 
should review the ECG during the study and any relevant findings will be reported as AE in 
the eCRF.
5.3.5
Other safety parameters: 
Height, weight and ECOG performance score, pregnancy test will be performed at the time 
points specified in the Flow chart.
5.3.6
Assessment of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.


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Dose Limiting Toxicity (DLT)
Only DLTs which occur during the first cycle will be taken into consideration for the 
determination of the MTD. 
DLT is defined as any of the following AEs considered to be related to nintedanib: 
1.
Drug related CTCAE grade 3 or greater non haematological drug related AEs. 
2.
Drug related CTCAE grade 2 diarrhoea for more than 7 days despite supportive care.
3.
Drug related CTCAE grade 3 or greater nausea despite supportive care.
4.
Drug related CTCAE grade 2 or greater vomiting despite supportive care.
5.
A drug related increase of ALT and/or AST to CTCAE grade 3 or greater.
6.
A drug related increase of ALT and/or AST to CTCAE grade 2 or greater in 
conjunction with CTCAE grade 1 or greater total bilirubin increase.
7.
Platelets < 50000 / mm3 with bleeding (Drug related CTCAE ≥ 3). 
8.
Drug related Neutropenia of any grade/duration accompanied by fever > 38°5C.
9.
Drug related Neutropenia grade 4 without fever > 7 days duration.
10.
Inability to resume nintedanib dosing within 21 days after stopping due to drug related 
toxicity.
The DLT occurring during cycle 1 has to be reported immediately to the Sponsor Clinical 
Monitor.
All AEs fulfilling the definition of DLT listed above, but occurring after cycle 1, will be 
termed DLT-Like events and there is no need to report them immediately to the Sponsor 
Clinical Monitor.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or


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
is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
If cancer is the indication for treatment, only cancers of new histology and cases where there
is clear evidence of exacerbation of an existing cancer qualify as a serious event.
Every new cancer occurrence must be reported as a SAE regardless of the duration of time 
between the drug discontinuation and the occurrence of the cancer. If progressive disease 
occurs and is associated with symptoms or meets one of the seriousness criteria, the verbatim 
“Progressive disease” should not be reported, , instead the signs and symptoms of progressive 
disease will be reported as an adverse event or a serious AE (if applicable).
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the RDC system. These events 
should always be reported as SAEs as described in Section 5.3.7.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.7.
The following are considered as AESIs:
Drug-induced liver injury (Appendix 10.1)
Drug-induced liver injury is under constant surveillance by the sponsor and regulators and is 
considered an adverse event of special interest based on the following definitions. The timely 
detection, evaluation, and follow-up of laboratory alterations of selected liver laboratory 
parameters to distinguish an effect of the investigational drug from other causes are important 
for patient’s safety and for the medical and scientific interpretation of the finding.
The following changes in the laboratory values are considered to be an adverse event of 
special interest for all patients:


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-
an elevation of ALT and/or AST > 5x ULN without bilirubin elevation measured in 
the same blood draw sample.
-
an elevation of AST and/or ALT >2.5 fold ULN combined with an elevation of 
bilirubin to >1.5 fold ULN measured in the same blood draw sample.
These lab findings constitute a drug-induced liver injury alert and the patients showing these 
lab abnormalities need to be followed according to the “DILI checklist” provided in the ISF.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(AST, ALT, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
In addition, the following need to be reported to BI as AESIs: 
Any gastrointestinal and non-gastrointestinal perforation, leakage, fistula formation, abscess
In such case the following additional information needs to be collected, documented in the 
respective comment field of the eCRF page and forwarded to BI:

Location of perforation, leakage, fistula, abscess.

Location/extent of abdominal tumour manifestations.

Imaging & reports (CT, ultrasound, endoscopy, pathology, etc).

Prior surgery (location, wound healing complications).

Concomitant diseases with gastrointestinal (GI) involvement (e.g. Crohn’s disease, 
vasculitis, tuberculosis, diverticulitis).

Thromboembolic events (or predisposition).
AESIs can be classified as serious or non-serious, but all AESIs must be reported in an 
expedited manner similar to SAE on an SAE form (i.e., non-serious and serious AESIs must 
be reported on the SAE form and follow serious timelines) – for details see Section 5.3.7
The intensity of adverse events should be classified and recorded in the eCRF according to 
the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
Causal relationship of AEs
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.
Yes:
There is a reasonable causal relationship between the study medication
administered and the AE.


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No:
There is no reasonable causal relationship between the study medication
administered and the AE.
5.3.7
Adverse event collection and reporting
AE collection: 
The following must be collected and documented on the appropriate eCRF by the 
investigator:
From signing the informed consent onwards through the Residual Effect period, until 
individual patient’s end of trial:
-
All AEs (non-serious and serious) and all AESIs.
Figure 5.3.7: 1 
AE Collection
After the individual patient’s end of trial:
-
The investigator does not need to actively monitor the patient for AEs but should 
only report relevant SAEs and relevant AESIs and considered as related to the study 
drug of which the investigator may become aware of.
Residual effect period (REP)
The residual effect period (REP) is defined as 28 days after the last trial medication 
application. All AEs which occurred through the treatment phase and throughout the REP 
will be considered as on treatment. Events which occurred after the REP will be considered 
as post treatment events. 
The EOR is the visit which will be performed at the end of REP, 28 days after permanent 
discontinuation of trial medication.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 


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The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
eCRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug(s). 
The Investigator should determine the causal relationship to the trial medication.
The following should also be recorded as an (S)AE in the eCRF and SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as baseline 
conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In rare cases, that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the investigator must report immediately (within 24 hours) the 
drug exposure during pregnancy (DEDP) to the Sponsor’s unique entry point (country
specific contact details will be provided in the ISF). The Pregnancy Monitoring Form for 
Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
Exemptions to SAE Reporting: see Section 5.3.6.


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5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Plasma concentration monitoring of nintedanib (BIBF 1120) and its two main metabolites,
BIBF 1202 and BIBF 1202-glucuronide will be performed in order to assess drug exposure in 
the patients. The obtained predose concentrations will be listed and compared for steady state 
evaluation.
A detailed PK sampling schedule is provided in section 10.2.2
5.4.1
Assessment of Pharmacokinetics
Nintedanib and its metabolites
Cpre,ss
(predose concentration of the analyte in plasma at steady state immediately before 
administration of the next dose)
5.4.2
Methods of sample collection 
A detailed description of sample collection and handling is provided in the ISF/ lab manual. 
For quantification of drug plasma concentrations of nintedanib (BIBF 1120) and its 
metabolites BIBF 1202 and BIBF 1202- glucuronide, venous blood will be collected using a 
pre-labeled potassium ethylenediamine-tetraacetic acid (EDTA) containing blood drawing 
tube. 
Date and exact clock time of drug administration and blood sampling on PK sampling days 
must be recorded on the eCRF.
5.4.3
Analytical determinations 
Nintedanib (in form of its free base BIBF 1120 BS), its metabolites BIBF 1202 (in form of 
the free zwitter ion BIBF 1202 ZW), and the acylglucuronid thereof (BIBF 1202 
glucuronide), plasma concentrations will be determined by a validated assay based on liquid 
chromatography- tandem mass spectrometry (LC-MS/MS) assay.
The procedures and specifications of the analytical method are available at the bioanalytical
site (
).
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship:
Not applicable


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5.5
ASSESSMENT OF EXPLORATORY BIOMARKERS
Not applicable
5.5.1
Biobanking
Not applicable
5.6
OTHER ASSESSMENTS 
Not applicable
5.7
APPROPRIATENESS OF MEASUREMENTS
The RECIST 1.1 to be used for evaluation of tumour response are well established and 
scientifically accepted (see Appendix 10.3). The CTCAE version 4.0 is used in the 
assessment of AEs in cancer patients.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Patients will visit the investigator at the time points specified in the Flow chart. In case, a 
patient missed a visit and the patient reports to the investigator between this and the next 
scheduled visit, the missed visit should be done with the actual date. The next visit, however, 
should take place at the scheduled time after the first administration of the trial drug in the 
respective treatment cycle.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
The investigations as outlined in the Flow chart will be performed at the respective visits as 
described in detail in the following sections.
6.2.1
Screening and treatment period(s)
Screening Period
The screening phase (screening visit) is the phase after informed consent and before the first 
administration of the trial drug (between Day -14 and Day -1). After having obtained the 
written informed consent, the investigator may perform the procedures required for 
screening.
The following will be obtained and/or performed before registration. 
•
Informed consent for study participation.
•
Demographics (sex, birth year, oncological history, smoking status, alcohol consumption, 
previous therapy, concomitant therapy, baseline condition).
•
Medical history.
•
Physical examination including resting electrocardiogram (ECG), body height, weight, 
vital signs and ECOG performance status (PS).
•
Tumour staging and assessment: including baseline imaging (e.g. CT or MRI no repeat 
imaging requested if imaging already done within 28 days prior to Cycle 1). 
•
Occurrence of adverse events (AEs) since informed consent.
•
Concomitant therapy.
•
Safety laboratory (no repeat examination in case a safety laboratory investigation has 
been performed within 7 days prior to registration), including haematology, biochemistry, 
coagulation parameters and urinalysis.
•
Pregnancy test in women of childbearing potential.           
•
Patient eligibility (inclusion and exclusion criteria).
•
Assignment of treatment after reviewing in- and exclusion criteria and registration would 
be done following Remote Data Capture. As there are no pre-defined cohorts, the IRT 
system can assign nintedanib and docetaxel kit numbers. For the nintedanib, the site 
would enter the dose that is needed and the IRT system would allocate a kit number.


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•
Patients who failed screening may repeat the screening after discussion between
investigator and sponsor providing that reasons for screening failure have resolved.
6.2.2
Treatment cycles
For the cohorts of the patients of level-1, 1 and 2: continuous administration with nintedanib 
except the days of docetaxel administration.
For the cohort of patients of level 3: continuous treatment with nintedanib 200 mg b.i.d 
without interruption during docetaxel infusion.
6.2.2.1
Cycle 1 Day 1 (C1D1)
The following will be obtained and/or performed before administration of docetaxel:
•
The patients may be hospitalized (outpatient hospital) at Day 1 to receive docetaxel 
infusion after premedication. The premedication is as follows: Oral corticosteroid, such 
as dexamethasone (8mg twice daily orally the day before and after docetaxel infusion; 8 
mg intravenously 30 minutes before docetaxel) and antiemetics before docetaxel infusion 
(Section 4.1.1).
•
Occurrence of AEs since last visit
•
Changes in concomitant therapies
•
Physical examination, vital signs (pre-dose and after docetaxel infusion) and ECOG
•
Body weight 
•
Resting ECG (may be performed within 2 days prior to the administration of docetaxel)
•
Safety laboratory: haematology, biochemistry,  coagulation including urinalysis (may be 
performed within 2 days prior to the administration of docetaxel)
•
Pregnancy test (in females of childbearing potential). If the test was already performed at 
screening within 72 hours prior to docetaxel administration it may be skipped
•
Nintedanib dispensation and treatment: :
-
For the cohort of the patients of level -1, level 1 and level 2: treatment of nintedanib 
continuously except the days of docetaxel infusion. The patients will begin nintedanib 
treatment at Day 2.
-
For the cohort of patients of level 3: continuous treatment with nintedanib 200 mg 
b.i.d without interruption during docetaxel infusion. The patients will take the 
morning dose of nintedanib at hospital after docetaxel infusion.
6.2.2.2
Cycle 1 Day 8 (C1D8) and Cycle 1 Day 15 (C1D15)
•
Eligibility of the patients to receive nintedanib treatment and docetaxel infusion (sections
4.1.4.1 – 4.1.4.2).
•
In case retreatment criteria of docetaxel are not met, the administration of docetaxel 
will be not done. If omission of two consecutive docetaxel infusions occurs, the 


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continuation of docetaxel should be discussed between the investigator and the 
sponsor. 
•
If retreatment criteria are met, the patients will be hospitalized (outpatient hospital) at 
Day 8 and at Day 15 to receive docetaxel infusion after premedication. Premedication 
is detailed in Section 4.1.1.
•
Nintedanib treatment and PK sampling: 
-
For the patients of the cohort level 3: At Cycle 1 Day 8 and at Cycle 1 Day 
15, PK blood samples will be withdrawn before nintedanib treatment and 
before docetaxel infusion. The patients will begin their nintedanib treatment 
at the hospital after the PK blood sample, during breakfast. The next dose of 
nintedanib will be taken during the next meal after an interval of 12 hours.
-
For the cohort of the patients of level -1, level 1 and level 2: treatment of 
nintedanib continuously except the days of docetaxel infusion. The patients 
will restart nintedanib treatment at Day 9 and at Day 16, respectively.
•
Vital signs (pre-dose and after docetaxel infusion) and weight.
•
Safety laboratory (haematology and biochemistry) will be obtained before docetaxel 
infusion.
•
AEs occurring during or after docetaxel administration
•
Changes in concomitant therapy.
6.2.2.3
Cn Day 1 ± 2 days of every treatment onwards
This CnD1 of the new treatment cycle will be performed on Day 29 (duration of 1 cycle = 28 
days, 2 weeks of rest). The last administration of docetaxel was at Day 15 of the previous 
cycle. A treatment cycle may be postponed for administrative reasons for up to 2 days (e.g. 
vacation, public holiday). 
•
Patient eligibility (treatment criteria for docetaxel and for nintedanib, see Sections
4.1.4.):
-
In case retreatment criteria of docetaxel are not met, the administration of docetaxel 
will be not done. If omission of two consecutive docetaxel infusions occurs, the 
continuation of docetaxel should be discussed between the investigator and the 
sponsor. 
If retreatment criteria are met, the patients may be hospitalized (outpatient hospital) at Cn 
Day 1 to receive docetaxel infusion after premedication. At Cycle 2 Day 1: For the cohort of 
patients of dose level 3 (continuous administration of nintedanib 200 mg b.i.d. without 
interruption during docetaxel infusion), PK blood samples will be withdrawn before 
nintedanib treatment and before docetaxel infusion. The patients will begin their nintedanib 
treatment at the hospital after PK blood sample during breakfast. The next dose of nintedanib 
will be taken during the next meal after an interval of 12 hours.
The following will be obtained and/or performed before administration of docetaxel.
•
Occurrence of AEs since last visit.
•
Changes in concomitant therapies.


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•
Compliance check of nintedanib intake.
•
Collection of unused trial medication of nintedanib.
•
Physical examination, vital signs (pre-dose and after docetaxel infusion), ECOG PS.
•
Body weight.
•
Resting ECG (may be performed on Day 1 of every odd number of treatment cycle (3, 5 
and so on).within 2 days prior to the administration).
•
Safety laboratory including haematology, biochemistry, coagulation parameters and 
urinalysis (may be performed within 2 days prior to the administration).
•
Pregnancy test (in females of childbearing potential) on Day 1 of every odd number of
treatment cycle (3, 5, and so on) within 2 days prior to the administration).
•
Tumour assessment (CT or MRI) have to be performed on Day 1 of every odd number of 
treatment cycle (3, 5and so on) until tumour progression. These tumoral assessments 
could be done within 7 days prior to planned date and outside of scheduled visit if 
progression is suspected.
•
Nintedanib dispensation and treatment: 
-
Dispense medication kit nintedanib for the treatment cycle. 
-
The patients of the cohorts level -1, level 1 and level 2: continuous administration 
with interruption during docetaxel infusion. The patients will restart nintedanib 
treatment at Day 2.
-
The patients of the cohort level 3: continuous treatment without interruption during 
docetaxel infusion.
6.2.2.4
Cn Day 8 and Cn Day 15 of treatment cycle 2 onwards : 
CnDay 8 and Cn Day 15 will be performed at Day 8 ± 2 days and at Day 15± 2 days.
•
Patient eligibility (treatment criteria for docetaxel) (see Section 4.1.4.1) :
-
In case retreatment criteria of docetaxel are not met, the administration of docetaxel 
will be not done. If omission of two consecutive docetaxel infusions occurs, the 
continuation of docetaxel should be discussed between the investigator and the 
sponsor. 
-
If retreatment criteria are met, the patients may be hospitalized (outpatient hospital) at 
Day 8 and Day 15 to receive docetaxel infusion after premedication.
At Cycle 2 Day 8 and Day 15: For the cohort of patients of dose level 3 (continuous 
administration of nintedanib 200 mg b.i.d. without interruption during docetaxel infusion), 
PK blood samples will be withdrawn before nintedanib treatment and before docetaxel 
infusion. The patients will begin their nintedanib treatment at the hospital after PK blood 
sampling, during breakfast. The next dose of nintedanib will be taken during the next meal 
after an interval of 12 hours.
The following will be obtained and/or performed before administration of docetaxel:
•
Occurrence of AEs since last visit.
•
Changes in concomitant therapies.
•
Vital signs (pre-dose and after docetaxel treatment) and weight.


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•
Safety laboratory including haematology and biochemistry (may have been performed 
within 2 days prior to the administration).
•
Nintedanib treatment:
-
The patients of the cohorts level -1, level 1 and level 2: continuous administration 
with interruption during docetaxel infusion. The patients will restart nintedanib 
treatment at Day 9 and at Day 16 respectively.
-
The patients of the cohort level 3: continuous treatment without interruption during 
docetaxel infusion.
6.2.2.5
Cn (Day 1) of a treatment cycle with monotherapy nintedanib
Patients who are not eligible for further treatment with docetaxel anymore may be treated 
with monotherapy of nintedanib if the criteria defined in Section 4.1.4.1.4. are met. 
Treatment cycles will have duration of 28 days (postponed up to 7 days). Discussion and 
agreement between investigator and sponsor is mandatory in case retreatment criteria are not 
met on the scheduled treatment day and a delay for more than 21 days is required.
The following checks will be obtained and/or performed:
•
Reason for stopping docetaxel treatment is collected with a specific Trial Termination 
page at EOT visit.
•
Occurrence of AEs since last visit.
•
Changes in concomitant therapies.
•
Compliance check of nintedanib intake.
•
Collection of unused nintedanib.
•
Physical examination, vital signs, ECOG PS.
•
Body weight and resting ECG (may have been performed within 2 days prior to the 
administration);
•
Safety laboratory: haematology, biochemistry, coagulation parameters including 
urinalysis (may have been performed within 2 days prior to the administration).
•
Pregnancy test (in women of childbearing potential every odd number of treatment cycle
within 2 days prior to the administration).
•
Patient eligibility for monotherapy/retreatment.
•
Tumour assessment (performed on Day 1 of every odd number of treatment cycle).
•
Dispense medication kit of nintedanib for the treatment cycle, starting intake on Day 1, 
plus reserve medication if required (see Section 4.1.1).
6.2.2.6
Optional visits between scheduled visits
Additional unscheduled visits can be performed (on demand) if pathological laboratory 
findings were observed which have not yet recovered or if close observation of anticoagulant
therapy is required or if other issues would require additional visit(s) and/or control. These 
additional visits will be recorded under the respective scheduled previous visit of an 
individual treatment cycle in the electronic case report form (eCRF). Differentiation between 
the various days would be by date.
The following checks will be obtained and/or performed.


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•
Occurrence of AEs since last visit.
•
Changes in concomitant therapies.
•
Safety laboratory parameters (haematology, biochemistry, coagulation and urinalysis) of 
the pathological values only and/or of those which require control.
Other examination and therapy by medical judgement are allowed if required
6.2.3
End of treatment (EOT) and EOR ( End of Residual Effect Period (REP)
6.2.3.1
End of treatment
The end of treatment (EOT) visit is to be performed within 7 days after permanent 
discontinuation of all trial medication (docetaxel and nintedanib).
•
Occurrence of AEs since last visit.
•
Changes in concomitant therapies.
•
Compliance check of nintedanib intake.
•
Collection of unused trial medication of nintedanib.
•
Physical examination, resting ECG, body weight, vital signs, and ECOG PS.
•
Safety laboratory including haematology, biochemistry, coagulation parameters and 
urinalysis.
•
Pregnancy test.
•
Tumour assessment and imaging must be performed (If a patient finishes active treatment 
without having progressive disease unless done within the past 21 days).
•
Conclusion of patient’s active treatment (including reason for stopping active treatment, 
date of last administration of the drug[s]).
In case if the patient stops active treatment on scheduled visit, this date should be considered 
as EOT, and the above investigations should be performed at the visit. If the patient has to 
stop the active treatment at other than scheduled visit, above investigations should be 
performed promptly. If the investigator decided to discontinue the trial medication during 
treatment interruption, examinations that were performed after interruption may be used as 
data of EOT. Other examinations that were not performed after interruption will be 
performed at EOT visit as soon as possible.
6.2.3.2
EOR (End of Residual Effect Period (REP)
The EOR visit should be performed at 28 days +7 days after permanent discontinuation of the 
trial medication. The following will be obtained at the EOR visit:
•
Occurrence of AEs since EOT visit and a follow-up of AEs that are not recovered at 
EOT. 
•
Any new concomitant therapies or changes in ongoing concomitant therapies
•
ECOG PS
•
Name and date of any other anti-cancer drug treatment if received


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6.2.3.3
Trial completion for an individual patient
A patient has to be considered to have completed the trial in case any of the following 
applies:
•
Completion of planned EOR, and follow-up for AE if required
•
Lost to follow up
•
Withdrawal of informed consent
•
Death
At the earliest of the above criteria, the patient completion information should be entered in 
the eCRF.


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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 trial is to 
determine the MTD of nintedanib in combination with weekly docetaxel. To determine the 
MTD, patients are entered sequentially using the 3+3 design (see Section 3.1). The statistical 
methods used in this trial will be descriptive.
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
No per protocol set will be used in the analysis. However, important protocol violations will 
be summarised. The TSAP will specify the important protocol violations in detail. For the 
determination of the MTD, only MTD evaluable patients will be considered. All patients who 
received at least one dose of study medication (nintedanib or docetaxel) will be included in 
the analyses of the further endpoints.
7.3.1
Primary endpoint analyses
The primary objective of this study is the tolerability and safety of nintedanib in combination 
with weekly docetaxel as reflected by the MTD. In order to identify the MTD, the number of 
patients with DLTs at each dose level must be presented. For the analysis of tolerability and 
safety, refer to Section 7.3.4.
7.3.2
Secondary endpoint analyses
Not applicable, as there are no secondary endpoints defined.
7.3.3
Further endpoint analyses
Efficacy signals of nintedanib in combination with weekly docetaxel will be explored as 
further endpoints in this phase I trial. PFS, objective response according to RECIST criteria 
version 1.1, and duration of objective response will be analysed descriptively for all treated 
patients.
The PK parameters specified as further endpoints will be analysed according to BI standards 
(see Section 7.3.5).


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7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the REP will be assigned 
to the on-treatment period for evaluation.
All treated patients will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’. Adverse events that 
start before first drug intake and deteriorate under treatment will also be considered as 
‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of MedDRA.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.4 will be calculated according to the 
relevant Corporate Procedure of the Sponsor (MCS-36-472, current version). 
Only concentration values within the validated concentration range and actual sampling times
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report). 
Plasma concentrations of nintedanib, BIBF 1202 and BIBF 1202 glucuronide will be 
presented in tabular and, if feasible, in graphic form for all subjects and sampling points with 
drug concentrations above the lower limit of quantification. Individual values will be listed 
and standard summary statistics will be calculated per treatment group for pharmacokinetic 
parameters.


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7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
Missing baseline laboratory values will be imputed by the respective values from the 
screening visit.
No other imputations will be performed on missing data although every effort will be made to 
obtain complete information on all adverse events, with particular emphasis on potential 
DLTs.
7.5.1
Plasma drug concentration - time profiles
Handling of missing PK data will be performed according to the sponsor’s standard operating
procedure (MCS-36-472, current version).
Drug concentration data identified with NOS (no sample available), NOR (no valid result),
NOA (not analyzed), or BLQ (below the lower limit of quantification) will be displayed as 
such and not replaced by zero at any time point (this rule also applies to the lag phase, 
including the pre-dose values).
Descriptive statistics of concentrations at specific time points will be calculated only when at
least 2/3 of the individuals have concentrations within the validated concentration range. The
overall sample size to decide whether the “2/3 rule” is fulfilled will be based on the total
number of samples intended to be drawn for that time point (i.e. BLQ, NOR, NOS, NOA are 
included).
7.6
RANDOMISATION
No randomisation will be performed. Patients will be assigned to escalating dose groups by 
order of admission into the trial.
7.7
DETERMINATION OF SAMPLE SIZE
No formal statistical power calculations to determine sample size have been performed. In 
this open-label phase I trial, up to 24 patients will be allocated to the dosage tiers, in order to 
find the MTD. Each dose cohort used in this trial will contain at least three individuals. 
Further 6 patients will be included at dose level 3 and an extension cohort consisting of up to 
six additional patients will be evaluated. This results in a total number of approximately 30 
patients in the trial. However, the number of individuals entered in the trial may vary due to 
replacement of patients. The simulation study (see statistical appendix) confirms this 
assumption on patients needed for the dose escalation in this trial.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in accordance with the Medical Devices Directive (93/42/EEC) 
and the harmonized standards for Medical Devices (ISO 14155-01 and ISO 14155-02).
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP) 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 will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP*.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract. As a rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).”
8.1
TRIAL 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 Investigator must give a full explanation to trial patients including the items listed below 
in association with the use of the patient information form, which is prepared avoiding the 
use of technical terms and expressions. The patient is given sufficient time to consider 
participation in the trial. The Investigator obtains written consent of the patient’s own free 


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will with the informed consent form after confirming that the patient understands the 
contents. The Investigator must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
eCRFfor individual patients will be provided by the Sponsor. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For the CRF, the following data need to be derived from source documents:

Patient identification (gender, date of birth).

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed).

Dates of Patient’s visits, including dispensing of trial medication.

Oncological history (advanced solid tumour classification, histology result, stage at 
screening, location of metastasis sites, EGFR mutation status, ALK mutation status).

Previous therapies (previous systemic chemotherapies, previous other therapies 
(immunotherapy, hormone therapy, other), previous radiotherapy, previous surgery).

Medical history (including trial indication and concomitant diseases, if applicable).

Adverse events and outcome events (onset date (mandatory), and end date (if available)).

Serious adverse events (onset date (mandatory), and end date (if available)).

Concomitant therapy (start date, changes).

Originals or copies of laboratory results (in validated electronic format, if available).

Originals or copies of tumour assessments (imaging).

Completion of Patient’s Participation in the trial”.

Prior to allocation of a patient to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 


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meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records or testing conducted specific for a protocol) to support 
inclusion/exclusion criteria does not make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
eCRF and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the 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 eCRF, and written informed 
consents. The accuracy of the data will be verified by reviewing the documents described in 
section 8.3.1.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source documents and essential documents for a period 
defined by the European GCP regulation and trial site’s contract with the sponsor.
Sponsor:
The Sponsor must retain the essential documents according to the Sponsor’s SOPs.
When it is no longer necessary for the trial site to retain the source documents and essential 
documents, the Sponsor must notify the head of trial site.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided. 
For nintedanib this is the current version of the Investigator’s Brochure (Number: c 01632700 
– 18))-
For the investigational medicinal product, docetaxel, the reference document is the SmPC or 
another regulatory label document.
The current versions of these reference documents are provided in the ISF. 


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8.4.2
Expedited reporting to health authorities and IEC / IRB
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSAR) to health authorities and IEC / IRB, will be done according to local 
regulatory requirements.
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.
8.6
END OF TRIAL
The trial will end when the last patient has completed the EOR visit, 28 days after permanent 
discontinuation of trial medication and follow up for AE if required.
The IEC / competent authority in each participating EU member state needs to be notified 
about the end of the trial or early termination of the trial.
8.7
PROTOCOL VIOLATIONS
The investigator should document any deviation from the protocol regardless of their reasons. 
Only when the protocol was not followed in order to avoid an immediate hazard to trial 
subjects or for other medically compelling reason, the principal investigator should prepare 
and submit the records explaining the reasons thereof to the sponsor, and retain a copy of the 
records.
8.8
COMPENSATION AVAILABLE TO THE PATIENT IN THE 
EVENT OF TRIAL RELATED INJURY
In the event of health injury associated with this trial, the Sponsor is responsible for 
compensation based on the contract signed by the trial site.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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and primary breast cancer cultures in vitro. Angiogenesis 2005;8:197-204.
R13-4198
Yang F, Tang X, Riquelme E, Behrens C, Nilsson MB, Giri U, et al. Increased 
VEGFR-2 gene copy is associated with chemoresistance and shorter survival 
in patients with non-small-cell lung carcinoma who receive adjuvant 
chemotherapy. Cancer Res 2011;7(16):5512-5521.
R14-2236
Ferlay J, Steliarova-Foucher E, Lortet-Tieulent J, Rosso S, Coebergh JWW, 
Comber H, et al. Cancer incidence and mortality patterns in Europe: estimates 
for 40 countries in 2012. Eur J Cancer 2013;49:1374-1403.
R15-1184
Schuette W, Nagel S, Blankenburg T, Lautenschlaeger C, Hans K, Schmidt 
EW, Dittrich I, Schweisfurth H, Weikersthal LF von, Raghavachar A, Reissig 
A, Serke M. Phase III study of second-line chemotherapy for advanced non-
small-cell lung cancer with weekly compared with 3-weekly docetaxel. J Clin 
Oncol 23 (33), 8389 - 8395 (2005)


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R15-3057
Paz-Ares L, Horn L, Borghaei H, Spigel DR, Steins M, Ready N, Chow LQM, 
Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaeufl M, Rodriguez O, Burgio 
MA, Fayette J, Gettinger SN, Harbison C, Dorange C, Finckenstein FG, 
Brahmer JR Phase III, randomized trial (CheckMate 017) of nivolumab 
(NIVO) versus docetaxel (DOC) in advanced non-squamous cell (non-SQ) 
non-small cell lung cancer (NSCLC). 51st Ann Mtg of the American Society
of Clinical Oncology (ASCO), Chicago, 29 May - 2 Jun 2015 ; J Clin Oncol 
33 (Suppl),, Abstr LBA109 (2015)
R15-3058
Spigel DR, et al. A phase III study (CheckMate 017) of nivolumab (NIVO; 
anti-programmed death-1 [PD-1]) vs docetaxel (DOC) in previously treated 
advanced or metastatic squamous (SQ) cell non-small cell lung cancer 
(NSCLC). 51st Ann Mtg of the American Society of Clinical Oncology 
(ASCO), Chicago, 29 May - 2 Jun 2015 ; J Clin Oncol 33 (Suppl),, Abstr 8009 
(2015)
R15-5085
Maio M di, Perrone F, Chiodini P, Gallo C, Camps C, Schuette W, Quoix E, 
Tsai CM, Gridelli C. Individual patient data meta-analysis of docetaxel 
administered once every 3 weeks compared with once every week second-line 
treatment of advanced non small-cell lung cancer.
J Clin Oncol 25 (11), 1377 - 1382 (2007)
9.2
UNPUBLISHED REFERENCES
c01632700-18
 Investigator's Brochure Nintedanib
(BIBF1120) for Cancer. 19 Jan 2015
c03149997
. Pharmacokinetics, safety and 
tolerability of nintedanib single oral dose in male and female patients with 
different degrees of hepatic impairment (Child-Pugh classification A and B) as 
compared with nintedanib administration to male and female healthy subjects 
(a non-blinded, parallel group study of Phase I) 20 my 2015
U02-1109
.. Analysis of potency and selectivity of the vascular endothelial 
growth factor receptor-2 inhibitor BIBF1120. in vitro studies. Report/Study 
No. 01-02, 19-feb-2002.
U02-1482
 Investigator's brochure: nintedanib, Indication: Oncology
Project: 1199.P1, 1199.P2, 1199.P4, 1199.P5, 1199.P6, 1199.P7, 1199.P8, 
1199.P11, Version 13, 15-Nov-2013.
U08-1273-02
 A phase I 
open label dose escalation study of continuous (except on the days of 
chemotherapy infusion) oral treatment with BIBF 1120 together with  


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docetaxel and prednisone in patients with hormone refractory prostate cancer. 
BI Trial No.  1199.4. 16 May 2008.
U08-1946
 Effects of BIBF 1120 on MAPK and Akt signaling, cell
proliferation and induction of apoptosis in endothelial cells, smooth muscle 
cells and pericytes in vitro. Document/Study No. BIA09-08, 11-Sep-2008.
U10-1846-01
, A Phase I open-label dose-escalation 
study of continuous twice-daily oral treatment with BIBF 1120 in Japanese 
patients with advanced solid tumours. BI Trial No. 1199.19. 26 June 2009.
U11-1947-01
. X-ray structure analysis of VEGFR-2 kinase in complex with BIBF 
1120. Report/Study No. BIRCV09-11, 26-Jul-2011.


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10.
APPENDICES
10.1
CLINICAL EVALUATION OF LIVER INJURY
10.1.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.3.6 (adverse events of 
special interest [AESI]), are to be further evaluated using the following procedures:
10.1.2
Procedures
ALT and/or AST and total bilirubin increases falling into the categories as defined in Section 
5.3.6 have to be confirmed using the initial blood sample if possible (sample still available, 
no lysis etc). The alkaline phosphatase (ALP) should be measured using the same sample too.
In case local laboratories are being used, the laboratory parameters have to be repeated
locally. If site receives a potential drug induced liver injury (DILI) alert notice from the local 
laboratory, the following tasks have to be completed:
1. Repeat the following laboratory tests locally for confirmation within 48 hours:
•
AST, ALT, bilirubin measurement (total and direct bilirubin) and ALP.
•
Haptoglobin.
•
Complete blood count and cell morphology.
•
Reticulocyte count.
•
Creatine kinase (CK).
•
Lactate dehydrogenase (LDH).
The results of these repeated laboratory tests must be documented on the electronic case 
report form (eCRF) and reported immediately via the serious adverse event (SAE) form to 
BI.
2. An evaluation of the patient within 48 hours with respect to but not limited to:
•
Abdominal ultrasound or clinically appropriate alternate imaging and investigations 
adequate to rule out biliary tract, pancreatic, intra- or extrahepatic pathology e.g. bile 
duct stones, neoplasm, hepatic tumour involvement, biliary tract, pancreatic or 
intrahepatic pathology, vascular hepatic conditions such as portal vein thrombosis or 
right heart failure. These data need to be collected, documented in the respective field of 
the eCRF/DILI checklist, and the respective SAE form has to be updated and forwarded 
to BI.
•
The findings from the imaging and investigations (including comparison to prior imaging 
if available) must be discussed with representatives of the Sponsor via face to face 
meeting or phone.
For all patients fulfilling protocol specified criteria for liver injury, please collect and
document the following information in the eCRF and the SAE form according to the “DILI 
checklist” provided in the ISF:


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•
Detailed history of current symptoms, concurrent diagnoses and medical history.
•
Detailed history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplement preparations e.g. steroids as concomitant supportive treatment), 
alcohol use, recreational drug use, and special diets.
•
Detailed history of exposure to environmental chemical agents (consider home and work 
place exposure).
Please complete the following laboratory tests as detailed in the DILI checklist provided in 
the ISF in case that both imaging and laboratory value did not unequivocally confirm 
cholestasis as the reason for ALT/AST increase, in particular if ALP <2x ULN:
•
Clinical chemistry
ALP, cholinesterase (either plasma or red blood cell), albumin, prothrombin time
(PT) or international normalised ratio (INR), CK, CK-MB, coeruloplasmin*, α-1 
antitrypsin*, transferrin, ferritin, 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)*, 
HDV-RNA* analysis is accepted if Anti-IgM and Anti-IgG are not available at the 
laboratory)**, Hepatitis E (Anti-HEV, Anti-HEV IgM, RNA if Anti-HEV IgM 
positive)*, HEV-RNA* analysis is accepted if Anti-HEV and Anti-HEV IgM are not 
available at the laboratory)**, 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
Thyroid-stimulating hormone (TSH)*
•
Haematology
Thrombocytes*, eosinophils*
* If clinically indicated and in case additional investigations are needed (e.g.
immunocompromised patients)
** HDV and HEV related analyses have to be performed if possible at the study site 
or the external laboratory vender which is standard vender for the study site.
Initiate close observation of all patients with elevated liver enzyme and total bilirubin 
increases as defined in Section 5.3.6 by repeat testing of ALT, AST, bilirubin (with 
fractionation to total and direct) and ALP at least weekly until the laboratory values return to 
normal or to the values as defined in the protocol.


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In case that transaminases and/or total bilirubin increase despite cessation of the experimental 
therapy, more frequent intervals will be warranted.
Depending on further laboratory changes, additional parameters identified e.g. by reflex
testing will be followed up based on medical judgment and Good Clinical Practices.
10.2
PHARMACOKINETIC ANALYSES
10.2.1
Handling procedure of blood samples for plasma concentration-time
measurements
For the calculation of pharmacokinetic parameters, only concentrations within the validated 
concentration range will be used. The actual sampling times will be used. For pre-dose 
samples, the actual sampling time will be set to zero. Pharmacokinetic analyses will be done 
according Corporate Procedure of the Sponsor (SOP 001-MCS-36-472, current version).
10.2.2
Time schedule for Pharmacokinetic (PK) blood sampling
Table 10.2.2: 1
Time schedule for PK blood sampling Cycle 1
Treatment 
cycle
Day
Time Point [hh:min]
Event 
Sample 
No.
Nintedaniba)
Cycle 1
8
Just before 
docetaxel/nintedanib
administration
[-0:05]
PK Blood
1
X
15
Just before 
docetaxel/nintedanib
administration
[-0:05]
PK Blood
2
X
a)Analytes: BIBF 1120, BIBF 1202, BIBF 1202 glucuronide


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Table 10.2.2: 2
Time schedule for PK blood sampling Cycle 2
Treatment 
cycle
Da
y
Time Point [hh:min]
Event 
Sample 
No.
Nintedanib a)
Cycle 2
1
Just before 
docetaxel/nintedanib
administration
[-0:05]
PK Blood
1
X
8
Just before 
docetaxel/nintedanib
administration
[-0:05]
PK Blood
2
X
15
Just before 
docetaxel/nintedanib
administration
[-0:05]
PK Blood
3
X
a)Analytes: BIBF 1120, BIBF 1202, BIBF 1202 glucuronide
10.3
RECIST CRITERIA (VERSION 1.1)
The criteria below are based on RECIST 1.1 [R09-0262].
Measurability of the disease
Measurable lesions
Lesions that can be accurately measured in at least one dimension with longest diameter
≥10 mm (by CT scan, MRI, caliper measurement) or ≥20 mm (by chest X-ray).
Measurable disease
Measurable disease requires the presence of at least one measurable lesion. If the measurable 
disease is restricted to a solitary lesion, its neoplastic nature should be confirmed by 
cytology/histology.
Non-measurable disease
Non-measurable lesions are all other lesions, including small lesions (longest diameter
<10 mm with CT scan, MRI or caliper measurement or <20 mm with chest X-ray or 
pathological lymph nodes with shortest axis ≥10 and <15 mm) as well as truly
non-measurable lesions. Lesions considered truly unmeasurable include leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic 
involvement of skin or lung, abdominal masses/ abdominal organomegaly identified by 
physical exam that is not measurable by reproducible imaging techniques.


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New lesions in irradiated fields
Previously irradiated lesions should not be used as indicator lesions. However, new lesions 
occurring in previously irradiated fields can be used to assess the antitumour response.
Methods of measurement
All measurements must be recorded in metric notation, using a ruler or calipers. All baseline 
evaluations must be performed as close as possible to the treatment start and never more than
4 weeks before the beginning of the treatment. If a lesion is considered too small to measure, a
default measurement of 5 mm should be applied. If the lesion is not visible, a default 
measurement of 0 mm should be applied.
The same method of assessment and the same technique must be used to characterise each 
identified and reported lesion at baseline and during follow-up.
Clinical lesions will only be considered measurable when they are superficial (e.g., skin 
nodules, palpable lymph nodes). In the case of skin lesions, documentation by colour 
photography including a ruler to estimate the size of the lesion is obligatory.
CT and MRI are the best currently available and reproducible methods to measure target 
lesions selected for response assessment. Conventional CT and MRI should be performed 
with cuts of 5 mm or less in slice thickness contiguously. Spiral CT should be performed 
using a 5 mm contiguous reconstruction algorithm. This applies to the chest, abdomen and 
pelvis.
Ultrasound, endoscopy and laparoscopy should not be used to measure tumour lesions or 
evaluate tumour response. However, these techniques can be useful to supplement 
information from other techniques.
Tumour markers alone cannot be used to assess response. If markers are initially above the 
upper normal limit, they must normalise for a patient to be considered in complete clinical 
response.
Cytology and histology can be used to differentiate between PR and CR in rare cases (for 
example, residual lesions in tumour types such as germ cell tumours, where known residual 
benign tumours can remain).
Baseline Documentation of Target and Non-target Lesions
All measurable lesions up to a maximum of two lesions per organ and five lesions in total, 
representative of all involved organs should be identified as target lesions and will be 
recorded, measured (longest diameter = LD) and numbered at baseline. Target lesions should 
be selected on the basis of their size (lesions with the longest diameter) and their suitability for 
accurate repetitive measurements (either by imaging techniques or clinically). Lymph nodes
must be ≥15mm (short axis) in order to be considered as target lesions.


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A sum of the longest diameter (LD) for all target lesions will be calculated and reported as
the baseline sum LD. For lymph nodes, the short axis will contribute to the baseline sum. The 
baseline sum LD will be used as reference to further characterize the objective tumour 
response of the measurable dimension of the disease (see Table 10.3: 1).
Table 10.3: 1
Evaluation of target lesions
Complete
Response (CR)
Disappearance of all target lesions. Any pathological lymph nodes
(whether target or non-target) must have reduction in short axis to
<10 mm (the sum may not be “0” if there are target nodes)
Partial Response
(PR)
At least a 30% decrease in the sum of LD of target lesions taking as
reference the baseline sum LD.
Progression
(PD)
At least a 20% increase in the sum of LD of target lesions taking as
reference the smallest sum LD recorded since the treatment started, 
together with an absolute increase in the sum of LD of at least 5mm. 
OR
The appearance of one or more new lesions.
Stable Disease
(SD)
Neither sufficient shrinkage to qualify for PR, taking as reference the
baseline sum LD, nor sufficient increase to qualify for PD taking as 
reference the smallest sum LD since the treatment started.
All other lesions (or sites of disease) should be identified as non-target lesions and should also
be recorded at baseline. Measurements are not required and these lesions should be followed
as “present” or “absent” (see Table 10.3: 2).


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Table 10.3: 2
Evaluation of non-target lesions and new lesions
Complete
Response (CR)
Disappearance of all non-target lesions and normalisation of tumour
marker level. All lymph nodes must be non-pathological in size
(<10 mm short axis)
Non-CR/Non-PD
Persistence of one or more non-target lesions or/and maintenance of
tumour marker level above normal limits.
Progression (PD)
Appearance of one or more new lesions and/or unequivocal
progression of existing non-target lesions.
Although a clear progression of non-target lesions only is exceptional, in
such circumstances, the opinion of the treating physician should prevail
and the progression status should be confirmed later by the review panel
(or study chair).
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends upon this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) before 
confirming the complete response status.
Duration of stable disease
In the case of SD, follow-up measurements must have met SD criteria at least once after study
entry at a minimum interval of six weeks.
Evaluation of overall response
The overall response is determined via the assessment of target lesions, non-target lesions and 
the appearance of new lesions. The algorithm for evaluation of overall response in patients 
with measurable disease at baseline is given in table 10.3: 3. For patients with non-
measurable disease at baseline, the algorithm for evaluation of overall response is defined in
Table 10.3: 4.


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Table 10.3: 3
Algorithm for evaluation of overall response in patients with 
measurable disease at baseline
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
Table 10.3: 4
Algorithm for evaluation of overall response in patients with non-
measurable disease at baseline
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/ Non-PD
No
Non-CR/ Non-PD
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
Patients with a global deterioration of health status requiring discontinuation of treatment 
without objective evidence of disease progression at that time should be reported as 
“symptomatic deterioration”. Every effort should be made to document the objective 
progression even after discontinuation of treatment.


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10.4
STATISTICAL APPENDIX
A 3+3 design will be used to define the dose escalation steps in this study. This design is 
introduced in Section 3.1. The purpose of this statistical appendix is to present performance 
metrics (operating characteristics) that illustrate the precision of the design in determining the 
MTD under various dose-toxicity relationships through computer simulations. Table 10.4: 1
describes 5 assumed true dose-toxicity scenarios which were used to assess the operating 
characteristics of the design. These scenarios reflect a wide range of possible cases as 
follows:
-
Scenario 1: aligned with prior toxicity expectations
-
Scenario 2: high-toxicity scenario
-
Scenario 3: low-toxicity scenario
Table 10.4: 1
Assumed true dose-toxicity scenarios
Scenario
Dose combination
100mg / 
35mg/m2
150mg / 
35mg/m2
200mg / 
35mg/m2
1: Expect
P(DLT)
0.13
0.20
0.32
2: High 
Tox
0.26
0.35
0.48
3: Low 
Tox
0.05
0.12
0.19
For each of these scenarios, 1000 trials were simulated. Each cohort consisted of 3 patients 
and dose escalation complied with the rules described in Section 3.1.
The MTD was considered reached at the highest dose combination where not more than 1 out 
of 6 patients experienced a DLT. If the MTD could not be reached, because already the first 
specified dose combination was too toxic, the simulated trial was stopped. In case no DLT 
has been observed during the simulated trial, the highest dose combination that was specified 
has been declared as MTD.
It was then assessed how often a dose combination was declared as MTD. Furthermore, the 
average, minimum and maximum number of patients per trial are reported. Results are shown 
in Table 10.4: 2.


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Table 10.4: 2 
Simulated operating characteristics
Scenario
% of trials declaring MTD at dose 
[combination]
% of 
stopped 
trials
# Patients
100mg / 
35mg/m2
150mg / 
35mg/m2
200mg / 
35mg/m2
Mean 
(Min-Max)
1
20.1
35.8
32.2
11.9
9.94 (6-18)
2
22.5
25.7
7.6
44.1
10.31 (6-18)
3
11.6
22.8
63.6
2.0
8.79 (6-18)
In scenario 1, which reflects the case that the true dose-toxicity is aligned with the prior 
expectations regarding toxicity probabilities, dose combination 200mg / 35mg/m2 has been 
declared as MTD in approximately the same amount of trials as dose combination 150mg / 
35mg/m2 and almost 12% of the trials stopped because the first specified dose combination 
was too toxic.
In Scenario 2 (high-toxicity scenario), 44% percent of the simulated trials have been stopped 
prematurely because of toxicity. Therefore, patients are sufficiently protected from being 
treated with an overly toxic dose.
Scenario 3 (low-toxicity scenario) shows that with low underlying toxicity probabilities, the 
3+3 design escalates in many simulated trials up to the highest specified dose combination 
and declares this as MTD.
The mean patient numbers range from 8.79 patients (Scenario 3) to 10.31 patients (Scenario 
2) and the maximum number of patients was 18. Therefore, the patient numbers are as 
expected for the 3+3 design.
Overall, by reviewing the metrics presented in Table 10.4: 2, it can be seen that the 3+3 
design serves as an adequate design to determine the MTD of nintedanib in combination with 
weekly docetaxel.
R version 3.0.3 was used for the simulations.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
“This is the original protocol.”
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
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
Description of change
Rationale for change


 
 
 
 
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Title: 
 
 
 
 
                                                                                                                   
 
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03239885
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clinical-trial-protocol
An open label Phase I of oral nintedanib plus weekly docetaxel therapy in patients
with locally advanced or metastatic lung adenocarcinoma after failure of
platinum-based first line chemotherapy
Author-Trial Clinical Monitor
05 Nov 2015 13:54 CET
Author-Trial Statistician
05 Nov 2015 14:07 CET
Author-Trial Clinical
Pharmacokineticist
05 Nov 2015 14:45 CET
Approval-Therapeutic Area 
05 Nov 2015 14:55 CET
Approval-Team Member Medicine
06 Nov 2015 12:29 CET
Verification-Paper Signature
Completion
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SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c09133040-02
BI Trial No.:
1199.224
Title:
An open label Phase I of oral nintedanib plus weekly docetaxel
therapy in patients with locally advanced or metastatic lung 
adenocarcinoma after failure of platinum-based first line 
chemotherapy
Investigational
Product(s):
Nintedanib, BIBF 1120
Responsible trial 
statistician(s):
Phone:
Fax:
Date of statistical 
analysis plan:
21 FEB 2017 SIGNED
Version:
Final
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................3
2.
LIST OF ABBREVIATIONS ..............................................................................4
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................7
5.
ENDPOINTS .........................................................................................................8
5.1
PRIMARY ENDPOINTS.....................................................................................8
5.2
SECONDARY ENDPOINTS...............................................................................8
5.2.1
Key secondary endpoints......................................................................................8
5.2.2
Other Secondary endpoints..................................................................................8
5.3
FURTHER ENDPOINTS.....................................................................................8
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................12
6.1
TREATMENTS...................................................................................................12
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................12
6.3
PATIENT SETS ANALYSED...........................................................................13
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........16
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................17
7.3
TREATMENT COMPLIANCE........................................................................17
7.4
PRIMARY ENDPOINTS...................................................................................17
7.5
SECONDARY ENDPOINTS.............................................................................17
7.5.1
Key secondary endpoints....................................................................................17
7.5.2
Other Secondary endpoints................................................................................17
7.7
EXTENT OF EXPOSURE.................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................20
7.8.1
Adverse events.....................................................................................................20
7.8.2
Laboratory data ..................................................................................................23
7.8.3
Vital signs.............................................................................................................24
7.8.4
ECG......................................................................................................................24
7.8.5
Others...................................................................................................................24
10.
HISTORY TABLE..............................................................................................27


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LIST OF TABLES
Table 6.2: 1 
Important protocol violations ...........................................................................13
Table 6.3: 1 
Patient sets analysed .........................................................................................14
Table 10: 1 
History table .....................................................................................................27


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis data set
AE
Adverse event
AESI
Adverse Event of Special Interest
ATC
Anatomical, Therapeutic, Chemical
BI
Boehringer Ingelheim
BSA
Body Surface Area
CR
Complete Response
CT
Concomitant Therapy
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBLM
Database Lock Meeting
DLT
Dose Limiting Toxicity
ECOG
Eastern Co-operative Oncology Group
eCRF
Electronic Case Report Form
EoT
End-of-Text
ICH
International Conference on Harmonisation
IPV
Important Protocol Violation
MedDRA
Medical Dictionary for Regulatory Activities
MQRM
Medical Quality Review Meeting
MTD
Maximum Tolerated Dose
OR
Objective Response
PFS
Progression-free survival
PK
Pharmacokinetics
PKS
Pharmacokinetic Set
PR
Partial Response
PT
Preferred Term
PV
Protocol Violation
RECIST
Response Evaluation Criteria In Solid Tumours
RPM
Report Planning Meeting
SAE
Serious Adverse Event


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Term
Definition / description
SD
Stable Disease
StD
Standard Deviation
SOC
System Organ Class
TCM
Trial Clinical Monitor
TS
Treated set
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
WHO DD
World Health Organisation - Drug Dictionary


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3.
INTRODUCTION
As per International Conference on Harmonisation (ICH) E9, the purpose of this document is 
to provide a more technical and detailed elaboration of the principal features of the analysis 
described in the protocol, and to include detailed procedures for executing the statistical 
analysis of the primary and secondary variables and other data.
This Trial Statistical Analysis Plan (TSAP) assumes familiarity with the Clinical Trial 
Protocol (CTP, c03239885-01), including Protocol Amendments. In particular, the TSAP is 
based on the planned analysis specification as written in CTP Section 7 “Statistical Methods 
and Determination of Sample Size”. Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, and 
randomization. This TSAP follows the Boehringer Ingelheim (BI) internal reference (1).
In the following, study medication always refers to nintedanib and docetaxel.
SAS® Version 9.4 (or higher) will be used for all analyses if not stated otherwise.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Although CTP Section 5.1.3.2 states that objective response will be confirmed by imaging 
after 4 weeks or later after the first occurrence of the response, the further endpoints Objective 
Response and Duration of Objective Response will be displayed in terms of unconfirmed 
response, as defined in Section 5.3 of this TSAP. 
Otherwise, all analysis will be performed as planned in the CTP. 


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5.
ENDPOINTS
All endpoints are defined in CTP Section 5.
5.1
PRIMARY ENDPOINTS
The primary objective of this trial is to determine the safety and tolerability of nintedanib in 
combination with weekly docetaxel by defining the Maximum Tolerated Dose (MTD) and 
recommending the dose for further trials in the development of this combination. Dose 
Limiting Toxicity (DLT) as assessed by the investigator and occurring during the first 
treatment cycle (first 28 days after start of trial medication) is the primary endpoint and will 
be used to determine dose escalation and the MTD. Definition of DLT is specified in CTP 
Section 5.3.6.
The MTD is defined as the highest dose combination studied for which the incidence of DLTs 
is no more than one out of six patients with a DLT during the first treatment cycle. In case 
escalation reaches dose level 3 (200 mg bid nintedanib given without interruption on days of 
docetaxel infusion) and no more than 1 out of 6 patients in experiences a DLT during the first 
28-day cycle at this dose level, dose level 3 will be considered as the MTD.
Patients who were replaced during the first treatment cycle will not be considered for MTD 
determination. Those patients that have completed the first treatment cycle without having 
been replaced will be referred to as patients evaluable for MTD. 
5.2
SECONDARY ENDPOINTS
There are no formal secondary endpoints defined in the CTP.
5.2.1
Key secondary endpoints
Not applicable, as no key secondary endpoints have been specified in the CTP.
5.2.2
Other Secondary endpoints
Not applicable, as no secondary endpoints have been specified in the CTP.
5.3
FURTHER ENDPOINTS
Further endpoints as specified in CTP Section 5.1.3 are:

The pharmacokinetics (Cpre,ss) of nintedanib and its two metabolites (BIBF 1202 and 
BIBF 1202 glucuronide) for dose level 3 (nintedanib 200 mg bid in combination with 
docetaxel)

Objective Response (OR), defined as best Overall Response of Complete Response 
(CR) or Partial Response (PR), where best Overall Response is determined according 
to Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 recorded 
from the date of first treatment administration until the earliest of disease progression, 
death, or last adequate tumour assessment before new anti-cancer therapy. 


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
Duration of OR, defined as the time from first documented CR or PR until the earliest 
of disease progression or death among patients with objective response. 

Progression free survival (PFS), defined as the time from first treatment administration 
until tumour progression or death from any cause, whichever occurs earlier. 


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
In this Phase I trial treatments are not randomized. Different dose levels of nintedanib in 
combination with weekly docetaxel will arise. The data will be presented for all cohorts 
separately and in total. To justify the MTD determination, DLTs occurring during the first 
treatment cycle will be presented separately from those occurring during the complete on-
treatment period. 
For the on-treatment period, the initial trial medication assigned at the beginning of the first 
treatment cycle will be used as label of the analysing treatment. Tables for the on-treatment 
period will contain a “total” column, representing all doses of trial medication combined.
The first treatment cycle starts with the first administration of any trial medication and lasts 
for 28 days.
Adverse Events (AEs) that have onset date during the Screening or Follow-Up periods will be 
displayed in separate listings from those occurred during the on-treatment period. Listings of 
AEs will not present a “total” category.
Labels of each analysing treatment period, analysis numbers, the labels used for display in the 
tables and listings in the CTR, as well as codes, decodes, sort order and labels for each trial 
medication used in this trial are provided in the  technical document “ADS Plan”.
6.2
IMPORTANT PROTOCOL VIOLATIONS
In this Phase I trial no per protocol population is defined. However, Important Protocol 
Violations (IPVs) should be identified for patients in the treated set.
Data discrepancies and deviations from the CTP will be identified for all treated patients.
Listings of protocol deviations and of unresolved discrepancies will be provided to be 
discussed at the medical quality review meetings (MQRMs), e.g. deviations in drug 
administration, in blood sampling etc. At these meetings, it will be decided whether the 
discrepant data can be used as they are or whether the data have to be corrected in the clinical 
database.
Each protocol deviation must be assessed to determine whether it is an important protocol 
violation. A protocol violation (PV) is important if it affects the rights or safety of the study 
patients or if it can potentially influence the primary outcome measure(s) for the respective 
patients in a way that is neither negligible nor in accordance with the study objectives. PVs 
that do not influence the patient's rights and safety or the evaluability of the patients for the 
main study objectives are called non-important PVs. These are only considered when 
checking the trial quality in general.
If any manual IPVs are identified, they are to be summarised into categories and will be 
captured in the MQRM/RPM minutes via an accompanying Excel spreadsheet (2). The 
following table (Table 6.2: 1) contains the categories which are considered to be possible 
IPVs in this trial.


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Table 6.2: 1
Important protocol violations
Category /
Code
Description
Requirements
Excluded 
from
A
Entrance criteria not met
A1[1]
Inclusion criteria not met
Inclusion criteria 1-5 not met as specified in 
the protocol.
None
A2[1]
Exclusion criteria met
Exclusion criteria met as specified in the 
protocol
None
B
Informed consent
B1[1]
Informed consent not available/not 
done
Informed consent date missing
None
B2[1]
Informed consent too late
Informed consent date was after Screening
None
C
Trial medication and 
randomisation
C1[2]
Incorrect dose taken
Medication kit assigned not matching 
treatment patient was assigned to
None
C2[2]
Non-compliance
Patient missed more than 14 doses of 
nintedanib in one cycle, except for 
interruption due to AE
None
D
Concomitant medication
D1[2]
Prohibited medication use
Use of medication during the on-treatment 
period that is not allowed according to CTP
None
E
Missing data
E1[2]
DLT not recorded
AE that fulfils definition of a DLT is not 
indicated as DLT in the CRF
None
[1] IPV will be derived automatically
[2] IPV will be identified via individual review at MQRM/RPM/DBLM
6.3
PATIENT SETS ANALYSED
Screened Set:
This patient set includes all patients who have signed the informed consent. The screened set 
will be used for patient disposition tables.
Treated Set (TS):
This patient set includes all patients who were documented to have received at least one dose 
of study medication. The TS will be used for all safety and efficacy analyses. 
MTD Evaluation Set:
This patient set includes all patients who were documented to have received at least one dose 
of study medication and were not replaced for the MTD determination. The MTD evaluation 
set will be used for the primary analysis of DLTs and MTD determination.
Rules for replacement are defined in CTP Section 3.3.4.3. The list of replaced patients will be 
provided by the Trial Clinical Monitor (TCM) no later than the last report planning meeting 
(RPM).


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Pharmacokinetic Set (PKS):
This patient set includes all patients who received at least one dose of study medication at 
dose level 3 (200 mg bid nintedanib without interruption on days of docetaxel infusion) and 
that provide at least one observation for the pharmacokinetic (PK) endpoint value if they are 
not flagged for exclusion due to PK non-evaluability or an IPV relevant to the evaluation of 
PK endpoints, which will be decided no later than in the DBL meeting. It is used for the 
analysis of PK parameters.
Table 6.3: 1
Patient sets analysed
Patient set
Class of endpoint
TS
SCS
MTD evaluation 
set
PKS
Primary and key secondary 
endpoints 
X
Primary analysis
(other) Secondary and further 
endpoints 
X
PK endpoints
Safety analyses
X
Demographic/baseline 
endpoints
X
X
6.5
POOLING OF CENTRES
Not applicable.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Pharmacokinetics:
For the handling of missing PK data see CTP Section 7.5.1.
Laboratory values:
For the handling of missing baseline laboratory values see CTP Section 7.5.
Partial or missing dates:
For the following dates the rule described below applies: Last date patient known to be alive, 
drug discontinuation dates, start and end dates of concomitant therapies, start and end dates of 
docetaxel pre-medication, start and end dates of subsequent anti-cancer therapies, date of first 
histological diagnosis, and death date.
In general, all reasonable effort should be undertaken during the study to obtain these dates
completely. If despite all efforts, the complete date cannot be provided but only the month and 


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the year, then the 15th of the month will be imputed. If only the year is reported, July 1st will 
be imputed. However, the imported date should never be later than the death date. 
Adverse Events:
Missing or incomplete AE dates are imputed according to BI standards (3). The imputation 
algorithm is based on a worst case approach, i.e. the imputed AE dates will:
1. maximise the possibility for AE to be counted as treatment emergent AE
2. result in 'longest' duration of treatment emergent AEs
3. result in 'shortest' duration of non-treatment emergent AEs
Missing docetaxel infusion time:
If the time of infusion is missing, then start time of the infusion will be imputed as “0:00” and 
the stop time will be imputed as “1:00”.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study days and visits will be labelled according to the flowchart 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. Note that for some trial procedures (for example Eastern Co-operative Oncology 
Group (ECOG) performance score, body weight, vital signs, laboratory tests) this may be the 
value measured on the same day when 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 nominal time points and windows of tumour imaging, see Table 7.6: 2.
Laboratory values:
Baseline is defined as the latest time point before the very first administration of any study 
medication. For laboratories where not only the examination date but also time are recorded, a 
laboratory value on the same date as first study drug administration is considered as baseline 
value if and only if the time of laboratory value is before or at the same time as the time of 
first study drug administration.  If any of those 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.


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7.
PLANNED ANALYSIS
The labelling and display format of statistical parameters will follow the guideline “Reporting 
of Clinical Trials and Project Summaries” (4).
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / Standard deviation 
(StD)/ Min / Median / Max. 
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to Mean, StD, Min and Max.
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 the time to event will be displayed in months and a final decision will be 
made at the last RPM.
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 (unless otherwise specified, all patients in the respective patient set 
whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
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 intended 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 
only.
Abbreviations (e.g. Wors.) should not be displayed without any explanations. 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
Standard descriptive analyses and summary tables are planned for this section of the report. 
Data will be summarised by dose cohort and a “total” column will be included in the 
summary tables.


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7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. 
Concomitant diseases will be coded similarly as AEs based on the most current Medical 
Dictionary for Regulatory Activities (MedDRA) version. 
Concomitant therapies (CTs) will be coded according to the World Health Organisation Drug 
Dictionary (WHO DD). CTs 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.
The CTR will contain tables for previous and concomitant therapies started at baseline 
including CTs stopped prior to the first intake of study medication as well as CTs started 
before the first intake of study medication and continued during study drug treatment and 
separately CTs that were initiated after the start of study medication.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
7.4
PRIMARY ENDPOINTS
The primary endpoints of this trial are the MTD and the number of patients with DLTs during 
the first treatment cycle. The MTD is determined from the occurrences of DLTs during the 
first treatment cycle. The primary analysis is for the determination of the MTD. The purpose 
of this analysis is to summarize and document the data that led to the selection of the MTD. 
Therefore, an overall summary of patients with DLTs (see CTP Section 5.3.6 for the 
definition of DLTs) which occurred during the first treatment cycle will be provided for each 
dose cohort. Patients, if any, who did not complete the first treatment cycle for reasons other 
than DLT will be excluded from the analysis of the primary endpoint.
A summary of the number of patients with DLTs overall in the on-treatment period will be 
also given by initial treatment and displayed in a similar format to the summary of DLTs 
occurring in the first treatment cycle.
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
This section is not applicable as no secondary endpoint has been specified in the protocol.


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7.7
EXTENT OF EXPOSURE
The duration of drug intake and the estimated dose intensity will be summarised descriptively. 
The frequency of patients with dose reductions as well as the time to first dose reduction will 
be described for nintedanib.
7.8
SAFETY ANALYSIS
All safety analyses besides the determination of the MTD will be performed on the TS. The 
determination of the MTD will be based on the MTD evaluation set. Patients who were 
replaced within the first treatment cycle will be excluded from the MTD evaluation set but 
will be considered for all other safety evaluations based on the treated set. Replaced patients 
will be listed. 
7.8.1
Adverse events
The analyses of adverse events will be descriptive in nature and will be based on BI standards. 
All analyses of AEs will be based on the number of patients with AEs and not on the number 
of AEs. AEs will be coded with the most recent version of MedDRA. The severity of AEs 
will be scaled according to common terminology criteria for adverse events (CTCAE) version 
4.03 (5) According to the BI standards, multiple recordings of adverse events will be 


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collapsed to episodes on the MedDRA lowest level term and multiple episodes will be 
condensed to records on the preferred term and SOC level. Please refer to 001-MCG-156 
version 5.0 (6) for detailed explanations of the collapsing and condensing procedures applied 
in AE data handling and analyses.
CTCAE grade will be an additional criterion for collapsing and condensing AEs. The worst 
(maximum) CTCAE grade will be assigned to episodes and records. CTCAE grade will be 
displayed in AE listings.
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events, where a treatment emergent AE has an onset in the analysing treatment period. The 
main AE analysis using the treated set will be based on the “on-treatment period”. AEs with 
onset date in the screening-period or post-treatment-period will listed separately. That means 
that all AEs occurring between first drug intake till 28 days after last drug intake will be 
assigned to the allocated treatment. All AEs occurring before first drug intake will be assigned 
to ‘screening’ and all adverse events occurring after last drug intake + 28 days will be 
assigned to ‘post-treatment’ (for listings only). For details on the treatment definition, see 
Section 6.1.
Adverse events will be displayed by the initial assigned dose of nintedanib and docetaxel
administered on the first day of treatment with study medication in the summary tables. In 
addition, a listing will be provided, detailing the actual dose of nintedanib and docetaxel 
administered on the day when the AE starts. Patients with treatment information missing will 
not be displayed in the safety tables. A separate listing will be provided for these patients.
Adverse events will be reported with start day and end day calculated relative to the first day 
of treatment with study medication. The system organ classes (SOCs) will be sorted 
alphabetically. Preferred terms (PTs) will be sorted by descending frequency of adverse 
events (within SOC) in the “total” group.
An analysis of DLTs during the first treatment cycle for patients from the MTD evaluation set 
will be displayed. This analysis will reflect the dose escalation and MTD determination. In 
addition, analyses showing DLTs during the on-treatment period for all patients from the 
treated set will be done to further characterise the MTD and determine a recommended phase 
II dose.
Listings of adverse events will be displayed by patients and also by medical PT. 
Reporting of CTCAE grades in tables: AEs with a given CTCAE definition will be displayed 
in tables showing AEs by worst CTCAE grade. The preferred option for displaying the 
CTCAE grading within AE tables (Section 15) should be “All Grades”, “Grade 1/2” and 
“Grade 3/4/5”. AEs with missing CTCAE or CTCAE grades not equal to 1 to 5 will be 
displayed under the category "All Grades", but no category “Missing Grade” should be 
displayed and therefore the categories “Grade 1/2” and “Grade 3/4/5” might not add up to the 
category “All Grades”.
A separate table will show AEs leading to death. 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. In the appendix (section 16.1.9.2), the categorization “All grades”, “Missing


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Grade”, “Grade 1”, “Grade 2“; “Grade 3”, “Grade 4” and “Grade 5” should be used, but the
“Missing Grade” column should only be displayed in case AEs with a missing CTCAE grade
occurred.
An overall summary of adverse events will be presented.
Incidence and severity of adverse events
The incidence of AEs overall (irrespective of relatedness to study medication), related AEs, 
and of 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 (nintedanib or docetaxel, dose reductions 
only allowed for nintedanib per CTP). The incidence of 

AEs leading to dose reduction of nintedanib

AEs leading to overall permanent discontinuation of last study medication

AEs leading to discontinuation of nintedanib or docetaxel

AEs leading to discontinuation of nintedanib and docetaxel

AEs leading to discontinuation of nintedanib

AEs leading to discontinuation of docetaxel
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.
Adverse events of special interest
AESIs as defined in the CTP and collected in the eCRF will be analysed descriptively.
Deaths and fatal AEs
AEs leading to death during the on-treatment period will be tabulated. Reported fatal AEs that 
occurred in the post-study phase will be listed.
Adverse Events by UDAEC
User defined adverse event categories (UDAECs) as defined on project level will be derived 
and the latest version will be used for analysis. AEs by UDAECs will be displayed as follows:
1. AEs by UDAEC tables presenting the UDAECs only: UDAECs sorted by 
frequency of UDAEC.
2. AEs by UDAEC tables presenting the UDAECs and preferred terms: The 
UDAECs will be sorted alphabetically. Preferred terms will be sorted by 
descending frequency of adverse events (within UDAEC),
3. A listing of the used coding of the UDAECs will be provided in Appendix 16.2 of 
the CTR.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
(see “Display and Analysis of Laboratory Data”, 7). The analysis of laboratory data will use 
the same “analysing treatments” as described for the AEs, 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 v4.03. 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 on treatment, and from baseline to last laboratory value during 
the on-treatment phase.
Worst laboratory value and its CTCAE grade (highest CTCAE grade) over all courses will be 
calculated for each laboratory parameter specified in CTP Section 5.3.3.
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”.
Generally, in case only one direction of worsening (high or low laboratory values) is specified 
in the CTCAE document, there is no need to examine the other direction. Therefore for 
calculating the change in CTCAE grade from baseline / pre-dose level, patients with a 
CTCAE Grade of "-9" (no CTCAE grade defined) will be treated as a CTCAE Grade 0 for all 
analyses. In laboratory listings, the CTCAE grade will be displayed as "-9".
For Uric Acid and Hypokalemia, the CTCAE grade cannot always be assigned by the 
laboratory parameter itself as two different CTCAE grades have the same laboratory 
constellation, but are distinguished by additional clinical parameter. In this case a CTCAE 
grade of "-1" will be assigned initially. Patients with a CTCAE Grade of "-1" will be treated 
as
-
Grade 1 for Uric Acid
-
Grade 1 for Hypokalemia
for all analyses. In laboratory listings, the CTCAE grade will be displayed as "-1".
Possible clinically significant abnormal laboratory values are defined as those laboratory 
values that are of CTCAE Grade ≥ 2 and show an increase from baseline value by at least one 
CTCAE grade. For those parameters for which no CTCAE has been defined, BI standard 
definition will be used to determine possible clinical significance. Frequency of patients with 
possible clinically significant abnormal laboratory values will be provided whenever 
applicable. If no baseline value is available but the patient has a post-baseline laboratory value 
of CTCAE Grade ≥ 2 an increase from baseline will be assumed, i.e. the laboratory value 
considered as possible clinically significant.


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Hepatic enzyme elevations (potential Hy’s law cases):
Patients fulfilling the criteria for potential Hy’s law cases will be tabulated. These are defined 
as those cases where a combination of all the following events occurs: any on-treatment value 
of AST or ALT (or both) is > 3x ULN with total bilirubin ≥2x ULN and ALP < 2x ULN. The 
events can occur in any order, but must occur within 14 days from the previous event, i.e. the 
second event must occur within 14 days from the first event and the third event must occur 
within 14 days from the second event, etc.
In addition, a separate listing will be given showing patients with missing parameters in the 
above given time frames.    
7.8.3
Vital signs
Descriptive statistics are planned for this section of the report. 
7.8.4
ECG
Newly emergent abnormalities will be recorded and analysed as AEs.
7.8.5
Others
Other parameters relevant for safety as height, weight, and ECOG score will be analysed 
descriptively and displayed in patient listings.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Initial
26-AUG-16
None
This is the initial TSAP with necessary 
information for trial conduct.
Final
21-FEB-17
1 - 10
This is the final TSAP