Clinical trial NCT01907100
Conditions: Mesothelioma
Sponsor: Boehringer Ingelheim
Start date: 2013-09-19; Completion date: 2018-08-31
Enrollment: 545 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase II/III confirmatory study designed to evaluate the safety and efficacy of nintedanib (BIBF 1120) in combination + (pemetrexed / cisplatin) followed by nintedanib (BIBF 1120) versus placebo + pemetrexed / cisplatin followed by placebo for the treatment of patients with unresectable malignant pleural mesothelioma.

Detailed description:

Arms: arm 1: Placebo controlled arm arm 2: Experimental arm
Interventions: intervention 1: Nintedanib intervention 2: Pemetrexed intervention 3: Cisplatin intervention 4: Cisplatin intervention 5: Pemetrexed intervention 6: Placebo
Intervention descriptions: intervention 1: triple kinase inhibitor; 200mg starting dose intervention 2: backbone chemo intervention 3: backbone chemo intervention 4: backbone chemo intervention 5: backbone chemo intervention 6: Nintedanib matching placebo

Protocol documents:
Prot_000.pdf: 
  
Clinical Trial Protocol
Doc. No.: c02035745-05
EudraCT No.:
BI Trial No.:
2012-005201-48
1199.93
BI Investigational
Product:
Nintedanib, BIBF 1120
Title:
LUME-Meso: Double blind, randomised, multicentre, phase II/III study 
of nintedanib in combination with pemetrexed / cisplatin followed by 
continuing nintedanib monotherapy versus placebo in combination with 
pemetrexed / cisplatin followed by continuing placebo monotherapy for 
the treatment of patients with unresectable malignant pleural 
mesothelioma
Clinical Phase:
II/III
Trial Clinical 
Monitor:
Phone: 
Fax
Co-ordinating 
Investigator:
Telephone:
Fax
Status:
Final Protocol (Revised Protocol (based on global amendment(s))
Version and Date:
Version:
3.0
         
Date: 22 Jun 2016
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TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Nintedanib
Name of active ingredient:
BIBF 1120
Protocol date:
Trial number:
Revision date:
22 Jun 2016
22 Mar 2013
1199.93
Title of trial:
LUME-Meso: Double blind, randomised, multicentre, phase II/III study of 
nintedanib in combination with pemetrexed / cisplatin followed by continuing 
nintedanib monotherapy versus placebo in combination with pemetrexed / cisplatin 
followed by continuing placebo monotherapy for the treatment of patients with 
unresectable malignant pleural mesothelioma
Co-ordinating 
Investigator:
Trial sites:
Multicentre trial
Clinical phase:
II/III
Objective:
To evaluate the safety and efficacy in terms of progression-free survival (PFS) and 
overall survival (OS) of nintedanib + pemetrexed / cisplatin followed by nintedanib 
versus placebo + pemetrexed / cisplatin followed by placebo as first line treatment 
for patients with unresectable malignant pleural mesothelioma (MPM).
The primary objective of this study is to evaluate whether treatment with nintedanib 
+ pemetrexed / cisplatin followed by nintedanib monotherapy is more effective than 
treatment with placebo + pemetrexed / cisplatin followed by placebo monotherapy, 
as assessed by PFS.
The key secondary objective is to evaluate whether treatment with nintedanib +
pemetrexed / cisplatin followed by nintedanib monotherapy is more effective than 
treatment with placebo + pemetrexed / cisplatin followed by placebo monotherapy, 
as assessed by OS.
The secondary objectives are to assess the objective tumour response rate and the 
disease control rate.
Methodology:
Two-arm, randomised, double-blind, placebo-controlled, parallel-group comparison 
of nintedanib plus chemotherapy versus placebo plus chemotherapy 
No. of patients: 
total entered:
537 (87 Phase II and 450 Phase III patients)


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Nintedanib
Name of active ingredient:
BIBF 1120
Protocol date:
Trial number:
Revision date:
22 Jun 2016
22 Mar 2013
1199.93
each treatment:
50% of the patients will be randomised and treated with nintedanib and 50% of the 
patients will be randomised and treated with nintedanib matching placebo (1:1 
randomisation)
Patients in both arms will receive standard treatment with pemetrexed/cisplatin for up 
to 6 cycles
Diagnosis :
Histologically confirmed, unresectable MPM
Main criteria
for inclusion:

Histologically confirmed MPM (subtype: epithelioid or biphasic for Phase II or 
subtype epithelioid only for Phase III)

Not eligible to undergo surgical resection

Measurable disease according to modified Response Evaluation Criteria In Solid 
Tumours (RECIST) criteria (R12-1990) 

No prior first line therapies for MPM

Eastern Cooperative Oncology Group (ECOG) Performance Status 0 -1
Test product:
Nintedanib 
      dose:
200 mg twice daily
      mode of admin.:
Oral
Comparator product:
Nintedanib matching placebo
      dose:
Not applicable
      mode of admin.:
Oral
Duration of treatment: Nintedanib or matching placebo will be administered in combination with standard 
pemetrexed and cisplatin for a maximum of 6 cycles of a 21-day cycle.
For patients who have not progressed, nintedanib or matching placebo will continue 
to be administered orally on a daily basis until disease progression, unmanageable 
toxicity, withdrawal of consent or death.
Criteria for efficacy: 
Primary Endpoint:
Progression free survival (PFS) 
Secondary Endpoints: 

Overall survival (OS) (key secondary endpoint) 

Objective tumour response according to modified RECIST criteria

Disease control according to modified RECIST criteria


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Nintedanib
Name of active ingredient:
BIBF 1120
Protocol date:
Trial number:
Revision date:
22 Jun 2016
22 Mar 2013
1199.93
Criteria for safety:

Frequency and severity of adverse events (AEs) graded according to Common 
Terminology Criteria for Adverse Events (CTCAE) version 3.0 (R06-1666) for 
Phase II and Version 4.03 (R15-5988) for Phase III patients.

Changes in safety laboratory parameters 

Statistical methods:
Phase II
The analyses will be exploratory using Kaplan-Meier methods and a stratified Cox 
proportional hazards model.
Phase III
The analysis of the primary endpoint PFS and the key secondary endpoint OS will 
be performed according to a hierarchical testing procedure. The log-rank test will be 
used for PFS to test for the effect of nintedanib at the one-sided alpha level of 0.025.
For OS, an adaptive design with event number reassessment will be used. The 
analysis of OS will be performed using the weighted inverse normal method with 
one sided p-values from the log-rank test. The alpha-level for OS will follow an 
O`Brien and Fleming spending function to preserve the overall alpha of 0.025 (one-
sided) for the final OS analysis.


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PHASE II FLOW CHARTS
Phase II Combination: Nintedanib (BIBF 1120) or Placebo + Pemetrexed / Cisplatin 
Treatment Cycles 1 – 61
Study Activity
Screening
Cycle 11
Cycles 2-61
EoT2
FU3
Visit
V1
V2
V3
V1
V2
V3
Days
- 14 to -1
1
2
8
±2
15
±2
1
±2
2
8
±2
15
±2
FU1 ≥28 days 
after last study 
medication intake
FU2 - FUn every 
6-12 weeks 
Informed consent
X4
 
 
Demographics
X
Medical history
X
Inclusion/exclusion criteria
X
X
Randomisation
X
Eligibility for next cycle8
X
Physical examination
X
X
X
X
X
Vital signs
X
X
X
X
X
X
X
X
Body weight and height9
X
X
X
X
ECOG score
X
X
X
X
X
ECG10
X
X
X
X
X
X
X
Safety lab parameters12
X
X
X
X
X
X
X
X
Urinalysis12
X
X
X
X
Pregnancy test13
X
X
X
Tumour assessment
X14
X15
Pre-medication for chemotherapy16
X
X
X
X
X
X
X
X
X
X
Pemetrexed and cisplatin 
administrations17
X
X
Dispense nintedanib / placebo18
X
X
Nintedanib / Placebo treatment18
X
X
X
X
X
X
Compliance check19
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X20
Concomitant therapy
X
X
X
X
X
X
X
X
X 
Patient vital status and other anti-
cancer therapy
X
Conclusion of active treatment
X


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1
Duration of each treatment cycle is 21 days.
2
End of Treatment (EoT) to be performed at the time of the last visit when patient discontinues study treatment
(pemetrexed/cisplatin and nintedanib/placebo); to be documented only once in the EoT visit electronic case report 
form (eCRF) page. If a patient discontinues treatment without progression, additional imaging does not need to be 
performed at EoT if performed within the past three weeks. If progression is suspected at EoT, imaging must be 
done irrespective of last imaging timepoint. If patient continues treatment with nintedanib / placebo, see 
monotherapy flow chart.
3
See Section 6.2.3.2. The first follow up visit (FU1) will be performed ≥28 days after discontinuing study 
medication. Further follow up visits will be performed every 6 weeks for progressive disease (PD) and every 12
weeks for OS:
Follow-up for PD: Patients who did not progress on treatment will continue to perform imaging every 6 weeks
until PD, start of new subsequent anti-cancer therapy, death, lost-to follow up, withdrawal of consent, or when the 
required OS events for the primary analyses of the key secondary endpoint OS for Phase II have been reached.
Follow-up for OS: Patients remaining on study as of the primary analysis for the key secondary endpoint OS for 
Phase II, regardless of whether they progressed on treatment, will be followed every 12 weeks until death, lost to 
follow-up, withdrawal of consent, or until the time of the primary PFS analysis for Phase III (follow-up for OS can 
be conducted by phone interview).
 
 
 
 
 
8
Evaluation of eligibility for next cycle will be performed prior to administration of chemotherapy. See Sections 
4.1.4.4, 4.1.4.5 and 6.2.2.
9
Height at screening visit only.
10
12-lead resting Electrocardiogram (ECG) to be performed at every cycle up to 3 days before administration of 
chemotherapy.
 
12
For safety lab parameters and urinalysis, see Section 5.2.3. Laboratory parameters must be obtained prior to re-
treatment, see Sections 4.1.4.4 and 4.1.4.5.
13
Serum or urine pregnancy test will be performed in women of childbearing potential at screening and on Day 1 of 
cycle 1. The results have to be checked prior to the first chemotherapy administration. Pregnancy test will be 
repeated at EoT visit, see Section 5.2.2.4. Additional pregnancy test can be performed during treatment period if 
required according to local regulations.
14
Tumour assessment (imaging) at screening must be performed within 4 weeks prior to first treatment
15
Tumour assessments according to modified RECIST criteria (R12-1990) to be performed every 6 weeks starting 
from the time of the first pemetrexed/cisplatin administration irrespective of any delay in treatment courses, until 
progression of the tumour or initiation of any other anti-cancer therapy outside of current study. Imaging is 
acceptable +/- 1 week around the scheduled date. If patients continue on study treatment beyond progression, 
imaging should continue to be performed every 6 weeks. Imaging can be performed outside of scheduled visits if 
progression is suspected. See Section 5.1.2.1 for further details.
16
All patients should be pre-medicated during the study starting at least 7 days before the first dose of pemetrexed, 
and continue daily during pemetrexed therapy courses and for 21 days after the last dose of pemetrexed, see 
Section 4.1.4.3.
17
Chemotherapy (pemetrexed/cisplatin) will be administered during the combination chemotherapy period for a 
maximum of 6 cycles. If one of the combination partners has to be stopped, the other chemotherapy can continue 
for up to 6 cycles. In case nintedanib/placebo will be discontinued before combination cycle 6, administration of 
the chemotherapy should be continued until combination cycle 6. See Section 3.3.4.1 and Section 4.1.4.
18
Nintedanib / placebo will be dispensed on Day 1 of each treatment cycle. Patient should start nintedanib / placebo 
in the morning of Day 2 of each treatment cycle (i.e. the day after each chemotherapy administration), and 
continue daily until Day 21 of the cycle. In case the next visit is delayed, patient should continue taking daily 
treatment as instructed.
19
Check patient’s compliance with administration schedule for nintedanib / placebo and chemotherapy pre-
medication, see Section 4.3.
20
See Section 6.2.3.2 for management of AEs ongoing at EoT.


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Phase II Monotherapy: Nintedanib or Placebo
From End of Combination Therapy (Treatment Cycle ≤ 6) to EoT
Study Activity
Repeated Cycles1
EoT2
FU3
Visit
V1
FU1 ≥28 days after 
last study 
medication intake
FU2 - FUn every 6-
12 weeks
Day
1
Variance allowed (± days)
±2
Physical examination
X
X
X
Eligibility for monotherapy with nintedanib / placebo4
X
Vital signs
X
X
Body weight
X
X
ECOG score
X
X
X
ECG
X
X
 
Safety lab parameters6
X
X
Urinalysis6
X
X
Pregnancy test7
X
 
Tumour assessment9
X
Dispense nintedanib / placebo medication10
X
Nintedanib / placebo treatment11
X
Nintedanib / placebo compliance check12
X
X
Adverse events
X
X
X13
Concomitant therapy
X
X
X
Patient status and other anti-cancer therapy
X
Conclusion of nintedanib / placebo treatment
X
1
Duration of treatment cycle is 21 days. 
2
EoT to be performed at the time of the last visit when patient discontinues treatment with nintedanib / placebo; to 
be documented only once in the EoT visit eCRF page. If a patient discontinues treatment without progression, 
additional imaging does not need to be performed at EoT if performed within the past three weeks. If progression 
is suspected at EoT, imaging must be done irrespective of last imaging time point.
3
See Section 6.2.3.2. The first follow up visit (FU1) will be performed ≥28 days after discontinuing study 
medication. Further follow up visits will be performed every 6 weeks for PD and every 12 weeks for OS:
Follow-up for PD: Patients who did not progress on treatment will continue to perform imaging every 6 weeks
until PD, start of new subsequent anti-cancer therapy, death, lost-to follow up, withdrawal of consent, or when the 
required OS events for the primary analyses of the key secondary endpoint OS for Phase II have been reached.
Follow-up for OS: Patients remaining on study as of the primary analysis for the key secondary endpoint OS for 
Phase II, regardless of whether they progressed on treatment, will be followed every 12 weeks until death, lost to 
follow-up, withdrawal of consent, or until the time of the primary PFS analysis for Phase III (follow-up for OS can 
be conducted by phone interview).
4
Evaluation of eligibility for next cycle will be performed prior to administration of nintedanib/placebo. See 
Sections 4.1.4.5 and 6.2.2.
 
6
For safety lab parameters and urinalysis, see Section 5.2.3. Laboratory parameters must be obtained prior to re-
treatment, see Section 4.1.4.5.
7
Serum or urine pregnancy test to be performed in women of childbearing potential at EoT, see Section 5.2.2.4. 
Additional pregnancy test can be performed during treatment period if required according to local regulations.


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9
Tumour assessments according to modified RECIST criteria (R12-1990) to be performed every 6 weeks starting 
from the time of the first pemetrexed/cisplatin administration irrespective of any delay in treatment courses, until 
progression of the tumour or initiation of any other anti-cancer therapy outside of current study. Imaging is 
acceptable +/- 1 week around the scheduled date. If patients continue on study treatment beyond progression, 
imaging should continue to be performed every 6 weeks. Imaging can be performed outside of scheduled 
timepoints if progression is suspected. See Section 5.1.2.1 for further details.
10
Nintedanib / placebo will be dispensed on Day 1 of each treatment cycle. 
11
Patient should start nintedanib / placebo in the morning of Day 1 of each treatment cycle and continue daily until 
Day 21 of the cycle. In case next visit is delayed, patient should continue taking daily treatment as instructed.
12
Check patient’s compliance with administration schedule for nintedanib / placebo, see Section 4.3.
13
See Section 6.2.3.2 for management of AEs ongoing at EoT.


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PHASE III FLOW CHARTS
Phase III Combination: Nintedanib (BIBF 1120) or Placebo + Pemetrexed / Cisplatin 
Treatment Cycles 1 – 61
Study Activity
Screen
Cycle 11
Cycle 21
Cycles 3-61 EoT2 FU13 FUP 
PD3
FUP 
OS3
Visit
V1
V2
V1
V2
V1
V2
Days
- 14 to -1
1
8
±2
1
±2
8
±2
1
±2
8
±2
Informed consent
X4
 
 
Demographics
X
Medical history
X
Inclusion/exclusion criteria
X
X
Randomisation
X
Eligibility for next cycle9
X
X
Physical examination
X
X
X
X
X
X
X
Vital signs
X
X
X
X
X
Body weight and height10
X
X
X
X
X
ECOG score
X
X
X
X
X
X
X
ECG11
X
X
X
X
Safety lab parameters12
X
X
X
X
X
X
X
X
Urinalysis12
X
X
X
X
X
Pregnancy test13
X
X
X
 
Tumour assessment
X15
X16
Pre-medication for chemotherapy18
X
X
X
X
Pemetrexed and cisplatin 
administration19
X
X
X
Dispense nintedanib / placebo20
X
X
X
Nintedanib / placebo treatment21
X
X
X
Compliance check22
X
X
X
X
Adverse events
X
X
X
X
X
X23
Concomitant therapy
X
X
X
X
X
X 
Patient vital status and other anti-
cancer therapy
X
X
X
Conclusion of active treatment
X


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1
Duration of each treatment cycle is 21 days.
2
End of Treatment (EoT) to be performed at the time of the last visit when patient discontinues study treatment
(pemetrexed / cisplatin and nintedanib / placebo); to be documented only once in the EoT visit electronic case 
report form (eCRF) page. If a patient discontinues treatment without progression, additional imaging does not need 
to be performed at EoT if performed within the past three weeks. If progression is suspected at EoT, imaging must 
be done irrespective of last imaging timepoint. If patient continues treatment with nintedanib / placebo, see 
monotherapy flow charts.
3
See Section 6.2.3.2. The first follow up visit (FU1) will be performed ≥30 days after discontinuing study 
medication. Further follow up visits will be performed every 6 weeks for progressive disease (PD) and every 12
weeks for OS:
Follow-up for PD: Patients who did not progress on treatment will continue to perform imaging every 6 weeks
until PD, start of new subsequent anti-cancer therapy, death, lost-to follow up, withdrawal of consent, or when the 
required OS events for the primary analyses of the key secondary endpoint OS have been reached.
Follow-up for OS: Patients who progressed on treatment will be followed every 12 weeks until death, lost to 
follow-up, withdrawal of consent, or when the required OS events for the primary analyses of the key secondary 
endpoint OS have been reached (follow-up for OS can be conducted by phone interview if patients cannot visit the 
site in person).
 
 
 
 
 
9
Evaluation of eligibility for next cycle will be performed prior to administration of chemotherapy. See Sections 
4.1.4.4, 4.1.4.5 and 6.2.2.
10
Height at screening visit only.
11
12-lead resting Electrocardiogram (ECG) to be performed up to 3 days before administration of chemotherapy at 
every other cycle.
12
For safety lab parameters and urinalysis, see Section 5.2.3. Laboratory parameters must be obtained prior to re-
treatment, see Sections 4.1.4.4 and 4.1.4.5.
13
Serum or urine pregnancy test will be performed in women of childbearing potential at screening and on Day 1 of 
Cycle 1 Visit 1. The results have to be checked prior to the first chemotherapy administration. Pregnancy test will 
be repeated at EoT visit, see Section 5.2.2.4. Additional pregnancy test can be performed during treatment period 
if required according to local regulations.
 
15
Tumour assessment (imaging) at screening must be performed within 4 weeks prior to first treatment (including 
brain scan).
16
Tumour assessments according to modified RECIST criteria (R12-1990) to be performed every 6 weeks starting 
from the time of the first pemetrexed/cisplatin administration irrespective of any delay in treatment courses, until 
progression of the tumour or initiation of any other anti-cancer therapy outside of current study. Imaging is 
acceptable +/- 1 week around the scheduled date. If patients continue on study treatment beyond progression, 
imaging should continue to be performed every 6 weeks. Imaging can be performed outside of scheduled visits if 
progression is suspected. Patients with stable brain metastases at trial entry must be evaluated at each imaging time 
point for assessment for brain metastases. See Section 5.1.2.1 for further details.
18
All patients should be pre-medicated during the study starting at least 7 days before the first dose of pemetrexed, 
and continue daily during pemetrexed therapy courses and for 21 days after the last dose of pemetrexed. See 
Section 4.1.4.3.
19
Chemotherapy (pemetrexed / cisplatin) will be administered during the combination chemotherapy period for a 
maximum of 6 cycles. If one of the combination partners has to be stopped, the other chemotherapy can continue 
for up to 6 cycles. In case nintedanib / placebo will be discontinued before combination Cycle 6, administration of 
the chemotherapy should be continued until combination Cycle 6. See Section 3.3.4.1 and Section 4.1.4.
20
Nintedanib / placebo will be dispensed on Day 1 of each treatment cycle


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21
Patient should start nintedanib / placebo in the morning of Day 2 of each treatment cycle (i.e. the day after each 
chemotherapy administration), and continue daily until Day 21 of the cycle. In case the next visit is delayed, 
patient should continue taking daily treatment as instructed.
22
Check patient’s compliance with administration schedule for nintedanib / placebo and chemotherapy pre-
medication. See Section 4.3.
23
See Section 6.2.3.2 for management of AEs ongoing at EoT.


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Phase III Monotherapy: Nintedanib or Placebo
From End of Combination Therapy (Treatment Cycle ≤ 6) to EoT
Study Activity
Repeated Cycles1
EoT2
FU13
FUP 
PD3
FUP 
OS3
Visit
V1
Day
1
Variance allowed (± days)
±2
Physical examination
X
X
X
X
Eligibility for monotherapy with nintedanib / placebo4
X
Vital signs
X
X
Body weight
X
X
ECOG score
X
X
X
X
ECG
X
X
Safety lab parameters5
X
X
Urinalysis5
X
X
Pregnancy test6
X
Tumour assessment9
X
Dispense nintedanib / placebo medication11
X
Nintedanib / placebo treatment12
X
Nintedanib / placebo compliance check13
X
X
Adverse events
X
X
X14
Concomitant therapy
X
X
X
Patient status and other anti-cancer therapy
X
X
X
Conclusion of nintedanib / placebo treatment
X
1
Duration of treatment cycle is 21 days. 
2
EoT to be performed at the time of the last visit when patient discontinues treatment with nintedanib / placebo; to 
be documented only once in the EoT visit eCRF page. If a patient discontinues treatment without progression, 
additional imaging does not need to be performed at EoT if performed within the past three weeks. If progression 
is suspected at EoT, imaging must be done irrespective of last imaging time point.
3
See Section 6.2.3.2. The first follow up visit (FU1) will be performed ≥30 days after discontinuing study 
medication. Further follow up visits will be performed every 6 weeks for PD and every 12 weeks for OS:
Follow-up for PD: Patients who did not progress on treatment will continue to perform imaging every 6 weeks
until PD, start of new subsequent anti-cancer therapy, death, lost-to follow up, withdrawal of consent, or when the 
required OS events for the primary analyses of the key secondary endpoint OS have been reached.
Follow-up for OS: Patients who progressed on treatment will be followed every 12 weeks until death, lost to 
follow-up, withdrawal of consent, or when the required OS events for the primary analyses of the key secondary 
endpoint OS have been reached (follow-up for OS can be conducted by phone interview if patients cannot visit the 
site in person).
4
Evaluation of eligibility for next cycle will be performed prior to administration of nintedanib / placebo. See 
Sections 4.1.4.5 and 6.2.2.
5
For safety lab parameters and urinalysis, see Section 5.2.3. Laboratory parameters must be obtained prior to re-
treatment, see Section 4.1.4.5.
6
Serum or urine pregnancy test to be performed in women of childbearing potential at EoT, see Section 5.2.2.4. 
Additional pregnancy test can be performed during treatment period if required according to local regulations.
 


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9
Tumour assessments according to modified RECIST criteria (R12-1990) to be performed every 6 weeks starting 
from the time of the first pemetrexed / cisplatin administration irrespective of any delay in treatment courses, until 
progression of the tumour or initiation of any other anti-cancer therapy outside of current study. Imaging is 
acceptable +/- 1 week around the scheduled date. If patients continue on study treatment beyond progression, 
imaging should continue to be performed every 6 weeks. Imaging can be performed outside of scheduled 
timepoints if progression is suspected. Patients with stable brain metastases at trial entry must be evaluated at each 
imaging time point for assessment for brain metastases. See Section 5.1.2.1 for further details.
 
11
Nintedanib / placebo will be dispensed on Day 1 of each treatment cycle. 
12
Patient should start nintedanib / placebo in the morning of Day 1 of each treatment cycle and continue daily until 
Day 21 of the cycle. In case next visit is delayed, patient should continue taking daily treatment as instructed.
13
Check patient’s compliance with administration schedule for nintedanib / placebo, see Section 4.3.
14
See Section 6.2.3.2 for management of AEs ongoing at EoT.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
PHASE II FLOW CHARTS ..............................................................................5
PHASE III FLOW CHARTS.............................................................................9
TABLE OF CONTENTS ................................................................................ 14
ABBREVIATIONS.......................................................................................... 19
1.
INTRODUCTION.................................................................................... 22
1.1
MEDICAL BACKGROUND............................................................................22
1.2
DRUG PROFILE...............................................................................................23
1.2.1
Nintedanib (BIBF 1120) .......................................................................23
1.2.2
Pemetrexed ............................................................................................26
1.2.3
Cisplatin.................................................................................................27
1.2.4
Combination of nintedanib with pemetrexed.....................................27
1.2.5
Combination of nintedanib with cisplatin (+ gemcitabine)...............28
1.2.6
Combination of nintedanib with other compounds...........................28
1.2.7
Combination of nintedanib with pemetrexed and cisplatin..............29
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 30
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................30
2.2
TRIAL OBJECTIVES.......................................................................................31
2.3
BENEFIT - RISK ASSESSMENT ...................................................................31
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 33
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................33
3.1.1
Administrative structure of the trial...................................................35
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................37
3.3
SELECTION OF TRIAL POPULATION ......................................................37
3.3.1
Main diagnosis for study entry............................................................38
3.3.2
Inclusion criteria...................................................................................38
3.3.3
Exclusion criteria ..................................................................................38
3.3.4
Removal of patients from therapy or assessments.............................41
3.3.4.1
Removal of individual patients................................................41
3.3.4.2
Discontinuation of the trial by the sponsor..............................42
4.
TREATMENTS........................................................................................ 43
4.1
TREATMENTS TO BE ADMINISTERED....................................................43


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4.1.1
Identity of investigational and comparator products........................43
4.1.1.1
Nintedanib (investigational product) .......................................43
4.1.1.2
Placebo (comparator)...............................................................43
4.1.1.3
Non-investigational product.....................................................44
4.1.2
Method of assigning patients to treatment groups ............................44
4.1.3
Selection of doses in the trial................................................................44
4.1.4
Drug assignment and administration of doses for each patient .......45
4.1.4.1
Nintedanib (BIBF 1120) and placebo......................................45
4.1.4.2
Pemetrexed and cisplatin .........................................................45
4.1.4.3
Pre-medication Regimen..........................................................46
4.1.4.4
Re-treatment criteria for pemetrexed and cisplatin therapy.....46
4.1.4.5
Temporary treatment interruption of nintedanib / placebo......47
4.1.4.6
Re-treatment criteria for nintedanib / placebo .........................47
4.1.5
Blinding and procedures for unblinding ............................................48
4.1.5.1
Blinding....................................................................................48
4.1.5.2
Procedures for emergency unblinding .....................................49
4.1.6
Packaging, labelling, and re-supply ....................................................49
4.1.7
Storage conditions.................................................................................49
4.1.8
Drug accountability ..............................................................................49
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................50
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................51
4.2.1.1
Dose Reduction Recommendations.........................................51
4.2.1.2
Management of non-haematological toxicity ..........................51
4.2.1.2.1 Management of diarrhoea .......................................................51
4.2.1.2.2 Management of liver enzyme elevations ................................52
4.2.1.2.3 Management of nausea and vomiting .....................................53
4.2.1.2.4 Management of mucositis and rash.........................................54
4.2.1.2.5 Management of neurotoxicity.................................................54
4.2.1.3
Management of haematological toxicity..................................54
4.2.2
Restrictions............................................................................................55
4.2.2.1
Restrictions regarding concomitant treatment .........................55
4.2.2.2
Drug specific restrictions.........................................................56
4.3
TREATMENT COMPLIANCE.......................................................................56
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 57
5.1
EFFICACY.........................................................................................................57
5.1.1
Endpoints of efficacy.............................................................................57
5.1.2
Assessment of efficacy...........................................................................59
5.1.2.1
Tumour assessment by imaging...............................................59
5.1.2.1.1 Definitions...............................................................................60


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5.1.2.1.2 Evaluation of target lesions.....................................................62
5.1.2.1.3 Evaluation of non-target lesions..............................................62
5.1.2.1.4 Evaluation of overall response ................................................62
5.1.2.1.5 Progression of disease .............................................................63
5.2
SAFETY..............................................................................................................64
5.2.1
Endpoints of safety................................................................................64
5.2.2
Assessment of adverse events...............................................................64
5.2.2.1
Definitions of adverse events...................................................64
5.2.2.2
Protocol-specified adverse events of special interest (AESI)..66
5.2.2.3
Adverse event and serious adverse event reporting.................67
5.2.2.4
Pregnancy.................................................................................68
5.2.3
Assessment of safety laboratory parameters......................................68
5.2.4
Electrocardiogram................................................................................69
5.2.5
Assessment of other safety parameters...............................................70
5.2.5.1
Physical examination, height, weight, ECOG performance 
score.........................................................................................70
5.2.5.2
Vital signs ................................................................................70
5.3
OTHER...............................................................................................................70
5.3.1
Demographics and history ...................................................................70
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................72
 
6.
INVESTIGATIONAL PLAN.................................................................. 78
6.1
VISIT SCHEDULE............................................................................................78
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................78
6.2.1
Screening and run-in period ................................................................78
6.2.2
Treatment period ..................................................................................78


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6.2.3
End of trial and follow-up period........................................................79
6.2.3.1
End of Treatment (EoT) visit...................................................79
6.2.3.2
Follow-up visit.........................................................................79
6.2.3.3
Follow-up for progression........................................................80
6.2.3.4 Follow-up for OS (Phase II patients).......................................80
6.2.3.5 Follow-up for OS (Phase III patients)......................................80
6.2.3.6
End of trial ...............................................................................81
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 82
7.1
STATISTICAL DESIGN - MODEL................................................................82
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................82
7.3
PLANNED ANALYSES....................................................................................83
7.3.1
Primary analyses...................................................................................84
7.3.2
Secondary analyses ...............................................................................86
7.3.2.1 Overall Survival (key secondary endpoint) .............................86
7.3.2.4 Objective Tumour Response (Phase II and Phase III).............90
7.3.2.5 Disease Control (Phase II and Phase III) .................................91
7.3.3
Safety analyses.......................................................................................92
7.3.4
Interim analyses ....................................................................................93
7.4
HANDLING OF MISSING DATA ..................................................................94
7.5
RANDOMISATION ..........................................................................................96
7.6
DETERMINATION OF SAMPLE SIZE ........................................................96
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS .............................................................................................. 101
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ........................................................................................................101
8.2
DATA QUALITY ASSURANCE ...................................................................102
8.3
RECORDS........................................................................................................102
8.3.1
Source documents ...............................................................................102
8.3.2
Direct access to source data and documents.....................................102
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS............................................................................................................102


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8.4.1
Listedness.............................................................................................102
8.4.2
Expedited reporting to health authorities and IECs/IRBs..............103
8.5
STATEMENT OF CONFIDENTIALITY.....................................................103
8.6
COMPLETION OF TRIAL............................................................................103
9.
REFERENCES....................................................................................... 104
9.1
PUBLISHED REFERENCES.........................................................................104
9.2
UNPUBLISHED REFERENCES...................................................................109
10. APPENDICES ........................................................................................ 111
10.1
CLINICAL EVALUATION OF LIVER INJURY .......................................111
10.2
ECOG PERFORMANCE STATUS...............................................................111
11. DESCRIPTION OF GLOBAL AMENDMENTS............................... 117


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ABBREVIATIONS
5-HT3
AE
5-Hydroxy-Tryptamin Receptor 3
Adverse Event
AESI
ALP
Adverse Events of Special Interest
Alkaline Phosphatase
ALT
Alanine AminoTransferase
ANC
Absolute Neutrophil Count 
AST
Aspartate Aminotransferase
AUC
bFGF
Area Under the Curve
Basic Fibroblast Growth Factor
BI
b.i.d.
Boehringer Ingelheim
Twice a Day
BUN
Blood Urea Nitrogen
CA
Competent Authority
CI
Confidence Interval
CML
Clinical Monitor Local
CR
Complete Response
CRA
Clinical Research Associate
CRO
Contract Research Organisation
CRP
CT
CTCAE
C-Reactive Protein
Computed Tomography 
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CRT
Clinical Trial Report
DILI
DLT
Drug-Induced Liver Injury
Dose Limiting Toxicity
DMC
Data Monitoring Committee
DNA
ECG
ECOG
Deoxyribonucleic Acid
Electrocardiogram
Eastern Cooperative Oncology Group
eCRF 
Electronic Case Report Form
EORTC
European Organisation for Research and Treatment of Cancer
EDTA
EMA
EoT
EudraCT
Ethylene-Diamine-Tetra-Acetic Acid
European Medicines Agency
End of Treatment
European Clinical Trials Database
FDA
Food and Drug Administration 
FGFR
Fibroblast Growth Factor Receptor
FOLFOX
FOLinic acid, Fluorouracil and OXaliplatin 
FU
FVC
Follow Up
Forced Vital Capacity
GCP
Good Clinical Practice
GFR
γ-GT
GI
Glomerular Filtration Rate
Gamma-Glutamyl Transferase
Gastrointestinal


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HR
HRQoL
Hazard Ratio
Health Related Quality of Life
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
IEC
International Conference on Harmonisation
Independent Ethics Committee
IL-6
Interleukin-6
INN
INR
International Nonproprietary Name
International Normalised Ratio
IPF
Idiopathic Pulmonary Fibrosis
IRB
Institutional Review Board
ISF
Investigator Site File
i.v.
Intravenous
IVRS
Interactive Voice Response System
IWRS
Interactive Web-based Response System
LCSS
Lung Cancer Symptom Scale
LCSS-Meso
Lung Cancer Symptom Scale Mesothelioma
LDH
mFOLFOX6
MMRM
MPM
Lactate Dehydrogenase
Modified FOLFOX6
Mixed-effect Model with Repeated Measures
Malignant Pleural Mesothelioma
MRI
MTD
Magnetic Resonance Imaging
Maximum Tolerated Dose
NE
Not Evaluable
NSAID
Non-Steroidal Anti Inflammatory Drug
NSCLC
Non-Small Cell Lung Cancer
OPU
Operative Unit
OS
Overall Survival
PD
Progressive Disease
PDGF
Platelet-Derived Growth Factor
PDGFR
Platelet-Derived Growth Factor Receptor
PFS
Progression Free Survival
PFT
Pulmonary Function Test
PGx
PlGF
PK
PR
Pharmacogenomics
Placenta Growth Factor
Pharmacokinetic
Partial Response
PT
Prothrombin Time
PTT
Partial Thromboplastin Time 
RECIST
Response Evaluation Criteria In Solid Tumours
SAE
Serious Adverse Event
SD
Stable Disease
SOP
SMRP
SPC
Src
SUSAR
Standard Operating Procedures
Soluble Mesothelin-Related Peptide
Summary of Product Characteristics
Sarcoma Tyrosine Kinase
Suspected Unexpected Serious Adverse Reaction


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TCM
Trial Clinical Monitor
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
ULN
Upper Limit of Normal
UV
Ultraviolet
VAS
Visual Analogue Scale
VEGF
Vascular Endothelial Growth Factor
VEGF(-C)
Vascular Endothelial Growth Factor (-C)
VEGFR
Vascular Endothelial Growth Factor Receptor
WBC
White Blood Cell


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Mesothelioma is a rare malignant tumour originating from the cells lining the mesothelial 
surface of the coelomic cavities of the body. It is estimated to occur in about 2,500 people in 
the United States every year but its incidence continues to rise worldwide. MPM is the most 
common type of mesothelioma and typically originates from the lower parietal pleura and the 
costodiaphragmatic sinus. The disease is deadly and difficult to treat. Median OS is about 1 
year. MPM occurs primarily in older men (median age, 72 years). 
Chemotherapy is recommended either alone for medically inoperable patients with MPM or 
as part of a regimen for patients with medically operable MPM. A combined first-line 
regimen using cisplatin and pemetrexed is considered the gold standard for MPM and is 
currently the only regimen approved for mesothelioma. The results of the pivotal trial 
demonstrating the safety and efficacy of the pemetrexed / cisplatin showed significantly 
longer median OS (12.1 vs. 9.3 months, p = 0.02) and time to progression (6.1 vs. 3.9 
months, p = 0.008) for the pemetrexed / cisplatin arm compared with the cisplatin arm (R12-
2677).
Angiogenesis is involved in tumour growth and development of metastases. Proteins involved 
in regulating the angiogenic process such as vascular endothelial growth factor (VEGF) and
platelet-derived growth factor (PDGF) and their receptors have been implicated in the 
prognosis of MPM (R12-2651). The vascular endothelial growth factor receptor (VEGFR) is 
a receptor tyrosine kinase that is over-expressed in a variety of malignancies. The VEGF 
ligand and VEGF receptors have been shown to be co-expressed in MPM (R12-1928, R02-
0591). An inverse relationship has been found between VEGF expression and OS of MPM 
patients (R02-0591). Both VEGF and VEGF(-C) function as autocrine growth factors for the 
development of MPM and have been reported to be overexpressed in tissue samples from 
MPM patients and primary cultures derived from patient samples (R12-2676). VEGF-C is 
known to stimulate lymphatic vascular growth. A strong correlation has been reported 
between the expression of VEGF(-C), its receptor, VEGFR-3 (Flt-4), and microlymphatic 
vessel density in tissue samples from MPM patients (R12-1922). 
In addition to the antiangiogenic pathways, there are preclinical data suggesting a potential 
role of sarcoma tyrosine kinase (Src) as a potential target for the treatment of mesothelioma 
(R12-2652). Use of the Src-inhibitor dasatinib is being evaluated clinically (R12-2653).
The present trial is designed to evaluate the safety and efficacy of nintedanib in combination 
with standard pemetrexed / cisplatin followed by nintedanib versus placebo in combination 
with standard pemetrexed / cisplatin followed by placebo for the treatment of patients with 
unresectable MPM.


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1.2
DRUG PROFILE
1.2.1
Nintedanib (BIBF 1120)
Nintedanib is a potent, orally available triple kinase inhibitor specifically targeting VEGFR 
1-3, platelet-derived growth factor receptor (PDGFR) and β, and fibroblast growth factor 
receptor (FGFR) 1-3 (c01632700).
VEGFR-2 is considered the crucial receptor involved in initiation of the formation as well as 
the maintenance of tumour vasculature. The specific and simultaneous abrogation of these 
pathways results in effective growth inhibition of both endothelial and perivascular cells, 
which may be more effective than inhibition of endothelial cell growth alone, as achieved 
solely via disruption of the VEGF pathway. Furthermore, signalling by FGF-receptors has 
been identified as a possible escape mechanism for tumour angiogenesis when the VEGF 
pathway is disrupted (R08-4315, R08-5173).
In vivo experiments demonstrated anti-tumour efficacy of nintedanib, leading to a substantial 
delay of tumour growth or even complete tumour stasis in xenografts of a broad range of 
differing human tumour types, including non-small-cell lung cancer, ovarian cancer, renal 
cell carcinoma, colorectal cancer, and head and neck squamous cell carcinoma
Histological examination of treated tumours showed a marked reduction of tumour vessel 
density by approximately 80%. In vivo, the combination of nintedanib with docetaxel, 
pemetrexed or vinorelbine in xenografts showed clear anti-tumour efficacy with a 
tumour/control ratio of 30%, 23% and 124% at suboptimal dose levels with the single agents. 
In a xenograft model of human ovarian cancer using the SKOV-3 tumour line, nintedanib 
was active (tumour control ratio of 25% at 50 mg/kg daily) and the combination of low doses 
of nintedanib and cisplatin showed more than additive efficacy.
In addition preclinical models show that nintedanib may have a direct anti-tumour effect on 
those malignant cells which overexpress PDGFR and/or FGFR (e.g. H1703 Non-small cell 
lung cancer [NSCLC] cells).
Considering its anti-angiogenic mechanism of action, it is anticipated that treatment with 
nintedanib will slow tumour growth in human cancers. Moreover, tumour regression may 
also be achieved by induction of apoptosis of immature tumour vessels. In addition, a 
therapeutic effect may also result from inhibition of tumour autocrine and paracrine growth 
factor loops involving VEGF, PDGF and basic fibroblast growth factor (bFGF). It is likely 
that long-term treatment may be needed to ensure maximal clinical benefit.
Data from 4-week, 13-week, and 26-week toxicity studies in rats as well as 4-week, 13-week 
and 52-week toxicity studies in monkeys are available. Relevant histopathological findings in 
these studies were observed in the gastrointestinal (GI) tract, lymphatic tissues, kidneys, bone 
marrow, liver, extrahepatic bile duct, exocrine glands and the skin. Bone changes in growing 
animals (thickening of epiphyseal growth plate) were interpreted as a typical mechanism-
related toxicity associated with a VEGFR-2 inhibitor. Mild changes in haematological and 
clinical chemistry parameters (increases in gamma-glutamyl transferase [γ-GT], aldolase, 
alanine aminotransferase [ALT], aspartate aminotransferase [AST], leucine aminopeptidase 


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[LAP], glutamate dehydrogenase [GLDH]) were seen in rats. Minimal to slight changes in 
immunotoxicological parameters (T-cell antigen [CD4] count) and lymphoid tissues may 
correlate to the additional inhibition of Src family non-receptor tyrosine kinases such as 
lymphocyte specific protein kinase (lck) and lyn. Overall, the histopathological findings and 
changes of laboratory parameters were mild to moderate and generally confined to the high 
dose groups.
Nintedanib is non-mutagenic, even at high doses. One compound in a batch of potential 
degradation products that may be formed under systemic and/or acidic conditions was found 
to be weakly Ames positive at high concentration after metabolic activation, while a second 
batch of the same products was Ames negative. The compound was not found in any of the 
drug substance batches of nintedanib used and thus did not occur within the limits of 
detection. Further experiments (mouse lymphoma assay, micronucleus assay) indicated that 
the compound does not raise a safety concern for cancer patients.
Two exploratory studies in rats revealed a teratogenic effect of nintedanib with a steep 
dose/effect relationship and an early onset of embryofoetal deaths at low dosages. This effect 
was observed at dose levels resulting in plasma drug concentrations comparable to or below 
those in humans. Because the concentration of nintedanib in semen is unknown, males 
receiving nintedanib and having sexual intercourse with females of childbearing potential 
should use latex condoms.
The main metabolite of nintedanib was BIBF 1202 (25% in liver microsome preparations). 
Both nintedanib and BIBF 1202 were further glucuronidated to the corresponding 
glucuronide via the uridine diphosphate glucuronosyltransferase (UGT) 1A1 enzyme. In 
humans, 93.4% of total [14C] radioactivity was excreted in the faeces within 120 hours after 
oral administration of nintedanib. Only 0.7 % of total [14C] radioactivity was eliminated via 
the urine.
In experiments with human liver microsomes (U03-1386, U08-1256-01), no relevant 
inhibition of CYP450 isoenzymes was observed for nintedanib or its main metabolite BIBF 
1202. In animal experiments, no relevant changes of CYP450 enzymes were found to occur 
during treatment with nintedanib (U04-2195). 
Phase I dose selection studies revealed that nintedanib is generally well tolerated with mild to 
moderate adverse effects (U05-2191-01 and U06-1697).
The predominant AEs were nausea, diarrhoea, vomiting, abdominal pain and fatigue of 
mostly low to moderate intensity after monotherapy with nintedanib. Dose limiting toxicities 
were dose dependent hepatic enzyme elevations that were reversible after discontinuation of 
nintedanib treatment. 
These liver enzyme elevations were only in few cases accompanied by a simultaneous 
increase of bilirubin. In general, common terminology criteria for AEs (CTCAE) version 3.0, 
(R04-0474) grade three liver enzyme increases were reported in the dose groups of 250 mg 
twice daily or higher. They also were reversible and usually occurred within the first two 
months of treatment.


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Combination of nintedanib with other anti-cancer drugs revealed a similar AE profile as 
compared to nintedanib monotherapy except for the chemotherapy related toxicities. There 
was no change of the pharmacokinetic parameters of nintedanib or of the cytotoxic 
compounds due to the combined treatment. Dose limiting toxicity (DLT) consisted mostly of 
liver transaminase elevations as in the monotherapy Phase I trials with the exception of the 
combination of nintedanib with pemetrexed, where fatigue was the most relevant DLT. 
Hypertension or thromboembolic events were rare and did not suggest an increased frequency 
as a consequence of therapy with nintedanib.
All AEs observed in healthy volunteers after single administration of nintedanib were of 
CTCAE Grade 1 intensity and fully reversible.
Available pharmacokinetic data indicate that the systemic exposure required for biological 
activity can be achieved in cancer patients. Maximum plasma concentrations occurred mainly 
1 to 4 hours after administration. There was no deviation detected in dose proportionality in 
the pharmacokinetic state of nintedanib. The latest steady state was reached within 9 days of 
treatment. The geometric mean value (gMean) terminal half-life was between 7 to 19 hours. 
In the Phase I trials where nintedanib was combined with chemotherapeutic regimens, there 
was no change of the PK parameters of nintedanib or of the cytotoxic compounds due to the 
combined treatment.
Data from patients with advanced solid tumours demonstrate a pharmacodynamic effect of 
nintedanib treatment on selected tumour lesions as shown by dynamic contrast-enhanced 
magnetic resonance imaging (MRI). Based on pharmacokinetic analysis, a sufficient systemic 
exposure for biologic activity was observed in these advanced cancer patients.
A randomised Phase II maintenance trial in ovarian cancer in which the efficacy and safety of 
nine months of continuous twice daily doses of nintedanib following chemotherapy was 
investigated, has identified the potential activity of nintedanib with a 36-week PFS of 14.3 % 
compared to 5.0 % in the control group. The safety profile was consistent with findings 
previously reported for nintedanib administered as monotherapy as mentioned above (P09-
08422). Nintedanib (Vargatef ®), in combination with docetaxel, was granted marketing 
authorization by the European Medicines Agency (EMA) for the treatment of adult patients 
with locally advanced, metastatic or locally recurrent NSCLC of adenocarcinoma tumour 
histology after first‑line chemotherapy. In addition, the Food and Drug Administration 
(FDA) granted a marketing authorization for nintedanib in patients with idiopathic pulmonary 
fibrosis (IPF).
The European marketing authorization was based on the data from the LUME LUNG 1 trial. 
LUME-Lung 1 was an international, randomised, double-blind, phase III trial assessing the 
efficacy and safety of docetaxel plus nintedanib as second line therapy for NSCLC. In total, 
1314 patients with Stage IIIB/IV or recurrent NSCLC (all histologies) who had progressed 
after 1st line chemotherapy were randomised in 1:1 fashion to either receive nintedanib 
200mg twice a day (b.i.d.) + docetaxel (n=655) or Placebo b.i.d. + docetaxel (n=659). 
LUME-Lung 1 showed a significant and clinically meaningful improvement in OS in patients 
with adenocarcinoma (HR 0.83, p=0.0359, median 10.3 to 12.6 months) (P14-00479).


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Grade 3 or worse AEs that were more common in the docetaxel plus nintedanib group than in 
the docetaxel plus placebo group were diarrhoea (43 [6·6%] of 652 vs 17 [2·6%] of 655), 
reversible increases in ALT (51 [7·8%] vs six [0·9%]), and reversible increases in AST (22 
[3·4%] vs three [0·5%]).
In the studies investigating the monotherapy with nintedanib, the predominant AEs were 
nausea, diarrhoea, vomiting, abdominal pain, fatigue and reversible liver enzyme elevation of 
mostly low to moderate intensity.
 
 
Overall in Phase I and II monotherapy studies, the pattern of AEs was similar with 
gastrointestinal AEs as the most frequent events. The majority of CTCAE Grade 3 liver 
enzymes increases were reported in the higher dose group of 250 mg b.i.d. in Phase II trials. 
Overall in the Phase I and II studies, ALT increases were generally more frequent than AST 
increases. In patients with advanced NSCLC, nintedanib showed comparable signs of 
efficacy in ECOG 0-1 patients compared to historical data of other VEGFR inhibitors in a 
similar patient population. 
In summary, based on the available preclinical and clinical data, nintedanib displays a 
manageable safety profile and signal of efficacy in various tumour types. The observed AEs
are considered manageable in the context of the therapeutic area. Efficacy data of Phase I to 
III trials indicate that patients with advanced solid tumours may benefit from therapy with 
nintedanib either as component in a combination treatment with standard chemotherapy or as 
monotherapy. 
For more details please refer to the Investigator’s Brochures (IB) (c01632700).
1.2.2
Pemetrexed
Pemetrexed is an antifolate agent which inhibits folate-dependent enzymes in both the 
thymidylate and purine synthetic pathways essential for DNA nucleotide synthesis required 
for cell division. Pemetrexed gains entry into the cell through the reduced folate carrier, 
where it is polyglutamated, thereby enhancing its intracellular retention. Three folate 
dependent enzymatic pathways, thymidylate synthetase, dihydrofolate reductase, and 
glycinamide ribonucleotide formyltransferase, necessary for purine and pyrimidine synthesis 
are inhibited, resulting in cytotoxicity and cell death (R05-1060).
The toxicity profile of pemetrexed when used as a single agent includes neutropenia, 
thrombocytopenia, mucositis, fatigue, diarrhoea, rash and/or anorexia. Additional side effects 
include asthenia, pedal oedema and decreased creatinine clearance (R05-1061). Drug related 
bone marrow suppression and mucositis associated with decreased folate levels can be 
prevented by supplementation of patients with folic acid prior to the first pemetrexed dose 


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and continued daily through the 21-day treatment cycle and by administration of vitamin B12 
one week prior to therapy, repeated every 3 cycles while on therapy. 
Pemetrexed in combination with cisplatin is the approved standard of care chemotherapy 
treatment for patients with unresectable MPM.
1.2.3
Cisplatin
Cisplatin was first synthesised in the nineteenth century and was approved by US FDA for 
the clinical use of ovarian and testicular cancer treatment in 1978. Cisplatin is a platinum-
based chemotherapy agent used either as a single agent or in combination with other 
chemotherapies to treat various types of cancers, including sarcomas, some carcinomas (e.g. 
small cell lung cancer, and ovarian cancer), lymphomas and germ cell tumours. Cisplatin is 
also used for treatment of mesothelioma. It was the first member of a class of platinum-based 
anti-cancer drugs which now also includes carboplatin and oxaliplatin. These platinum 
complexes act during all parts of the cell cycle and impair DNA synthesis which ultimately 
triggers apoptosis (programmed cell death).
Side effects of cisplatin include nausea, vomiting, nephrotoxicity, neurotoxicity, ototoxicity, 
alopecia, electrolyte imbalance, decrease of blood cells in bone marrow, thrombocytopenia, 
leucopenia, myelosuppression, dysgeusia, diarrhoea and fatigue. The toxicity of cisplatin 
probably results from the formation of lesions that block polymerases or disrupt the integrity 
of the genome. The side effects are generally reversible and subside when treatment ends. 
However, renal toxicity is cumulative and can result in complications months after treatment 
ends. Myelosuppression also accumulates over the course of the treatment but it subsides 
with the end of treatment.
Cisplatin in combination with pemetrexed is the approved standard of care chemotherapy 
treatment for first-line treatment of unresectable MPM.
1.2.4
Combination of nintedanib with pemetrexed
Pemetrexed 
An open label Phase I study (U08-3886-01) was conducted to determine the maximum-
tolerated dose (MTD) using a standard 3+3 dose escalation design in patients with recurrent 
NSCLC, who had been treated with one prior platinum based chemotherapy regimen. Patients 
received standard dose pemetrexed (500 mg/m2) on day 1 of a 21-day cycle and nintedanib 
twice a day (b.i.d.) on Days 2 to 21. A total of 26 patients (13 male, 13 female, median age 
61.5 years, range 36-81, ECOG performance status of 0-1) entered the trial, 24 patients 
concluded at least the first treatment course. In this trial nintedanib was escalated from 100 to 
250 mg administered twice daily. The MTD was determined to be 200 mg orally b.i.d. 
Fatigue Grade 3 represented the most common DLT in the first treatment course and all 
courses overall. Almost all AEs were fully reversible and mostly of low to moderate intensity 
(CTCAE Grade 1 and 2) irrespective of the dose. There were no CTCAE grade 4 toxicities 
observed. At the DLT determining dose of nintedanib given as 250 mg b.i.d. among 2 
patients, one episode each of Grade 3 fatigue, Grade 3 ALT elevation and Grade 3 
oesophageal pain occurred. Looking at all courses of therapy at the MTD dose of 200 mg 


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b.i.d. nintedanib a total of 5 of 12 patients had drug related CTCAE Grade 3 toxicity: fatigue: 
(25%), anorexia (16.7%), diarrhoea (8.3%), ALT elevation (8.3%), insomnia (8.3%). Below 
the MTD at the 150 mg bid dose a total of 6 patients were treated. One patient had Grade 3 
fatigue and one patient had Grade 3 fatigue and Grade 3 nausea and vomiting. The 
relationship of fatigue to therapy with nintedanib is uncertain in the former patient as there 
was no recovery from fatigue more than 1 year after therapy discontinuation. In the 
nintedanib cohort of 100 mg b.i.d. one of six patients showed ALT and AST increases of 
CTCAE Grade 3 during the first treatment course. This patient was known to be infected with 
hepatitis C. The frequency of Grade 3 liver enzyme elevation for the combination of 
nintedanib and pemetrexed was low and did not suggest an increased incidence compared to 
historical pemetrexed data.  For further listing of all AEs please see the IB (c01632700).
1.2.5
Combination of nintedanib with cisplatin (+ gemcitabine)
Cisplatin (+ gemcitabine)
A Phase I/II study evaluated the combination of nintedanib with cisplatin and gemcitabine for 
the treatment of squamous-cell NSCLC patients. During the initial phase of the study patients 
were enrolled in a 3+3 design. The dose of nintedanib was administered on days 2 – 21 of 
each cycle starting at 150 mg b.i.d. in the first cohort of patients and, if no DLTs were
observed, was escalated to a maximum dose of 200 mg b.i.d. for the second cohort. The MTD 
for nintedanib was 200 mg bid when used in combination with cisplatin (75 mg/m2) + 
gemcitabine (1250 mg/m2). The continuous bid dosing of 200 mg nintedanib with 
cisplatin/gemcitabine combination was found to be tolerable, and PK data demonstrated no 
interaction. The triplet showed promising antitumour activity for 1st-line treatment of patients 
with advanced sqNSCLC (M15-0007).
1.2.6
Combination of nintedanib with other compounds 
Carboplatin (+ paclitaxel)
The combination of nintedanib with carboplatin / paclitaxel was evaluated in two Phase I 
studies. The first study was conducted with paclitaxel (200 mg/m2), carboplatin (AUC 6) and 
nintedanib (doses 50 – 250 mg b.i.d continuous except on the day of chemotherapy 
administration) in 26 previously untreated patients with advanced stage NSCLC. The MTD 
of nintedanib in combination with carboplatin AUC 6 and paclitaxel 200 mg/m2 was 
determined to be 200 mg b.i.d. (U08-3890-01).
The second study was conducted with paclitaxel (175 mg/m2), carboplatin (AUC 5) and 
nintedanib (doses 100 – 250 mg b.i.d. continuous except on the day of chemotherapy 
administration), in 22 patients with advanced gynaecological malignancies. The MTD of 
nintedanib in combination with carboplatin AUC 5 and paclitaxel 175 mg/m2 was determined 
to be 200 mg b.i.d. (U08-1000-02).
Oxaliplatin (mFOLFOX6)
A Phase I/II study evaluated the combination of nintedanib with modified FOLFOX6
(mFOLFOX6) compared to bevacizumab in combination with mFOLFOX6 in first line 
metastatic colorectal cancer patients. The nintedanib recommended phase II dose was 200 mg 


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b.i.d. plus mFOLFOX6 based on safety data from phase I (n = 12). Of 128 patients 
randomised in the phase II part of the study, 126 received treatment (nintedanib plus 
mFOLFOX6, n = 85; bevacizumab plus mFOLFOX6, n = 41). PFS at 9 months was 62.1% 
with nintedanib and 70.2% with bevacizumab [difference: −8.1% (95% confidence interval
(CI) −27.8 to 11.5)]. Confirmed objective responses were recorded in 63.5% and 56.1% of 
patients in the nintedanib and bevacizumab groups, respectively. The incidence of AEs 
considered related to treatment was 98.8% with nintedanib and 97.6% with bevacizumab; the 
incidence of serious AEs was 37.6% with nintedanib and 53.7% with bevacizumab. The PK 
of nintedanib and the components of mFOLFOX6 were unaffected by their combination.
Nintedanib in combination with mFOLFOX6 showed efficacy as first-line therapy in patients 
with metastatic colorectal cancer with a manageable safety profile and further studies in this 
population are warranted (U12-2578-03).
Docetaxel (+ prednisone)
Twenty-one patients with hormone-refractory prostate cancer were included in this dose 
escalation trial assessing the combination of continuous oral nintedanib (dose escalation from 
100 mg b.i.d. to 250 mg b.i.d. administration daily except on the days of chemotherapy 
infusion) with docetaxel (75 mg/m2) and prednisone (5 mg b.i.d.) (U08-1273-02).
No DLTs were observed ≤ 200 mg b.i.d. of nintedanib. Only one patient was considered to 
have developed a DLT at the highest dose level of 250 mg b.i.d. (reversible ALT and γ-GT 
increase of CTCAE grade 3) during the first course. Therefore, the formal MTD as per 
protocol was 250 mg b.i.d. of nintedanib in combination with docetaxel (75 mg/m2). 
However, based on the frequency of clinically significant increases of liver laboratory values 
of 6/12 patients (50%) at the MTD versus 0/9 patients at the doses below the MTD, 200 mg 
b.i.d. nintedanib should be the recommended dose for further trials investigating the 
combination of nintedanib with docetaxel.
1.2.7
Combination of nintedanib with pemetrexed and cisplatin
 
 
The most commonly reported drug-related AEs in the placebo arm were nausea (75.6%), 
vomiting (39.0%), and fatigue (34.1%); in the nintedanib arm, the most frequently reported 
drug-related AEs were nausea (70.5%), diarrhoea (54.5%), and vomiting (43.2%). AEs 
requiring dose reduction were reported for 14.6% of patients in the placebo arm and 31.8% of 
patients in the nintedanib arm. AEs leading to permanent discontinuation of last study 
medication were reported for 14.6% (placebo) and 6.8% (nintedanib) of patients.
 
 


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
The treatment of MPM remains a major challenge. A combined first-line regimen using 
pemetrexed /cisplatin is considered the gold standard with a median OS of approximately one 
year. Therefore, there is still an urgent need to find innovative treatments for this rare disease.
Proteins involved in regulating the angiogenic process such as VEGF and PDGF and their 
receptors have been implicated in the prognosis of MPM (R12-2651). The vascular 
endothelial growth factor receptor (VEGFR) is a receptor tyrosine kinase that is over-
expressed in a variety of malignancies. The VEGF ligand and VEGF receptors have been 
shown to be co-expressed in MPM (R12-1928, R02-0591). An inverse relationship has been 
found between VEGF expression and OS of MPM patients (R02-0591). Both VEGF and 
VEGFC function as autocrine growth factors for the development of MPM and have been 
reported to be overexpressed in tissue samples from MPM patients and primary cultures 
derived from patient samples (R12-2676). VEGF-C is known to stimulate lymphatic vascular 
growth. A strong correlation has been reported between the expression of VEGF-C, its 
receptor, VEGFR-3 (Flt-4) and microlymphatic vessel density in tissue samples from MPM 
patients (R12-1922). 
Nintedanib exerts migration and proliferation inhibition in MPM cells in vitro and prolongs 
survival in an orthotopic xenograft model (M15-0005)
Bevacizumab, a monoclonal antibody against VEGF (R12-1922) and several small molecule 
inhibitors of the VEGF receptor tyrosine kinase (sorafenib [R12-1923], vatalanib [R12-1933), 
sunitinib [R12-1926], cediranib and pazopanib) have been tested in Phase II studies in first-
line and second-line settings primarily as monotherapy, except for bevacizumab which is 
being evaluated in combination with chemotherapy. Bevacizumab is specific for VEGF but it 
does not neutralize other members of the VEGF family including VEGF-C (R10-4862). The 
other agents are multikinase inhibitors but have not been evaluated in combination with 
standard chemotherapy in MPM.
Proof of efficacy of the inhibition of VEGF pathway was demonstrated in the MAPS trial 
investigating the combination of bevacizumab, pemetrexed and cisplatin versus pemetrexed 
and cisplatin. OS was significantly longer in the bevacizumab arm (median: 18.8 months, 
95%CI[15.9-22.6] vs. 16.1 months, 95%CI[14.0-17.9] for the reference arm, (adj.HR = 0.76, 
95%CI[0.61; 0.94], p = 0.012). Median PFS was 9.6 months, 95%CI[8.5-10.6] in 
bevacizumab arm vs. 7.5 months, 95%CI[6.8-8.1] (adj.HR = 0.62, 95%CI[0.50-0.75], p < 
0.0001). Though grade 3/4 hematological toxicities did not significantly differ in the two 
arms (49.5% vs. 47.3%) , there were significantly more grade 3 proteinuria (0.0 vs. 3.1%), 
grade 3 hypertension (0.0 vs. 23%), grade 3/4 arterial thrombotic events (0.0 vs. 2.7%) 
observed in bevacizumab arm (R15-4440).
Nintedanib is a tyrosine kinase inhibitor that can be combined with chemotherapy (see 
Section 1.2.4). It has been proposed that coadministration of angiogenesis inhibitors and 
chemotherapy acts to improve delivery of small molecules, such as chemotherapy, to the 


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tumour (R12-2690). In as much as all three major components of pro-angiogenic signalling 
are inhibited (VEGFR 1-3, PDGFR and β and FGFR 1-3 (c01632700), nintedanib offers a 
particularly wide spectrum of activity.  Its potent activity against VEGFR-3, the receptor for 
VEGF-C, makes it a strong candidate for evaluation in MPM. In addition, nintedanib shows 
in vitro inhibitory activity against Src and Abl signalling proteins. In light of exploratory 
studies with other molecules that inhibit Src, it would be of interest to see if this pathway 
contributes to the effect of nintedanib in MPM.
The present study was initiated as an exploratory Phase II study and has been amended as a 
confirmatory study (based on data monitoring committee [DMC] recommendation) by adding 
a confirmatory Phase III part. In addition, as noted above in Section 1.2.7, the data from the 
87 Phase II patients were unblinded and analyzed (data on file). Based on these results, the 
population to be studied in the Phase III part of the study will be limited to patients with
unresectable MPM of epithelioid histology to evaluate the efficacy and safety of nintedanib 
versus placebo when added to pemetrexed/cisplatin.
2.2
TRIAL OBJECTIVES
The primary objective of the randomised, parallel-controlled Phase II/III study is to evaluate 
the safety and efficacy in terms of progression-free survival of nintedanib + pemetrexed / 
cisplatin followed by nintedanib (arm A) versus placebo + pemetrexed / cisplatin followed by 
placebo (arm B), as first line treatment for patients with unresectable MPM. 
The key secondary objective is to evaluate OS in patients treated with the nintedanib regimen 
(arm A) versus the placebo regimen (arm B). Further secondary objectives are to evaluate the 
objective tumour response rate and to evaluate the disease control rate.
 
 
 
 
 
2.3
BENEFIT - RISK ASSESSMENT
In this randomised Phase II/III study, all patients will receive the standard of care therapy 
regimen (pemetrexed+cisplatin) approved for the treatment of patients with unresectable 
MPM – the target patient population. The addition of the orally bioavailable agent nintedanib 
to this regimen, offers the opportunity to evaluate the potential benefit of antiangiogenic 
treatment in combination with standard chemotherapy. Furthermore, the study will evaluate 
whether there may be potential additive benefit to continuing treatment with nintedanib after 
completion of the chemotherapy treatment.
Antiangiogenic treatment with the orally available triple angiokinase inhibitor nintedanib
offers the chance to control both locally recurrent and distant metastatic disease on an 
outpatient basis. Treatment with nintedanib may have the potential to provide significant 
benefit to patients with unresectable MPM by slowing tumour progression and metastasis, 
since its cellular target is expressed on the tumour vasculature in most malignancies.


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Induction of endothelial cell apoptosis may result in subsequent degradation of tumour 
vessels and subsequent tumour necrosis. 
In addition to these known targets, nintedanib has demonstrated preclinical activity against 
Src and Abl tyrosine kinases. These intracellular, non-receptor kinases have been implicated 
in the pathogenesis of MPM and therefore are potential additional targets for the activity of 
nintedanib in this disease. 
The risks of antiangiogenic therapy with nintedanib in adult patients are primarily related to:

the gastro-intestinal tract (nausea, vomiting, diarrhoea, abdominal pain) 

increases in liver enzymes (AST, ALT, γ-GT)

fatigue, asthenia and anorexia 
Liver enzymes must be followed closely during treatment with nintedanib. Although rare, a 
potential for drug-induced liver injury is under constant surveillance by sponsors and 
regulators. Therefore, this study requires timely detection, evaluation, and follow-up of 
laboratory alterations of selected liver laboratory parameters to ensure patients´ safety.
Therapy with the trial drugs must be interrupted in the event of relevant hepatic toxicity and 
further treatment is to be withheld until recovery of the abnormal laboratory parameters. The 
respective dose reduction schemes should be followed (see Section 4.2.1.2.2). 
Impairment of immune and of kidney function, thromboembolic events and GI perforations 
and increases in blood pressure are considered potential class-side effects of angiogenesis 
inhibitors as they have been reported for some other drugs in the class of angiogenesis 
inhibitors. Thus far these side effects have not been observed to a relevant degree in the trials 
conducted with nintedanib. 
The major clinical side effects observed after therapy with pemetrexed and cisplatin are 
distinct from nintedanib induced AEs, yet some overlap may occur e.g. regarding mild GI
toxicity or hepatotoxicity (please refer to the current local Summary of Product 
Characteristics (SPC) included in the investigator site file (ISF) for listed AEs). In view of the 
low potential for drug-drug interactions of nintedanib, it is not likely that enhanced toxicity 
due to pharmacokinetic interaction between the drug and the cytotoxic chemotherapy will 
occur. Due to the partially overlapping GI side effect profile, the occurrence of nausea, 
vomiting, diarrhoea and fatigue may be increased.
The DMC has raised no safety concerns and have recommended expanding from a Phase II 
exploratory trial to a Phase III confirmatory trial. Based on the results of the Phase II 
analysis, as described in Sections 1.2.7, 2.1 and 3.1, the benefit-risk assessment for this trial 
is considered positive.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The trial is designed as an international, multicentre, randomised, double-blind, placebo-
controlled, two-arm study to evaluate the efficacy and safety profile of nintedanib + 
pemetrexed / cisplatin followed by nintedanib monotherapy (Arm A), in comparison with a 
matching placebo + pemetrexed / cisplatin followed by placebo monotherapy (Arm B) until 
disease progression, in patients with histologically confirmed, unresectable MPM. A graphic 
illustration of the study designs for Phase II and Phase III are shown below.
Figure 3.1: 1
Illustration of study design for Phase II part
Figure 3.1: 2
Illustration of study design for Phase III part


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All patients randomised as of 08-Dec-2014 will be considered Phase II patients and all 
patients randomised after 08-Dec-2014 will be considered Phase III patients. A total of 87
Phase II patients were randomised in this trial in a 1:1 ratio to receive either Arm A or Arm B
treatment in a parallel group study design. Randomisation was stratified for epithelioid versus
biphasic histology for the Phase II part. No stratification will be used for the Phase III part of 
this trial.
 
 
 
 
The trial will continue with randomising 450 additional patients (otherwise referred to as 
Phase III patients) of epithelioid tumour histology. All Phase III patients will be randomised 
in a 1:1 ratio to receive either Arm A or Arm B treatment in a parallel group study design. 
The primary PFS analysis will be conducted after approximately 199 PFS events of the Phase 
III patients have occurred. 
1. If PFS is positive and significant, an interim OS analysis will be conducted.

If OS is positive and statistically significant (based on a hierarchical testing 
procedure), the trial will be declared positive for the primary and key secondary 
endpoint, and enrolment into the trial will be stopped.

If OS is not yet statistically significant, the DMC will adjust the number of OS 
events needed for the primary OS analysis of Phase III.
2. If PFS is not statistically significant, the trial will be declared negative, and enrolment 
into this trial will be stopped.
The primary PFS analysis and interim OS analysis for the Phase III part is expected to occur 
approximately 23 months after the start of enrolment into the Phase III part of the study. At 
the time of these analyses, it is expected that recruitment into the Phase III part will still be 
ongoing.
A graphical illustration of the trial design as well as of the enrolment and follow-up periods 
and of the calendar time points can be found in Figure 3.1: 3.


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Figure 3.1: 3
Illustration of study analyses of the Phase III part
Pemetrexed / cisplatin will be administered at standard doses of 500 mg/m2 and 75 mg/ m2
respectively. Nintedanib / placebo will be administered at a starting dose of 200 mg twice 
daily. Safety will be monitored on a continuous basis throughout the study. In the event of 
treatment-limiting AEs, dose delay and dose reduction criteria are provided in Section 4.2.1.
Patients will be evaluated for eligibility to receive study drug prior to initiation of each 
treatment cycle (see Sections 4.1.4.4; 4.1.4.5 and 6.2.2).
The trial will comprise four periods:

Screening period (up to 2 weeks): During this period the investigators will screen the 
patient’s eligibility.

Combination chemotherapy period (maximum of 6 cycles): A total of 537 patients (all 
Phase II and Phase III patients) will be randomised to receive treatment with either 
nintedanib + pemetrexed / cisplatin (Arm A) or placebo + pemetrexed / cisplatin (Arm B). 

Monotherapy period: Once the treatment of pemetrexed / cisplatin is discontinued at the 
end of cycle 6 or earlier if necessary, patients who have not experienced disease 
progression will continue to receive nintedanib monotherapy (Arm A) or placebo 
monotherapy (Arm B) until disease progression.

End of Treatment and Follow-up period: All patients will attend an EoT visit when 
they discontinue study treatment permanently. All patients will then return for the first 
follow-up visit ≥28 days after end of study treatment for Phase II patients and ≥30 days 
for Phase III patients. Patients who do not discontinue due to PD will be followed for 
unequivocal progression every 6 weeks (follow-up for PD) and those who discontinue 
due to unequivocal PD will be followed up for survival every 12 weeks (follow-up for 
OS). Please find more details in Section 6.2.
3.1.1
Administrative structure of the trial
Boehringer Ingelheim (BI) has appointed a Trial Clinical Monitor (TCM), responsible for 
coordinating the activities required in order to manage the trial in accordance with applicable 
regulations and internal standard operating procedures (SOPs), directing the clinical trial 
team in the preparation, conduct, and reporting of the study, and ensuring appropriate training 
and information for Clinical Monitors Local (CMLs), Clinical Research Associates (CRAs), 
and investigators of participating countries.


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The organisation of the study in the participating countries will be performed by the 
respective local BI-organisation Operative Unit (OPU) or a by a Contract Research 
Organisation (CRO) with which the responsibilities and tasks have been agreed and a written 
contract filed before initiation of the clinical study. In each OPU participating in this study, a 
CML will be appointed responsible for coordinating the activities required in order to manage 
the study in accordance with applicable regulations and internal SOPs in the countries 
covered by the respective BI OPU.
The co-ordinating investigator, who will sign the clinical trial report of this trial, has been
appointed by BI. The co-ordinating investigator has experience in this type of trial and 
investigations.
 
 
 
 
 
 
 
 
 
Further DMC reviews will be performed as required according to the DMC charter (for 
details, see Section 7.3.4).
Tumour images evaluated according to modified RECIST criteria (R12-1990) for disease 
progression and response to treatment will be assessed at regular intervals at the investigator 
sites by the investigators experienced in the evaluation of MPM. The tumour measurements 
and clinical assessment will be recorded in the eCRF and will be used for clinical decisions 
on whether or not patient should continue study treatment. 
 
The safety laboratory investigations will be performed at local laboratories associated with 
the sites and no central laboratory will be used for this purpose. The certification for each 
laboratory or evidence that it participates in an established quality program must be provided 
by the investigator and filed at the Sponsor and the local ISF of the site. 


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An Interactive Voice Response System (IVRS) or Interactive Web-based Response System 
(IWRS) will be provided by a CRO/vendor. Details will be provided in the IVRS/IWRS
manual available in the ISF.
An ISF containing all relevant study related documentation will be maintained according to 
local regulations and BI-SOPs at each study site. A copy of the ISF documents will also be 
kept as an electronic trial master file (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
Nintedanib has been successfully co-administered with various classes of chemotherapeutic 
drugs. These studies revealed that continuous treatment with 200 mg b.i.d. of nintedanib is 
the recommended dose for the combination of nintedanib with docetaxel, pemetrexed, 
paclitaxel/carboplatin or folinic acid, fluorouracil and oxaliplatin (FOLFOX) (see Section 
1.2.6). The combination regimen of pemetrexed / cisplatin has been selected as the 
background therapy because it is established as the approved standard of care for the 
treatment of patients with unresectable MPM. The safety and efficacy of nintedanib in 
combination with pemetrexed / cisplatin will be evaluated in comparison to the standard of 
care chemotherapy regimen pemetrexed / cisplatin combined with matching placebo. 
Furthermore, patients who do not exhibit evidence of progressive disease after completion of 
the combination regimen will continue treatment with the investigational agent 
(nintedanib/placebo) to evaluate whether they may derive additional benefit. Patients will be 
stratified by histology (epithelioid vs. biphasic) to balance any potential effect of this baseline 
variable on efficacy.
Patients will continue trial treatment until disease progression as confirmed by imaging. 
However, in case of clinical benefit as judged by the investigator after careful clinical 
assessment, patients may be allowed to continue study treatment beyond radiological 
progression as defined by modified RECIST criteria (R12-1990). Patients who continue 
beyond radiological progression will follow the trial schedule (see the flow charts), including 
the imaging and clinical tumour evaluations. Trial treatment may be continued as long as 
judged beneficial by the investigator; however, the time of progression will not change if it 
was decided to continue the treatment.  The decision to continue study treatment should be 
discussed with the sponsor and documented in the study records.
3.3
SELECTION OF TRIAL POPULATION
A total of 537 patients will be entered into the trial (87 Phase II and 450 Phase III patients)
from approximately 27 countries and 140 sites. A log of all patients included into the study 
(i.e. having given informed consent) will be maintained in the ISF at the investigational site
irrespective of whether they commenced trial drug.


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3.3.1
Main diagnosis for study entry
Adult patients with unresectable MPM can be entered into this trial. The ECOG performance 
score must be 0 or 1.
3.3.2
Inclusion criteria
1. Male or female patients age 18 years or older
2. Histologically confirmed MPM:
a) Epithelioid or biphasic subtype (Phase II patients)
b) Epithelioid subtype only (Phase III patients)
3. Life expectancy of at least 3 months in the opinion of the investigator
4. ECOG score of 0 or 1
5. Measurable disease according to modified RECIST criteria (R12-1990)
6. Signed and dated written informed consent prior to admission to the study in 
accordance with ICH-GCP guidelines and the local legislation
3.3.3
Exclusion criteria
1. Previous systemic chemotherapy for MPM 
2. Prior treatment with nintedanib or any other prior line of therapy
3. Patients with:
a) Sarcomatoid subtype MPM (Phase II patients)
b) Sarcomatoid and biphasic subtype MPM (Phase III patients)
4. Patients with symptomatic neuropathy 
5. Patients with mild to moderate renal insufficiency (creatinine clearance of 60-79 
mL/minute) taking Non-steroidal Anti Inflammatory Drugs (NSAIDs) with short half 
lives unable or unwilling to interrupt NSAIDs for 5 days (2 days before, day of and 2 
days after treatment with pemetrexed) 
6. Patients with mild to moderate renal insufficiency (creatinine clearance of 60-79 
mL/minute) taking NSAIDs with long half lives unable or unwilling to interrupt 
NSAIDs for 8 days (5 days before, day of and 2 days after treatment with pemetrexed)
7. Known hypersensitivity or any contraindications to the trial drugs, including 
pemetrexed/cisplatin, to their excipients or to contrast media


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8. Radiotherapy (except extremities) within 3 months prior to baseline imaging
(localised radiotherapy treatment for symptomatic relief is allowed if occurred at least 
2 weeks before randomisation and the measurable disease is outside of the field of 
radiotherapy; radiotherapy of the scars post thoracoscopy is allowed)
9. In opinion of the investigator, persistence of clinically relevant therapy related 
toxicity from previous radiotherapy
10. Patients that may be eligible for or being considered for radical resection or elective 
surgery during the course of the study. Note: prior surgery is allowed if occurred at 
least 4 weeks prior to randomisation, there is complete healing and there is residual 
measurable disease
11. Radical surgery within 4 weeks prior to randomisation 
12. Active brain metastases (e.g. stable for < 4 weeks, no adequate previous treatment 
with radiotherapy, symptomatic, requiring treatment with anti-convulsants; 
dexamethasone therapy will be allowed if administered as stable dose for at least one 
month before randomisation)
13. Leptomeningeal disease 
14. Radiographic evidence (CT or MRI) of cavitary or necrotic tumours or local invasion 
of major blood vessels by MPM
15. Treatment with other investigational drugs or treatment in another clinical trial within 
the past 4 weeks before randomisation or concomitantly with the trial
16. Therapeutic anticoagulation (except low-dose heparin and/or heparin flush as needed 
for maintenance of an in-dwelling intravenous devise) or anti-platelet therapy (except 
for low-dose therapy with acetylsalicylic acid < 325 mg per day
17. Major injuries within the past 4 weeks prior to randomisation with incomplete wound 
healing 
18. History of clinically significant haemorrhagic or thromboembolic event within 6 
months of screening
19. Known inherited predisposition to bleeding or thrombosis
20. Significant cardiovascular diseases (i.e. hypertension not controlled by medication, 
unstable angina, history of myocardial infarction within the past 12 months prior to 
randomisation, congestive heart failure > NYHA II, serious cardiac arrhythmia, 
pericardial effusion)
21. Proteinuria ≥ CTCAE Grade 2 (if 24 hour urine is collected > 1.0 g/24 hrs)
22. Total bilirubin above the upper limit of normal


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23. ALT and/or AST > 1.5 x ULN in patients without liver metastasis 
ALT and/or AST > 2.5 x ULN in patients with liver metastasis 
24. International normalised ratio (INR) > 2 
25. Prothrombin time (PT) and/or partial thromboplastin time (PTT) > 50% deviation 
from institutional ULN
26. Absolute neutrophil count (ANC) < 1,500/l (1.5x109/L)
27. Platelets < 100,000/l (100x109/L)
28. Haemoglobin < 9.0 g/dl or requiring transfusions
29. Creatinine clearance <60 mL/min (using the standard Cockcroft and Gault formula 
(below) or Glomerular Filtration Rate (GFR) measured by Tc99m-DPTA serum 
clearance method:
Males: 
[140 – Age in years] × Actual Body Weight (kg) – mL/min
72 × Serum Creatinine (mg/dL) 
Females: Estimated creatinine clearance for males × 0.85
30. Other malignancies within 3 years prior to screening other than basal cell skin cancer 
or carcinoma in situ of the cervix
31. Active serious infections in particular if requiring systemic antibiotic or antimicrobial 
therapy
32. Known active or chronic hepatitis C and/or B infection
33. Gastrointestinal disorders or abnormalities that would interfere with absorption of the 
study drug
34. Serious illness or concomitant non-oncological disease such as neurologic, 
psychiatric, infectious disease or active ulcers (gastro-intestinal tract, skin) or 
laboratory abnormality that may increase the risk associated with study participation 
or study drug administration and in the judgment of the investigator would make the 
patient inappropriate for entry into the study
35. Patients who are sexually active and unwilling to use a medically acceptable method 
of contraception (e.g. such as implants, injectables, combined oral contraceptives, 
some intrauterine devices, sexual abstinence or vasectomised partner) during the trial 
and for at least three month after ceasing nintedanib / placebo and for at least twelve
months after ceasing chemotherapy (see Section 5.2.2.4) 
36. Pregnancy or breast feeding


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37. Psychological, familial, sociological or geographical factors potentially hampering 
compliance with the study protocol and follow-up schedule
38. Active alcohol or drug abuse
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
A patient has to be withdrawn from active treatment in case any of the following applies:

Documented unequivocal progressive disease according to modified RECIST (R12-
1990). Study treatment can only be continued beyond radiological progression if it is 
deemed in the patients' interest following a careful risk benefit assessment by the 
investigator (refer to Section 5.1.2.1.5). For equivocal findings of progression (e.g. very 
small and uncertain new lesions, cystic changes or necrosis in existing lesions, etc.), 
treatment should continue until next scheduled assessment. 

The patient requests discontinuation of active treatment

The patient is no longer able to participate in the study (e.g. AE, surgery, pregnancy, 
concomitant diagnoses, concomitant therapies, or administrative reasons). The 
investigator may also stop a patient’s treatment, if the patient is no longer able to attend 
study visits 

Significant deviation from the protocol or eligibility criteria. The decision to continue or 
withdraw treatment will be made after discussion between the sponsor and the 
investigator 

The patient cannot tolerate nintedanib / placebo treatment either as monotherapy or in 
combination with pemetrexed /cisplatin despite dose reductions. Patients who interrupt or 
discontinue nintedanib/placebo during the combination therapy period can continue 
pemetrexed and/or cisplatin for up to 6 cycles, without being removed from the trial. 
Likewise, patients who discontinued chemotherapy (pemetrexed and/or cisplatin) during 
the combination therapy period can continue with one remaining compound combined
with nintedanib/placebo or nintedanib/placebo monotherapy.

The patient receives prohibited concomitant medication (refer to Section 4.2.2)
The EoT information has to be obtained. All patients who end active treatment (but not the 
trial) will be followed up as described in Section 6.2.3.2.
All withdrawals will be documented and the reason for withdrawal recorded in the eCRF and 
discussed, as necessary, in the clinical trial report.
Patients who fail screening will not be included in the analysis but will be entered into the 
trial database. The reason for failure will be documented and reported descriptively and by 
patient listing in the report of this trial.
Patients who fail screening will be replaced (Phase III patients only). Patients who initially 
may not meet eligibility criteria (e.g. for administrative reasons or assessments are out of time 
window) may be re-screened at investigator’s discretion after consulting with the Sponsor.


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Regardless, all screening assessment requirements as detailed in the flow charts must be
followed.
Patients who withdraw from the study after randomisation will not be replaced.
3.3.4.2
Discontinuation of the trial by the sponsor
BI reserves the right to discontinue the trial overall or at a particular trial site at any time for 
the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site,
2. Emergence of any efficacy/safety information that could significantly affect
continuation of the trial, 
3. Violation of good clinical practice (GCP), the clinical trial protocol (CTP), or the 
contract by a trial site or investigator, disturbing the appropriate conduct of the trial.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
Patients will initially be treated with nintedanib / placebo in combination with standard
chemotherapy (pemetrexed / cisplatin) for a maximum of 6 cycles of 21 days duration. 
After completion of combination therapy, patients who have not progressed will continue to 
be treated with nintedanib / placebo monotherapy.
4.1.1
Identity of investigational and comparator products
4.1.1.1
Nintedanib (investigational product)
Substance (International 
Nonproprietary Name
[INN]):
Nintedanib
Pharmaceutical form:
Soft gelatine capsule
Pharmaceutical code
BIBF 1120
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
100 mg and 150 mg capsules
Daily dose:
Route of administration:
400 mg (200 mg twice daily)
Oral
Duration of use:
Continuous daily dosing until disease progression or until 
criteria for treatment interruption are met.
4.1.1.2
Placebo (comparator)
Substance (INN):
Not applicable
Pharmaceutical form:
Soft gelatine capsule
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit strength:
Daily Dose
Route of administration:
Duration of use:
Placebo contains 0 mg of nintedanib in capsules matching 
100 mg and 150 mg of Nintedanib
Capsules matching 400 mg of nintedanib (200 mg twice 
daily) 
Oral
Continuous daily dosing until disease progression or until 
criteria for treatment interruption are met


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4.1.1.3
Non-investigational product
4.1.2
Method of assigning patients to treatment groups
When a patient qualifies for entry into the study, treatment randomisation to nintedanib or 
placebo will be implemented by either IVRS and/or IWRS. Instructions for using 
IVRS/IWRS will be provided to the investigator.
An internal Clinical Trial Support Group will provide the randomisation scheme and the 
stratification factors. The randomisation code will be kept blinded by Clinical Trial Support 
Group until database lock. For all details of the randomisation please refer to Section 7.5.
4.1.3
Selection of doses in the trial
Nintedanib in combination with standard treatment of pemetrexed / cisplatin is being
investigated in this study. 
Nintedanib 200 mg b.i.d. has been studied in combination with pemetrexed (U08-3886-01) 
and is the recommended dose for this and other combinations (see Section 1.2.4 to 1.2.6). 
The starting dose of nintedanib will be 200 mg b.i.d. The dose of pemetrexed will be 500 
mg/m2 and cisplatin will be 75 mg/m2. In the event of treatment-limiting AEs, dose delay and 
dose reduction criteria are provided in Section 4.2.1.
During the combination treatment phase, both pemetrexed and cisplatin will be administered 
intravenously on Day 1 of a 21-day cycle for a maximum of 6 cycles. Nintedanib / placebo 
will be administered orally twice daily starting on Day 2 and continue daily for 20 days in a 
Substance (INN):
Pemetrexed / Cisplatin 
Pharmaceutical form:
Injectable
Source:
Manufacturer for (local) market
Unit strength:
Pemetrexed: 100 mg or 500 mg single-use vials
Cisplatin: 50 mL of 1 mg/ml solution
Daily dose:
500 mg/m2 Pemetrexed followed by
75 mg/m2 Cisplatin on day 1 of each cycle
Route of administration:
Duration of use:
Additional information:
Intravenous infusion
Each cycle is 21 days in duration. Patient may receive a 
maximum of 6 cycles
Drugs should be administered according to the SPC. The 
recommendations for supportive care should be followed 
(see SPC)


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21-day cycle. Study medications should not be administered before PK sampling is 
performed on Day 8 of Cycle 2.
If pemetrexed/cisplatin administration needs to be interrupted and patient tolerates therapy 
with nintedanib/placebo, daily treatment with nintedanib/placebo should continue until the 
next pemetrexed /cisplatin administration.
After completion of combination therapy and if patients have not progressed, 
nintedanib/placebo will be administered orally twice daily starting on Day 1 to Day 21 of 
each treatment cycle.
4.1.4
Drug assignment and administration of doses for each patient
During the combination phase, stopping rules and retreatment criteria for each compound 
should be considered separately, e.g. if pemetrexed has to be interrupted or permanently 
discontinued, cisplatin and nintedanib/placebo should continue for the remainder of the 
combination therapy period provided stopping criteria are not met for either compound.
4.1.4.1
Nintedanib (BIBF 1120) and placebo
Nintedanib (200 mg) and placebo (matching capsule) will be swallowed twice daily un-
chewed with a glass of water of about 250 mL every 12 hours (± 1 hour) after food intake, at 
about the same time in the morning and in the evening. 
No nintedanib/placebo will be taken on the days of pemetrexed and cisplatin administration.
If a patient misses one or more doses of nintedanib/placebo, the patient should continue to 
take the next treatment as per schedule and notify the study team looking after them that they 
have missed doses. 
4.1.4.2
Pemetrexed and cisplatin
The pemetrexed and cisplatin infusion should be administered under the supervision of the 
investigator or designated personnel at the trial site. 
For treatment of MPM, the starting dose of pemetrexed is 500 mg/m2 administered as an 
intravenous (i.v.) infusion over approximately 10 minutes on Day 1 of each 21-day cycle, 
followed by cisplatin 75 mg/m2 infused over 2 hours approximately 30 minutes after 
completion of pemetrexed administration. Patients should receive adequate anti-emetic 
treatment and appropriate hydration prior to and/or after receiving cisplatin in accordance 
with the local current SPC.
The duration (actual start and end time) of the infusion needs to be documented in the eCRF. 
Every attempt should be made to adhere to the planned infusion time with a constant infusion 
rate. The use of an infusion pump is recommended.
The details of the procedure to prepare the infusion solution and the instructions for
intravenous (i.v.) administration will be provided in the ISF. 


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4.1.4.3
Pre-medication Regimen
Corticosteroid - skin rash has been reported more frequently in patients not pretreated with a 
corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and 
severity of cutaneous reaction. All patients should be pre-medicated with dexamethasone 4 
mg by mouth twice daily the day before, the day of, and the day after pemetrexed
administration.
Vitamin Supplementation - to reduce toxicity, patients treated with pemetrexed must be 
instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid (350 
µg to 1000 µg, most commonly used dose of 400 µg) on a daily basis. At least 5 daily doses 
of folic acid must be taken during the 7-day period preceding the first dose of pemetrexed; 
and dosing should continue during the full course of therapy and for 21 days after the last 
dose of pemetrexed. Patients must also receive an intramuscular injection of vitamin B12
(1000 µg) during the week preceding the first dose of pemetrexed and once every 3 cycles (9 
weeks) until pemetrexed is discontinued. Subsequent vitamin B12 injections may be given on 
the same day as pemetrexed. 
Hydration - Adequate hydration must be maintained from 2 to 12 hours prior to 
administration until minimum 6 hours after the administration of cisplatin. Hydration is 
necessary to cause sufficient diuresis during and after treatment with cisplatin.
It is necessary that the patient drinks large quantities of liquids for 24 hours after the cisplatin 
infusion to ensure adequate urine secretion.
4.1.4.4
Re-treatment criteria for pemetrexed and cisplatin therapy
Re-treatment criteria for further pemetrexed and cisplatin course are as follows (the 
laboratory parameters must be obtained prior to re-treatment):

ANC of at least 1.5 x 109/L 

Platelet count of at least 100 x 109/L

Bilirubin values within normal ranges

ALT and AST ≤ 1.5 x upper limit of normal (ULN) for patients without liver metastasis 
and ≤ 2.5 x ULN for patients with liver metastasis with concomitant alkaline phosphatase
(ALP) ≤ 2.5 x ULN, respectively

Creatinine clearance >45 mL/min
In addition to the above mentioned criteria, the following values have to be reached for 
cisplatin re-treatment (the laboratory parameters must be obtained prior to re-treatment):

Serum creatinine ≤ 130 µmol/l or ≤ 1.5 mg/100 ml

Blood urea < 25 mg/100 ml or < 8.92 mmol/l
Stopping criteria for pemetrexed / cisplatin therapy: 
If any of the following events occur, pemetrexed or cisplatin must be permanently
discontinued:


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
Peripheral neuropathy of CTCAE grade ≥3

Cisplatin induced hearing loss of CTCAE grade ≥ 3

Severe hypersensitivity reaction to pemetrexed or cisplatin is noted

The occurrence of AEs that would require a third dose reduction
If any of the above events occur, patients can continue therapy with nintedanib / placebo if:

None of the withdrawal criteria have been met

All drug-related AEs that occurred during the previous treatment courses have recovered 
to baseline levels, or to CTCAE grade levels that would allow further therapy with 
nintedanib / placebo
4.1.4.5
Temporary treatment interruption of nintedanib / placebo
Treatment with nintedanib / placebo shall be temporarily interrupted for up to 2 weeks and 
adequate therapy should be initiated as per outlined in Section 4.2.1 if one of the following 
AEs occurs:
Diarrhoea:

CTCAE grade 2 for > 7 consecutive days despite optimal medical management

CTCAE grade ≥ 3 or diarrhoea event leading to hospitalisation
Nausea / vomiting (if onset >3 days since pemetrexed/cisplatin administration):

Vomiting of CTCAE grade ≥ 2 

Nausea of CTCAE grade ≥ 3
Liver enzyme elevations:

ALT and/or AST >2.5 x ULN in conjunction with Bilirubin of ≥ 1.5 x ULN

ALT and/or AST > 5 x ULN
Haematological Adverse Events:

Platelet < 50 x 109/L associated with bleeding of CTCAE grade ≥2 regardless of nadir 
ANC

Neutropenia of any grade accompanied by fever >38.5°C

Neutropenia of CTCAE grade 4 without fever > 7 days
Other non-haematological drug related AEs of CTCAE grade ≥ 3
In case a delay for more than 2 weeks would be required by the investigator or the patient,
this needs to be discussed and agreed between the investigator and the sponsor.
4.1.4.6
Re-treatment criteria for nintedanib / placebo
Treatment with nintedanib / placebo may be resumed as long as the events causing temporary 
treatment interruption had recovered to baseline levels or to a CTCAE grade which would 
allow further therapy:

Nausea CTCAE Grade ≤1


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
Vomiting CTCAE Grade ≤1

Diarrhoea CTCAE Grade ≤1

Other non-hematological or hematological toxicity recovered to baseline levels or to a 
CTCAE grade 1
Dose modifications of nintedanib / placebo should be followed and the criteria should be met
in order to allow the recommencing of nintedanib / placebo treatment at a reduced dose as
outlined in Section 4.2.1.
With respect to liver enzyme elevations, the following values have to be reached:

Bilirubin values within normal ranges

ALT and AST ≤ 1.5 x ULN for patients without liver metastasis and ≤ 2.5 x ULN for 
patients with liver metastasis with concomitant alkaline phosphatase (ALP) ≤ 2.5 x ULN, 
respectively
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This trial will be performed according to a parallel group, double-blind, placebo controlled 
design. Patients, investigators and the sponsor’s trial team involved in the analysis of this 
double-blind trial will remain blinded with regard to the randomised treatment assignments 
up to database lock of the respective parts of the trial, with the exception of particular 
instances which require immediate unblinding according to BI’s standard operation 
procedures (e.g. emergency situations).
An internal Clinical Trial Support Group will arrange for the randomisation. The 
randomisation code will be kept separate from the trial team by Clinical Trial Support up to 
database lock. The randomisation code will only be released according to protocol. With 
regard to the two separate parts of this trial, two separate randomisation lists have been 
created. The first randomisation list refers only to the Phase II patients in this trial; the second 
randomisation list refers to the Phase III patients in this trial.
Investigators, patients, and the trial team involved in the continuing trial will not be 
unblinded until final analysis of the study. The first 87 randomised patients (Phase II) were 
internally unblinded on 04-Mar-2016 as recommended following consultation with regulatory 
authorities (EMA and FDA) and prior to any enrolment in the Phase III part. This analysis 
represents the primary PFS analysis of the Phase II part. The primary OS analysis of the 
Phase II part will be conducted when approximately 61 OS events of the Phase II patients 
have occurred. 
For the primary PFS analysis and the interim OS analysis of the Phase III part, the trial 
database will be locked and unblinded by a team independent from the trial team tasked to 
analyze the data and write the primary PFS analysis report and, subsequently a regulatory 
submission dossier if requested. Investigators, patients, clinical monitors, trial team and 
others involved in the continuing trial will remain blinded. Details about the unblinding and 
firewalls to protect the blinding will be described separately in an interim logistics plan.


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For the planned adaptive design at the time of the interim OS analysis as well as for all DMC 
safety meetings, the external DMC will be unblinded to the data of the patients. The 
unblinding will be done by a CRO on a secure data platform that can only be accessed by 
DMC members and the CRO. Further details of the unblinding of these data will be described 
in the DMC charter. It will be ensured that investigators, patients and the trial team will be 
kept blinded with regard to all Phase III patients until the final analysis of this trial.
4.1.5.2
Procedures for emergency unblinding
For this blinded trial, emergency unblinding procedures will be available to the investigator / 
pharmacist / investigational drug storage manager via IVRS/IWRS. This code break may 
only be opened in emergency situations when the identity of the trial drug must be known to 
the investigator in order to provide appropriate medical treatment or if required to assure 
safety of trial participants. If the code break for a patient is opened, the sponsor must be 
informed immediately. The reason for the unblinding should be documented in the patient’s 
medical record along with the date and the initials of the person who broke the code.
4.1.6
Packaging, labelling, and re-supply
Nintedanib or matching placebo will be packaged in one-week blister cards. Blister cards will
be labelled with a unique identifier for drug accountability and will be labelled according to
the participating countries’ regulatory requirements. Blisters will be packaged in one month
boxes (21 days treatment plus 1 week reserve medication).
Packaging and labelling will not be applicable for pemetrexed / cisplatin as these will be
sourced locally.
For details of packaging and description of the labels, refer to the ISF.
4.1.7
Storage conditions
Nintedanib and matching placebo must be stored in the original package, at study site in a 
temperature-controlled area maintained at room temperature (between 15o C and 30o C) and 
with restricted access. 
Pemetrexed and Cisplatin must be stored in the original package according to the 
manufacturer’s storage instructions. 
If the storage temperature deviates from the required range, immediately contact the local 
clinical monitor (see Contact List filed in the ISF).
4.1.8
Drug accountability
Nintedanib and matching placebo will be provided by the sponsor, and pemetrexed / cisplatin 
will be procured locally. Drug supplies must be kept in a secure, limited access storage area 
under the storage conditions defined by the sponsor. A temperature log must be maintained to 
make certain that the drug supplies are stored at the correct temperature.


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The investigator and/or pharmacist and/or investigational drug storage manager will receive 
the investigational drugs delivered by the sponsor when the following requirements are 
fulfilled:

approval of the study protocol by the institutional review board (IRB) / ethics committee,

availability of a signed and dated clinical trial contract between the sponsor and the trial 
site

approval/notification of the regulatory authority, e.g. competent authority (CA),

availability of the curriculum vitae of the principal investigator,

availability of a signed and dated CTP or immediately imminent signing of the CTP, 

if applicable, availability of the proof of a medical licence for the principal investigator, 

availability of the Form 1572 (for USA only).
The investigator and/or pharmacist and/or investigational drug storage manager must 
maintain records of the product’s delivery to the trial site, the inventory at the site, the use by 
each patient, and the return to the sponsor or alternative disposition of unused products. 
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational products and trial patients. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor and/or appointed CRO, the investigator / pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the investigator’s possession when 
the trial site is closed out.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
Before infusion of pemetrexed / cisplatin, patients must be pre-medicated as described in 
Section 4.1.4.3 and according to the local current SPC.
Concomitant medications, or therapy to provide adequate care, may be given as clinically 
necessary. Restrictions in Section 4.2.2 apply.
All concomitant (non-oncological) medications which are taken between trial informed 
consent and follow-up visit 1, as well as the required pre-medication and further anti-cancer 
treatment should be recorded in the eCRF. If patients receive parenteral nutrition during the 
trial, the components need not be specified in detail, it should just be indicated as “parenteral 
nutrition”. If a patient requires anaesthesia, it will be sufficient to indicate “anaesthesia” 
without specifying the details.
For screen failures, only concomitant medications given for trial related AEs will be 
collected.


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4.2.1
Rescue medication, emergency procedures, and additional treatments
Rescue medication to reverse the actions of nintedanib is not available. Potential side effects 
of nintedanib have to be treated symptomatically. Recommended symptomatic treatments of 
study medication side effects or tumour-associated symptoms that may occur are listed 
below.
Investigators should use the following guidelines for the management of side effects related 
to the treatment of nintedanib / placebo in combination with pemetrexed / cisplatin and 
nintedanib / placebo monotherapy.
Full details can be found in the SPC for pemetrexed and cisplatin filed in the ISF.
4.2.1.1
Dose Reduction Recommendations
Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic 
counts or maximum non-hematologic toxicity experienced by the patient according to 
CTCAE (version 3.0 for Phase II and version 4.03 for Phase III patients) from the preceding 
cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon 
recovery, patients should be retreated using the guidelines in Sections 4.2.1.2 and 4.2.1.3
below.
Only two dose reductions will be allowed throughout the study duration. Once a patient has 
undergone a dose reduction as required per the following recommendations, the dose will not 
be re-escalated. If a patient receives a reduced dose in error, the dose can be re-escalated to 
allow adequate treatment.
Dose reductions for cisplatin induced ototoxicity or nephrotoxicity: in case of significant 
clinical hearing loss or renal dysfunction, cisplatin therapy should be reduced or stopped. The 
clinician will make the decision regarding cisplatin dosing and also whether to continue 
pemetrexed alone or to withdraw the patient from the combination treatment.
4.2.1.2
Management of non-haematological toxicity
In general, for grade ≥3 non-haematological toxicity, therapy should be withheld or 
decreased depending on the judgment of the treating physician. Doses should be withheld 
until toxicity has resolved either to baseline or values which would allow further re-treatment. 
4.2.1.2.1
Management of diarrhoea
In the event of diarrhoea considered to be related to nintedanib the following algorithm 
should be used:
Table 4.2.1.2.1:1
Recommendation for the management of drug-induced diarrhoea
CTCAE Grade
Anti-diarrhoeal treatment
Dose of nintedanib/placebo
Grade 1 or 2
Anti-diarrhoeal treatment e.g. loperamide 
Continue treatment, no dose reduction


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Table 4.2.1.2.1:1 (cont’d)
Recommendation for the management of drug-induced 
diarrhoea
CTCAE Grade
Anti-diarrhoeal treatment
Dose of nintedanib/placebo
Grade 2  > 7 consecutive days despite optimal medical management
Or
Grade >3
or any diarrhoea independent of CTCAE grade leading to hospitalisation of the patient
First episode
Anti-diarrhoeal treatment e.g. loperamide 
Treatment pause and resume upon recovery* and
reduce dose from 200 mg b.i.d. to 150 mg b.i.d.  
Second episode
Treatment as above
Treatment pause and resume upon recovery* and 
reduce dose from 150 mg b.i.d. to 100 mg b.i.d.
Third episode
Treatment as above
Discontinue treatment
* until resolution to less than, or equal to baseline value or CTCAE ≤ grade 1
4.2.1.2.2
Management of liver enzyme elevations
In the event of liver enzyme elevations, the following algorithm should be followed:
Table 4.2.1.2.2:1
Recommendation for management of liver enzyme elevations
CTCAE Grade
Combination Therapy
(cycle 1 – 6)
nintedanib /placebo monotherapy
(after cycle 6)
ALT and/or AST ≤5
x ULN with bilirubin < 
1.5 x ULN
No dose reduction
No dose reduction
Elevation of AST and/or ALT values to > 2.5 x ULN in conjunction with total bilirubin elevation to ≥1.5 x ULN 
OR
Elevation of AST and/or ALT values to > 5x ULN
First Episode
Treatment pause until recovery to less than, or equal to, patient’s pre-therapy value at study 
enrolment.
Nintedanib / placebo: reduce dose from 200 mg b.i.d. to 150 mg b.i.d.
Pemetrexed: reduce dose to 75% of 
starting dose
Second Episode
Treatment pause until recovery to less than, or equal to, patient’s pre-therapy value at study 
enrolment.
Nintedanib /placebo: reduce dose from 150 mg b.i.d. to 100 mg b.i.d.
Pemetrexed: reduce dose to 50% of 
starting dose
Third Episode
Treatment discontinuation
In case of an elevation of AST/ALT > 3 x ULN in conjunction with bilirubin ≥ 2 x ULN and 
ALKP < 2 x ULN treatment with nintedanib should be interrupted. Unless there is an 
alternative cause established, nintedanib should be permanently discontinued.


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4.2.1.2.3
Management of nausea and vomiting
Nausea and vomiting may significantly affect patients’ adherence to the treatment and quality 
of life. In order to reduce the occurrence and the intensity of emesis the patients should be 
treated according to the recommendations / guidelines below.
Table 4.2.1.2.3:1
Management of nausea and vomiting
CTCAE Grade  
of Emesis
Antiemetic treatment
Note: Tropisetron or dolasetron should be 
avoided due to genetically polymorphic 
metabolism by CYP2D6.
Emesis occurring ≤ day 3 
after combination 
treatment of cisplatin / 
pemetrexed 
Emesis occurring ≥ day 
4 after combination 
treatment of cisplatin / 
pemetrexed or during 
nintedanib /placebo 
monotherapy
Nausea =1
No antiemetic treatment
No dose reduction
No dose reduction 
Nausea = 2 
and / or 
vomiting =1 
No Nintedanib treatment pause.
Antiemetic treatment  
e.g. metoclopramide or dimenhydrinate, or
prochlorperazine
If ineffective, patients should be treated 
according to treatment of vomiting 
CTCAE Grade ≥2 or nausea CTCAE
Grade ≥ 3
No dose reduction
No dose reduction 
Vomiting ≥2 
and / or Nausea ≥ 3  
First episode
Treatment with nintedanib /placebo 
discontinued and resumed upon recovery1
Antiemetic treatment with 5-Hydroxy-
Tryptamin Receptor 3 (5-HT3) receptor 
antagonist and / or corticosteroid 
Prophylactic antiemetic treatment with 
5-HT3 receptor antagonist and 
corticosteroid at all subsequent 
administrations of chemotherapy from 
Days 1-3 of chemotherapy. If this is 
already standard of care, follow second 
episode
Cisplatin / pemetrexed: 
no dose reduction
Nintedanib / placebo: 
no dose reduction 
Cisplatin / pemetrexed: 
no dose reduction
Nintedanib / placebo: 
reduce dose from 200 mg 
b.i.d. to 150 mg b.i.d.
Second episode
Treatment with nintedanib /placebo 
discontinued and resumed upon recovery1
Cisplatin / pemetrexed: 
dose reduction
Nintedanib / placebo: 
reduce dose from 200 mg 
b.i.d. to 150 mg b.i.d.
Cisplatin / pemetrexed: 
no dose reduction
Nintedanib /placebo: 
reduce dose from 150 mg
b.i.d. to 100 mg b.i.d.
Third episode
Treatment as above
Cisplatin / pemetrexed: 
dose reduction
Nintedanib /placebo: 
reduce dose from 150mg 
b.i.d. to 100 mg b.i.d.
Cisplatin / pemetrexed: 
no dose reduction
Nintedanib /placebo: 
discontinuation
Fourth episode
Treatment as above
Cisplatin / pemetrexed: 
discontinuation
Nintedanib / placebo: 
discontinuation
Not applicable
1 until resolution to less than, or equal to the patient’s pre-therapy value at study enrollment
* add NK1 receptor antagonist in case that prophylactic antiemetic treatment is foreseen in the protocol


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In case vomiting occurs shortly after intake of nintedanib/placebo, patient should not take a 
replacement dose.
4.2.1.2.4
Management of mucositis and rash
Table 4.2.1.2.4:1
Dose reductions for mucositis and rash
CTCAE Grade ≥3
Combination Therapy:
Nintedanib / placebo Monotherapy
First Episode
Treatment pause until recovery*
Nintedanib / placebo: dose reduce from 200 mg bid to 150 mg bid
Pemetrexed: 50% of previous dose (mucositis)
Pemetrexed: 75% of previous dose (rash)
Second Episode
Treatment pause until recovery*
Nintedanib / placebo: dose reduce from 150 mg bid to 100 mg b.i.d.
Pemetrexed: 50% of previous dose (mucositis)
Pemetrexed: 75% of previous dose (rash)
Third Episode
Treatment discontinuation
* until resolution to less than, or equal to baseline value or CTCAE ≤ grade 1
4.2.1.2.5
Management of neurotoxicity
Table 4.2.1.2.5:1
Dose reductions for pemetrexed and cisplatin - neurotoxicity
CTCAE Grade
Dose of  Pemetrexed (mg/m2)
Dose of Cisplatin (mg/m2)
0-1
No dose reduction
No dose reduction
2
No dose reduction
50% of previous dose
≥3
Treatment discontinuation
4.2.1.3
Management of haematological toxicity
Nintedanib/placebo monotherapy: Based on the current data for monotherapy, nintedanib 
does not induce haematological side effects.  However, in the event of occurrence of CTCAE 
grade >3 haematological side effects under the nintedanib / placebo monotherapy, treatment 
should be interrupted and re-initiated at a reduced dose upon recovery.
Nintedanib in combination with pemetrexed / cisplatin: Patients should have an ANC of 
at least 1.5 x 109/L and platelet count of at least 100 x 109/L prior to receiving the next cycle 
of chemotherapy. Dose modifications should be performed according to the guidelines below:


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Table 4.2.1.3:1
Dose reductions for hematologic adverse events during combination 
treatment
Haematologic adverse event
Pemetrexed / cisplatin*
Nintedanib / placebo*
ANC < 0.5 x 109/L and Platelets ≥ 50 x 109/L
First episode
Second episode
Third episode
75% of previous dose (both drugs)
75% of previous dose (both drugs)
Discontinuation
No dose reduction
No dose reduction
No dose reduction
Platelets ≤ 50 x 109/L without bleeding 
regardless of nadir ANC
First episode
Second episode
Third episode
75% of previous dose (both drugs)
75% of previous dose (both drugs)
Discontinuation
No dose reduction
No dose reduction
No dose reduction
Platelets < 50 x 109/L with bleeding CTCAE 
grade ≥ 2 regardless of nadir ANC
First episode
Second episode
Third episode
50% of previous dose (both drugs)
50% of previous dose (both drugs)
Discontinuation
Dose reduce from 200 mg b.i.d. to 
150 mg b.i.d.
Dose reduce from 150 mg b.i.d. to 
100 mg b.i.d.
Discontinuation
Neutropenia of any grade accompanied by
fever > 38.5⁰C or
Neutropenia grade 4 without fever > 7 days
First episode
Second episode
Third episode
75% of previous dose (both drugs)
75% of previous dose (both drugs)
Discontinuation
Dose reduce from 200 mg b.i.d. to 
150 mg b.i.d.
Dose reduce from 150 mg b.i.d. to 
100 mg b.i.d.
Discontinuation
* pause treatment and resume when ANC ≥ 1.5 x 109/L and the platelet count ≥100 x 109/L
The use of Granulocyte-Colony Stimulating Factor to treat chemotherapy-induced 
neutropenia is allowed according to local clinical practice.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Additional antineoplastic therapy not specified in this protocol such as chemo-, immuno-, 
hormone (with the exception of Hormone Replacement Therapy or palliative radiotherapy)
are not allowed during the study. For symptom control, palliative radiotherapy may be 
permitted after discussion with the CML, provided that other target lesions remain, and the 
reason for the radiotherapy does not reflect progressive disease.
Patients who require full-dose anticoagulation or heparinisation cannot be enrolled into the 
study. Intervention with low-dose therapeutic anticoagulation (such as low-dose heparin 


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and/or heparin flush as needed for maintenance of an in-dwelling i.v. device) or anti-platelet 
therapy (such as acetylsalicylic acid < 325mg per day) may be allowed if clinically required 
for a patient to treat AEs. These patients will be monitored at close intervals (refer to Section 
5.2.3) until they achieve a stable anticoagulation status. 
Concomitant therapy with the 5-HT3 receptor antagonists tropisetron and/or dolasetron which 
are metabolised by cytochrome 2D6 should be avoided since anti-emetic efficacy may be low
in patients who are ‘fast metabolisers’. If treatment with a 5-HT3 receptor antagonist is 
required, another one should be selected.
Treatment with other investigational drugs or enrolment in another clinical trial must not be 
initiated prior to progression of the disease. 
4.2.2.2
Drug specific restrictions
Pemetrexed and cisplatin: refer to the local current SPC for specific restrictions for 
pemetrexed and cisplatin.
4.3
TREATMENT COMPLIANCE
Pemetrexed and cisplatin will be administered as i.v. infusion in accordance with the current 
SPCs and in the practice or hospital of the investigator under supervision of authorised 
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 eCRF.
Nintedanib/placebo will be given as an oral administration in accordance with the study 
protocol and under the instruction of the investigator. The patients will be asked to return all 
unused nintedanib and/or matching placebo capsules at the next scheduled visit. The 
investigator or his/her deputy will check whether the patient has taken the medication 
according to the protocol. Any discrepancies will be explained in the eCRF by the 
investigator or his/her deputy.
It is recommended that patients take all doses of nintedanib / placebo according to the trial 
protocol unless dosing is limited by AEs. However, patients with prolonged treatment 
interruptions not necessitated by AEs will not automatically be taken off study.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY
5.1.1
Endpoints of efficacy
Primary endpoint:

Progression free survival measured from the time of randomisation to the time of disease 
progression according to modified RECIST criteria (R12-1990) or death of any cause, 
whichever occurs earlier.

For Phase II, the observation period for PFS is defined from randomisation until the 
earliest of disease progression, death or the cut-off of 04-Mar-2016 for the primary PFS 
analysis.

For Phase III, the observation period for PFS will continue until the earliest of disease 
progression, death or until approximately 199 PFS events have occurred for Phase III
patients or until approximately 23months has elapsed since the first Phase III patient was 
randomised.
Secondary endpoints:

OS measured from the time of randomisation to the time of death of any cause (key 
secondary endpoint). 
For Phase II, the observation period for OS is until the earliest of death or until 
approximately 61 Phase II patients have died, , whichever occurs first.
For Phase III, the observation period for OS is from randomisation until the earliest case 
of death or until approximately 279 to 346 (depending on the event reassessment) OS 
events have occurred for Phase III patients or until approximately 54 months has elapsed 
since the first Phase III patient was randomised. If the trial is declared positive also for 
OS at the time of the interim Phase III OS analysis, the observation period for OS will 
continue until approximately 199 PFS events have occurred.

Objective response according to modified RECIST (R12-1990) analysed by objective 
response rate. Tumour imaging is to be performed every 6 weeks up to approximately 54
months since the first Phase III patient was randomised or until disease progression, death 
or start of subsequent anti-cancer therapy, whichever occurs earlier

Disease control according to modified RECIST (R12-1990) analysed by disease control 
rate. Tumour imaging is to be performed every 6 weeks up to approximately 54 months
since the first Phase III patient was randomised or until the disease progression, death or 
start of subsequent anti-cancer therapy, whichever occurs earlier.


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Objective Tumour Response
Objective response is defined as best overall response of CR or PR, where best overall 
response is determined according to modified RECIST (R12-1990) recorded from 
randomisation until the earliest of disease progression, death or last evaluable tumour 
assessment before subsequent non-study anti-cancer therapy, and in case CR and/or PR was 
confirmed by imaging four weeks or later after the first occurrence of the response. Time to 
objective response is defined from the time of randomisation until first documented CR or PR
among patients with objective response. Duration of objective response is defined as the time 
from first documented CR or PR until the earliest of disease progression or death among 
patients with objective response.
Disease Control
Disease control is defined as best overall response of CR or PR or SD where best overall 
response is defined according to modified RECIST (R12-1990) recorded from randomisation 
until the earliest of disease progression, death or last evaluable tumour assessment before 
subsequent non-study anti-cancer therapy. 
Duration of disease control is defined as the time from randomisation until the earliest of 
disease progression or death among patients with disease control.
 
 
 
 


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5.1.2
Assessment of efficacy
5.1.2.1 Tumour assessment by imaging
Tumour assessment by computed tomography (CT) scan or MRI will be performed at the 
time points specified in the flow charts and will be evaluated according to the modified 
RECIST criteria (R12-1990) based on RECIST 1.0. The results will be recorded in the eCRF.
All measurable lesions representative of all involved organs should be identified at screening 
by CT or MRI, as target lesions and will be recorded, measured and numbered at baseline. 
Target lesions should be selected on the basis of their size and their suitability for accurate 
repetitive measurements (either by imaging techniques or clinically).  
All other lesions should be identified as non-target lesions and should also be recorded at
baseline. Measurements are not required; these lesions should be assigned the responses for 


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non-target lesions (CR, Incomplete response/SD, PD or not evaluable) and taken into 
consideration in tumour response evaluation.
Progression will be assessed by tumour measurements and will be evaluated by the 
investigator according to modified RECIST (R12-1990)
 
 
 
Imaging will be performed at baseline (within four weeks prior to administration of first dose 
of study medication) and every six weeks (± 1 week) from the time the first dose of study 
medication (pemetrexed/cisplatin) is taken until unequivocal disease progression or initiation 
of new non-study anti-cancer treatments. If study treatment continues beyond radiological 
progression in the case of clinical benefit, as judged by the investigator, imaging should 
continue until discontinuation of study treatment. At baseline imaging must be performed to 
fully assess the extent of primary tumour and metastases in an individual patient. This should 
include CT or MRI of the brain, chest and abdomen (i.e. liver and adrenal glands). 
All patients will complete a brain scan (CT or MRI) during screening. Patients with stable 
brain metastases (for definition please refer to the exclusion criteria in Section 3.3.3) at trial 
entry must be evaluated at each imaging time point for assessment of their brain metastases. 
If brain metastasis is not noted on initial screening exam, then brain scanning should only be 
performed for clinical suspicion.
Bone scans need to be performed at screening 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 ALP).If the patient has known bone 
metastases or if bone metastases are detected at screening, correlative conventional imaging 
should be done of the respective lesion(s) during study treatment. These images should then 
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). In case treatment has to be rescheduled and/or postponed,
imaging should be performed at the pre-specified time points (i.e., every six weeks). Any site 
radiology findings from imaging that is not forwarded to the central imaging unit need to be 
described concerning abnormalities and forwarded to the imaging centre.
Post-baseline tumour assessments must utilize the same imaging method and acquisition 
technique as used for screening assessments to ensure comparability (except for brain 
metastases where CT and/or MRI can be used).
5.1.2.1.1 Definitions
Details of the guideline for measuring mesothelioma will be provided in the ISF. Responses 
will be evaluated according to modified RECIST criteria (R12-1990). Confirmation of 
response will be assessed by the investigator and will require repeat observation at the next 
scheduled assessment visit. Their assessment will be the basis for continuation or 
discontinuation of treatment in an individual patient.


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Measurable lesions
All imaging in the chest must follow modified RECIST (R12-1990):

Tumour thickness perpendicular to the chest wall or mediastinum will be measured in two 
positions of three separate transverse cuts of CT scan.

The sum of the six measurements will define a pleural unidimensional measure. 

Transverse cuts will be collected at least 1cm apart and related to anatomical landmarks 
in the thorax.  

If measurable tumour is present, transverse cuts in the upper thorax, above the level of 
division of the main bronchi are preferred. 

At reassessment, pleural thickness will be measured at the same position.
If any additional nodal, subcutaneous and other bidimensionally measurable lesions are 
available, they should be measured unidimensionally as per the RECIST 1.0 criteria. 
Measurable lesions, according to RECIST 1.0, are defined as those that can be accurately 
measured in at least one dimension (longest diameter to be recorded) as ≥10 mm in a short 
axis diameter with conventional techniques (CT, MRI). Bone lesions will be considered 
measurable when lytic with measurable soft tissue component (blastic lesions will be 
considered non-measurable). 
Unidimensional measurements are to be added to obtain the total tumour measurement.  All 
tumour measurements must be recorded in millimeters. 
Non-measurable lesions
All other lesions (or sites of disease), including small lesions (longest diameter < 10 mm with
conventional techniques or < 10 mm using spiral CT scan), are considered non-measurable
lesions. Bone blastic lesions, leptomeningeal disease, ascites, pleural or pericardial effusions,
lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses/abdominal
organomegaly identified by physical exam that is not measurable by reproducible imaging
techniques (not confirmed or followed by CT or MRI), and cystic lesions are all non-
measurable.
Lesions in areas irradiated within the past three months are not considered measurable at 
baseline. However, new lesions occurring in previously irradiated areas have to be considered 
for assessment of tumour response.
Target lesions
All measurable lesions up to a maximum of five lesions per organ and ten lesions in total,
representative of all involved organs, should be identified as target lesions and recorded and
measured at baseline. Target lesions should be selected on the basis of their size and their 
suitability for accurate repeated measurements by imaging techniques. Unidimensional 
measurements are to be added to obtain the total tumour measurement at baseline and will be
used as reference by which to characterize the objective tumour response.


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Non-target lesions
All other lesions (or sites of disease) should be identified as non-target lesions and should
also be recorded at baseline. Non-target lesions include measurable lesions that exceed the
maximum numbers per organ or total of all involved organs as well as non-measurable
lesions. Measurements of these lesions are not required, but should be assessed throughout 
follow-up.
5.1.2.1.2 Evaluation of target lesions
Complete Response (CR): disappearance of all target lesions
Partial Response (PR): at least a 30 % decrease in the total tumour measurement of target
lesions, taking as reference the baseline total tumour measurement.
Progressive Disease (PD): at least a 20 % increase in the total tumour measurement of target
lesions, taking as reference the nadir (the smallest total tumour measurement recorded since 
the treatment started), and/or the unequivocal appearance of new lesions.
Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD.
To be assigned a status of CR or PR, the respective changes in tumour measurements must be 
confirmed by repeat assessments that should be performed not earlier than four weeks after 
the criteria for response are first met. In case of SD, follow-up measurements must have met 
the criteria for SD at least once after randomisation at a minimum interval of six weeks.
5.1.2.1.3 Evaluation of non-target lesions
Complete Response (CR): disappearance of all non-target lesions
Incomplete response/Non-PD: persistence of one or more non-target lesion(s)
Progressive Disease (PD): appearance of at least one new lesion or unequivocal progression 
of existing non-target lesions.
5.1.2.1.4 Evaluation of overall response
The best overall response is the best response recorded from the start of study treatment until
disease progression or initiation of new non-study anti-cancer treatments, taking into account
any requirements for confirmation. Post-treatment assessments will be considered in the
determination of best overall response as long as a patient does not initiate new non-study
anti-cancer treatments. Overall response at each assessment will be evaluated according to
Table 5.1.2.1.4:1.


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Table 5.1.2.1.4: 1 
Overall response determination*
Target lesions
Non target lesions
New lesions
Overall responses
CR
CR
No
CR
CR
Incomplete response/SD
No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or no
PD
Any
PD
Yes or no
PD
Any
Any
Yes
PD
* CR = complete response; PR = partial response; SD = stable disease; and PD = progressive disease.
5.1.2.1.5 Progression of disease
Date of disease progression will be recorded based upon modified RECIST (R12-1990). 
Individual patients should continue treatment with the trial drug(s) until unequivocal
progression of the disease is observed.
However, in case of clinical benefit as judged by the investigator after careful clinical 
assessment, patients may be allowed to continue study treatment beyond radiological 
progression. Before resuming study treatment, the following criteria should be met:

Written informed consent should be obtained

Absence of clinical symptoms or signs of disease progression

No decline in performance status

Absence of rapid disease progression or threat to vital organs or critical anatomical 
sites requiring urgent alternative medical intervention
Trial treatment may be continued as long as judged beneficial by the investigator; however, 
the time of progression as defined by investigator will not change. The decision to continue 
study treatment should be discussed with the sponsor and documented in the study records.
Unequivocal progression of the disease will be considered to be present in case of the 
development of:

New lesions, including new lesions in a previously irradiated field

An unequivocal increase in a tumour, including lesions within a previously irradiated 
field
For equivocal findings of progression (e.g. very small and uncertain new lesions, cystic
changes or necrosis in existing lesions, etc.), treatment should continue until next scheduled
assessment. If at the next assessment, progression is confirmed, the date of progression
should be the earlier date when progression was suspected regardless of date when therapy
was discontinued. If progression is not confirmed, treatment should be continued until the
criteria for unequivocal radiological progression are met. Other anti-cancer therapies should 
not be started until unequivocal disease progression is documented.


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In those cases where patients moved into the follow up (FU) period prior to progression of 
disease, disease evaluations should be continued every 6 weeks until progression of disease is
documented (see Section 6.2.3).
 
 
 
 
 
5.2
SAFETY
5.2.1
Endpoints of safety
There will be no formal endpoints based on safety in this trial.

Frequency and severity of AEs graded according to the common terminology criteria for 
adverse events (CTCAE version 3.0 for Phase II and CTCAE version 4.03 for Phase III)
will be assessed for:

Unexpected toxicities 

Overall incidence and intensity of AE, as well as seriousness and relatedness

AE leading to dose reduction or treatment discontinuation

AE leading to death

AE of special interest

Changes in safety laboratory parameters (see Section 5.2.3) will be assessed for:

Change from baseline

Change from worst value
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events


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Adverse event
An AE is defined as any untoward medical occurrence, including an exacerbation of a pre-
existing condition, in a patient in a clinical investigation who received a pharmaceutical 
product. The event does not necessarily have to have a causal relationship with this treatment.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, is a congenital anomaly / birth defect, or is to be deemed serious for 
any other reason if it is an important medical event when based upon appropriate medical 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions.
Intensity of adverse event
The intensity of AEs should be classified and recorded according to CTCAE, version 3.0 in 
Phase II and version 4.03 in Phase III, in the eCRF.
Causal relationship of adverse event
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history. Assessment of causal relationship should be recorded in the case report forms.
Yes:
There is a reasonable causal relationship between the trial drug(s) administered and
the AE. 
No:
There is no reasonable causal relationship between the trial drug(s) administered and 
the AE. 
If a SAE is reported from a blinded trial, the causal relationship must be provided by the 
investigator for all potential trial drugs, i.e. the investigational drug (nintedanib/placebo) and 
for all other non-investigational drugs (pemetrexed/cisplatin).
Worsening of the underlying disease or other pre-existing conditions
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the eCRF.
If progressive disease occurs and is associated with symptoms or meets one of the seriousness 
criteria, the signs and symptoms of progressive disease will be reported as an AE or an SAE 
(if applicable). 
Changes in vital signs, electrocardiogram (ECG), physical examination, and laboratory test 
results


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Changes in vital signs, ECG, physical exam and laboratory test results will be recorded as an 
(S)AE in the eCRF, if they are judged clinically relevant by the investigator.
Exemption to (S)AE Reporting (Phase III patients only)
Disease Progression (PD) is a trial endpoint for analysis of efficacy and as such is exempted 
from reporting as an (S)AE. Progression of the patient’s underlying malignancy will be 
recorded on the appropriate pages of the eCRF as part of efficacy data collection only and 
will not be reported on the SAE Form. Death due to disease progression is also to be recorded 
on the appropriate eCRF page and not on the SAE Form.
However, when there is evidence suggesting a causal relationship between the study drug(s) 
and the progression of the underlying malignancy (PD), the event must be reported as an SAE 
on the SAE Form and on the eCRF.
Examples of exempted events of PD may be:

Progression of underlying malignancy (if PD is clearly consistent with the suspected 
progression of the underlying malignancy as defined by the respective response criteria). 

Hospitalization/Procedures due solely to the progression of underlying malignancy

Clinical symptoms and/or signs of PD (without confirmation by objective criteria e.g. 
imaging, clinical measurement): if the symptom can exclusively be determined to be due 
to the progression of the underlying malignancy and does meet the expected pattern of 
progression for the disease under study.
Exempted events are monitored at appropriate intervals by the external DMC.
5.2.2.2
Protocol-specified adverse events of special interest (AESI)
The following protocol-specified AESIs are to be reported in an expedited manner similar to 
SAEs, even if they do not meet any of the seriousness criteria – for details please see Section 
5.2.2.3 below.
1. For any GI and non-gastrointestinal perforation, leakage, fistula formation, abscess, 
the following additional information need to be collected, documented in the 
respective comment field of the eCRF page and forward the SAE form 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 GI involvement (eg, M Crohn, vasculitis, tuberculosis, 
diverticulitis)

thromboembolic events (or predisposition)
2. Liver enzyme elevations: Drug-induced liver injury (DILI) is under constant 
surveillance by sponsors and regulators. ALT, AST and bilirubin will be monitored 
closely during therapy. The timely detection, evaluation, and follow-up of laboratory 


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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.  

An elevation of ALT and / or AST > 5 x ULN without bilirubin elevation 
measured in the same blood draw sample

An elevation of AST and/or ALT >2.5 x ULN combined with an elevation of 
bilirubin to >1.5 x ULN measured in the same blood draw sample
Patients showing above laboratory abnormalities need to be followed up until the protocol 
specific retreatment criteria have been met and according to Appendix 10.1 of this CTP and 
the “DILI checklist” provided in the ISF.
5.2.2.3
Adverse event and serious adverse event reporting
All AEs, serious and non-serious, and protocol-specified AESI, occurring between signing of 
informed consent until the end of the residual effect period (i.e. 28 days after the last 
administration of the trial drug for Phase II and 30 days for Phase III), see Section 6.2.3.2,
will be collected, documented and reported to the sponsor immediately by the investigator on
the appropriate eCRFs/SAE reporting forms.
The residual effect period is the time period after the last dose administration of trial 
medication when measurable drug levels or pharmacodynamics effects are still likely to be 
present. Only SAEs or AESIs that are related to study medication or study design and that 
occur after the residual effect period has ended need to be reported. However, if the 
investigator becomes aware of an (S)AE that occurred after the patient has completed the 
clinical trial (including protocol required residual effect period) it should be reported by the 
investigator to the sponsor if considered relevant by the investigator.
For screen failures, only trial related AEs occurring from signing the ICF until the date the 
patient is considered a screen failure will be collected. 
Reporting will be done according to the specific definitions and instructions detailed in the 
‘Adverse Event Reporting’ section of the ISF. 
For each AE, the investigator will provide the onset date, end date, CTCAE grade, treatment 
required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in
Section 5.2.2.1. 
All AEs, including those persisting at the end of study treatment must be followed up until 
they have resolved or have been sufficiently characterised or the local clinical monitor and 
the investigator agree to not further pursue them.
If not stipulated differently in the ISF, the investigator must report the following events via 
fax using the paper SAE form immediately (within 24 hours or the next business day 
whichever is shorter) to the sponsor: SAEs, protocol-specified AESIs, and non-serious AEs 
which are relevant for the reported SAE or AESI.   


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BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non-serious 
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the event.  If the event description is correct, the 
item “serious” needs to be ticked and an SAE has to be reported in expedited fashion 
following the same procedure as above. The list of these AEs can be found via the Remote 
Data Capture system.
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the ISF). This immediate report is 
required irrespective of whether the investigational product has been administered or not and 
irrespective of causal relationship. It also applies if new information to existing SAEs or 
protocol-specified AESIs becomes available. 
5.2.2.4
Pregnancy
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 two 
years. 
Women of childbearing potential should use a highly effective method of birth control during 
the study and should continue for at least three months after ceasing nintedanib/placebo and 
for at least 12 months after ceasing chemotherapy. In any case, continuing contraception after 
ceasing study medication should be done based on the latest information available for 
nintedanib (see most updated IB (c01632700) and for pemetrexed / cisplatin (see SPC)).
As a precaution, male or female partners of patients should use an acceptable form of
contraception while the patient is on study treatment and for three months thereafter.
Should a woman become pregnant or suspect she is pregnant while she or her partner is 
participating in this study (including 3 months thereafter), she should inform her treating 
physician immediately.
In rare cases, pregnancy might occur in clinical trials. Once a female patient has been 
enrolled into the clinical trial, after having taken study medication, the investigator must 
report immediately any drug exposure during pregnancy to the sponsor. Drug exposure 
during pregnancy has to be reported immediately (within 24 hours or next business day 
whichever is shorter) to the defined unique entry point for SAE forms of the respective BI 
OPU (country-specific contact details will be provided in the ISF). The outcome of the 
pregnancy associated with the drug exposure during pregnancy must be followed up. In the 
absence of an (S)AE, only the Pregnancy Monitoring Form for Clinical Trials and not the 
SAE form is to be completed. The ISF will contain the Pregnancy Monitoring Form for 
Clinical Trials (Part A and Part B).
5.2.3
Assessment of safety laboratory parameters
Blood samples must be collected at the time points specified in the protocol flow charts. 
Additional laboratory tests as medically indicated may be performed at the discretion of the 


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investigator. Safety laboratory examinations include haematology, biochemistry, coagulation, 
and thyroid parameters. 
During the combination treatment period, safety lab parameters must be performed on Day 1 
and on Day 8 and assessed by the site. Lab results should be received by the site within 24 
hours. 
In case a patient has to commence anticoagulation therapy during the study, laboratory 
examinations concerning the coagulation status of the patient have to be performed at 
intervals deemed necessary by the investigator until stable anticoagulation is reached. Once a 
stable therapeutic anticoagulation status has been attained, the therapeutic anticoagulation 
status should be checked every week for 3 weeks. Thereafter, the anticoagulation status 
should be monitored at closer intervals if deemed necessary by the investigator.
The following parameters will be determined:

Haematology: haemoglobin, white blood cell (WBC) count, ANC, and platelets 

Biochemistry: glucose, sodium, potassium, calcium, phosphorus, magnesium, serum 
creatinine, aspartate transferase (AST), alanine transferase (ALT), ALP, lactate 
dehydrogenase (LDH), bilirubin (in case of increased bilirubin, direct and indirect 
bilirubin have to be measured), blood urea or blood urea nitrogen (BUN), total protein, 
uric acid

Coagulation parameters: PT and INR and PTT
If laboratory investigations have been performed within 2 weeks prior to screening, the 
results may be used to assess eligibility at screening. At C1V1, eligibility for inclusion in the 
study should be based on lab analyses completed within 3 days of randomisation. During the
treatment period, if the lab investigations have been performed within 3 days prior to a visit 
and complete results are available, they do not have to be repeated. However, the reference 
ranges should be provided to the sponsor in case a different laboratory was used.
Urine (pH, glucose, erythrocytes, leukocytes, protein, nitrite) will be analysed by dipstick 
(semi quantitative measurements: -, +, ++, +++) at the time points specified in the flow 
charts. In case of pathological findings, further evaluation should be performed and the 
findings documented in the eCRF on the AE pages.
If the dipstick result is positive, urinary sediment should be examined (microscopic 
urinalysis). Clinical relevant abnormal findings in the urinary sediment should be treated or 
further evaluated according to standard of care. In patients with repeated positive dipstick 
(++, +++, ++++), creatinine clearance and protein excretion in 24-hour urine or 
protein/creatinine ratio in a random urine sample should be determined. Proteinuria should be 
followed up until resolution or until final diagnosis is available.
5.2.4
Electrocardiogram
A 12-lead resting ECG will be performed at every cycle for Phase II and at every other cycle 
for Phase III according to standard local procedures at the time points specified in the flow 
charts. If the ECG has been performed within 3 days prior to a visit, it does not need to be 


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repeated. The investigator should review the ECG during the study and any clinically 
significant findings will be reported in the eCRF on the AE pages.
5.2.5
Assessment of other safety parameters
5.2.5.1
Physical examination, height, weight, ECOG performance score
A general physical exam will be performed at screening and at the time points specified in the 
flow charts. 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 score will be performed at the time points specified in the flow charts.
5.2.5.2
Vital signs
Vital signs (blood pressure and pulse rate after two minutes supine rest) and temperature (oral 
and/or tympanic) will be recorded at the time points specified in the flow charts.
5.3
OTHER
5.3.1
Demographics and history
Demographics (sex, birth date, race if allowed by local laws), information on smoking, 
alcohol history, asbestos exposure and baseline conditions will be collected during the 
Screening Visit.
The date of first histological diagnosis, the histological subtype (epithelioid or biphasic), the 
tumour stage (tumour nodes metastases [TNM] and union for international cancer 
control/American joint committee on cancer [UICC/AJCC]), the number and location of 
local, lymphogenous or distant metastatic sites, and European organisation for research and 
treatment of cancer (EORTC) prognosis factor will be documented as obtained at diagnosis 
and at the time of inclusion into the study. Previous surgeries and radiotherapies must be 
reported.
 
 
 
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor safety aspects. 
The scheduled measurements are appropriate to see drug induced changes in vital signs, 
standard laboratory values, biomarkers specific to efficacy and ECG. The primary and 
secondary endpoints are standard and accepted for evaluation of safety and tolerability of an 
anticancer drug, and they are widely used in this kind of study. AEs are graded according to 
the CTCAE criteria (version 3.0 for Phase II and version 4.03 for Phase III), which are 
commonly used in the assessment of AEs in cancer patients. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All patients are to adhere to the visit schedule as specified in the flow charts. In case a patient 
misses a visit and the patient reports to the investigator between the missed and the next 
scheduled visit, the delayed visit should be done and the actual date and the reason should be 
documented for the delayed visit. Subsequent visits should follow the original visit schedule.
Additional unscheduled clinic visits might be arranged at the discretion of the investigator. 
For unscheduled visit, it is sufficient to record only the clinically relevant labs and safety 
findings on the AE eCRF.
For a detailed overview of the trial procedures and time windows for visits, please refer to the 
flow charts.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period
Written informed consent must be obtained before any protocol specific screening 
assessments are performed. Screening should be completed within the next 14 days, and if the 
patient qualifies, the first study drug administration should occur within 15 days after 
informed consent. The screening period may be longer in case of administrative issues and/or 
if the patient needs to recover from an intercurrent disease.
Patients must satisfy all inclusion and exclusion criteria prior to treatment administration. 
Details of any patient who is screened for the study but is found ineligible must be entered in 
an enrolment log (see ISF) and documented in the eCRF.
For a detailed description of the trial procedures at the screening visit, refer to flow chart –
Combination Therapy. 
6.2.2
Treatment period
A treatment cycle is defined as 21 days. If initiation of a subsequent cycle is delayed due to 
medical reasons, a visit beyond day 21 may be necessary. Additional unscheduled visits may 
be performed at investigator’s discretion if medically indicated, which should be recorded in 
the eCRF. For a detailed description of trial procedures during the treatment periods, refer to
flow charts.
Patients will be eligible for a new treatment cycle if they:

Do not present with clinical signs of tumour progression as assessed by the investigator,

Have not met the criteria for PD assessed with the most recent imaging evaluation, 

Are continuing to benefit from study treatment (in the opinion of the investigator), despite 
progression,

Do not present with unacceptable drug related AEs


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The investigator will be asked to document in the eCRFs each time they wish to give patient 
another treatment cycle of study medication.
Once the treatment of pemetrexed / cisplatin has discontinued at the end of cycle 6 (or earlier
if necessary), patients who have not experienced disease progression or patients that are 
benefiting from treatment beyond radiological progression (see Section 5.1.2.1.5) will 
continue to receive nintedanib monotherapy or placebo monotherapy until the decision to end 
study treatment. Refer to flow charts – Monotherapy
6.2.3
End of trial and follow-up period
6.2.3.1
End of Treatment (EoT) visit
The EoT visit will be performed in the event of disease progression or decision to end all 
study medication. The EoT visit should be performed as soon as possible after the permanent 
discontinuation of study medication. For a detailed description of trial procedures at EoT,
please refer to flow charts – only additional critical information is listed below:

Completion of active treatment including reason for conclusion or if applicable premature 
discontinuation of study treatment, date of last administration of the trial drug must be 
recorded.

If patient has not progressed (unless tumour assessment performed within the past 3 
weeks), or if PD is suspected at time of visit, imaging must be performed.
6.2.3.2
Follow-up visit
The whole follow-up period is defined from the end of active treatment with trial medication 
until death or lost to follow-up, refusal to be followed up, end of the whole trial or until the 
required OS events have been reached. In case the trial is declared negative at the Phase III 
interim OS analysis, the follow-up period of Phase III patients will also stop at that time. For 
Phase II patients, the follow-up period will end after the primary Phase III PFS analysis (see 
Section 7.3). All patients should return to the investigational site ≥28 days for Phase II and 
≥30 days for Phase III after last administration of study treatment for the FU1 visit and 
preferably before starting a new anti-cancer therapy.
The following will be obtained and/or performed during FU1:

Date of contact

Physical exam

Follow-up of ongoing AEs that were not yet recovered at EoT

Record performance score (e.g. ECOG) 


Subsequent anti-cancer treatment (if applicable)

Outcome (date of and reason for death, in case the patient had PD the actual date of PD 
shall be recorded)


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6.2.3.3
Follow-up for progression
Patients who did not progress before discontinuing study treatment will enter the follow-up 
for progression period. Follow up for progression visits should be performed at six week 
intervals or earlier if appropriate (i.e. to meet the six week imaging schedule which starts 
with the day of first administration of pemetrexed/cisplatin in the first combination cycle). 
The follow-up for progression period will end when one of the following events is met:

Lost to follow-up / refusal of follow up

Disease progression

Start of subsequent anti–cancer therapy 

Death

End of the whole trial (see Section 6.2.3.5)

Phase II patients only: time point of the primary Phase II OS analysis (see Section 7.3)

Phase III patients only: Required number of OS events have been reached (Section 7.3)
The following will be obtained and/or performed during the follow-up visits for progression.

Date of contact

Related SAE/AESI and concomitant medication

Record performance score (e.g. ECOG) 

Perform tumour assessment and imaging 

Subsequent anti-cancer treatment (if applicable)

Outcome (date of and reason for death, in case the patient had PD the actual date of PD 
shall be recorded)
6.2.3.4 Follow-up for OS (Phase II patients)
For Phase II patients, the follow-up for OS period will end after the primary Phase III PFS
analysis. Regardless of whether they progressed on treatment, Phase II patients will be 
followed every 12 weeks until death, lost to follow-up, withdrawal of consent (follow-up for 
OS can be conducted by phone interview). Aside from survival status, no additional data will 
need to be collected.
6.2.3.5 Follow-up for OS (Phase III patients)
All Phase III patients will be followed-up for OS every 12 weeks until death, lost to follow-
up, end of the whole trial or until the required number of OS events have been reached for the 
primary analysis, whichever occurs earlier. In case the trial is declared negative at the interim 
OS analysis of the Phase III part, the follow-up period will also stop at that time. 
Patients who progressed before and have discontinued study medication will enter the follow-
up for OS period. Patients that progress during the follow-up for progression period will enter 
the follow up for OS period once they have progressed. These visits may also be performed 
by telephone interview or via written correspondence in case the patient is unable to visit the 
investigator.
The following information will be collected during the follow-up for OS period:


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
Date of contact

Subsequent anti-cancer treatment (if applicable)

Related SAE/AESI and concomitant medication

Outcome event (e.g. death: Record date of and reason for outcome event / death)
6.2.3.6
End of trial
A patient is considered to have completed the trial in case any of the following applies:

Completion of planned follow-up period 

Lost to follow-up

Refusal to be followed-up

Death
The end of the whole trial will occur when one of the following situations occurs:

When the required number of OS events has occurred and the last patient has completed 
the first follow-up visit.

When the trial is declared positive for PFS and OS at the interim OS analysis of the Phase 
III part (enrolment into the trial will be stopped) and the last patient has completed the 
first follow-up visit.

When the trial is declared negative at the interim OS analysis of the Phase III part (see 
Section 7.3.1 and Section 7.3.4) (enrolment into the trial will be stopped) and the last 
patient has completed the first follow-up visit.
If patients are still ongoing or in follow-up at the time of the clinical trial report for the 
primary OS analysis of the Phase III part, the clinical trial database will be kept open to 
collect the additional data. After end of trial, the final results will be reported either in a 
separate clinical trial report or in a revised trial report. The final analysis of the Phase II part 
of the study will be reported in an analysis report. No unblinding of Phase III data will 
happen at this time. The Phase III primary PFS analysis and the Phase III primary OS 
analysis will be reported in a CTR.
If the trial is ended by the sponsor for any reason when patients are still being treated with a 
clinical benefit, the patients will be offered treatment in a follow-up trial which will allow 
patients to continue to receive treatment as long as the treating investigator deems it 
appropriate. If the trial is terminated by the sponsor for safety reasons, patients will not 
continue treatment with the trial drug.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a randomised, double-blind, placebo-controlled phase II/III clinical trial in which the 
efficacy and safety of nintedanib + pemetrexed / cisplatin followed by nintedanib will be 
evaluated against the matching placebo + pemetrexed / cisplatin followed by placebo, as first-
line treatment for unresectable MPM patients. Randomisation is stratified by epithelioid vs. 
biphasic histology for the Phase II part but is not stratified for the Phase III part.
The Phase III part of this trial will be conducted as a two-stage adaptive design for OS with 
OS event number reassessment at the interim OS analysis which will take place at the time of 
the primary Phase III PFS analysis. The Phase II patients will not be included into the 
confirmatory analyses of this trial (analysed separately).
Progression-free survival, as measured from the time of randomisation to the time of disease 
progression or death of any cause, is the primary efficacy endpoint. OS, as measured from the 
time of randomisation to the time of death of any cause, is the key secondary endpoint and 
objective tumour response and disease control are the secondary efficacy endpoints.
 
 
For PFS and OS in the Phase II part as well as PFS in the Phase III part, Kaplan-Meier 
estimation and log-rank test will be the primary analysis method. For the adaptive design for 
OS with OS event number reassessment with regard to the Phase III patients, the weighted 
inverse normal method described by Lehmacher and Wassmer (R14-1197) combining one-
sided p-values from a log-rank test will be the primary analysis method for OS. The 
Lehmacher and Wassmer method is a generalisation of the method described by Cui et al 
(R08-2069).
7.2
NULL AND ALTERNATIVE HYPOTHESES
Statistical hypotheses will be formally only tested for the Phase III patients. For Phase II 
patients, all analyses are exploratory, no formal hypotheses will be tested and all p-values are 
to be understood as exploratory. 
For Phase II, two-sided exploratory p-values will be presented throughout. For Phase III, one-
sided p-values will be presented throughout since one-sided p-values are required for the 
weighted inverse normal method. For consistency, they will then be used for all endpoints. If 
two-sided p-values are to be considered, their derivation will be described in the TSAP.
For Phase III, the alternative hypothesis for the primary analysis of the primary endpoint PFS 
and the key secondary endpoint OS is that PFS and OS are longer for patients treated with 
nintedanib plus pemetrexed/cisplatin than for patients treated with placebo plus 
pemetrexed/cisplatin. According to a hierarchical testing procedure, a benefit of PFS will be 


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tested first. If this test proves to be significant in favour of nintedanib, a benefit of OS will be 
tested.
Based on a one-sided test, the null hypothesis for PFS in this trial is
H01: SPFS, Nin+Pem/Cis(t) <= SPFS, Plac + Pem/Cis(t) for t>0,
where SPFS(t) is the probability that a patient passes time t without dying or experiencing 
disease progression. The further subscripts represent the two treatment groups. If this null 
hypothesis can be rejected, the null hypotheses for OS will be tested 
H02: SOS, Nin+Pem/Cis(t) <= SOS, Plac + Pem/Cis(t) for t>0,
where SOS(t) is the probability that a patient passes time t without dying.
The corresponding alternative hypotheses are
HA1: SPFS, Nin+Pem/Cis(t) > SPFS, Plac + Pem/Cis(t) for some t>0
and
HA2: SOS, Nin+Pem/Cis(t) > SOS, Plac + Pem/Cis(t) for some t>0.
The effect of nintedanib on PFS and on OS will be based on two one-sided tests, both with a 
one sided alpha level of 0.025. Due to the hierarchical testing procedure chosen, no alpha 
adjustment is required to account for multiple testing. However, adjustments accounting for 
the planned interim Phase III OS analyses are done by using an O’Brien-Fleming like error 
spending function (see Section 7.3.2.1) and using the weighted inverse normal combination 
function approach for OS. Thus, control of the global overall significance level of 0.025 (one-
sided) for PFS and OS is assured (see Section 7.3.1).
7.3
PLANNED ANALYSES
Efficacy analyses will follow the intention-to-treat principle and will include all randomised
patients whether the patient is treated with the study medication or not. For the primary 
confirmatory analyses of all endpoints in this trial, only the data of the Phase III patients will 
be included. For the analyses of the Phase II patients the analyses methods for all endpoints 
are described separately. The time point of primary PFS analysis of the Phase II patients was 
04–Mar-2016, the primary OS analysis of the Phase II patients will be done when 
approximately 61 OS events with regard to the Phase II patients have occurred. 
 
Safety analyses will include all 
treated patients who are documented to have taken any dose of the study medication, and will 
be reported separately for Phase II and Phase III patients, as well as pooled for all treated 
Phase II and Phase III patients together. For the pooled safety analyses, a residual effect 
period of 30 days will be used to determine the on-treatment period.


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No per protocol set will be used in the analyses. However potential important protocol 
violations will be summarised and violations of inclusion and exclusion criteria will be 
provided in a subject data listing. The Core Trial Statistical Analysis Plan will specify the 
potential important protocol violations in detail.
Phase II
The analyses for the Phase II primary PFS analysis have been specified in a separate Interim 
Phase II TSAP. The Phase II primary OS analysis will occur when approximately 61 OS 
events with regard to the Phase II patients have occurred (see Section 7.6). For the Phase II 
patients continuing follow for survival after the primary OS analysis, an analysis will be 
performed approximately one year after the primary OS analysis and in addition at the time 
of the primary PFS analysis of the Phase III part of this study. The respective analyses will be 
described in the Phase II TSAP.
Phase III
The primary Phase III PFS analysis will be performed once the required number of 
approximately 199 PFS events has been reached. At the same time, the interim Phase III OS 
analysis will be performed. Details about the Phase III analyses will be described in the Phase 
III TSAP.
In case a statistically significant result for the primary endpoint PFS is observed at the time of 
the primary PFS analysis, the trial will be declared positive for the primary endpoint. If 
statistically significant results for the primary endpoint PFS and the key secondary endpoint 
OS (tested in a hierarchical order) are already observed at the time of the primary PFS 
analysis, the trial will be declared positive for the primary endpoint PFS and the key 
secondary endpoint OS, and all secondary and further endpoints will be analysed, and 
enrolment into the trial will be stopped. If no statistically significant result for PFS is 
observed at the primary PFS analysis, the trial will be declared negative, and enrolment into 
the trial will be stopped. Otherwise, the DMC will reassess the needed number of OS events 
for the primary OS analysis. The number of OS events for the primary OS analysis can then 
be increased from 279 up to 346 OS events (see Section 7.6). In case a statistically significant 
result for the key secondary endpoint OS is observed at the time of the primary OS analysis, 
the trial can be declared also positive for the key secondary endpoint. The testing scheme is 
further described in Sections 7.3.1 and 7.3.2 below and illustrated in Figure 3.1: 2.
7.3.1
Primary analyses
For Phase II, the primary analysis of PFS has been conducted on 04-Mar-2016 based on 69 
PFS events from the 87 Phase II patients.
For Phase III, the primary analysis of the primary endpoint PFS will be conducted when 
approximately 199 PFS events have occurred for the Phase III patients. This is expected to 
take approximately 20-27 months after the first Phase III patient has been randomised
assuming an accrual rate of 14-22 patients per months. At this point, the database will be 
locked and un-blinded as described in Section 7.3.4. The investigators, patients, clinical 
monitors, trial team and others involved in the further conduct of this trial will not be 


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unblinded. The PFS analysis will be based upon the evaluation of tumour imaging and 
clinical information as performed by the investigators, who are blinded to treatment 
assignments. Tumour assessments will be evaluated according to the modified RECIST 
criteria (R12-1990).
For patients with known date of progression or death:
PFS [days] = earlier date of progression or death – date of randomisation + 1.
For patients who will be censored:
PFS [days] = date of last imaging assessment without disease progression – date of 
randomisation + 1.
For Phase II, Kaplan-Meier estimates of the survival function of PFS, median PFS and the 
corresponding 95% CI using Greenwood variance that is incorporated into the Brookmeyer 
and Crowley method (R09-6372) with a loglog transformation, as well as the p-value of the 
two-sided stratified (epithelioid vs. biphasic histology) log-rank test on PFS will be provided. 
For the Phase II analysis, this p-value is only to be understood as exploratory. In addition, 
stratified Cox proportional hazards model (stratified on epithelioid vs. biphasic histology) 
will be fitted to estimate the hazard ratio (HR) and the corresponding 95% CI between the 
two treatment arms. For Phase III, the p-value will be inferred from a one-sided log-rank test 
without any stratification factor. The HR and the corresponding 95% CI will be estimated by 
fitting a Cox proportional hazards model.
 
 
 
 
 
 
 
 
 


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7.3.2
Secondary analyses
7.3.2.1 Overall Survival (key secondary endpoint)
For patients with known date of death of any cause:


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OS [days] = date of death – date of randomisation + 1.
For patients who died but with unknown date of death of any cause:
            OS [days] = date of last contact when the patient is known to be alive – date of 
randomisation + 1 (for patients in the nintedanib arm)
            OS [days] = date of data snapshot – date of randomisation + 1 (for patients in the 
placebo arm)
For patients who will be censored:
OS [days] = date of last contact when the patient is known to be alive – date of 
randomisation + 1.
For Phase II, the same statistical methods and analyses applied for PFS will also be 
conducted for OS (primary analysis model, 
 
For Phase III, OS will be analysed along with the primary analysis of PFS in a hierarchical 
order. Thus, no multiplicity adjustment will be made for analysing the two endpoints, PFS 
(primary endpoint) and OS (key secondary endpoint). The alpha-level for OS will follow an 
O`Brien and Fleming spending function to preserve the overall alpha of 0.025 (one-sided) for 
the final OS analysis. 
The analysis of the key secondary endpoint OS will be performed using the weighted inverse 
normal method described by Lehmacher and Wassmer (R14-1197) with right-censoring the 
patients without event at the interim OS analysis and left-truncation of all patients with regard 
to the interim analysis time point and right censoring at the time of the primary OS analysis. 
This is asymptotically equivalent to using the independent, normally distributed increment 
structure of the respective log-rank statistics (R15-0928). The approach of independent 
increments is justified since solely OS information will be used for the event number 
reassessment. The follow-up time will be split into two stages: time for stage 1 (right 
censoring) and time for stage 2 (left censoring). Two one-sided p-values will be calculated, 
one for each stage. For the first stage, the p-values is based on the initial log-rank statistics 
until the interim OS analysis, and for the second stage, the p-value is based on the increment 
of the log-rank statistics from the time of the primary OS analysis as compared to the interim 
OS analysis. The final test for statistical significance at the primary OS analysis will be then
based on combining these p-values via the weighted inverse combination function. 
For the calculation of the final and the interim test statistics, the inverse-normal stagewise p-
value based approach will be used according to Lehmacher and Wassmer (R14-1197). This is 
a generalization of the method described by Cui et al (R08-2069). Here, the p-values of the 
two different parts will be combined. Based on that principle, the test statistics TiOS (i=1,2),
on the p-scale for Stage 1 and Stage 2 are defined as:


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Formula 5.1.1:1
based on Stage 1
Formula 5.1.1:2
based on Stage 1 
and Stage 2
where wi (i=1,2) are the predefined weights for Stage 1 and 2 with w1
2 + w2
2=1 
.Φ denotes the standard normal distribution function and z1-piOS (i=1,2) denote 
the (1-piOS) -quantiles of the standard normal distribution function. p1OS denotes the stagewise 
one-sided p-value derived from the log-rank test statistics for OS (for stage 1) and p2OS the 
one-sided p-value from the increment of the log-rank statistics at the time of the primary OS 
analysis (for stage 2), respectively. 
Here, the weights are chosen to be approximately proportional to the expected stage-wise 
numbers of OS events. 
The expected number of OS events at the time of the interim OS analysis (at the time when 
approximately 199 PFS events have occurred) is approximately 140 OS events. Depending 
on the event number reassessment, the total number of OS events can be increased from 279 
to 346 OS events. Thus, the fraction of OS events at the interim analyses will be around 0.4 
to 0.5. Therefore, the weights are chosen as 
and 
.
The stopping boundaries in a classical group-sequential design are usually specified by an 
error spending function. The commonly used O’Brien-Flemming-like error-spending function 
π* will be used for OS.
The O’Brien-Fleming-like error-spending function π* with one-sided α is given by
Formula 5.1.1:3
            
where τi is the information fraction at the i-th stage τi will be calculated as
Formula 5.1.1:4
,                  
where di is the observed number of events for the i-th stage and D is the planned number of 
OS events at the primary OS analysis. The error-spending function π* gives the cumulative 
error spent up to the information fraction τi. 
The error spending function will ensure an overall alpha level of α (one-sided). 


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For this trial, the error to spend at stage 1 is 
, where τ1 will be calculated as 
described in Formula 5.1.1:4, d1 is the observed number of OS events at the interim Phase III 
OS analysis (events for stage 1) and D = 279 the planned number of OS events at the primary 
OS analysis. 
At the interim OS analysis the log-rank-test will be used to derive the stage-wise one-sided p-
value p1OS. p1OS will be derived from the log-rank test based on stage 1(right censoring for all 
patients without event at the interim OS analysis). The test statistics T1OS on the p-scale for 
OS will be calculated as described in Formula 5.1.1:1. The stage-wise 
-value is
.
At the time of the primary Phase III PFS analysis/interim Phase III OS analysis, first PFS will 
be tested for a statistically significant result as described in Section 7.3.1. If PFS is not 
significant, OS will not be tested and the trial will be declared negative, and further 
recruitment into the trial will be stopped. If PFS is significant (i.e. the trial can be declared 
positive for the primary endpoint), OS will be tested and if 
, a statistically 
significant result for both endpoints at the primary PFS analysis/interim OS analysis is 
reached. The trial will then be declared positive for the primary and the key secondary 
endpoint, and further recruitment into the trial will be stopped.
If the trial is declared positive at the Phase III primary PFS analysis/interim OS analysis for 
the primary endpoint PFS and the key secondary endpoint OS, all patients will be unblinded. 
Patients in the nintedanib arm will remain on nintedanib treatment while treatment with 
placebo will be discontinued and these patients will be offered to switch to nintedanib 
treatment. All patients will be followed up until they have stopped treatment, and additional 
safety and efficacy data will be collected. Still, due to the bias introduced by patients 
switching from the placebo arm to the nintedanib arm, the OS and PFS analyses will not be 
repeated after all patients have completed treatment. OS and PFS will be only analysed 
descriptively with regard to all patients (no treatment comparison).
If the study is declared positive for the primary endpoint PFS only at the interim OS analysis, 
the DMC will reassess the OS event number needed for primary OS analysis based solely on 
OS data available at the time of the interim OS analysis. In particular, no PFS information 
will be used to reassess the OS event number. The reassessment rules will be based on a 
conditional power approach (more details will be described in the DMC Charter). Depending 
on the event reassessment, the total number of OS events for the primary OS analysis can be 
increased from approximately 279 to 346 OS events.
For the primary OS analysis, 
= 0.025 -
The stage-wise p-value 
will be derived 
from the increment of the log-rank test at the time of the primary OS analysis (left truncation 
of patients at the time of the interim analysis). The test statistics 
based on the p-scale 
will be calculated as described in Formula 5.1.1:2.
The stopping boundary 
will be determined such that


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If 
, the key secondary endpoint OS will be met, and the trial will be declared 
positive for the key secondary endpoint as well.
Kaplan-Meier estimates of the survival function of OS, median OS and the corresponding 
95% CI using Greenwood variance that is incorporated into the Brookmeyer and Crowley 
method (R09-6372) with a loglog transformation will be provided. 
To estimate the HR for OS, the median unbiased estimator (R14-2334) will be used as 
primary estimator. In addition, as a secondary estimator, the partial maximum likelihood 
estimator from the Cox proportional hazards model will be used. The corresponding 95% 
repeated CIs (R14-2334) and the repeated overall p-value (R99-1290) will be calculated.
Additionally, analyses will be conducted to describe the pattern of time to death, while 
accounting for the extent and influence of post-progression anti-cancer treatments.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.3.2.4 Objective Tumour Response (Phase II and Phase III)
Objective tumour response is defined as a best overall response of CR or PR. Objective 
tumour response rate (ORR) gives the percentage of patients with objective tumour response. 
Logistic regression will be used to test for a difference between regimens for objective 


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tumour response rate. For Phase II, the model will be adjusted for the stratification factor
tumour histology (epithelioid vs. biphasic). Kaplan-Meier methods will be used for the 
calculation of duration of objective tumour response.
7.3.2.5 
Disease Control (Phase II and Phase III)
Disease control is defined as a best overall response of CR, PR, or SD. Disease control rate 
gives the percentage of patients with disease control.
Logistic regression will be used to test for a difference between regimens for disease control 
rate. For Phase II, the model will be adjusted for the stratification factor tumour histology 
(epithelioid vs. biphasic). Kaplan-Meier methods will be used for the calculation of duration 
of disease control.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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7.3.3
Safety analyses
At the time of the primary OS analysis for Phase II, all treated Phase II patients will be 
included in the safety analyses. At the time of the primary PFS analysis and the primary OS 
analysis for Phase III, all treated Phase III patients will be included in the safety analyses.
In case the trial is already declared positive for PFS as well as for OS at the Phase III primary 
PFS/interim OS analysis, patients on placebo will be offered to switch to nintedanib 
treatment. For final reporting of all safety data at the end of the whole trial, patients switching 
from placebo to the nintedanib arm will be analysed separately from all other patients.
In addition, at the time of the primary Phase III PFS analysis and at the time of the primary 
Phase III OS analysis, safety analysis will be conducted with pooled data of Phase II and 
Phase III patients together using a REP of 30 days. 
For all treated patients the incidence and severity, as graded according to CTCAE (version 
3.0 for Phase II and version 4.03 for Phase III) of AEs will be analysed descriptively and the 
following key safety assessments will be conducted and presented:

Adverse event overall summary

Adverse events leading to dose reduction or permanent treatment discontinuation

Serious adverse events

Adverse events leading to death

Related adverse events

Protocol-specified AESI
Descriptive statistics will also be used to describe changes in laboratory values over time and 
between the two treatment groups. Furthermore, all abnormal laboratory values of potential 
clinical significance will be reported.


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7.3.4
Interim analyses
Primary PFS analysis of Phase II patients
On 04-Mar-2016, as requested by authorities, data for the 87 Phase II patients in this trial was 
unblinded to allow for a more precise planning of the Phase III part of this trial. Since the 
data of these patients will not be included in the confirmatory analyses of this trial, this 
analysis has been conducted by the trial team. Details about the analyses are described in the 
interim Phase II TSAP. Once unblinded, access to the summary data was available to BI and 
externally under confidentiality. Only a limited number of people from the sponsor had 
access to unblinded patient level data. Details about the restricted access to unblinded 
information on a patient level are described in the interim Phase II TSAP. 
Primary OS analysis of Phase II patients
When approximately 61 OS events from the Phase II patients have occurred, the primary OS 
analysis of the Phase II part of this trial will be conducted. Only Phase II patients will be 
unblinded at this time. This analysis will be reported in a clinical trial report. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Formal interim analysis of the key secondary endpoint OS
In line with the Phase III Primary PFS analysis (after approximately 199 PFS events have 
occurred), the interim Phase III OS analysis will be performed. The trial database will be 
locked and unblinded by a team independent from the trial team tasked to write a report and, 


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subsequently, a regulatory dossier if indicated. Thus, investigators, patients, clinical monitors, 
trial team and others involved in the continuing trial will not be unblinded. An interim 
logistics plan will be set up to describe the firewalls and how data protection will be ensured.
 
 
 
 
 
7.4
HANDLING OF MISSING DATA
In general, missing data will not be imputed. Every effort will be undertaken to obtain the 
date of progression for patients known to have progressed, obtain the date of death for 
patients known to have died, and to obtain complete information on all AEs.
For partial or missing AE onset and/or end dates, BI internal rules will be applied for 
imputation. For the primary PFS analysis of Phase II and Phase III, the censoring rules as 
outlined in Table 7.4: 1 will be used.
Table 7.4: 1 
Description of censoring rules for PFS
Situation**
Outcome (event 
or censored)
Date of outcome
No baseline radiological assessment
Patient with death on or before the second 
planned radiological assessment
Event 
Date of death
Patient without death or patient with death 
after second performed radiological 
assessment
Censored
Date of randomisation 


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Table 7.4: 1 (cont’d)
Description of censoring rules for PFS
Situation**
Outcome (event or censored)
Date of outcome
Without post-baseline radiological assessments
Vital status is unknown or patient is known to be 
alive
Censored
Date of randomisation  
Death prior or on the second planned radiological 
assessment
Event
Date of death
Death beyond the second planned radiological 
assessment
Censored
Date of randomisation  
With baseline and post-baseline radiological assessments BUT no subsequent anti-cancer therapy
Alive and not progressed, no more than one 
consecutively missed radiological assessments
Censored
Date of last radiological 
assessment
Alive and not progressed, two or more 
consecutively
  missed radiological assessments
Censored
Date of last radiological 
assessment prior to missed 
radiological assessments
Progressed, zero or one missed radiological 
assessment prior to progression 
Event
Date of radiological assessment of 
progression
Progressed, but two or more consecutively missed 
radiological assessments prior to progression
Censored
Date of last radiological 
assessment prior to missed 
assessment
Death but no progression, zero or one missed 
radiological assessment prior to death
Event
Date of death
Death without progression, but two or more 
consecutively missed radiological assessments 
prior to death
Censored
Date of last radiological 
assessment prior to missed 
assessments
Initiation of subsequent anti-cancer therapy
Subsequent anti-cancer therapy started before 
progression or death*
Censored
Date of last radiological 
assessment before subsequent 
anti-cancer therapy
No baseline and/or post-baseline imaging and 
subsequent-anti cancer therapy started prior to a 
death
Censored
Date of randomisation 
*Subsequent treatment with pemetrexed/cisplatin/nintedanib will not trigger censoring of PFS
**If appropriate, a sensitivity analysis will be done using interval censoring methods
Table 7.4: 2
Description of the classification of patients for the analysis of OS. 
Status at time of analysis
Outcome (event 
or censored)
Date of outcome
Patient died and the date of death is 
known 
Event
Date of death
Patient died and date of death is 
unknown
Event
Nintedanib arm: Date patient last known 
to be alive
Placebo arm: Date of data snapshot
Patient alive
Censored
Date of last contact when the patient is 
known to be alive
Unknown
Censored
Date of last contact when the patient is 
known to be alive
These OS censoring rules will be applied for Phase III only. For Phase II, censoring rules as 
described in the Phase II TSAP will be used. For the pooled analysis, the censoring rules as
described here will be used.


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7.5
RANDOMISATION
Permuted block randomisation will be used to randomise patients in 1:1 ratio to nintedanib in 
combination with pemetrexed and cisplatin or the matching placebo in combination with 
pemetrexed and cisplatin. In addition, the randomisation was stratified by epithelioid vs. 
biphasic histology for the Phase II part. No stratification will be used for the Phase III part.
An IVRS/IWRS will be used to perform the randomisation centrally across all study sites. BI 
will arrange for the randomisation. A randomisation list will be generated by BI using a 
validated pseudo-random number generator, yielding reproducible and non-predictable 
results. For the Phase II and Phase III part of this trial, two separate randomisation lists have 
been generated. The randomisation scheme will not be disclosed to any on site personnel or 
BI internal trial team members until database lock and unblinding of the trial. For the 
unblinding of the data of Phase II patients in March 2016, only the randomisation list with 
regard to the Phase II patients has been unblinded to a limited number of persons, only the 
Phase II randomisation list will be used for unblinding of the Phase II patients for the primary 
Phase II OS analysis. The on-site personnel will also be blinded to the block size used in the 
randomisation. The randomisation scheme will be forwarded via a secure transmission to the 
CRO that produced the analyses for the DMC.
7.6
DETERMINATION OF SAMPLE SIZE
Phase II
The Phase II part of this randomised, double blind, placebo-controlled trial was carried out as 
a proof-of-clinical-concept trial to explore the efficacy and safety profiles of the combination 
regimen of nintedanib 200 mg b.i.d. on top of the standard treatment with pemetrexed and 
cisplatin in comparison with the matching placebo on top of the standard treatment with 
pemetrexed and cisplatin. The intent was to provide evidence that will allow informed 
decision making in terms of the next stages of development. The Phase II part of this trial was 
therefore sized such that, if the true effect of nintedanib + standard treatment versus the 
standard treatment alone was a HR of 0.75 (median PFS 8 vs. 6 months), the probability of 
observing a small HR was sufficiently large. On the other hand, if there was no treatment 
effect and the true HR was 1, the probability of erroneously observing a small HR was small 
enough.
Table 7.6: 1 summarizes for different numbers of PFS events the associated probabilities for 
observing HRs less than some thresholds under two assumptions for the true HR, 0.75 and 1 
respectively.


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Table 7.6: 1
Number of PFS events and corresponding probability of observing 
HRs below thresholds
Probability1 observing HR of ≤
PFS Events
True HR
0.8
0.9
1.0
50
0.59
0.74
0.85
65
0.75
0.60
0.77
0.88
80
0.61
0.79
0.90
Probability1 observing HR of ≤
PFS Events
True HR
0.75
0.8
0.9
50
1.0
0.15
0.22
0.35
65
0.12
0.18
0.34
80
0.10
0.16
0.32
1 Calculation based on the approximate normal distribution of the estimated log HR [R07-4680].
With 65 PFS events, if the true HR was 0.75, the chance of observing a treatment effect with 
HR ≤0.9 was 77%, while the risk of erroneously observing a HR > 1 was 12%. However, if 
there was no treatment effect, the risk of erroneously observing a HR of ≤0.75 was 12%, 
while the chance of observing a HR > 0.9 was 66%.
Sixty-five PFS events were considered sufficient for the Phase II part of this trial as extra 
benefit brought in by more events did not justify the cost and effort in the trial conduct.
Assuming the recruitment rate would be 6 patients per month, and 10% of the PFS events 
would not be observed due to early drop out, with 43 patients per treatment arm, the study 
duration until 65 observed PFS events was estimated to be approximately 27 months (Table 
7.6:2).
Table 7.6: 2
Study duration until 65 observed PFS events for different numbers of 
randomised patients
Patients 
randomised
Accrual time [months]
Trial duration until 65 PFS events 
[months]1
76
13
38
86
14
27
106
18
22
1 Assuming a true HR of 0.75 (median PFS 8 vs. 6 months), a recruitment rate of 6 patients per month, and that 10% of the
PFS events will not be observed due to early drop out.
Based on the recommendation of the DMC to change the trial to a confirmatory trial, and 
based on the results of the 04-Mar-2016 analysis for Phase II patients, an additional 450
Phase III patients will be randomised into this trial.
The primary PFS analysis of the Phase II part was conducted on 04-Mar-2016 for decision 
making and sample size estimation for planning of the Phase III part. At this time, 69 PFS 
and 37 OS events have been observed. The primary OS analysis of the Phase II part of this 
trial is planned be conducted when approximately 70% of the Phase II patients had an OS 
event (approximately 61 OS events). This is expected to occur in February 2017. Still, the 


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analyses might be performed with fewer OS events within the time until March 2017. At this 
time, assuming a true HR for OS of 0.73, the probability of observing a small HR is 
considered sufficiently large. On the other hand, if there is no treatment effect and the true 
HR is 1, the probability of erroneously observing a small HR is small enough. In addition, in 
an effort to continue to follow up patients on the Phase II part of the study, an analysis of OS 
data will be performed approximately one year after the primary OS analysis, and at the time 
of the primary PFS analysis for Phase III.
Table 7.6: 3 summarizes for different numbers of OS events the associated probabilities for 
observing HRs less than some thresholds under two assumptions for the true HR 0.73 and 1 
respectively (further details below).
Table 7.6: 3
Number of OS events and corresponding probability of observing 
HRs below thresholds
Probability1 observing HR of ≤
OS Events
True HR
0.8
0.9
1.0
50
0.63
0.77
0.87
61
0.73
0.64
0.79
0.89
70
0.65
0.81
0.91
Probability1 observing HR of ≤
PFS Events
True HR
0.75
0.8
0.9
50
1.0
0.15
0.22
0.35
61
0.13
0.19
0.34
70
0.11
0.18
0.33
1 Calculation based on the approximate normal distribution of the estimated log HR [R07-4680].
Phase III
Based on the observations of the Phase II analysis from March 2016 for patients with 
epithelioid tumour histology and accounting for a potential selection bias, it is assumed that 
nintedanib in combination with pemetrexed/cisplatin will increase median PFS by 3.5 months 
beyond treatment of placebo with pemetrexed/cisplatin when assuming a median PFS of 6 
months (HR 0.63). To achieve a power of 90% for the analysis of PFS, 199 PFS events are 
required. Assuming that 15% of the patients cannot be followed up until progression due to 
the censoring rules, 199 events are expected at the time of 23 months after start of 
randomisation into Phase III when assuming a recruitment rate of 18 patients per month (see 
Table 7.6: 4). According to these assumptions, not all 450 patients will be randomised at the 
time of the primary PFS analysis. These calculations have been performed with the statistical 
software Addplan, Version 6.0.4, using Schoenfeld formula for the calculation, and SAS 
Version 9.4.


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Table 7.6: 4
Statistical Power for Progression Free Survival (one-sided alpha 
2.5%)
Events
Patients
Median PFS*
Hazard ratio*
Statistical power
199a
450
6 vs. 9.5 months
0.63
90%
199b
450
6 vs. 9.3 months
0.65
87%
199c
450
6 vs. 9.0 months
0.67
82%
* Pemetrexed / cisplatin and placebo versus pemetrexed / cisplatin and nintedanib
a) For accrual rate 18 pts / month, time to events is 23 months. For accrual rate of 14 pts / month, time to events is 27 
months. For accrual rate of 22 pts / month, time to events is 20 months (assuming that 15% of PFS events are not 
observed)
b) For accrual rate 18 pts / month, time to events is 23 months. For accrual rate of 14 pts / month, time to events is 27 
months. For accrual rate of 22 pts/month, time to events is 20 months (assuming that 15% of PFS events are not observed)
c) For accrual rate 18 pts / month, time to events is 23 months. For accrual rate of 14 pts / month, time to events is 27 
months. For accrual rate of 22 pts / month, time to events is 20 months (assuming that 15% of PFS events are not 
observed)
Based on the observations of the Phase II analysis from March 2016 for patients of 
epithelioid tumour histology, and taking into account the selection bias and that the OS 
results are still considered premature, it is assumed that nintedanib in combination with 
pemetrexed and cisplatin will increase median OS by approximately 33-40% beyond 
combination treatment of placebo with pemetrexed and cisplatin assuming a median OS of 
14.5 months. Since OS data at the time of the Phase II analysis is considered premature (only 
48% of patients with epithelioid tumour histology had an event), an adaptive design with 
event number reassessment at the interim Phase III OS analysis will be implemented to 
account for the uncertainty of the OS treatment effect. At the time of the primary PFS 
analysis, around 140 death events are expected which will be used to analyse OS for the 
interim OS analysis and to perform an event number reassessment for OS.
Depending on the event number reassessment of OS at the time of the interim Phase III OS 
analysis, the final number of OS events needed for the primary Phase III OS analysis can be 
increased from approximately 279 OS events up to a maximum of approximately 346 OS 
events. Details about the adaptive design and the event number reassessment will be 
described in the DMC charter.
Table 7.6: 5 indicates that with 450 patients 279 death events would provide 80% power % 
power for OS if the underlying treatment difference were 5.8 months (HR=0.71). Assuming 
an underlying treatment difference of 5.1 months (HR 0.74), 346 death events would provide 
80% power for OS. With the event number reassessment, the Phase III part of this trial is 
designed to provide 80% power for OS for a treatment effect within the range of 0.71 – 0.74. 
279-346 OS events would be expected to occur within approximately 38-50 months if 450 
patients were randomised at a rate of approximately 18 patients per month. These calculations 
have been performed with the statistical software Addplan, Version 6.0.4, using Schoenfeld 
formula for the calculation, and an O’Brien and Fleming class spending function for an 
overall alpha of 0.025 (one-sided) for OS when adjusting for the interim look at the time of 
the primary analysis for PFS.


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Table 7.6: 5
Statistical Power for Overall Survival
Events
Patients
Median OS*
Hazard ratio*
Statistical power
346a
450
14.5 vs. 19.6 months
0.74
80%
305b
450
14.5 vs 20 months
0.73
80%
279c
450
14.5 vs 20.3months
0.71
80%
*  Pemetrexed/Cisplatin and placebo versus Pemetrexed/Cisplatin and nintedanib
a) For accrual rate 18 pts / month (accrual time 25 months), time to events is 50 months. For accrual rate 14 pts / month
(accrual time 32 months), time to events is 54 months. For accrual rate of 22 pts/month (accrual time 21 months), time to 
events is 47 months
b) For accrual rate 18 pts / month (accrual time 25 months), time to events is 42 months. For accrual rate 14 pts / month
(accrual time 32 months), time to events is 46 months. For accrual rate of 22 pts/month (accrual time 21 months), time to 
events is 39 months.
c) For accrual rate 18 pts / month (accrual time 25 months), time to events is 38 months. For accrual rate 14 pts / month 
(accrual time 32 months), time to events is 42 months. For accrual rate 22 pts / months (accrual time 21 months), time to 
event is 35 months.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the International Conference on Harmonisation 
(ICH) Harmonised Tripartite Guideline for GCP and relevant BI SOPs. Standard medical 
care (prophylactic, diagnostic and therapeutic procedures) remains in the responsibility of the 
treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol/ICH-GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a general rule, no trial results should be 
published prior to finalisation of the CTR. Interim trial related information (e.g. trial design, 
blinded safety data) may be presented in abstract form at medical congresses if agreed to by 
the co-ordinating investigator and BI.
Insurance Cover: The terms and conditions of the insurance cover are made available to the 
investigator and the patients via documentation in the ISF.
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective IRB / Independent Ethics Committee (IEC) and 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 ICF and any additional patient information form 
retained by the investigator as part of the trial records. A signed copy of the ICF and any 
additional patient information must be given to each patient or the patient’s legally accepted 
representative.
The patient must be informed that his/her personal trial-related data will be used by BI in 
accordance with the local data protection law. The level of disclosure must also be explained 
to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by BI, by appropriate 
IRB / IEC members, and by inspectors from regulatory authorities.


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8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the ICF documentation of this clinical trial.
8.3
RECORDS
Electronic Case Report Forms (eCRFs) for individual patients will be provided by the 
sponsor via remote data capture. See Section 4.1.5.2 for rules about emergency code breaks. 
For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
eCRFs and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The CRA / on site monitor 
and auditor may review all eCRFs, and ICFs. The accuracy of the data will be verified by 
reviewing the documents described in Section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular AE 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 (BIBF 1120), this is the current version of the IB (c01632700). 
For Pemetrexed and Cisplatin this is the current, local SPC. The current versions of these 
reference documents are to be provided in the ISF. No AEs are classified as listed for 
matching placebo, study design, or invasive procedures.


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8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of SAEs, e.g. suspected unexpected serious adverse reactions (SUSARs) 
to health authorities and IECs/IRBs, will be done according to local regulatory requirements. 
Further details regarding this reporting procedure are provided in the ISF.
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
COMPLETION OF TRIAL
The IEC/CA in each participating European Union member state needs to be notified about 
the end of the trial (last patient/patient out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial. 


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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HS. Randomized phase III trial of capecitabine compared with bevacizumab 
plus capecitabine in patients with previously treated metastatic breast cancer. J 
Clin Oncol 2005; 23(4):792-799.
R08-5172
Motzer RJ, Michaelson MD, Redman BG, Hudes GR, Wilding G, Figlin 
RA, Ginsberg MS, Kim ST, Baum CM, DePrimo SE, Li JZ, Bello CL, Theuer 
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Berger G, Hanahan D. Modes of resistance to anti-angiogenic therapy. Nat 
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vascular endothelial growth factor receptor and platelet-derived growth factor 
receptor, in patients with metastatic renal cell carcinoma and various other 
solid tumors. J Steroid Biochem Mol Biol 2008; 108:261-66.
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Fischer C, Jonckx B, Mazzone M, Zacchigna S, Loges S, Pattarini 
L, Chorianopoulos E, Liesenborghs L, Koch M, Mo M de, Autiero M, Wyns 
S, Plaisance S, Moons L, Rooijen N van, Giacca M, Stassen JM, Dewerchin 
M, Collen D, Carmeliet P. Anti-PlGF inhibits growth of VEGF(R)-inhibitor 
resistant tumors without affecting healthy vessels. Cell 2007; 131:463-475.
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Biometrics 38, 29 - 41 (1982)
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Dubey, Sarita; Jänne, Pasi A.; Krug, Lee; Pang, Herbert ; Wang, Xiaofei; 
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of Sorafenib in Malignant Mesothelioma: Results of Cancer and Leukemia 
Group B 30307. October 2010 - Volume 5 - Issue 10 - pp 1655-1661
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mesothelioma. Br J Cancer 2001;85:863–8.
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T. M. Jahan, L. Gu, X. Wang, R. A. Kratzke, A. Z. Dudek, M. R. Green, E. E. 
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advanced malignant mesothelioma (MM): a phase Iin study by the Cancer and 
Leukemia Group B (CALGB 30107). J Clinn Oncol 2006;(Suppl. 18):24 
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B. Robinson and R. Lake - Advances in Malignant Mesothelioma – Nengl J
Med. 353:1591-1603. 2005.
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Src expression and activation in malignant pleural mesothelioma tissues leads 
to apoptosis, cell cycle arrest, and decreased migration and invasion. Mol 
Cancer Ther. 6:1962-1972. July 2007.
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R.Masood, A.Kundra, ST.Zhu, G.Xia, P.Scalia, DL.Smith, PS.Gill: 
Mamalignant mesothelioma growth inhibition by agents that target the VEGF 
and VEGF-C autocrine loops - Int J Cancer 104, 603-610, 2003.
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R.J.Gralla, P.J.Hollen, A.M.Liepa, J.T.Symanowski, M.J.Boyer, R.Abraham, 
J.J. Rusthoven, L. Paz-Ares, N. J. Vogelzang: Improving quality of life in 
patients with malignant pleural mesothelioma: Results of the randomised
pemetrexed + cisplatin vs. cisplatin trial using the LCSS-meso instrument –
Proc ASCO 22 (abstr 2496) 2003.
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Health Policy 16, 199 - 208 (1990)
9.2
UNPUBLISHED REFERENCES
c01632700 
and
: Investigator’s Brochure. Nintedanib 
(BIBF 1120). Version No. 14. 19 January 2015.
M15-0005
 
,
, 
, 
 Nintedanib exerts migration and proliferation 
inhibition in malignant pleural mesothelioma cells in vitro and prolongs 
survival in an orthotopic xenograft model. 06 Sep 2015 – 09 Sep 2015
M15-0006
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quality of life in patients with pleural mesothelioma using a modified version 
of the Lung Cancer Symptom Scale (LCSS): psychometric properties of the 
LCSS-Meso. Support Care Cancer 14, 11 - 21 (2006)
M15-0007
,
 
 
Nintedanib in combination with cisplatin/gemcitabine as 1st-line 
therapy for adcanced squamous non-small cell lung cancer.
U03-1386
 BIBF 1120 ES: In vitro inhibition studies  
on cytochrome P450 dependent metabolic reactions. (A114/02LU) 26 August 
2003.
U04-2195
The effect of BIBF 1120 ES and known model CYP inducers on
hepatic levels of cytochrome P450 and related parameters in male Wistar rats
after administration for 4 days. (DODF 1012, B2454) 24 November 2004
U05-2191-01 
 An open label dose 
escalation study of BIBF 1120 administered orally for four weeks in patients 
with advanced solid tumours with repeated administration in patients with 
clinical benefit. 1199.1, 26-Jun-2006
U06-1697
 A Phase 1 open label dose 
escalation study of continuous once-daily oral treatment with BIBF 1120 in 
patients with advanced solid tumours. 1199.3, 28-Jul-2006
U08-1000-02 
 A phase I open label dose
escalation study of oral treatment with BIBF 1120 in combination with
standard treatment of paclitaxel and carboplatin in patients with advanced
gynaecological malignancies. Study no. 1199.6. 29-Jun-2009


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U08-1256-01
 BIBF 1202 ZW: In vitro inhibition studies on
cytochrome P450 dependent metabolic reactions (B3300, A219/07LU) 2 April
2008
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 
docetaxel and prednisone in patients with hormone refractory prostate cancer 
1199.4. 16-May-2008
U08-3886-01 
A Phase I open label study of
continuous oral treatment with BIBF 1120 ES together with pemetrexed in
previously treated patients with non-small cell lung cancer. (1199.18) 5 Dec
2008
U08-3890-01
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U12-2578-03
 A phase I-II study of BIBF 
1120 and Folfox compared to Bevacizumab and Folfox in first line metastatic 
colorectal cancer patients. 24-Jun-2014


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10.
APPENDICES
10.1
CLINICAL EVALUATION OF LIVER INJURY
Alterations of liver laboratory parameters, as described in Section 5.2.2.2 (Protocol-Specified
Significant Events), are to be further evaluated using the procedures specified in the “DILI 
checklist” provided in the ISF.
10.2
ECOG PERFORMANCE STATUS
Grade
Definition
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work 
of a light or sedentary nature, e.g. light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
to about more than 50% of waking hours
3
Capable of only limited self care, confined to bed or chair more than 50% of waking 
hours
4
Completely disabled, cannot carry on any self-care, totally confined to bed or chair
5
Dead


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1
Date of CTP revision
21 Sep 2015
EudraCT number
2012-005201-48
BI Trial number
1199.93
BI Investigational Product
Nintedanib, BIBF 1120
Title of protocol
Double blind, randomised, multicentre, phase 
II/III study of nintedanib in combination with 
pemetrexed / cisplatin followed by continuing 
nintedanib monotherapy versus placebo in 
combination with pemetrexed / cisplatin followed 
by continuing placebo monotherapy for the 
treatment of patients with unresectable malignant 
pleural mesothelioma
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
Throughout document
Description of change
Administrative changes
Rationale for change
Updates including terminology, abbreviations and 
references
Section to be changed
Title Page
Description of change
Sponsor contact change
Rationale for change
To provide updated sponsor contact information
Section to be changed
Protocol Synopsis
Description of change
Several sections, including the title, objectives, 
main criteria for inclusion, number of patients, 
endpoints and statistical method
Rationale for change
Updated per DMC recommendation
Section to be changed
Flowcharts


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Number of global amendment
1
Description of change
Changes in the procedures and timing of 
assessments for patients in combination therapy 
and monotherapy
Rationale for change
The flowcharts are updated to clarify the changes 
in assessments and timing of added assessments
Section to be changed
Section 1 – Introduction
Description of change
Updated research results and details regarding 
safety and efficacy of nintedanib, pemetrexed and 
cisplatin
Rationale for change
Updated results became available for studies with 
nintedanib alone and in combination with 
pemetrexed/cisplatin and other combination 
therapies for multiple indications
Section to be changed
Section 2 – Rationale, Objectives, and Benefit –
Risk Assessment
Description of change
Updated research results and details regarding 
treatment for mesothelioma.
Rationale for change
Revised based on updated data
Section to be changed
Section 3 – Description of Design and Trial 
Population
Description of change
1. a) Changed from an exploratory Phase II 
study to a confirmatory Phase II/III study
b) Increased sample size
c) Plan for adaptive design is described
d) Internal DMC replaced by external DMC
3. Continuation of study treatment beyond 
progression permitted
Rationale for change
1. Changes made to reflect transition to a 
confirmatory Phase II/III study as per DMC 
recommendations. Adaptive design will be 
further described based on feedback from 
regulatory authorities.
 
3. Revised to allow patients that are benefitting 
to remain on study treatment
Section to be changed
Section 4 – Treatments
Description of change
1. a) Hydration added as pre-medication regimen 
b) Study treatment interruption and stopping 
criteria clarified
c) Management of adverse events clarified
2. Timing of patient data unblinding revised
Rationale for change
1. Updates made based on guidance available in 
cisplatin SPC and updated safety information 
in the IB (c01632700).  


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Number of global amendment
1
2. The timing of data unblinding will be 
determined based on later analyses 
Section to be changed
Section 5 – Variables and Their Assessment
Description of change
1. a) Efficacy endpoints revised
 
2. a) Evaluation of lesions clarified
b) Assessment of adverse events clarified
c) Timing of labs and required lab parameters
revised
d) Management of proteinuria clarified
 
Rationale for change
1. Endpoints, procedures and assessments 
revised/added to support confirmatory study 
design
2. Clarifications and allowance for optional on-
site visits during the combination treatment 
period
 
 
Section to be changed
Section 6 – Investigational Plan
Description of change

Clarified the timing of the run-in and 
screening period

Continuation of study treatment beyond 
progression permitted

Specified procedures performed at FU1 and at 
further follow up visits

Updated the definition of the end of trial
Rationale for change
Clarified timing of procedures and assessments
throughout the study and the definition of the end 
of trial to ensure consistency throughout protocol
Section to be changed
Section 7 – Statistical Methods and Determination 
of Sample Size
Description of change
Revised the planned statistical analysis of all 
endpoints
Rationale for change
Changes made to reflect transition to a 
confirmatory Phase II/III study as per DMC 
recommendations
Section to be changed
Section 10 – Appendices
Description of change
 
 


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Number of global amendment
1
Rationale for change
Detailed procedure is described in the “DILI 
checklist” provided in the ISF and 
 
Number of global amendment
2
Date of CTP revision
22 Jun 2016
EudraCT number
2012-005201-48
BI Trial number
1199.93
BI Investigational Product
Nintedanib, BIBF 1120
Title of protocol
Double blind, randomised, multicentre, phase 
II/III study of nintedanib in combination with 
pemetrexed / cisplatin followed by continuing 
nintedanib monotherapy versus placebo in 
combination with pemetrexed / cisplatin followed 
by continuing placebo monotherapy for the 
treatment of patients with unresectable malignant 
pleural mesothelioma
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
Throughout document
Description of change
Administrative changes
Rationale for change
Updates including terminology and references
Section to be changed
Protocol Title
Description of change
Abbreviated study name added
Rationale for change
Clarified reference
Section to be changed
Protocol Synopsis
Description of change
Several sections including the title, main criteria 
for inclusion, number of patients, criteria for 
safety, and statistical methods
Rationale for change
Updated per regulatory authority (EMA/FDA) 


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Number of global amendment
2
recommendation and Phase II analysis
Section to be changed
Flowcharts
Description of change
Separate flow charts for Phase II and III.  
Changes in the procedures and timing of 
assessments for patients in combination therapy 
and monotherapy in Phase III
Rationale for change
Updated to clarify the changes in assessments and 
timing of assessments in separate Phases
Section to be changed
Section 1 - Introduction
Description of change
Updated research results and details regarding 
safety of nintedanib in combination with 
pemetrexed and cisplatin
Rationale for change
Updated results became available from the Phase 
II part of the study
Section to be changed
Section 2 – Rationale, Objectives, and Benefit –
Risk Assessment
Description of change
1. Updated research results regarding treatment 
for mesothelioma and limitation of Phase III 
patients to epithelioid histology
2. Corrected primary objectives
Rationale for change
1. Revised results based on updated data 
available from the Phase II part of the study
2. OS was incorrectly listed as a primary 
objective
Section to be changed
Section 3 – Description of Design and Trial 
Population
Description of change
1. Limit Phase III to epithelioid histology
2. Describe the time of the primary OS analysis
for Phase II
3. Describe the time of the primary PFS and the 
interim and primary OS analyses for Phase III
4. Increase sample size to 450 Phase III patients
5. Describe adaptive design with OS event 
number adjustment
6. Revise inclusion and exclusion criteria
a) Limit Phase III enrollment to epithelioid 
histology only
b) Adjust creatinine clearance value
Rationale for change
1. Updated data available from the Phase II part 
of the study
2. Separate time point for Phase II primary OS 
analysis since Phase II data will not be 
included in confirmatory analyses
3. Clarification of time point for primary 
analyses for Phase III
4. Sample size for Phase III confirmatory trial


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Number of global amendment
2
5. Adaptive design implemented to account for 
the uncertainty of the OS treatment effect
6. a) Updated data available from the Phase II 
part of the study
b) Updated to adjust for starting dose of 
cisplatin and to fulfill SmPC criteria
Section to be changed
Section 4 – Treatments
Description of change
1. Update dose reduction and retreatment criteria
2. Update criteria for liver enzyme elevations
3. Describe the unblinding of Phase II and Phase 
III patients
4. Describe unblinding of independent team 
from sponsor with regard to primary PFS 
analysis/interim OS analysis of Phase III
5. Update procedures for emergency unblinding
6. Remove lifestyle restriction to UV exposure
Rationale for change
1. Updates based on CTCAE version 4.03 and 
nintedanib standard
2. Updated per nintedanib standard
3. Phase II patients will be unblinded 
independent of Phase III patients
4. Independent team needed to maintain blind
5. Clarification
6. UV exposure no longer listed as a risk per the 
investigator brochure
Section to be changed
Section 5 – Variables and Their Assessment
Description of change
1. Observation period for primary and secondary
endpoints updated
 
4. Collection of bone scans clarified
5. Criteria for continuing study treatment beyond 
progression added
6. Change CTCAE from version 3.0 to 4.03 for 
Phase III patients
7. Exemption for reporting of (S)AEs added
8. Residual effect period prolonged for Phase III
9. Study procedures changed for Phase III 
patients
10.
 
b) Weekly on-site visits removed
c) Timing of ECG procedure revised for 
Phase III patients
 


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Number of global amendment
2
for Phase III patients
 
Rationale for change
1. Clarification with regard to different phases of 
the trial
2. Clarification
3. Clarification
4. Clarification
5. Updated as per FDA request
6. Update based on feedback from regulatory 
authorities
7. Updated per sponsor standard
8. Updated to fulfill FDA requirements
9. To reduce complexity and to reduce burden to 
patients
Section to be changed
Section 6 – Investigational Plan
Description of change
1. Follow up for PD and follow up for OS 
clarified for separate trial phases described
2. Updated the definition of the end of the whole 
trial and reporting of the trial
Rationale for change
1. Clarification
2. Clarification
Section to be changed
Section 7 – Statistical Methods and Determination 
of Sample Size
Description of change
1. Revised description of analyses for Phase II 
and Phase III part
a) Change hypotheses for Phase III part to 
one-sided
b) Change the alpha level from two-sided 0.1 
to one-sided 0.025
c) Describe analyses method for adaptive 
design with OS event number reassessment
 
e) Change of the OS censoring rule if patient 
died with death date unknown
 
g) Revise sample size section for Phase II and 
Phase III
Rationale for change
1. Clarification of adaptive design and 
adjustment of sample size based on regulatory 
authority feedback and on results of Phase II 
analysis


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02035745
5.0
clinical-trial-protocol-revision-02
LUME-Meso: Double blind, randomised, multicentre, phase II/III study of nintedanib
in combination with pemetrexed / cisplatin followed by continuing nintedanib
monotherapy versus placebo in combination with pemetrexed / cisplatin followed by
continuing placebo monotherapy for the treatment of patients with unresectable
malignant pleural mesothelioma
Approval-Clinical Pharmacokinetics
23 Jun 2016 14:52 CEST
Approval-Trial Clinical Monitor
23 Jun 2016 14:52 CEST
Approval-Team Member Medicine
23 Jun 2016 14:56 CEST
Approval-Therapeutic Area 
23 Jun 2016 15:01 CEST
Author-Trial Statistician
27 Jun 2016 09:25 CEST
Approval-Other
29 Jun 2016 16:03 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02035745
5.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan (Phase II
primary OS analysis)
c02218855-03
BI Trial No.:
1199.93
Title:
LUME-Meso: Double blind, randomised, multicentre, phase II/III
study of nintedanib in combination with pemetrexed / cisplatin 
followed by continuing Nintedanib monotherapy versus placebo in 
combination with pemetrexed / cisplatin followed by continuing 
placebo monotherapy for the treatment of patients with unresectable 
malignant pleural mesothelioma
Including Protocol amendment 1 c02035745-04 and Protocol 
amendment 2 c02035745-05
Investigational
Product(s):
Nintedanib, BIBF 1120
Responsible trial 
statistician(s):
Germany
Phone:
Fax:    
Date of statistical 
analysis plan:
08 DEC 2016 REVISED
Version:
Revised
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1.
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1.
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................4
2.
LIST OF ABBREVIATIONS ...............................................................5
3.
INTRODUCTION..................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......8
4.2
BEST OVERALL RESPONSE...........................................................................8
4.3
RESIDUAL EFFECT PERIOD..........................................................................8
5.
ENDPOINTS ..........................................................................................9
5.1
PRIMARY ENDPOINT ......................................................................................9
5.1.1
Derivation of endpoint PFS ............................................................................9
5.1.2
Censoring of PFS...........................................................................................10
5.2
SECONDARY ENDPOINTS............................................................................12
5.2.1
Key secondary endpoints..............................................................................12
5.2.2
Other Secondary endpoints..........................................................................12
5.2.2.1
Overall survival ..........................................................................................12
5.2.2.3 Objective response.........................................................................................14
5.2.2.4 Disease control...............................................................................................14
...................................................14
...................................................14
...................................................14
...................................................15
...................................................15
...................................................15
....................................................15
6.
GENERAL ANALYSIS DEFINITIONS...........................................17
6.1
TREATMENTS..................................................................................................17
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................17
6.3
PATIENT SETS ANALYSED..........................................................................18
....................................................................................20
6.5
POOLING OF CENTRES ................................................................................20
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................20
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................21
7.
PLANNED ANALYSIS.......................................................................23
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........24
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................24
7.3
TREATMENT COMPLIANCE .......................................................................24
7.4
PRIMARY ENDPOINT ....................................................................................24
7.5
SECONDARY ENDPOINTS............................................................................25


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7.5.1
Key secondary endpoints..............................................................................25
7.5.2
Other Secondary endpoints..........................................................................26
7.5.2.1
Overall survival ..........................................................................................26
7.5.2.3 Objective response.........................................................................................27
................................28
...............................28
...............................28
...............................28
...............................28
...............................29
...............................29
...............................29
...............................29
7.8
SAFETY ANALYSIS.........................................................................................30
7.8.1
Adverse events ...............................................................................................30
7.8.2
Laboratory data.............................................................................................34
7.8.3
Vital signs.......................................................................................................36
7.8.4
ECG ................................................................................................................36
7.8.5
Others .............................................................................................................36
8.
REFERENCES.....................................................................................37
..........................................................38
10.
HISTORY TABLE...............................................................................39


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LIST OF TABLES
Table 5.1.2:1 Derivation rules for PFS ....................................................................................10
Table 5.1.2:2 Nominal time-points and windows for imaging................................................12
Table 5.2.2.1:1 Derivation rules for OS...................................................................................13
Table 6.2: 1
Important protocol violations..........................................................................17
Table 7.8.2: 1 Conversion of urine measurements based on dipsticks....................................35
Table 10: 1
History table ....................................................................................................40


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse event
ATC
Anatomical Therapeutic Chemical
BI
Boehringer Ingelheim
BMI
Body mass index
BRPM
Blinded report planning meeting
BSA
Body surface area
CR
Complete response
CRF
Case report form
CT
Concomitant therapy
CTCAE
Common Terminology Criteria for Adverse Events
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database lock
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DMG
Dictionary Maintenance Group
EoT
End of Text
FVC
Forced vital capacity
ICH
International Conference on Harmonisation
ITT
Intent-to-treat
IPV
Important protocol violation
LLT
Lowest level term
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
Mixed-effect Model with Repeated Measures
MQRM
Medical Quality Review Meeting
MS
Monotherapy set
NE
Not evaluable
O*C
Oracle Clinical
OS
Overall survival


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Term
Definition / description
PD
Progressive disease
PFS
Progression-free survival
PG
Pharmacogenomics
PK
Pharmacokinetics
PPS
Per protocol set
PR
Partial Response
PT
Preferred term
PV
Protocol violation
Q1
Lower quartile
Q3
Upper quartile
RECIST
Response Evaluation Criteria in Solid Tumours
REP
Residual effect period
RS
Randomised set
SD
Stable Disease
StD
Standard deviation
SFS
Safety set
SMQ
Standardised MedDRA query
SOC
System organ class
ScS
Screened set
TOC
Table of contents
TS
Treated set
TSAP
Trial statistical analysis plan
UDAEC
User-defined AE category


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol 
Amendments. In particular, the TSAP is based on the planned analysis specification as 
written in CTP Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, 
TSAP readers may consult the CTP for more background information on the study, e.g., on 
study objectives, study design and population, treatments, definition of measurements and 
variables, planning of sample size, randomization. This TSAP follows the Boehringer 
Ingelheim (BI) internal references (1).
Trial 1199.93 has been changed from an exploratory Phase II trial to a Phase II/III trial by 
extending the trial with a confirmatory Phase III part. 
As described in CTP amendment 2, the primary PFS analysis for the Phase II part has been 
conducted on 4 March 2016 and the respective analyses are described in the Phase II Interim 
Analysis TSAP c09088167-01.
This TSAP will describe the analyses conducted for the primary OS analysis of the Phase II 
part of trial 1199.93. A separate Phase III TSAP will describe the analyses of the Phase III 
part of this trial.
Study medication will refer to the combination of backbone chemotherapy 
pemetrexed/cisplatin and/or Nintedanib/placebo, investigational drug will refer to 
nintedanib/placebo.
SAS® Version 9.2 (or later version) will be used for all analyses, unless stated otherwise.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.2
BEST OVERALL RESPONSE
 
 
The secondary endpoints 
objective tumour response and disease control as well as the further endpoints time to 
objective response, duration of objective response, and duration of disease control which are 
derived from best overall response will be also analysed regardless of confirmation. 
4.3
RESIDUAL EFFECT PERIOD
The CTP states that the residual effect period (REP) for the Phase II part of this trial is 28 
days. For safety analyses described in this TSAP, a REP of 30 days will be assumed. Thus, 
all adverse events occurring up to 30 days after the last administration of study medication 
(pemetrexed/cisplatin and/or nintedanib/placebo) will be considered as “on-treatment” (see 
Section 7.8.1).


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint of the study 1199.93 is progression-free survival (PFS) by investigator 
assessment. PFS is defined as the time between the date of randomisation to the date of either 
progression of disease (based on modified RECIST [R12-1990]), or date of death (from any 
cause), whichever occurs first. 
For each RECIST assessment multiple images may be available, i.e. multiple images may be 
available for each of the scheduled assessments at week 6, 12, 18 etc. Furthermore, for each 
RECIST assessment it is possible that scans are performed on more than one day. Therefore, 
each RECIST assessment is referred to as an imaging time-point in this TSAP.
For each imaging time-point an overall tumour response will be determined according to the 
modified RECIST criteria. The overall tumour response for each imaging time-point will be 
selected from the following categories: Complete Response (CR); Partial Response (PR); 
Stable Disease (SD); Progressive Disease (PD) or Not evaluable (NE).
For details on the imaging process and RECIST evaluation, see Section 5.1.2 of the CTP.
5.1.1
Derivation of endpoint PFS
Derivations below are described in days. However, the endpoints below will be presented in 
months in the statistical tables produced for the Clinical Trial Report (CTR).
For patients with known date of progression or death:

PFS = earliest of date of progression or death - date of randomisation + 1.
Patients without any post-baseline imaging will be censored at day 1.
Patients administered a subsequent anti-cancer therapy recorded in the case report form 
(CRF) but not presenting with PD before the start of this new anti-cancer therapy will be 
censored at the date of imaging before the new anti-cancer therapy has started.
Patients not administered subsequent anti-cancer therapy and not presenting with PD or death 
during the trial will be censored at the date of the last evaluable radiological image.

PFS (censored) = date of last imaging when the patient is known to be progression-
free and alive - date of randomisation + 1 
It has been observed that patients have their radiological examinations over a number of days, 
i.e. target lesions assessed on day x and non-target lesions assessed on day y. However, a 
single date is required for the derivation of PFS for each patient. The following rules will be 
applied:

If the overall response is PD, the earliest date of multiple assessments will be taken.


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
If the overall response is SD, PR, CR or NE, the latest of multiple assessment dates 
will be taken, i.e. in the case of SD, PR, CR, the latest of multiple dates will be used 
to censor the patients.
5.1.2
Censoring of PFS
Scans for which NE is assigned as the overall response at an imaging time-point are 
considered to be missed assessments. It cannot be assumed that NE indicates progression has 
not occurred. Table 5.1.2:1 describes how patients will be classified for the analysis of PFS.
Table 5.1.2:1 Derivation rules for PFS 
Situation
Outcome (event or 
censored)
Date of PFS or censoring
No baseline tumour 
assessment, patient 
without death or patient 
with death after second 
radiological assessment
censored
Date of randomisation
No baseline tumour 
assessment, patient with 
death on or before the  
second scheduled 
radiological assessment
event
Date of death
Progressed according to 
investigator (no more 
than one consecutively 
missed radiological 
assessments)
event
Date of PD determined by 
investigator
Non-PD according to 
investigator, death before 
next scheduled 
assessment
event
Date of death
Non-PD according to 
investigator1, one missed 
assessment, death or 
progression after date of 
missed assessment, but 
before next scheduled 
assessment
event
Date of PD or death


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Table 5.1.2:1 Derivation rules for PFS (cont.)
Situation
Outcome (event or 
censored)
Date of PFS or censoring
Non-PD according to 
investigator1, more than 
one consecutively
missed assessment
censored
Date of last evaluable 
imaging before missed 
assessment
New anti-cancer therapy 
before PD or death2
censored
Date of last evaluable 
imaging before new anti-
cancer therapy
Death before the 
scheduled date of first 
imaging
event
Date of death
No imaging performed 
post-baseline, patient 
dies between first and 
second scheduled 
assessments
event
Date of death
No imaging performed 
post-baseline, patient 
dies after second 
scheduled assessment
censored
Date of randomisation
No imaging performed 
post-baseline, vital status 
is unknown or patient is 
known to be alive
censored
Date of randomisation
Alive and not progressed 
according to investigator 
(no missed radiological 
assessment)
censored
Date of last evaluable 
imaging
1This is from the last assessment at which non-PD (SD or better) was assessed.
2Subsequent treatment with pemetrexed/cisplatin/nintedanib will not trigger censoring of 
PFS.
Patients who are still alive at the time of the analysis without a PFS event will be censored at 
the time of the last evaluable radiological image. An evaluable radiological image for the 
censoring of PFS is a scan where an overall response assessment of SD, PR or CR has been 
assigned. A radiological image where an overall response of NE has been assigned is not 


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considered evaluable. Patients who have been randomised but never received the 
investigational drug will be censored on the day of randomisation for PFS.
In order to identify whether consecutive imaging time-points are missing for a given patient, 
a nominal time point [6, 12, 18, 24, 30 weeks etc.] will be assigned to each and every image. 
This is achieved by creating windows for every RECIST assessment. The windows are 
defined in Table 5.1.2:2 below.
Table 5.1.2:2 Nominal time-points and windows for imaging
Nominal time-point 
[weeks from start of 
therapy]
Due date of scans [days]*
Window [days]
6
43
1 to =< 64
12
85
65 to =< 106
18
127
107 to =< 148
24
169
149 to =< 190
30
211
191 to =<232
Etc, 6 week interval
etc
etc
*date of first dose of study medication is day 1, for randomised patients that have not been 
treated, date of randomisation is reference date.
If a patient does not have an image in one of the windows described above, he/she will be 
said to have 'missed an assessment' for that time-point.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
OS has been changed to the key secondary endpoint in this trial with CTP amendment 1.The 
analysis of overall survival (OS) is described in Section 5.2.2.
5.2.2
Other Secondary endpoints
The secondary endpoints in this study are overall survival (OS) as key secondary endpoint, 
objective response and disease control.
5.2.2.1
Overall survival
OS is the time from randomisation to the time of death of any cause. For patients with known 
date of death (regardless of the cause of death):


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
Overall survival = date of death - date of randomisation +1.
Otherwise:

Overall survival (censored) = date patient last known to be alive - date of 
randomisation +1.
The date when the patient was last known to be alive will be derived using the following data

Patient follow-up case report form: date of patient status obtained, last date patient 
known to be alive (in case patient is lost to follow up), date of refusal (in case the 
patient actively refused to be followed up)

Tumour response

Radiological imaging data

Administration pages of nintedanib/placebo, pemetrexed, cisplatin (including 
termination of trial medication page)

Start date of subsequent anti-cancer therapy.

Date of FVC assessment
The censoring rules for OS are as in Table 5.2.2:1.
Table 5.2.2.1:1 Derivation rules for OS
Situation
Outcome (event or 
censored)
Date of death or censoring
Patient died and the date of 
death is known
event
Date of death
Patient died and date of 
death is unknown
censored
Date of last contact when the 
patient is known to be alive
Patient alive
censored
Date of last contact when the 
patient is known to be alive
Unknown
censored
Date of last contact when the 
patient is known to be alive
Derivations for OS are performed in days. However, the endpoint will be presented in months 
in the statistical analysis tables produced for the CTR. Patients who have been randomised 
but never received the investigational drug will be censored on the day of randomisation for 
OS.


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5.2.2.3 Objective response
Objective response (CR and PR) will be derived from patients best overall response (see 
Section 5.3), and analysed via objective response rate, regardless of confirmation.
5.2.2.4 Disease control
Disease control (CR and PR and SD) will be derived from patients best overall response (see 
Section 5.3), and analysed via disease control rate, regardless of confirmation.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
Two treatment groups will be compared in the analyses; these will be the treatments
nintedanib plus pemetrexed /cisplatin followed by nintedanib monotherapy versus placebo
plus pemetrexed/cisplatin followed by placebo monotherapy. For efficacy analyses, patients 
will be analysed as randomised. For safety analyses, patients will be analysed as treated.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Even though all treated patients will be included in the safety and all randomised patients in 
the efficacy analyses, patients with potentially important protocol violations (IPV) will be 
documented.
Potentially important protocol violations are described as in Table 6.2:1 below. The final list 
of important PVs will be confirmed at the last blinded report planning meeting (BRPM) 
before the database lock at the time of the CTR.
Table 6.2: 1
Important protocol violations
Category/
Code
Description
Example/Comment
Excluded 
from
A
Entrance criteria not met
A11
Patient has condition that may cause 
additional risk from study 
medication
In 4, Ex 4-7, 18-20, 31-36.
None
A21
Patient has laboratory assessment 
that may cause additional risk
Ex 21-29
None
A31
Patient is unable to comply with the 
protocol
Ex 37-38
None
A41
Patient does not have trial diagnosis 
or is not part of the target population
In 2, 5, Ex 3
None
B
Informed consent
B11
Informed consent not given or too 
late
In 6
All
B21
Patient less than 18 years old
In 1
None
B31
Pharmacogenomic investigation 
performed without prior separate 
informed consent
CTP Section 5.3.3
None


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Table 6.2: 1
Important protocol violations (cont.)
Category/
Code
Description
Example/Comment
Excluded 
from
C
Trial medication and 
randomisation
C12
Incorrect investigational drug taken
Medication kit assigned not matching 
treatment patient was randomised to 
(cross-treatment) and/or not matching IXRS 
assignment. During trial conduct, this will be 
monitored via IXRS reports manually. At final 
analysis, this will be programmed.
None
C21
Patient treated but not randomized 
by IXRS or treated before 
randomized by IXRS
None
C32
Administration of Pemetrexed and 
Cisplatin not according to protocol
Drug administration according to protocol = 
“no” and medical review of data by the trial 
team (decision will be made at 
MQRM/BRPM/DBL meeting)
None
1IPV will be derived automatically
2IPV will be identified via individual review at MQRM/BRPM/DBL
6.3
PATIENT SETS ANALYSED

Screened set (ScS)
This patient set includes all patients who have signed the informed consent. The ScS 
will be used for patient disposition tables. 

Randomised set (RS)
This patient set includes all randomised patients, regardless of whether or not they 
have received treatment. Patients are assigned to nintedanib or placebo as randomised. 
The randomised set will be used for the efficacy analyses. This patient set reflects the 
Intent-to-treat (ITT) population.
            Remark on the randomised set:
With respect to those patients who were incorrectly randomised and must be included 
in the ITT analysis: such patients should continue in the trial and participate in all 
aspects of the trial other than taking study medication. From previous experience, it 
was observed that many of these patients will agree to continue in the trial. However 
some patients could withdraw consent for further participation. If a patient was not 


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willing to participate in the imaging component of the study design, the patient should 
be encouraged to at least participate in follow-up visits in order to document as much 
as possible, and at a minimum with vital status and cause of death.
Only in exceptional cases where randomisation has been performed by error, e.g., a 
patient did not exist, or typing error, etc. a randomisation by mistake may be accepted. 
Such patients will be flagged in the IVRS system as non-randomised. For such 
exceptional cases an immediate information is needed providing all information that 
would clearly outline the exceptional reason to a potential external auditor. Note that 
this should be the exception and should be avoided if possible.

Treated set (TS)
This patient set includes all patients who were dispensed study medication and were 
documented to have taken at least one dose of study medication. Patients are assigned 
to Nintedanib or placebo according to actual treatment received during the whole 
treatment period. The TS will be used for safety analyses.
In the BRPM a decision will be made how to assign patients who have received the 
incorrect treatment for only a limited time during their participation in the trial 
depending on the amount of incorrect treatment they received. Patients who received 
pemetrexed/cisplatin only will be assigned to their randomised treatment. 

Safety set (SFS)
This patient set includes all patients who were documented to have received at least 
one dose of investigational treatment (nintedanib/placebo). Patients are assigned to
nintedanib or placebo as actually treated. In the BRPM a decision will be made how 
to assign patients who have received the incorrect treatment for only a limited time 
during their participation in the trial depending on the amount of incorrect treatment 
they received.
The difference in the number of patients included in the TS and the SFS will be used 
to assess the number of patients who have received pemetrexed/cisplatin only. If the 
TS and the SFS differ by a high number of patients, then additional safety tables and 
listings should be provided in the CTR to illustrate and summarize the differences.

Monotherapy set (MS)
The MS will include all patients who were documented to have received at least 1 
dose of investigational drug during monotherapy phase. This set will be used for 
particular safety analyses during the monotherapy phase (see Section 7. 8.1).
No per protocol population will be used for analyses. 


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6.5
POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Missing or incomplete AE dates are imputed according to BI standards (2).
The handling of missing data for the FVC analysis is described in Section 7.5.2.
In general, missing data not discussed in this section or Section 7.5.2 will not be imputed, 
unless required for the following analyses and definitions. Then the rules as described below 
apply.
1) Change of laboratory values from baseline
Laboratory values at baseline: For missing laboratory data at visit 1 (before the very first 
administration of study medication) the data of preceding visits will be used. Refer also to 
Section 7.8.2 where the determination of possible clinically significant laboratory values in 
case of missing baseline values is described.
2) Definition of on-treatment period and actual treatment
Date of permanent discontinuation of last study medication: All reasonable efforts should be 
undertaken during the study to obtain the dates of permanent discontinuation of last study 
medication. However, if the date of the very last nintedanib/placebo intake is missing this 
will be imputed with the date of first investigational drug intake in the last cycle + 21 days 
for monotherapy cycles or the date of first investigational drug intake in the last cycle + 20 
days for combination therapy cycles. If also the first investigational drug intake in the last
cycle is unknown, then the date of last drug intake of the second last cycle + 22 days will be 
imputed. If the imputed date leads to a date that is later than the death date, then the imputed 
date will be the date of death.


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Missing infusion time: If the time of infusion is missing, then the start time of the infusion 
will be imputed as "0:00".
3) Randomisation and stratification
IVRS/IWRS (IXRS) versus eCRF data: In general, the data as reported in the eCRF will be 
used for analyses. If data are missing in the eCRF (e.g. stratification factors) or unknown they 
will be imputed with the data from IXRS. If the date of randomisation differs between IXRS 
and eCRF, the randomisation date as in IXRS will be used.
4) Partial death dates
If a partial (year and month) death date is reported, the date will be imputed with the end of 
the month for the analysis of PFS and OS. This is in line with the imputation of partial dates 
for the analysis of adverse events.
5) Partial or missing start date of subsequent anti-cancer therapy
If the day of the start date of subsequent anti-cancer therapy is missing, then the 1th of the 
months will be imputed unless the first day leads to a date before the stop date of study 
medication, then the study medication stop date + 1 day will be imputed. If “day and month” 
or “day and month and year” are missing, it will be distinguished whether the start date of 
new anti-cancer therapy is required for censoring of PFS or for other descriptive statistics 
(e.g. duration of subsequent therapy). For censoring of PFS: If only the year is reported, 
January, 1st will be imputed unless this leads to a date before the stop date of study drug, then 
the study drug stop date + 1 day will be imputed. In case of completely missing start date of 
subsequent anti-cancer therapy and the patient did not have any post-baseline tumor 
assessment and did not progress or die, the PFS of this patient will be censored at the day of 
randomisation / start date of study medication. Additionally, all imputed start dates of 
subsequent anti-cancer therapy should be before death date if available. For descriptive 
statistics, dates will not be imputed if more than only the day of the date is missing. Missing 
stop date of subsequent anti-cancer therapies will not be imputed.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Study days and visits will be labelled according to the flow chart of the CTP.
Unless otherwise specified, baseline is defined as the latest time-point before the very first 
administration of study medication. If there is no measurement earlier than the very first 
administration of study medication no baseline will be derived. For nominal timepoints and 
windows of tumour imaging, see Table 5.1.2:2.
For patients randomised but not treated, the last screening value will be used as baseline.


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2) Change of laboratory values from baseline
Laboratory values: Baseline is defined as the latest time-point before the very first 
administration of study medication. As for laboratories not only the examination date but also 
time is recorded, examination time has to be taken into account when defining baseline. That 
is, a laboratory value on the same date as the first study drug administration is considered as 
baseline value if and only if the time of laboratory value is before or the same as the time of 
first study drug administration.
If any of these times are missing and the date of laboratory 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 administration of study medication.


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7.
PLANNED ANALYSIS
The labelling and display format of statistical parameters will follow the BI guideline (3).
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / Standard deviation 
(Std)/ Min / Median / Max. 
For time-to-event analysis tables, the set of statistics is: number of patients [N(%)], Number 
of patients with event [N(%)], <Time to event> [months] followed by P25 (25th percentile), 
Median, P75 (75th percentile), Number of patients censored [N(%)]. If not specified 
otherwise, the duration as well as time to event will be displayed in months and a final 
decision will be made at the last BRPM.
For appendix tables, the set of summary statistics is: N / Mean / SD / Min / P25 / Median / 
P75 / Max / Missing.
If not otherwise specified, the abbreviation Pxx should be used for displaying the xxth 
percentiles.
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.
Two-sided p-values and confidence intervals will be displayed.
Sort order for general categorical variables: If categories correspond to the collected 
categories on the eCRF and the table shells do not explicitly specify the ordering, the “default 
ordering” defined by the eCRF is to be used in such cases. If categories are derived, the 
ordering as specified in the table shell document should be used; in general ordinal data (e.g. 
categorised continuous data) are to be displayed in ascending order.
The denominator of the main categories is defined by the number of patients in the used 
patient set. The main categories define the denominators of the subcategories. Subcategories 
should be 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.
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


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
Years = Days/365.25.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report. Concomitant diseases will 
be coded similarly as adverse events based on the most current Medical Dictionary for 
Regulary Activities (MedDRA) version. Concomitant therapies will be coded according to 
World Health Organization Drug Dictionary (WHO DD). Concomitant therapies (CT) will be 
classified according to the Anatomical Therapeutic Chemical (ATC) classification system. 
The third ATC level will be used to categorise CTs by therapy type. In situations where a 
medical product may be used for more than one equally important indication, there are often 
several classification alternatives. As appropriate, patients receiving CTs with more than one 
possible ATC level 3 category will be counted more than once; footnotes will clarify this 
possible double counting in tables.
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this part of the report. The amount and time for 
which nintedanib/placebo and pemetrexed/cisplatin therapy is taken will be interpreted in 
light of treatment exposure, efficacy and safety. 
7.4
PRIMARY ENDPOINT
The analysis for the primary endpoint PFS will be conducted for all patients of the 
randomised set. The primary analysis of the primary endpoint PFS was conducted on 4 
March 2016 according to an authority request. Still, an update of this analysis will be done at 
the time of the primary OS analysis. PFS will be assessed based on the Kaplan-Meier method 
for each treatment arm separately. Point estimates together with confidence intervals (based 
on Greenwood`s method) will be provided for median PFS. An estimation of nintedanib 
treatment effect on PFS compared to placebo treatment will be given by the hazard ratio and 
its 95% confidence interval using a Cox proportional hazards model. The Cox proportional 
hazards model will be stratified by the stratification factor tumour histology (epithelioid vs. 
biphasic) used at randomisation. Hazard ratios < 1 will favour treatment with nintedanib.
Furthermore, the stratified log-rank test will be used to test for the treatment effect of 
nintedanib. The log-rank test will include the stratification factor tumour histology 
(epithelioid vs. biphasic). The two-sided stratified log-rank test p-value will be obtained by 
fitting a stratified survival model using PROC PHREG in SAS. The model will be fitted 
using the default method for handling ties (Breslow`s method) and the p-value presented will 
be that from the score test. It should be emphasised here that the p-value is only to be 
understood in an exploratory way. The censoring rules for PFS are as stated in Section 5.1.2.
The Brookmeyer and Crowley method ([R09-6372]) with a linear transformation, which 


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incorporates the Greenwood variance formula will be used to produce 95% confidence 
intervals for the median PFS in each treatment arm.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
OS has been changed to the key secondary endpoint in this trial with CTP amendment 1. The 
analysis of OS is described below in Section 7.5.2.1.


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7.5.2
Other Secondary endpoints
7.5.2.1
Overall survival
The key secondary endpoint OS will be analysed for all patients of the randomised set. As 
described in CTP amendment 2, the primary OS analysis of Phase II will be conducted when 
approximately 70% of the Phase II patients had an OS event (approximately 61 OS events). 
The analysis might be performed with fewer OS events but no later than March 2017.
OS will be assessed based on the Kaplan-Meier method for each treatment arm separately. 
Point estimates together with confidence intervals (based on Greenwood`s method) will be 
provided for median OS. An estimation of nintedanib treatment effect on OS compared to 
placebo treatment will be given by the hazard ratio and its 95% confidence interval using a 
Cox proportional hazards model. The Cox proportional hazards model will be stratified by 
the stratification factor tumour histology (epithelioid vs. biphasic) used at randomisation. 
Hazard ratios < 1 will favour treatment with nintedanib.
Furthermore, the stratified log-rank test will be used to test for the treatment effect of 
Nintedanib. The log-rank test will include the stratification factor tumour histology 
(epithelioid vs. biphasic). The two-sided stratified log-rank test p-value will be obtained by 
fitting a stratified survival model using PROC PHREG in SAS. The model will be fitted 
using the default method for handling ties (Breslow`s method) and the p-value presented will 
be that from the score test. It should be emphasised here that the p-value is only to be 
understood in an exploratory way. The censoring rules for OS are as stated in Section 5.2.2.1.
The Brookmeyer and Crowley method ([R09-6372]) with a linear transformation, which 
incorporates the Greenwood variance formula, will be used to produce 95% confidence 
intervals for the median OS in each treatment arm.
 
 
 


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7.5.2.3 Objective response
Logistic regression will be used to test for a difference between the two arms for objective 
response rate. The model will be adjusted for the stratification factor tumour histology. The 
exploratory p-value will be generated from the likelihood ratio test statistic. An odds ratio 
and corresponding 95% CI will be generated using the likelihood ratio confidence interval in 
order to obtain a direct correspondence between the p-value and the odds ratio confidence 
interval. Odds ratios >1 will favour nintedanib.


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7.5.2.4 Disease control
Logistic regression will be used to test for a difference between the two arms for disease 
control rate. The model will be adjusted for the stratification factor tumour histology. The 
exploratory p-value will be generated from the likelihood ratio test statistic. An odds ratio 
and corresponding 95% CI will be generated using the likelihood ratio confidence interval in 
order to obtain a direct correspondence between the p-value and the odds ratio confidence 
interval. Odds ratios >1 will favour nintedanib.


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7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. 
7.8.1
Adverse events
The analyses of adverse events (AEs) will be descriptive in nature. All analyses will be based 
on the number of patients with AEs (not the number of AEs).
The analyses will be based on BI standards (3). Adverse events will be coded with the most 
recent version of MedDRA. The severity of AEs will be scaled according to common 
terminology criteria of adverse events (CTCAE) version 3.0 ([R04-0474]).
According to the BI standards, first, multiple occurrences of AEs, i.e. AE entries on the 
eCRF, will be collapsed to episodes on the lowest level term (LLT) provided that the 
occurrences were time-overlapping or time-adjacent (the second occurrence started before or 


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one day after the end of the first occurrence) and provided that the treatment did not change 
between the onset of the occurrences or treatment changed but no deterioration was observed 
for the later occurrence. Second, for each patient, all episodes with the same preferred term 
(PT) will be condensed to one AE record on the PT and System organ class (SOC) level 
using a worst case approach for all AE attributes including CTCAE version 3.0 grading.
The analyses 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 will be based on the “on-treatment period”, which starts with the date of 
first administration of any study medication (pemetrexed/cisplatin and/or nintedanib/placebo) 
and ends 30 days after the last administration of study medication (pemetrexed/cisplatin
and/or nintedanib/placebo).
AEs with onset date in the screening-period (time between informed consent date and date of 
first administration of study medication) or post-study-period (time after the on-treatment-
period) will be tabulated and listed separately. 
Sorting order: In tables presenting PTs only, PTs will be sorted by descending frequency of 
the nintedanib arm. In tables presenting SOCs and PTs, SOCs will be sorted alphabetically 
and PTs (within SOC) by descending frequency of AEs in the nintedanib arm. 
Reporting of CTCAE grades in tables: Displaying of CTCAE grades in AE tables (Section 
15) will be “All grades”, “Grade 1/2” and “Grade 3/4/5”. A separate table will show AEs 
leading to death. AEs with missing CTCAE grade or CTCAE grades not equal to 1 to 5 will 
be displayed in the column “All grades”. A separate table/listing will be created showing AEs 
either without a CTCAE grade definition or with a definition but with CTCAE grade missing 
or CTCAE grades not equal to 1 to 5.
In the appendix (Section 16), the categorization “All grades”, “Grade 1”, “Grade 2“; “Grade 
3”, “Grade 4” and “Grade 5” will be used.
Listings of adverse events will be displayed by patients. The actual planned dose of 
nintedanib/placebo and/or pemetrexed/cisplatin administered at the day of AE onset will be 
derived and included in the listings. Adverse events will be reported with start day and end 
day as calculated from the first day of treatment with study medication.
Incidence and severity of adverse events
The incidence of AEs overall (irrespective of relatedness to study medication), related AEs,
and of serious AEs (SAE) will be reported by severity according to CTCAE grades version 
3.0 ([R04-0474]).
Other significant adverse events
Other significant AEs are defined as serious and non-serious AEs that lead to dose reduction 
or permanent discontinuation of study medication. Their incidence will be reported by 
severity according to CTCAE grades.


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A listing of patients who developed ‘other significant’ AEs will be provided and a flag for 
serious and non-serious will be included.
AEs leading to dose reduction of any study medication (cisplatin or pemetrexed or 
nintedanib/placebo); cisplatin or pemetrexed and nintedanib/placebo; cisplatin; pemetrexed;
nintedanib/placebo; cisplatin or pemetrexed will be tabulated.
AEs leading to permanent discontinuation of last study medication, i.e. leading to 
discontinuation of the last administered study medication will be reported.
In addition, AEs leading to discontinuation of any study medication (cisplatin or pemetrexed 
or nintedanib/placebo); cisplatin or pemetrexed and nintedanib/placebo; cisplatin;
pemetrexed; nintedanib/placebo; cisplatin or pemetrexed will be tabulated.
Adverse events leading to death
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.
Protocol-specified adverse events of special interest (AESI)
Protocol-specified AEs of special interest (AESI) as defined in the CTP will be analysed.
 
 
 
 
 
 
 
 
 
 
 
 
 


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AE tables separated for the combination and monotherapy phase
In addition to the on-treatment period, AEs will be analysed separately for the combination 
and the monotherapy phase. The end of the combination phase will be defined as the date of 
the last administration of last study medication + 30 days for patients not continuing to 
monotherapy; for patients continuing to monotherapy, the end of the combination phase is the 
last day before the start of the monotherapy phase. The start of the monotherapy phase is the 
day of first administration of nintedanib/placebo during monotherapy. The monotherapy 
phase ends with last intake of nintedanib/placebo + 30 days. This way, combination therapy 
phase and monotherapy phase sum up to the on-treatment period. In case of an off-treatment 


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period in-between the combination therapy and the monotherapy phase, the off-treatment 
period is assigned to the combination therapy phase.
Patients receiving only one of the two chemotherapies; or patients only receiving 
chemotherapy but no nintedanib/placebo will be counted to combination therapy. The AEs 
during monotherapy will be displayed for the monotherapy set.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (4). The same on-treatment periods as considered for the analysis of adverse events
will be applied for laboratory values except for that the baseline laboratory value will be 
included in the on-treatment period. Patients having at least one post-baseline laboratory 
value will be displayed in the descriptive analyses. Patients with missing CTCAE grade at 
baseline or no baseline value but with post-baseline values will be displayed in a new 
category “missing CTCAE grade at baseline”.
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 v3.0 ([R04-0474]). 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 above. 
The last laboratory value on treatment is the last laboratory value during the on-treatment 
period.
Note: Patients with a CTCAE grade of -9 (no CTCAE grade defined) will be automatically 
treated as CTCAE grade 0 for all analyses. In laboratory listings, the CTCAE grade will be 
displayed as -9.
Patients with a CTCAE grade of -1 will be treated as Grade 1 for Uric Acid 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 


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value of CTCAE grade ≥2, an increase from baseline is assumed, i.e. the laboratory value 
considered as possible clinically significant.
In Section 15 of the CTR, the analysis will focus on the following laboratory parameters 
(low/high values define the ‘worsening’ direction), ie the primary laboratory values are the 
following:
Low values (-): Haemoglobin (HGB), White blood cell count (WBC, total leukocyte count), 
Neutrophils (NEUT), Platelets (PLTCT, Thrombocytes), Total protein (TPRO).
High values (+): Creatinine (CRE), SGOT-AST (SGOT), SGPT-ALT (SGPT), Alkaline 
phosphatase (ALKP), Total Bilirubin (TBILI), International normalised ratio of pro-thrombin 
time (INR), Partial thromboplastin time (PTT), Urea (UREA), Uric acid (URIC), urine 
protein (UPROZ).
High and low values (+ and -): Thyroid stimulating hormone (TSH), free Triiodothyronine 
(FT3), free Thyroxine (FT4), Potassium (K), Magnesium (MG), Sodium (NA).
All laboratory values other than those in the primary list will be considered as secondary, 
including but not limited to the parameters listed in the following. Secondary laboratory 
values will be displayed in Appendix 16.1.9.2 of the CTR.
Low values (-): not applicable
High values (+): Prothrombin time (PRT, PRT_SEC), Lactate dehydrogenase (LDH), Direct 
bilirubin (BILID), Indirect bilirubin (BILII).
High and low values (+ and -): Calcium (CA), Glucose (GLU), Phosphorus (P).
Urine analysis: semi quantitative; based on dipsticks with 0, +, ++, and +++; the more + the 
worse, Urine glucose (UGLU), Urine erythrocytes (URBCZ), Urine leucocytes (UWBCZ), 
Urine nitrite (UNIT), Urine pH (UPH).
For urine measurement based on dipsticks the indicated results will be converted as follows 
for the analysis:
Table 7.8.2: 1 Conversion of urine measurements based on dipsticks
Original dipstick measurement
Converted dipstick measurement
“-” ; “NEG” ; “NEGATIVE” ; “NORMAL”
0.0
“0.5” ; “TRACES” ;  “TRACE” ;  “+/-” ;  “+-” ;  “-/+”
0.5
“+” ; “1+”      
1.0
“++” ;  “2+”   
2.0
“+++” ; “3+”     
3.0
“++++” ; “4+”    
4.0


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Laboratory values of special interest (LVSI)
Hepatic enzyme elevations (potential Hy’s law cases): These are defined as those cases where 
a combination of all of the following events occurred: any on-treatment value of ALT and/or 
AST > 3ULN with total bilirubin ≥ 2ULN and ALKP < 2ULN. The events can occur in any 
order, but must occur within 14 days of the previous event, i.e. the second event must occur 
within 14 days of the first event, and the third event must occur within 14 days of the second 
event, etc. Patients with missing laboratory values for liver enzymes will be excluded from 
these analyses, but presented separately.
Tabulations of hepatic enzyme elevations and liver laboratory values will be done according 
to the FDA Drug Induced Liver Injury (DILI) guidance (5).
Neutropenia evaluation based on neutrophil counts: since Pemetrexed and Cisplatin induce 
neutropenia, it is important to elucidate whether the addition of Nintedanib increases the 
frequency and intensity of neutropenia. In addition, platelet count and haemoglobin count 
will be evaluated. For this, the laboratory values over time for patients with laboratory 
CTCAE grade 3 or 4 will be plotted, and the occurrence of laboratory values of grade 3 or 4
with regard to the administration of chemotherapy will be shown.
In addition, serum creatinine will be analysed in detail to evaluate kidney function of patients.
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.
7.8.4
ECG
Newly emergent abnormalities will be recorded and analysed as adverse events.
7.8.5
Others
PK – not applicable.


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8.
REFERENCES
1
001-MCG-160_RD-01: "TSAP annotations", current version; IDEA for
CON.
2
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", 
current version; IDEA for CON.
3
001-MCG-156: "Handling and summarisation of adverse event data for 
clinical trial reports and integrated summaries", current version; IDEA 
for CON.
4
001-MCG-157: "Display and Analysis of Laboratory Data", current 
version, IDEA for CON.
5
Guidance for Industry. Drug Induced Liver Injury: Premarketing 
Clinical Evaluation. U.S. Department of Health and Human Services 
Food and Drug Administration, 2009.
website:fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor
mation/Guidances/UCM174090.pdf
[R12-1990]
Byrne MJ, Nowak AK. Modified RECIST criteria for assessment of 
response in malignant pleural mesothelioma. Ann  Oncol (15): 257-260, 
2004.
[R09-6372]
Brookmeyer R, Crowley JA. Confidence interval for the median survival 
time. Biometrics (38):29-41, 1982.
[R04-0474]
Common terminology criteria for adverse events (CTCAE) (publish 
date: December 12, 2003). Weblink 
ctep.cancer.gov/forms/CTCAEv3.pdf ; Cancer Therapy Evaluation 
Program, Common Terminology Criteria for Adverse Events, Version 
3.0, DCTD, NCI, NIH, DHHS, March 31, 2003, Publish Date:
December 12, 2003
[R10-4485]
Hertz-Picciotto I, Rockhill B. Validity and efficiency of approximation 
methods for tied survival times in Cox regression. Biometrics (53):1151-
1156, 1997.


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10.
HISTORY TABLE
This is a revised TSAP including the following modifications to the final TSAP.


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Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
12-Mar-15
None
This is the final TSAP without any 
modification
Revised
08-Dec-16
All
Correction of spelling and grammar 
mistakes
3
Explanation about different TSAPs to 
be used in this Phase II/III trial added
 
 
 
4.3
Clarification that a REP of 30 days will 
be considered for safety analyses 
5
Revision of endpoints for the Phase II 
part according to CTP amendment 1
The definition and derivation of new 
endpoints has been added
5.2.2.1
Clarification about eCRF data from 
follow-up page to be used to derive 
patients last day known to be alive
Date of FVC assessment added to 
derive patient last known to be alive 
 
6.3
The monotherapy set added for safety 
analyses during the monotherapy phase
 
6.6
Clarification that date patient last 
known to be alive will not be used for 
derivation of date of discontinuation of 
last study medication
6.7
Derivation of baseline for randomised 
but not treated patients was added
7
Revision of the endpoints for the Phase 
II part as introduced by CTP 
amendment 1
The definition and derivation of new 
endpoints has been added
 
 
 
 


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Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
with these AEs have been observed. 
7.8.1
AE analyses separated for the 
combination and the monotherapy 
phase have been added
7.8.2
Correction of definition of last 
laboratory value for analyses
7.8.2
Correction of analysing patients with a 
CTCAE lab value of -1
7.8.2
Clarification how patients without 
baseline laboratory value will be 
treated for analyses of possible 
clinically significant
7.8.2
Correcting for missing laboratory value 
urine protein
7.8.2
Conversion of urine measurements 
based on dipstick added
7.8.2
Analyses with regard to neutrophil 
haemoglobin and platelet count added
8
Additional reference added