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Nintedanib (BIBF 1120) in Mesothelioma

Sponsor
Boehringer Ingelheim (Industry)
Overall Status
Terminated
CT.gov ID
NCT01907100
Collaborator
(none)
545
Enrollment
123
Locations
2
Arms
59.4
Actual Duration (Months)
4.4
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease Intervention/Treatment Phase
Phase 2/Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
545 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double
Primary Purpose:
Treatment
Official 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
Actual Study Start Date :
Sep 19, 2013
Actual Primary Completion Date :
Mar 16, 2018
Actual Study Completion Date :
Aug 31, 2018

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Placebo + pemetrexed/cisplatin

Placebo controlled arm

Drug: Pemetrexed
backbone chemo

Drug: Cisplatin
backbone chemo

Drug: Placebo
Nintedanib matching placebo
Experimental: Nintedanib 200mg + pemetrexed/cisplatin

Experimental arm

Drug: Nintedanib
triple kinase inhibitor; 200mg starting dose

Drug: Cisplatin
backbone chemo

Drug: Pemetrexed
backbone chemo

Outcome Measures

Primary Outcome Measures

  1. Progression-Free Survival (PFS) [From randomization until the earliest of disease progression, death or (Phase II: cut-off date of 4-March-2016; up to 889 days) (Phase III: cut-off date of 16-March-2018; up to 31 months)]

    This outcome measure presents progression-free survival. Disease progression was defined according to the modified Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Progression-free survival time was calculated as the duration from the date of randomization to the date of disease progression or death, whichever occurred first. For patients with known date of progression (or death): PFS (days) = min (date of progression, date of death) - date of randomization + 1 day. For patients without progression or death, PFS was censored at the last imaging date that showed no disease progression: PFS (days, censored) = date of last imaging showing no progression - date randomization + 1 day.

Secondary Outcome Measures

  1. Overall Survival (OS) [From randomization until the earliest of disease progression, death or (Phase II: cut-off date of 4-March-2016; up to 889 days) (Phase III: cut-off date of 16-March-2018; up to 31 months)]

    Overall survival was defined as the duration of time from randomization to time of death. This is the key secondary endpoint of the trial.

  2. Objective Response According to Modified RECIST- Investigator Assessment [Tumour imaging was to be performed every 6 weeks until disease progression, death or start of subsequent anti-cancer therapy, whichever occurred earlier; up to 54 months]

    Objective response (best overall tumour response of confirmed complete response [CR] or confirmed partial response [PR]). Complete Response: disappearance of all target lesions Partial Response: at least a 30 % decrease in the total tumour measurement of target lesions, taking as reference the baseline total tumour measurement. Percentage of Patients with confirmed objective response is presented. This endpoint was only evaluated for Phase III part.

  3. Disease Control According to Modified RECIST- Investigator Assessment [Tumour imaging was to be performed every 6 weeks until disease progression, death or start of subsequent anti-cancer therapy, whichever occurred earlier; up to 54 months]

    Disease control (best overall response of confirmed CR or PR, or Stable Disease (SD) that lasted ≥36 days) according to modified RECIST. Percentage of Patients with Disease control is presented. This endpoint was only evaluated for Phase III part.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion criteria:

  • Histologically confirmed malignant pleural mesothelioma (MPM) (Epithelioid or biphasic subtype for Phase II patients; epithelioid subtype only for Phase III patients)

  • Life expectancy of at least 3 months in the opinion of the investigator

  • Eastern Cooperative Oncology Group (ECOG) score of 0 or 1

  • Measurable disease according to modified RECIST (Response Evaluation Criteria In Solid Tumours) criteria

Exclusion criteria:

  • Previous systemic chemotherapy for MPM

  • Prior treatment with nintedanib or any other prior line of therapy

  • Phase II patients with sarcomatoid subtype MPM or Phase III patients with biphasic or sarcomatoid subtype MPM

  • Patients with symptomatic neuropathy

  • Radiotherapy (except extremities) within 3 months prior to baseline imaging

  • Active brain metastases (e.g. stable for < 4 weeks)

  • Radiographic evidence of cavitary or necrotic tumours or local invasion of major blood vessels by MPM

  • Significant cardiovascular diseases

  • Inadequate hematologic, renal, or hepatic function

Contacts and Locations

Locations

Site City State Country Postal Code
1 University of Alabama at Birmingham Birmingham Alabama United States 35249
2 University of California San Francisco San Francisco California United States 94115
3 Rocky Mountain Cancer Centers Littleton Colorado United States 80120-4413
4 Comprehensive Cancer Centers of Nevada Henderson Nevada United States 89052
5 University of Pittsburgh Medical Center Pittsburgh Pennsylvania United States 15232
6 Greenville Health System Greenville South Carolina United States 29615
7 The University of Texas MD Anderson Cancer Center Houston Texas United States 77030
8 Texas Oncology - McAllen McAllen Texas United States 78503
9 Texas Oncology-San Antonio Northeast San Antonio Texas United States 78217
10 Cancer Care Northwest Centers, PS Spokane Valley Washington United States 99216
11 Sanatorio Güemes Ciudad Autónoma de Bs As Argentina C1180AAX
12 Instituto Medico Especializado Alexander Fleming Ciudad Autónoma de Bs As Argentina C1426ANZ
13 Clínica Universitaria Reina Fabiola Ciudad de Cordoba Argentina X5004FHP
14 Northern Cancer Institute St Leonards New South Wales Australia 2065
15 Calvary Mater Newcastle Hospital Waratah New South Wales Australia 2298
16 The Prince Charles Hospital Chermside Queensland Australia 4032
17 Mater Cancer Care Centre South Brisbane Queensland Australia 4101
18 Box Hill Hospital Box Hill Victoria Australia 3128
19 Peninsula Haematology & Oncology Frankston Victoria Australia 3199
20 Austin Health Heidelberg Victoria Australia 3084
21 Border Onclogy Research Wodonga Victoria Australia 3690
22 Sir Charles Gairdner Hospital Nedlands Western Australia Australia 6009
23 Perth Oncology Perth Western Australia Australia 6000
24 LKH Leoben Leoben Austria 8700
25 AKH - Medical University of Vienna Vienna Austria 1090
26 Klinikum Wels - Grieskirchen GmbH Wels Austria 4600
27 Brussels - UNIV Saint-Luc Bruxelles Belgium 1200
28 Edegem - UNIV UZ Antwerpen Edegem Belgium 2650
29 UNIV UZ Gent Gent Belgium 9000
30 UZ Leuven Leuven Belgium 3000
31 AZ Sint-Maarten Mechelen Belgium 2800
32 QEII Health Sciences Centre (Dalhousie University) Halifax Nova Scotia Canada B3H 1V7
33 Health Sciences North Sudbury Ontario Canada P3E 5J1
34 Princess Margaret Cancer Centre Toronto Ontario Canada M5G 2M9
35 IUCPQ (Laval University) Quebec Canada GLV 4G5
36 Centro Internacional de Estudios Clínicos - CIEC Recoleta Chile 8420383
37 Orlandi Oncologia Vitacura Chile 7630372
38 University Clinic for Pulmonary Diseases Zagreb Croatia 10000
39 University Hospital Brno Brno Czechia 625 00
40 University Hospital Olomouc Olomouc Czechia 779 00
41 Rigshospitalet, København, Onkologisk afdeling Købenahvn Ø Denmark 2100
42 Clinical Research Center Alexandria Alexandria Egypt 21131
43 Medical Research Institute Alexandria Egypt 21648
44 National Cancer Institute, Cairo University Cairo Egypt 11796
45 Nasser Institute Cairo Egypt 12655
46 CLI Bordeaux Nord Aquitaine Bordeaux France 33000
47 HOP Morvan Brest France 29609
48 HOP Côte de Nacre Caen France 14033
49 HOP Calmette Lille France 59000
50 HOP Nord Marseille France 13015
51 HOP Lyon Sud Pierre-Bénite France 69230
52 HOP HIA Saint-Anne Toulon France 83800
53 HOP Larrey Toulouse France 31059
54 INS Gustave Roussy Villejuif France 94805
55 Vivantes Netzwerk für Gesundheit GmbH Berlin Germany 12351
56 Helios Klinikum Emil von Behring Berlin Germany 14165
57 Klinik Schillerhöhe GmbH Gerlingen Germany 70839
58 Pneumologisches Forschungsinstitut an der LungenClinic Grosshansdorf GmbH Großhansdorf Germany 22927
59 Thoraxklinik-Heidelberg gGmbH am Universitätsklinikum Heidelberg Heidelberg Germany 69126
60 Universitätsklinikum des Saarlandes Homburg/Saar Germany 66421
61 Klinik, Löwenstein Löwenstein Germany 74245
62 Rambam Medical Center Haifa Israel 31096
63 Rabin Medical Center Beilinson Petach Tikva Israel 49100
64 Sourasky Medical Center Tel-Aviv Israel 64239
65 Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo Alessandria Italy 15121
66 Centro di riferimento Oncologico Aviano (PN) Italy 33081
67 Humanitas Gavazzeni Bergamo Italy 24125
68 Istituto Nazionale per la Ricerca sul Cancro Genova Italy 16132
69 Azienda Sanitaria Ospedale S. Luigi Gonzaga Orbassano (TO) Italy 10043
70 A.O.U. Senese Policlinico Santa Maria alle Scotte Siena Italy 53100
71 University Hospital of Occupational and Environmental Health Fukuoka, Kitakyushu Japan 807-8556
72 Hyogo Prefectural Amagasaki General Medical Center Hyogo, Amagasaki Japan 660-8550
73 Hyogo College of Medicine Hospital Hyogo, Nishinomiya Japan 663-8501
74 Yokosuka Kyosai Hospital Kanagawa , Yokosuka Japan 238-8558
75 Japan Labour Health and Safety Organization Okayama Rosai Hospital Okayama, Okayama Japan 702-8055
76 Kindai University Hospital Osaka, OsakaSayama Japan 589-8511
77 Otemae Hospital Osaka, Osaka Japan 540-0008
78 Juntendo University Hospital Tokyo, Bunkyo-ku Japan 113-8431
79 Centro Oncologico de Chihuahua Chihuahua Mexico 31217
80 Instituto Nacional de Cancerologia Mexico Mexico 14080
81 Centro Oncologico Estatal ISSEMYM Toluca Mexico 50180
82 Medisch Spectrum Twente Enschede Netherlands 7513 ER
83 Zuyderland Medisch Centrum Heerlen Netherlands 6419 PC
84 Erasmus Medisch Centrum Rotterdam Netherlands 3015 CE
85 Oslo Universitetssykehus HF, Radiumhospitalet Oslo Norway N-0310
86 St. Olavs Hospital, Universitetssykehuset i Trondheim Trondheim Norway N-7006
87 University Clinical Center, Gdansk Gdansk Poland 80-952
88 Clin.Hosp.Med.Univ.Marcinkowski in Poznan Poznan Poland 60-569
89 Greater PL Cent.Pulmo.&Thor.Surg.Eugenia&Janusz Zeyland Poznan Poland 60-569
90 Onco.Cent. - Instit. of Maria Sklodowskiej-Curie Warsaw Poland 02-781
91 Centro Hospitalar Lisboa Norte Hospital Pulido Valente Lisboa Portugal 1769-001
92 Hospital CUF Porto Porto Portugal 4100-180
93 St.Budg.Heal.Inst."Chelyabinsk Reg.Clin.Cen.Onc&Nucl.Med" Chelyabinsk Russian Federation 454087
94 St.Auton.Heal.Inst."Rep.Clin.Onc.Disp.of MoH of Rep. Tatarstan" Kazan Russian Federation 420029
95 FSBI "N.N Blokhin Med.Res.Cent.Onc."MoH of RF Moscow Russian Federation 115478
96 1stPavlov St.Med.Univ.St.-Petersburg Res.Inst. Saint-Petersburg Russian Federation 197022
97 FSBI "N.N. Petrov National Medical Research Center of Oncology" of MoH of RF Saint-Petersburg Russian Federation 197758
98 SBI HC-Rep.Clin.Onc.Disp.MoH.Rep.Bashkortostan Ufa Russian Federation 450054
99 Wilgers Oncology Centre Pretoria South Africa 0041
100 Hospital Universitario de Cruces Barakaldo (Vizcaya) Spain 48903
101 Hospital Vall d'Hebron Barcelona Spain 08035
102 Hospital Clínic de Barcelona Barcelona Spain 08036
103 Hospital Universitario Donostia Donostia (Gipuzkoa) Spain 20080
104 Hospital Duran i Reynals L'Hospitalet de Llobregat Spain 08907
105 Hospital Ramón y Cajal Madrid Spain 28034
106 Hospital Virgen de la Victoria Malaga Spain 29010
107 Hospital Virgen del Rocío Sevilla Spain 41013
108 Hospital Clínico de Valencia Valencia Spain 46010
109 Sahlgrenska US, Göteborg Göteborg Sweden 413 45
110 Universitetssjukhuset, Linköping Linköping Sweden 581 85
111 Skånes universitetssjukhus, Lund Lund Sweden 221 85
112 Karolinska Univ. sjukhuset Stockholm Sweden 171 76
113 Akademiska sjukhuset Uppsala Sweden 751 85
114 Eskisehir Osmangazi Üni. Sag. Uygulama ve Arastirma Has. Eskisehir Turkey 26950
115 Marmara Universitesi Pendik Egitim ve Arastirma Hastanesi Istanbul Turkey 34899
116 Dr.Suat Seren EAH Izmir Turkey 35120
117 Western General Hospital Edinburgh United Kingdom EH4 2XU
118 Beatson West of Scotland Cancer Centre Glasgow United Kingdom G12 0YN
119 Leicester Royal Infirmary Leicester United Kingdom LE1 5WW
120 Guy's Hospital London United Kingdom SE1 9RT
121 The Royal Marsden Hospital London United Kingdom SW3 6JJ
122 The Royal Marsden Hospital Sutton United Kingdom SM2 5PT
123 Wythenshawe Hospital Wythenshawe United Kingdom M23 9LT

Sponsors and Collaborators

  • Boehringer Ingelheim

Investigators

  • Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Study Documents (Full-Text)

More Information

Additional Information:

Publications

None provided.
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01907100
Other Study ID Numbers:
  • 1199.93
  • 2012-005201-48
First Posted:
Jul 24, 2013
Last Update Posted:
Mar 18, 2019
Last Verified:
Mar 1, 2019
Additional relevant MeSH terms:
Mesothelioma
Mesothelioma, Malignant
Cisplatin
Pemetrexed
Nintedanib

Study Results

Participant Flow

Recruitment Details Patients were initially treated with combination therapy consisting of nintedanib or placebo plus standard chemotherapy (pemetrexed/cisplatin), for a maximum of 6 cycles of 21 days duration. After completion of combination therapy, patients who had not progressed continued with nintedanib or placebo monotherapy.
Pre-assignment Detail All participants were screened for eligibility to participate in trial. Subjects attended specialist sites to ensure that they (the participants) met all implemented inclusion/exclusion criteria. Participants were not to be entered to trial if any of the specific entry criteria was violated. PD: Progressive Disease
Arm/Group Title Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
Arm/Group Description Phase II part: Nintedanib matching placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase II part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase III part: Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase III part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Period Title: Overall Study
STARTED 43 44 229 229
Treated Patients 41 44 228 227
COMPLETED 1 4 82 83
NOT COMPLETED 42 40 147 146

Baseline Characteristics

Arm/Group Title Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III Total
Arm/Group Description Phase II part: Nintedanib matching placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase II part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase III part: Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase III part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Total of all reporting groups
Overall Participants 43 44 229 229 545
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]
65.9
(7.6)
66.4
(8.6)
64.3
(8.9)
63.6
(9.5)
64.3
(9.1)
Sex: Female, Male (Count of Participants)
Female
8
18.6%
10
22.7%
60
26.2%
64
27.9%
142
26.1%
Male
35
81.4%
34
77.3%
169
73.8%
165
72.1%
403
73.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino
0
0%
Not Hispanic or Latino
0
0%
Unknown or Not Reported
0
0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native
0
0%
0
0%
14
6.1%
12
5.2%
26
4.8%
Asian
0
0%
0
0%
16
7%
14
6.1%
30
5.5%
Native Hawaiian or Other Pacific Islander
0
0%
0
0%
0
0%
0
0%
0
0%
Black or African American
0
0%
0
0%
0
0%
2
0.9%
2
0.4%
White
38
88.4%
38
86.4%
180
78.6%
185
80.8%
441
80.9%
More than one race
0
0%
0
0%
0
0%
0
0%
0
0%
Unknown or Not Reported
5
11.6%
6
13.6%
19
8.3%
16
7%
46
8.4%

Outcome Measures

1. Primary Outcome
Title Progression-Free Survival (PFS)
Description This outcome measure presents progression-free survival. Disease progression was defined according to the modified Response Evaluation Criteria in Solid Tumours (RECIST) criteria. Progression-free survival time was calculated as the duration from the date of randomization to the date of disease progression or death, whichever occurred first. For patients with known date of progression (or death): PFS (days) = min (date of progression, date of death) - date of randomization + 1 day. For patients without progression or death, PFS was censored at the last imaging date that showed no disease progression: PFS (days, censored) = date of last imaging showing no progression - date randomization + 1 day.
Time Frame From randomization until the earliest of disease progression, death or (Phase II: cut-off date of 4-March-2016; up to 889 days) (Phase III: cut-off date of 16-March-2018; up to 31 months)

Outcome Measure Data

Analysis Population Description
Randomised Set: This patient set included all randomized patients.
Arm/Group Title Placebo Nintedanib
Arm/Group Description Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Measure Participants 272 273
Phase II
5.72
9.36
Phase III
6.97
6.77
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments Phase II Part
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.0174
Comments
Method Proportional hazards mode
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.555
Confidence Interval (2-Sided) 95%
0.340 to 0.907
Parameter Dispersion Type:
Value:
Estimation Comments Hazard ratio, confidence interval and p-value obtained from proportional hazards model stratified by tumour histology (epithelioid vs. biphasic).
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments Phase III part: A Cox proportional hazards model was fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the comparison of treatment arms (Nintedanib vs Placebo). If the hazard ratio is below 1 then it favours nintedanib.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.5430
Comments one-sided p-value
Method Proportional hazards model
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.01
Confidence Interval (2-Sided) 95%
0.79 to 1.30
Parameter Dispersion Type:
Value:
Estimation Comments Hazard ratio, confidence interval and p-value obtained from a non-stratified proportional hazards model.
2. Secondary Outcome
Title Overall Survival (OS)
Description Overall survival was defined as the duration of time from randomization to time of death. This is the key secondary endpoint of the trial.
Time Frame From randomization until the earliest of disease progression, death or (Phase II: cut-off date of 4-March-2016; up to 889 days) (Phase III: cut-off date of 16-March-2018; up to 31 months)

Outcome Measure Data

Analysis Population Description
Randomised Set: This patient set included all randomized patients.
Arm/Group Title Placebo Nintedanib
Arm/Group Description Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Measure Participants 272 273
Phase II
14.46
18.30
Phase III
16.07
14.36
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments Phase II
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.4132
Comments
Method Proportional hazards mode
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.782
Confidence Interval (2-Sided) 95%
0.433 to 1.412
Parameter Dispersion Type:
Value:
Estimation Comments Hazard ratio, confidence interval and p-value obtained from proportional hazards model stratified by tumour histology (epithelioid vs. biphasic).
Statistical Analysis 2
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments Phase III: A Cox proportional hazards model was fitted to estimate hazard ratios (HRs) and corresponding 95% confidence intervals (CIs) for the comparison of treatment arms (Nintedanib vs Placebo). If the hazard ratio is below 1 then it favours nintedanib.
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.7306
Comments one-sided p-value
Method Proportional hazards model
Comments
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 1.12
Confidence Interval (2-Sided) 95%
0.79 to 1.58
Parameter Dispersion Type:
Value:
Estimation Comments Hazard ratio, confidence interval and p-value obtained from a non-stratified proportional hazards model.
3. Secondary Outcome
Title Objective Response According to Modified RECIST- Investigator Assessment
Description Objective response (best overall tumour response of confirmed complete response [CR] or confirmed partial response [PR]). Complete Response: disappearance of all target lesions Partial Response: at least a 30 % decrease in the total tumour measurement of target lesions, taking as reference the baseline total tumour measurement. Percentage of Patients with confirmed objective response is presented. This endpoint was only evaluated for Phase III part.
Time Frame Tumour imaging was to be performed every 6 weeks until disease progression, death or start of subsequent anti-cancer therapy, whichever occurred earlier; up to 54 months

Outcome Measure Data

Analysis Population Description
Randomised Set: This patient set included all randomized patients.
Arm/Group Title Placebo Nintedanib
Arm/Group Description Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Measure Participants 229 229
Number (95% Confidence Interval) [Percentage of participants]
42.8
99.5%
45.0
102.3%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.3189
Comments one-sided p-value
Method Regression, Logistic
Comments Odds ratio and one-sided p-value are obtained from an un-adjusted logistic regression model (Nintedanib vs Placebo).
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.09
Confidence Interval (2-Sided) 95%
0.76 to 1.58
Parameter Dispersion Type:
Value:
Estimation Comments Odds ratio above 1 favours nintedanib.
Other Statistical Analysis Exact 95% CI by Clopper and Pearson.
4. Secondary Outcome
Title Disease Control According to Modified RECIST- Investigator Assessment
Description Disease control (best overall response of confirmed CR or PR, or Stable Disease (SD) that lasted ≥36 days) according to modified RECIST. Percentage of Patients with Disease control is presented. This endpoint was only evaluated for Phase III part.
Time Frame Tumour imaging was to be performed every 6 weeks until disease progression, death or start of subsequent anti-cancer therapy, whichever occurred earlier; up to 54 months

Outcome Measure Data

Analysis Population Description
Randomised Set: This patient set included all randomized patients.
Arm/Group Title Placebo Nintedanib
Arm/Group Description Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
Measure Participants 229 229
Number (95% Confidence Interval) [Percentage of participants]
92.6
215.3%
90.8
206.4%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib
Comments
Type of Statistical Test Other
Comments
Statistical Test of Hypothesis p-Value 0.7512
Comments one-sided p-value
Method Regression, Logistic
Comments Odds ratio and one-sided p-value are obtained from an un-adjusted logistic regression model (Nintedanib vs Placebo).
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 0.79
Confidence Interval (2-Sided) 95%
0.40 to 1.55
Parameter Dispersion Type:
Value:
Estimation Comments Odds ratio above 1 favours nintedanib.

Adverse Events

Time Frame SAE & Non SAE: From first dose until 28 days (Phase II) or 30 days (Phase III) after last dose, up to approximately (approx.) 30 months in Phase II and approx. 32 months in Phase III. All-cause mortality: From randomization until end of follow-up, up to approx. 30 months in Phase II and approx. 32 months in Phase III
Adverse Event Reporting Description All-cause mortality numbers are based on randomized set whereas Serious Adverse Events (SAE) and non-SAE are based on treated set.
Arm/Group Title Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
Arm/Group Description Phase II part: Nintedanib matching placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase II part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase III part: Nintedanib matching Placebo 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of placebo could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction. Phase III part: Nintedanib 200 mg twice daily (b.i.d.) on Day 2 to 21 of each 21-day treatment course administered orally in the form of a soft gelatin capsule (100 mg or 150 mg capsules) plus standard Pemetrexed 500 mg/m2 (100 mg or 500 mg vials) and Cisplatin 75 mg/m2 (50 mL of 1 mg/ml solution) on Day 1 of each 21-day treatment course administered intravenously. If required, the dose of Nintedanib could be reduced to 150 mg b.i.d. or 100 mg b.i.d. (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.
All Cause Mortality
Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 25/43 (58.1%) 22/44 (50%) 63/229 (27.5%) 64/229 (27.9%)
Serious Adverse Events
Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 17/41 (41.5%) 16/44 (36.4%) 89/228 (39%) 99/227 (43.6%)
Blood and lymphatic system disorders
Anaemia 1/41 (2.4%) 2/44 (4.5%) 8/228 (3.5%) 1/227 (0.4%)
Febrile bone marrow aplasia 0/41 (0%) 1/44 (2.3%) 3/228 (1.3%) 1/227 (0.4%)
Febrile neutropenia 0/41 (0%) 1/44 (2.3%) 3/228 (1.3%) 4/227 (1.8%)
Leukopenia 0/41 (0%) 1/44 (2.3%) 2/228 (0.9%) 0/227 (0%)
Neutropenia 1/41 (2.4%) 3/44 (6.8%) 7/228 (3.1%) 6/227 (2.6%)
Thrombocytopenia 0/41 (0%) 1/44 (2.3%) 4/228 (1.8%) 1/227 (0.4%)
Bone marrow toxicity 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Pancytopenia 0/41 (0%) 0/44 (0%) 2/228 (0.9%) 2/227 (0.9%)
Splenic infarction 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Bone marrow failure 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Lymphatic obstruction 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Cardiac disorders
Atrial fibrillation 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 2/227 (0.9%)
Atrial flutter 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 1/227 (0.4%)
Acute myocardial infarction 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Atrioventricular block second degree 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Bradycardia 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Bundle branch block left 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Cardiac tamponade 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Cardio-respiratory arrest 0/41 (0%) 0/44 (0%) 2/228 (0.9%) 1/227 (0.4%)
Myocardial infarction 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Pericardial effusion 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Pericarditis 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Sinus tachycardia 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Supraventricular tachycardia 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Tachycardia 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Angina unstable 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Tachyarrhythmia 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Congenital, familial and genetic disorders
Aplasia 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Ear and labyrinth disorders
Deafness 1/41 (2.4%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Hypoacusis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Eye disorders
Visual acuity reduced 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Gastrointestinal disorders
Constipation 0/41 (0%) 2/44 (4.5%) 2/228 (0.9%) 2/227 (0.9%)
Diarrhoea 0/41 (0%) 3/44 (6.8%) 7/228 (3.1%) 8/227 (3.5%)
Dysphagia 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 1/227 (0.4%)
Large intestine perforation 1/41 (2.4%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Nausea 1/41 (2.4%) 2/44 (4.5%) 4/228 (1.8%) 4/227 (1.8%)
Vomiting 1/41 (2.4%) 1/44 (2.3%) 8/228 (3.5%) 6/227 (2.6%)
Abdominal pain 0/41 (0%) 0/44 (0%) 2/228 (0.9%) 2/227 (0.9%)
Acute abdomen 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Ascites 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Enteritis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Gastric ulcer 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Gastritis 0/41 (0%) 0/44 (0%) 2/228 (0.9%) 1/227 (0.4%)
Gastrointestinal haemorrhage 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Haemorrhoids 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Intestinal obstruction 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Intestinal perforation 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Pneumoperitoneum 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Stomatitis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
General disorders
Asthenia 0/41 (0%) 1/44 (2.3%) 1/228 (0.4%) 1/227 (0.4%)
Fatigue 0/41 (0%) 1/44 (2.3%) 3/228 (1.3%) 2/227 (0.9%)
General physical health deterioration 1/41 (2.4%) 0/44 (0%) 2/228 (0.9%) 4/227 (1.8%)
Pyrexia 2/41 (4.9%) 3/44 (6.8%) 10/228 (4.4%) 4/227 (1.8%)
Chest pain 0/41 (0%) 0/44 (0%) 5/228 (2.2%) 5/227 (2.2%)
Death 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Malaise 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Mucosal inflammation 0/41 (0%) 0/44 (0%) 3/228 (1.3%) 2/227 (0.9%)
Pain 0/41 (0%) 0/44 (0%) 2/228 (0.9%) 1/227 (0.4%)
Performance status decreased 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Chills 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Feeling of body temperature change 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Hepatobiliary disorders
Cholecystitis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Immune system disorders
Drug hypersensitivity 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Infections and infestations
Lower respiratory tract infection 2/41 (4.9%) 0/44 (0%) 2/228 (0.9%) 4/227 (1.8%)
Sepsis 1/41 (2.4%) 0/44 (0%) 2/228 (0.9%) 0/227 (0%)
Bronchitis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Cellulitis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Device related infection 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Endocarditis 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Escherichia bacteraemia 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Gastroenteritis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Gastroenteritis norovirus 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Infection 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Influenza 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Lung infection 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Neutropenic sepsis 0/41 (0%) 0/44 (0%) 0/228 (0%) 3/227 (1.3%)
Oesophageal candidiasis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Onychomycosis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Oral bacterial infection 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Peritonitis 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Pneumonia 0/41 (0%) 0/44 (0%) 4/228 (1.8%) 6/227 (2.6%)
Tooth abscess 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Urinary tract infection 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Urosepsis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Pneumonia klebsiella 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Injury, poisoning and procedural complications
Overdose 1/41 (2.4%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Rib fracture 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Toxicity to various agents 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Investigations
Blood creatinine increased 1/41 (2.4%) 2/44 (4.5%) 1/228 (0.4%) 3/227 (1.3%)
Fibrin D dimer increased 0/41 (0%) 1/44 (2.3%) 1/228 (0.4%) 0/227 (0%)
Alanine aminotransferase increased 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 2/227 (0.9%)
Aspartate aminotransferase increased 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
C-reactive protein increased 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Ejection fraction decreased 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Hepatic enzyme increased 0/41 (0%) 0/44 (0%) 0/228 (0%) 2/227 (0.9%)
Neutrophil count decreased 0/41 (0%) 0/44 (0%) 0/228 (0%) 3/227 (1.3%)
Platelet count decreased 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Transaminases increased 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
White blood cell count decreased 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Blood potassium decreased 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Gamma-glutamyltransferase increased 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Glomerular filtration rate decreased 1/41 (2.4%) 0/44 (0%) 0/228 (0%) 0/227 (0%)
Metabolism and nutrition disorders
Dehydration 2/41 (4.9%) 2/44 (4.5%) 8/228 (3.5%) 4/227 (1.8%)
Hypokalaemia 0/41 (0%) 1/44 (2.3%) 2/228 (0.9%) 1/227 (0.4%)
Hypomagnesaemia 0/41 (0%) 1/44 (2.3%) 1/228 (0.4%) 0/227 (0%)
Decreased appetite 0/41 (0%) 0/44 (0%) 3/228 (1.3%) 3/227 (1.3%)
Hyponatraemia 0/41 (0%) 0/44 (0%) 2/228 (0.9%) 2/227 (0.9%)
Lactic acidosis 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Musculoskeletal and connective tissue disorders
Back pain 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Flank pain 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Muscular weakness 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Pain in extremity 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant neoplasm progression 2/41 (4.9%) 1/44 (2.3%) 2/228 (0.9%) 0/227 (0%)
Basal cell carcinoma 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Cancer pain 0/41 (0%) 0/44 (0%) 0/228 (0%) 2/227 (0.9%)
Malignant pleural effusion 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Pleural mesothelioma malignant 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Tumour associated fever 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Neuroendocrine tumour 1/41 (2.4%) 0/44 (0%) 0/228 (0%) 0/227 (0%)
Nervous system disorders
Cerebrovascular accident 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Dizziness postural 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Encephalopathy 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Headache 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Neuropathy peripheral 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Peripheral motor neuropathy 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Seizure 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Spinal cord compression 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Syncope 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Transient ischaemic attack 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Dizziness 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Psychiatric disorders
Depression 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Hallucination 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Confusional state 1/41 (2.4%) 0/44 (0%) 0/228 (0%) 0/227 (0%)
Renal and urinary disorders
Acute kidney injury 0/41 (0%) 0/44 (0%) 5/228 (2.2%) 9/227 (4%)
Calculus bladder 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Renal failure 0/41 (0%) 0/44 (0%) 4/228 (1.8%) 0/227 (0%)
Nephrotic syndrome 1/41 (2.4%) 0/44 (0%) 0/228 (0%) 0/227 (0%)
Urinary retention 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Reproductive system and breast disorders
Erosive balanitis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea 2/41 (4.9%) 2/44 (4.5%) 6/228 (2.6%) 5/227 (2.2%)
Pleural effusion 2/41 (4.9%) 0/44 (0%) 6/228 (2.6%) 4/227 (1.8%)
Pneumonitis 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 1/227 (0.4%)
Pulmonary embolism 4/41 (9.8%) 0/44 (0%) 7/228 (3.1%) 13/227 (5.7%)
Cough 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Epistaxis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Hiccups 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Hyperventilation 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Pneumothorax 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 3/227 (1.3%)
Pulmonary hypertension 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Respiratory failure 0/41 (0%) 0/44 (0%) 4/228 (1.8%) 0/227 (0%)
Laryngeal oedema 0/41 (0%) 1/44 (2.3%) 0/228 (0%) 0/227 (0%)
Skin and subcutaneous tissue disorders
Stasis dermatitis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Subcutaneous emphysema 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Rash erythematous 1/41 (2.4%) 0/44 (0%) 0/228 (0%) 0/227 (0%)
Vascular disorders
Deep vein thrombosis 1/41 (2.4%) 0/44 (0%) 2/228 (0.9%) 3/227 (1.3%)
Aortic aneurysm 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Aortic thrombosis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 2/227 (0.9%)
Embolism 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Hypertension 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Hypotension 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 1/227 (0.4%)
Jugular vein thrombosis 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Peripheral ischaemia 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Subclavian artery thrombosis 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Subclavian vein thrombosis 0/41 (0%) 0/44 (0%) 0/228 (0%) 2/227 (0.9%)
Thrombophlebitis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Vena cava thrombosis 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Venous thrombosis 0/41 (0%) 0/44 (0%) 1/228 (0.4%) 0/227 (0%)
Venous thrombosis limb 0/41 (0%) 0/44 (0%) 0/228 (0%) 1/227 (0.4%)
Other (Not Including Serious) Adverse Events
Placebo_Phase II Nintedanib_Phase II Placebo_Phase III Nintedanib_Phase III
Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 41/41 (100%) 44/44 (100%) 219/228 (96.1%) 218/227 (96%)
Blood and lymphatic system disorders
Anaemia 9/41 (22%) 16/44 (36.4%) 94/228 (41.2%) 76/227 (33.5%)
Leukopenia 5/41 (12.2%) 2/44 (4.5%) 28/228 (12.3%) 20/227 (8.8%)
Neutropenia 9/41 (22%) 22/44 (50%) 82/228 (36%) 83/227 (36.6%)
Thrombocytopenia 1/41 (2.4%) 7/44 (15.9%) 18/228 (7.9%) 13/227 (5.7%)
Ear and labyrinth disorders
Tinnitus 9/41 (22%) 4/44 (9.1%) 24/228 (10.5%) 15/227 (6.6%)
Hypoacusis 1/41 (2.4%) 4/44 (9.1%) 4/228 (1.8%) 7/227 (3.1%)
Eye disorders
Dry eye 3/41 (7.3%) 0/44 (0%) 4/228 (1.8%) 12/227 (5.3%)
Lacrimation increased 4/41 (9.8%) 7/44 (15.9%) 18/228 (7.9%) 14/227 (6.2%)
Gastrointestinal disorders
Abdominal pain 3/41 (7.3%) 11/44 (25%) 10/228 (4.4%) 24/227 (10.6%)
Abdominal pain upper 3/41 (7.3%) 9/44 (20.5%) 11/228 (4.8%) 14/227 (6.2%)
Constipation 19/41 (46.3%) 17/44 (38.6%) 73/228 (32%) 60/227 (26.4%)
Diarrhoea 15/41 (36.6%) 29/44 (65.9%) 47/228 (20.6%) 118/227 (52%)
Dyspepsia 11/41 (26.8%) 3/44 (6.8%) 20/228 (8.8%) 14/227 (6.2%)
Nausea 34/41 (82.9%) 37/44 (84.1%) 134/228 (58.8%) 156/227 (68.7%)
Stomatitis 5/41 (12.2%) 3/44 (6.8%) 16/228 (7%) 22/227 (9.7%)
Vomiting 20/41 (48.8%) 24/44 (54.5%) 66/228 (28.9%) 96/227 (42.3%)
Dry mouth 4/41 (9.8%) 2/44 (4.5%) 2/228 (0.9%) 4/227 (1.8%)
Gastrooesophageal reflux disease 4/41 (9.8%) 3/44 (6.8%) 11/228 (4.8%) 7/227 (3.1%)
Haemorrhoids 0/41 (0%) 3/44 (6.8%) 2/228 (0.9%) 5/227 (2.2%)
General disorders
Asthenia 12/41 (29.3%) 14/44 (31.8%) 46/228 (20.2%) 53/227 (23.3%)
Chest pain 9/41 (22%) 7/44 (15.9%) 23/228 (10.1%) 23/227 (10.1%)
Fatigue 15/41 (36.6%) 18/44 (40.9%) 62/228 (27.2%) 60/227 (26.4%)
Mucosal inflammation 4/41 (9.8%) 7/44 (15.9%) 22/228 (9.6%) 16/227 (7%)
Oedema peripheral 5/41 (12.2%) 5/44 (11.4%) 16/228 (7%) 16/227 (7%)
Pyrexia 4/41 (9.8%) 7/44 (15.9%) 22/228 (9.6%) 17/227 (7.5%)
Infections and infestations
Nasopharyngitis 1/41 (2.4%) 4/44 (9.1%) 12/228 (5.3%) 9/227 (4%)
Upper respiratory tract infection 5/41 (12.2%) 2/44 (4.5%) 6/228 (2.6%) 16/227 (7%)
Urinary tract infection 5/41 (12.2%) 0/44 (0%) 14/228 (6.1%) 12/227 (5.3%)
Conjunctivitis 2/41 (4.9%) 4/44 (9.1%) 11/228 (4.8%) 11/227 (4.8%)
Influenza 2/41 (4.9%) 3/44 (6.8%) 4/228 (1.8%) 5/227 (2.2%)
Investigations
Alanine aminotransferase increased 1/41 (2.4%) 17/44 (38.6%) 10/228 (4.4%) 35/227 (15.4%)
Aspartate aminotransferase increased 1/41 (2.4%) 13/44 (29.5%) 9/228 (3.9%) 32/227 (14.1%)
Blood creatinine increased 4/41 (9.8%) 6/44 (13.6%) 26/228 (11.4%) 21/227 (9.3%)
Blood magnesium decreased 6/41 (14.6%) 10/44 (22.7%) 12/228 (5.3%) 17/227 (7.5%)
Gamma-glutamyltransferase increased 1/41 (2.4%) 10/44 (22.7%) 13/228 (5.7%) 25/227 (11%)
Neutrophil count decreased 3/41 (7.3%) 8/44 (18.2%) 26/228 (11.4%) 28/227 (12.3%)
Weight decreased 9/41 (22%) 8/44 (18.2%) 23/228 (10.1%) 20/227 (8.8%)
White blood cell count decreased 1/41 (2.4%) 2/44 (4.5%) 15/228 (6.6%) 18/227 (7.9%)
Blood alkaline phosphatase increased 1/41 (2.4%) 9/44 (20.5%) 6/228 (2.6%) 7/227 (3.1%)
Blood glucose increased 1/41 (2.4%) 5/44 (11.4%) 1/228 (0.4%) 0/227 (0%)
Blood lactate dehydrogenase increased 0/41 (0%) 3/44 (6.8%) 1/228 (0.4%) 1/227 (0.4%)
Blood potassium decreased 2/41 (4.9%) 4/44 (9.1%) 0/228 (0%) 0/227 (0%)
Blood urea increased 3/41 (7.3%) 8/44 (18.2%) 10/228 (4.4%) 9/227 (4%)
Haemoglobin decreased 2/41 (4.9%) 4/44 (9.1%) 2/228 (0.9%) 1/227 (0.4%)
Platelet count decreased 4/41 (9.8%) 8/44 (18.2%) 7/228 (3.1%) 9/227 (4%)
Metabolism and nutrition disorders
Decreased appetite 16/41 (39%) 17/44 (38.6%) 66/228 (28.9%) 66/227 (29.1%)
Hypokalaemia 2/41 (4.9%) 4/44 (9.1%) 13/228 (5.7%) 12/227 (5.3%)
Hypomagnesaemia 8/41 (19.5%) 13/44 (29.5%) 20/228 (8.8%) 20/227 (8.8%)
Hyperglycaemia 1/41 (2.4%) 2/44 (4.5%) 15/228 (6.6%) 8/227 (3.5%)
Hyponatraemia 2/41 (4.9%) 1/44 (2.3%) 14/228 (6.1%) 14/227 (6.2%)
Dehydration 3/41 (7.3%) 4/44 (9.1%) 8/228 (3.5%) 4/227 (1.8%)
Hypocalcaemia 3/41 (7.3%) 0/44 (0%) 7/228 (3.1%) 4/227 (1.8%)
Musculoskeletal and connective tissue disorders
Arthralgia 2/41 (4.9%) 3/44 (6.8%) 5/228 (2.2%) 4/227 (1.8%)
Back pain 4/41 (9.8%) 4/44 (9.1%) 9/228 (3.9%) 8/227 (3.5%)
Musculoskeletal chest pain 4/41 (9.8%) 2/44 (4.5%) 10/228 (4.4%) 4/227 (1.8%)
Musculoskeletal pain 4/41 (9.8%) 2/44 (4.5%) 11/228 (4.8%) 5/227 (2.2%)
Nervous system disorders
Dizziness 5/41 (12.2%) 3/44 (6.8%) 18/228 (7.9%) 14/227 (6.2%)
Dysgeusia 11/41 (26.8%) 11/44 (25%) 27/228 (11.8%) 27/227 (11.9%)
Headache 4/41 (9.8%) 5/44 (11.4%) 23/228 (10.1%) 16/227 (7%)
Lethargy 13/41 (31.7%) 6/44 (13.6%) 5/228 (2.2%) 13/227 (5.7%)
Neuropathy peripheral 6/41 (14.6%) 9/44 (20.5%) 18/228 (7.9%) 13/227 (5.7%)
Paraesthesia 4/41 (9.8%) 4/44 (9.1%) 19/228 (8.3%) 20/227 (8.8%)
Neurotoxicity 3/41 (7.3%) 1/44 (2.3%) 4/228 (1.8%) 8/227 (3.5%)
Psychiatric disorders
Insomnia 4/41 (9.8%) 8/44 (18.2%) 12/228 (5.3%) 11/227 (4.8%)
Depression 3/41 (7.3%) 1/44 (2.3%) 2/228 (0.9%) 6/227 (2.6%)
Respiratory, thoracic and mediastinal disorders
Cough 6/41 (14.6%) 15/44 (34.1%) 33/228 (14.5%) 29/227 (12.8%)
Dyspnoea 7/41 (17.1%) 7/44 (15.9%) 26/228 (11.4%) 34/227 (15%)
Hiccups 3/41 (7.3%) 1/44 (2.3%) 20/228 (8.8%) 8/227 (3.5%)
Epistaxis 2/41 (4.9%) 1/44 (2.3%) 13/228 (5.7%) 20/227 (8.8%)
Dysphonia 0/41 (0%) 3/44 (6.8%) 2/228 (0.9%) 4/227 (1.8%)
Oropharyngeal pain 6/41 (14.6%) 2/44 (4.5%) 4/228 (1.8%) 6/227 (2.6%)
Skin and subcutaneous tissue disorders
Alopecia 5/41 (12.2%) 6/44 (13.6%) 8/228 (3.5%) 12/227 (5.3%)
Rash 7/41 (17.1%) 11/44 (25%) 23/228 (10.1%) 22/227 (9.7%)
Dry skin 3/41 (7.3%) 0/44 (0%) 7/228 (3.1%) 4/227 (1.8%)
Pruritus 1/41 (2.4%) 3/44 (6.8%) 10/228 (4.4%) 3/227 (1.3%)
Vascular disorders
Hypertension 6/41 (14.6%) 6/44 (13.6%) 21/228 (9.2%) 26/227 (11.5%)

Limitations/Caveats

In accordance with the specifications in the protocol, the trial was discontinued prematurely after the primary PFS analysis not because of any safety concerns but rather due to failure to meet the efficacy target.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.

Results Point of Contact

Name/Title Boehringer Ingelheim, Call Center
Organization Boehringer Ingelheim
Phone 1-800-243-0127
Email clintriage.rdg@boehringer-ingelheim.com
Responsible Party:
Boehringer Ingelheim
ClinicalTrials.gov Identifier:
NCT01907100
Other Study ID Numbers:
  • 1199.93
  • 2012-005201-48
First Posted:
Jul 24, 2013
Last Update Posted:
Mar 18, 2019
Last Verified:
Mar 1, 2019