Lume Lung 2 : BIBF 1120 Plus Pemetrexed Compared to Placebo Plus Pemetrexed in 2nd Line Nonsquamous NSCLC

Multicenter, Randomized, Double-blind, Phase III Trial to Investigate the Efficacy and Safety of Oral BIBF 1120 Plus Standard Pemetrexed Therapy Compared to Placebo Plus Standard Pemetrexed Therapy in Patients With Stage IIIB/IV or Recurrent Non Small Cell Lung Cancer After Failure of First Line Chemotherapy

The trial will be performed to evaluate if BIBF 1120 in combination with standard pemetrexed therapy is more effective than placebo (inactive capsule) plus standard pemetrexed therapy in patients with stage IIIB, IV or recurrent NSCLC. Safety information about BIBF1120/pemetrexed will be obtained.

Study Overview

• Status: Completed
• Conditions: Carcinoma, Non-Small-Cell Lung
• Intervention / Treatment: Drug: Nintedanib (BIBF1120); Drug: Pemetrexed; Drug: B12; Drug: dexamethasone (or corticosteroid equivalent); Drug: Folic Acid; Drug: pemetrexed; Drug: placebo

• Study Type: Interventional
• Enrollment (Actual): 718
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Bs. As. Codigo Buenos Aires, Argentina
    • Boehringer Ingelheim Investigational Site
  • Córdoba, Argentina
    • Boehringer Ingelheim Investigational Site
  • Pergamino, Argentina
    • Boehringer Ingelheim Investigational Site
  • Quilmes Buenos Aires, Argentina
    • Boehringer Ingelheim Investigational Site
  • Rosario, Santa Fe, Argentina
    • Boehringer Ingelheim Investigational Site
  • San Miguel de Tucuman, Argentina
    • Boehringer Ingelheim Investigational Site
  • San Miguel de Tucumán, Argentina
    • Boehringer Ingelheim Investigational Site
• Australia
  • Sydney, Australia
    • Boehringer Ingelheim Investigational Site
  • New South Wales
    • Sydney, New South Wales, Australia
      • Boehringer Ingelheim Investigational Site
  • Queensland
    • Brisbane, Queensland, Australia
      • Boehringer Ingelheim Investigational Site
  • South Australia
    • Adelaide, South Australia, Australia
      • Boehringer Ingelheim Investigational Site
    • Toorak Gardens, South Australia, Australia
      • Boehringer Ingelheim Investigational Site
  • Victoria
    • Melbourne, Victoria, Australia
      • Boehringer Ingelheim Investigational Site
  • Western Australia
    • Perth, Western Australia, Australia
      • Boehringer Ingelheim Investigational Site
• Bosnia and Herzegovina
  • Banja Luka, Bosnia and Herzegovina
    • Boehringer Ingelheim Investigational Site
  • Sarajevo, Bosnia and Herzegovina
    • Boehringer Ingelheim Investigational Site
• Brazil
  • Belo Horizonte, Brazil
    • Boehringer Ingelheim Investigational Site
  • Belo Horizonte,Minas Gerais, Brazil
    • Boehringer Ingelheim Investigational Site
  • Cachoeira do Itapemirim-ES, Brazil
    • Boehringer Ingelheim Investigational Site
  • Campinas SP, Brazil
    • Boehringer Ingelheim Investigational Site
  • Caxias do Sul, Brazil
    • Boehringer Ingelheim Investigational Site
  • Curitiba, Brazil
    • Boehringer Ingelheim Investigational Site
  • Florianopolis, Brazil
    • Boehringer Ingelheim Investigational Site
  • Goiania Goias, Brazil
    • Boehringer Ingelheim Investigational Site
  • Ijui, Brazil
    • Boehringer Ingelheim Investigational Site
  • Itajai, Brazil
    • Boehringer Ingelheim Investigational Site
  • Jau/SP, Brazil
    • Boehringer Ingelheim Investigational Site
  • Londrina, Parana, Brazil
    • Boehringer Ingelheim Investigational Site
  • Pelotas Rio Grande do Sul, Brazil
    • Boehringer Ingelheim Investigational Site
  • Porto Alegre, Brazil
    • Boehringer Ingelheim Investigational Site
  • Rio de Janeiro, Brazil
    • Boehringer Ingelheim Investigational Site
  • Salvador Bahia, Brazil
    • Boehringer Ingelheim Investigational Site
  • Santo Andre, Brazil
    • Boehringer Ingelheim Investigational Site
  • Santo Andre, Sao Paulo, Brazil
    • Boehringer Ingelheim Investigational Site
  • Sao Paulo, Brazil
    • Boehringer Ingelheim Investigational Site
  • Sao Paulo - SP, Brazil
    • Boehringer Ingelheim Investigational Site
  • Sorocaba Sao Paulo, Brazil
    • Boehringer Ingelheim Investigational Site
• Canada
  • Quebec, Canada
    • Boehringer Ingelheim Investigational Site
  • Ontario
    • Thunder Bay, Ontario, Canada
      • Boehringer Ingelheim Investigational Site
    • Toronto, Ontario, Canada
      • Boehringer Ingelheim Investigational Site
  • Quebec
    • Montreal, Quebec, Canada
      • Boehringer Ingelheim Investigational Site
• Chile
  • Jardin del Mar, Renaca, Chile
    • Boehringer Ingelheim Investigational Site
  • Las Condes, Chile
    • Boehringer Ingelheim Investigational Site
  • Santiago, Chile
    • Boehringer Ingelheim Investigational Site
  • Temuco, Chile
    • Boehringer Ingelheim Investigational Site
• Colombia
  • Monteria, Cordoba, Colombia
    • Boehringer Ingelheim Investigational Site
• Ecuador
  • Cuenca, Ecuador
    • Boehringer Ingelheim Investigational Site
  • Quito, Ecuador
    • Boehringer Ingelheim Investigational Site
• Germany
  • Augsburg, Germany
    • Boehringer Ingelheim Investigational Site
  • Berlin, Germany
    • Boehringer Ingelheim Investigational Site
  • Gauting, Germany
    • Boehringer Ingelheim Investigational Site
  • Halle (Saale), Germany
    • Boehringer Ingelheim Investigational Site
  • Hemer, Germany
    • Boehringer Ingelheim Investigational Site
  • München, Germany
    • Boehringer Ingelheim Investigational Site
• Hong Kong
  • Hong Kong, Hong Kong
    • Boehringer Ingelheim Investigational Site
• Hungary
  • Deszk, Hungary
    • Boehringer Ingelheim Investigational Site
  • Nyíregyháza, Hungary
    • Boehringer Ingelheim Investigational Site
  • Pécs, Hungary
    • Boehringer Ingelheim Investigational Site
• Ireland
  • Dublin 8, Ireland
    • Boehringer Ingelheim Investigational Site
• Korea, Republic of
  • Daegu, Korea, Republic of
    • Boehringer Ingelheim Investigational Site
  • Daejoen, Korea, Republic of
    • Boehringer Ingelheim Investigational Site
  • Gangdong-gu, Seoul, Korea, Republic of
    • Boehringer Ingelheim Investigational Site
  • Gyeonggi-do, Korea, Republic of
    • Boehringer Ingelheim Investigational Site
  • Jeonbuk, Korea, Republic of
    • Boehringer Ingelheim Investigational Site
  • Seochogu, Seoul, Korea, Republic of
    • Boehringer Ingelheim Investigational Site
  • Seoul, Korea, Republic of
    • Boehringer Ingelheim Investigational Site
  • Suwon, Korea, Republic of
    • Boehringer Ingelheim Investigational Site
• Latvia
  • Daugavpils, Latvia
    • Boehringer Ingelheim Investigational Site
  • Liepaja, Latvia
    • Boehringer Ingelheim Investigational Site
  • Riga, Latvia
    • Boehringer Ingelheim Investigational Site
• Macedonia, The Former Yugoslav Republic of
  • Bitola, Macedonia, The Former Yugoslav Republic of
    • Boehringer Ingelheim Investigational Site
  • Skopje, Macedonia, The Former Yugoslav Republic of
    • Boehringer Ingelheim Investigational Site
• Malaysia
  • Georgetown, Malaysia
    • Boehringer Ingelheim Investigational Site
  • Kota Kinabalu, Malaysia
    • Boehringer Ingelheim Investigational Site
  • Kuala Lumpur, Malaysia
    • Boehringer Ingelheim Investigational Site
  • Kuching, Malaysia
    • Boehringer Ingelheim Investigational Site
  • Penang, Malaysia
    • Boehringer Ingelheim Investigational Site
• Mexico
  • Chihuahua, Mexico
    • Boehringer Ingelheim Investigational Site
  • Morelia, Mexico
    • Boehringer Ingelheim Investigational Site
• Moldova, Republic of
  • Chisinau, Moldova, Republic of
    • Boehringer Ingelheim Investigational Site
• Netherlands
  • Hertogenbosch, Netherlands
    • Boehringer Ingelheim Investigational Site
• New Zealand
  • Auckland, New Zealand
    • Boehringer Ingelheim Investigational Site
  • Christchurch, New Zealand
    • Boehringer Ingelheim Investigational Site
  • Palmerston North, New Zealand
    • Boehringer Ingelheim Investigational Site
  • Wellington, New Zealand
    • Boehringer Ingelheim Investigational Site
• Panama
  • Carrasquilla Panama, Panama
    • Boehringer Ingelheim Investigational Site
  • Panama, Panama
    • Boehringer Ingelheim Investigational Site
• Peru
  • Arequipa, Peru
    • Boehringer Ingelheim Investigational Site
  • Cercado Arequipa, Peru
    • Boehringer Ingelheim Investigational Site
  • Lima, Peru
    • Boehringer Ingelheim Investigational Site
• Philippines
  • Cebu, Philippines
    • Boehringer Ingelheim Investigational Site
  • Davao City, Philippines
    • Boehringer Ingelheim Investigational Site
  • Makati, Philippines
    • Boehringer Ingelheim Investigational Site
  • Quezon, Philippines
    • Boehringer Ingelheim Investigational Site
• Poland
  • Olsztyn, Poland
    • Boehringer Ingelheim Investigational Site
• Romania
  • Baia Mare, Romania
    • Boehringer Ingelheim Investigational Site
  • Bucuresti, Romania
    • Boehringer Ingelheim Investigational Site
  • Cluj-Napoca, Romania
    • Boehringer Ingelheim Investigational Site
  • Iasi, Romania
    • Boehringer Ingelheim Investigational Site
  • Onesti, Romania
    • Boehringer Ingelheim Investigational Site
  • Timisoara, Romania
    • Boehringer Ingelheim Investigational Site
• Serbia
  • Belgrade, Serbia
    • Boehringer Ingelheim Investigational Site
  • Nis, Serbia
    • Boehringer Ingelheim Investigational Site
  • Sremska Kamenica, Serbia
    • Boehringer Ingelheim Investigational Site
• Sweden
  • Gävle, Sweden
    • Boehringer Ingelheim Investigational Site
  • Stockholm, Sweden
    • Boehringer Ingelheim Investigational Site
  • Umeå, Sweden
    • Boehringer Ingelheim Investigational Site
  • Uppsala, Sweden
    • Boehringer Ingelheim Investigational Site
• Taiwan
  • Kaohsiung, Taiwan
    • Boehringer Ingelheim Investigational Site
  • Taichung, Taiwan
    • Boehringer Ingelheim Investigational Site
  • Tainan, Taiwan
    • Boehringer Ingelheim Investigational Site
  • Tainan City, Taiwan
    • Boehringer Ingelheim Investigational Site
  • Taipei, Taiwan
    • Boehringer Ingelheim Investigational Site
• Thailand
  • Bangkok, Thailand
    • Boehringer Ingelheim Investigational Site
  • Chiang Mai, Thailand
    • Boehringer Ingelheim Investigational Site
• Turkey
  • Ankara, Turkey
    • Boehringer Ingelheim Investigational Site
  • Antalya, Turkey
    • Boehringer Ingelheim Investigational Site
  • Aydin, Turkey
    • Boehringer Ingelheim Investigational Site
  • Balcali-Adana, Turkey
    • Boehringer Ingelheim Investigational Site
  • Diyarbakir, Turkey
    • Boehringer Ingelheim Investigational Site
  • Gaziantep, Turkey
    • Boehringer Ingelheim Investigational Site
  • Kocaeli, Turkey
    • Boehringer Ingelheim Investigational Site
• Ukraine
  • Chernigiv, Ukraine
    • Boehringer Ingelheim Investigational Site
  • Dnipropetrovks, Ukraine
    • Boehringer Ingelheim Investigational Site
  • Kharkiv, Ukraine
    • Boehringer Ingelheim Investigational Site
  • Uzhgorod, Ukraine
    • Boehringer Ingelheim Investigational Site
  • Vinnytsia, Ukraine
    • Boehringer Ingelheim Investigational Site
• United States
  • California
    • Downy, California, United States
      • Boehringer Ingelheim Investigational Site
    • Fountain Valley, California, United States
      • Boehringer Ingelheim Investigational Site
    • Fullerton, California, United States
      • Boehringer Ingelheim Investigational Site
    • Long Beach, California, United States
      • Boehringer Ingelheim Investigational Site
  • Connecticut
    • Meriden, Connecticut, United States
      • Boehringer Ingelheim Investigational Site
  • Florida
    • Aventura, Florida, United States
      • Boehringer Ingelheim Investigational Site
    • Boynton Beach, Florida, United States
      • Boehringer Ingelheim Investigational Site
    • Jacksonville, Florida, United States
      • Boehringer Ingelheim Investigational Site
    • Miami, Florida, United States
      • Boehringer Ingelheim Investigational Site
    • New Port Richey, Florida, United States
      • Boehringer Ingelheim Investigational Site
    • Port St. Lucie, Florida, United States
      • Boehringer Ingelheim Investigational Site
    • Stuart, Florida, United States
      • Boehringer Ingelheim Investigational Site
  • Illinois
    • Galesburg, Illinois, United States
      • Boehringer Ingelheim Investigational Site
    • Skokie, Illinois, United States
      • Boehringer Ingelheim Investigational Site
  • Indiana
    • Indianapolis, Indiana, United States
      • Boehringer Ingelheim Investigational Site
    • New Albany, Indiana, United States
      • Boehringer Ingelheim Investigational Site
  • Kansas
    • Witchita, Kansas, United States
      • Boehringer Ingelheim Investigational Site
  • Kentucky
    • Ashland, Kentucky, United States
      • Boehringer Ingelheim Investigational Site
    • Louisville, Kentucky, United States
      • Boehringer Ingelheim Investigational Site
  • Massachusetts
    • Burlington, Massachusetts, United States
      • Boehringer Ingelheim Investigational Site
    • Springfield, Massachusetts, United States
      • Boehringer Ingelheim Investigational Site
  • Minnesota
    • St. Louis park, Minnesota, United States
      • Boehringer Ingelheim Investigational Site
  • Nebraska
    • Grand Island, Nebraska, United States
      • Boehringer Ingelheim Investigational Site
  • New Mexico
    • Farmington, New Mexico, United States
      • Boehringer Ingelheim Investigational Site
  • New York
    • Dunkirk, New York, United States
      • Boehringer Ingelheim Investigational Site
    • Goshen, New York, United States
      • Boehringer Ingelheim Investigational Site
    • Lake Success, New York, United States
      • Boehringer Ingelheim Investigational Site
    • Nyack, New York, United States
      • Boehringer Ingelheim Investigational Site
  • North Carolina
    • Asheville, North Carolina, United States
      • Boehringer Ingelheim Investigational Site
  • Ohio
    • Canton, Ohio, United States
      • Boehringer Ingelheim Investigational Site
    • Sandusky, Ohio, United States
      • Boehringer Ingelheim Investigational Site
  • Pennsylvania
    • Ephrata, Pennsylvania, United States
      • Boehringer Ingelheim Investigational Site
    • Langhorne, Pennsylvania, United States
      • Boehringer Ingelheim Investigational Site
    • Philadelphia, Pennsylvania, United States
      • Boehringer Ingelheim Investigational Site
  • Tennessee
    • Germantown, Tennessee, United States
      • Boehringer Ingelheim Investigational Site
  • Texas
    • Amarillo, Texas, United States
      • Boehringer Ingelheim Investigational Site
  • Washington
    • Seattle, Washington, United States
      • Boehringer Ingelheim Investigational Site
    • Spokane, Washington, United States
      • Boehringer Ingelheim Investigational Site
  • Wisconsin
    • Madison, Wisconsin, United States
      • Boehringer Ingelheim Investigational Site
    • Milwaukee, Wisconsin, United States
      • Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion criteria:

1. Male or female patient aged 18 years or older.
2. Histologically or cytologically confirmed Stage IIIB, IV (according to AJCC) or recurrent non small cell lung cancer (NSCLC) (non squamous histologies)
3. Relapse or failure of one first line chemotherapy (in the case of recurrent disease one additional prior regimen is allowed for adjuvant, neoadjuvant or neoadjuvant plus adjuvant therapy).
4. At least one target tumor lesion that has not been irradiated within the past three months and that can accurately be measured by magnetic resonance imaging (MRI) or computed tomography (CT) in at least one dimension (longest diameter to be recorded) as greater than or equal to 20 mm with conventional techniques or as greater than or equal to 10 mm with spiral CT.
5. Life expectancy of at least three months.
6. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1.
7. Patient has given written informed consent which must be consistent with the International Conference on Harmonization, Good Clinical Practice (ICH-GCP) and local legislation.

Exclusion criteria:

1. Previous therapy with other vascular endothelial growth factor (VEGF) inhibitors (other than bevacizumab) or pemetrexed for treatment of NSCLC
2. Treatment with other investigational drugs or treatment in another clinical trial within the past four weeks before start of therapy or concomitantly with this trial
3. Chemotherapy, hormone therapy, immunotherapy with monoclonal antibodies, treatment with tyrosine kinase inhibitors, or radiotherapy (except for treatment of extremities) within the past four weeks prior to treatment with the trial drug, i.e., the minimum time elapsed since the last anticancer therapy and the first administration of BIBF 1120 must be four weeks
4. Inability to stop intake of NSAIDS (non steroidal anti inflammatory drugs) for several days
5. 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)
6. Radiographic evidence of cavitary or necrotic tumors
7. Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels
8. History of clinically significant haemoptysis within the past 3 months
9. Therapeutic anticoagulation
10. History of major thrombotic or clinically relevant major bleeding event in the past 6 months
11. Significant cardiovascular diseases (i.e., hypertension not controlled by medical therapy, unstable angina, history of myocardial infarction within the past 6 months,
12. Inadequate kidney, liver, blood clotting function
13. Inadequate blood count
14. Significant weight loss (> 10 %) within the past 6 weeks prior to treatment in the present trial
15. Current peripheral neuropathy greater than or equal to Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 except due to trauma
16. Pre-existing ascites (abdominal fluid collection) and/or clinically significant pleural effusion ( fluid collection between the lung and chest wall)
17. Major injuries and/or surgery within the past ten days prior to start of study drug
18. Incomplete wound healing
19. Active or chronic hepatitis C and/or B infection Additional exclusion criteria apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

5

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: nintedanib (BIBF1120) plus pemetrexed; nintedanib (BIBF1120) along with standard therapy of pemetrexed	Drug: Nintedanib (BIBF1120); starting dose of 200 mg bid taken daily except on the day of pemetrexed infusion . The dose can be reduced to 150 bid and then to 100 mg bid.; Drug: Pemetrexed; 500 mg/metre squared administered as an intravenous infusion over 10 minutes on Day 1 of each 21 day cycle.; Drug: B12; 1000 ug IM injection starting a week before first pemetrexed infusion and every 9 weeks thereafter until discontinuation of pemetrexed; Drug: dexamethasone (or corticosteroid equivalent); 4 mg PO bid the day before, the day of and the day after each pemetrexed infusion; Drug: Folic Acid; 400 ug once daily starting 1-2 weeks prior to the first dose of pemetrexed and continuing for at least 3 weeks after stopping pemetrexed.
Placebo Comparator: Placebo plus pemetrexed; Pemetrexed standard therapy	Drug: B12; 1000 ug IM injection starting a week before first pemetrexed infusion and every 9 weeks thereafter until discontinuation of pemetrexed; Drug: dexamethasone (or corticosteroid equivalent); 4 mg PO bid the day before, the day of and the day after each pemetrexed infusion; Drug: Folic Acid; 400 ug once daily starting 1-2 weeks prior to the first dose of pemetrexed and continuing for at least 3 weeks after stopping pemetrexed.; Drug: pemetrexed; 500 mg/metre squared administered as an intravenous infusion over 10 minutes on Day 1 of each 21 day cycle.; Drug: placebo; starting dose of 200 mg bid taken daily except on the day of pemetrexed infusion . The dose can be reduced to 150 bid and then to 100 mg bid.
Experimental: nintedanib (BIBF1120) monotherapy; nintedanib (BIBF1120) monotherapy only for patients who discontinue pemetrexed	Drug: Nintedanib (BIBF1120); starting dose of 200 mg bid taken daily except on the day of pemetrexed infusion . The dose can be reduced to 150 bid and then to 100 mg bid.
Active Comparator: pemetrexed monotherapy; pemetrexed monotherapy only for patients who discontinue nintedanib (BIBF1120) or placebo	Drug: Pemetrexed; 500 mg/metre squared administered as an intravenous infusion over 10 minutes on Day 1 of each 21 day cycle.; Drug: B12; 1000 ug IM injection starting a week before first pemetrexed infusion and every 9 weeks thereafter until discontinuation of pemetrexed; Drug: dexamethasone (or corticosteroid equivalent); 4 mg PO bid the day before, the day of and the day after each pemetrexed infusion; Drug: Folic Acid; 400 ug once daily starting 1-2 weeks prior to the first dose of pemetrexed and continuing for at least 3 weeks after stopping pemetrexed.
Placebo Comparator: placebo monotherapy; placebo monotherapy only for patients who discontinue pemetrexed	Drug: placebo; starting dose of 200 mg bid taken daily except on the day of pemetrexed infusion . The dose can be reduced to 150 bid and then to 100 mg bid.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival (PFS) as Assessed by Central Independent Review	Progression Free Survival (PFS) as assessed by central independent review according to the modified RECIST (version 1.0) criteria. Progression free survival (PFS) is defined as the duration of time from date of randomisation to date of progression or death (whatever occurs earlier). Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.	From randomisation until cut-off date 9 July 2012

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (Key Secondary Endpoint)	Overall Survival (OS) defined as the duration from randomisation to death (irrespective of the reason of death). Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.	From randomisation until data cut-off (15 February 2013), Up to 30 months
Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Central Independent Review	Follow-up analysis was conducted at the time of overall survival analysis. Progression Free Survival (PFS) as assessed by central independent review according to the modified RECIST (version 1.0) criteria. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.	From randomisation until data cut-off (15 February 2013), Up to 30 months
Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Investigator	Follow-up analysis was conducted at the time of overall survival analysis. Progression Free Survival (PFS) as assessed by investigator according to the modified RECIST (version 1.0) criteria. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.	From randomisation until data cut-off (15 February 2013), Up to 30 months
Objective Tumor Response	Confirmed objective response is defined as confirmed Complete Response (CR) and Partial Response (PR) and evaluated according to the modified RECIST criteria version 1.0. This endpoint was analysed based on the central independent reviewer as well as the investigator	From randomisation until data cut-off (15 February 2013), Up to 30 months
Duration of Confirmed Objective Tumour Response	The duration of objective response is the time from first documented (CR) or (PR) to the time of progression or death and evaluated according to the modified RECIST criteria version 1.0. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. This endpoint was analysed based on the central independent reviewer as well as the investigator.	From randomisation until data cut-off (15 February 2013), Up to 30 months
Time to Confirmed Objective Tumour Response	Time to confirmed objective response is defined as time from randomisation to the date of first documented (CR) or (PR) and evaluated according to the modified RECIST criteria version 1.0. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. This endpoint was analysed based on the central independent reviewer as well as the investigator.	From randomisation until data cut-off (15 February 2013), Up to 30 months
Disease Control	Disease control was defined as a best overall response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) and evaluated according to the modified RECIST criteria version 1.0. This endpoint was analysed based on the central independent reviewer as well as the investigator.	From randomisation until data cut-off (15 February 2013), Up to 30 months
Duration of Disease Control	The duration of disease control was defined as the time from randomisation to the date of disease progression or death (which ever occurs first) for patients with disease control. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve. This endpoint was analysed based on the central independent reviewer as well as the investigator.	From randomisation until data cut-off (15 February 2013), Up to 30 months
Change From Baseline in Tumour Size	Percentage change from baseline in tumour size is defined as decrease in the sum of the longest diameter of the target lesion. Presented means are in fact adjusted best means percentage changes generated from ANOVA model adjusted for baseline ECOG PS (0 vs. 1), tumour histology (adenocarcinoma vs. non-adenocarcinoma), brain metastases at baseline (yes vs no) and prior treatment with bevacizumab (yes vs no) This endpoint was analysed based on the central independent reviewer as well as the investigator.	From randomisation until data cut-off (15 February 2013), Up to 30 months
Clinical Improvement.	Clinical improvement was defined as the time from randomisation to deterioration in body weight and/or Eastern Cooperative Oncology group performance score (ECOG PS) whichever occurred first. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.	From randomisation until data cut-off (15 February 2013), Up to 30 months
Quality of Life (QoL)	QoL was measured by standardised questionnaires (EQ-5D, EORTC QLQ-C30, EORTC QLQ-LC13). The EORTC QLQ-C30 comprises of 30 questions, using both multi-item scales and single-item measures. EORTC LC-13 comprises of 13 questions incorporating 1 multi-item scale and a series of single items. The following were the main points of interest: Time to deterioration of cough (QLQ-LC13 question 1), Time to deterioration of dyspnoea (QLQ-LC13, composite of questions 3 to 5), Time to deterioration of pain (QLQ- C30, composite of questions 9 and 19). Time to deterioration of cough, dyspnoea and pain was defined as the time to a 10-point increase from the baseline score. Median, 25th and 75th percentiles are calculated from an unadjusted Kaplan-Meier curve.	From randomisation until data cut-off (15 February 2013), Up to 30 months
Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide	Geometric mean of dose normalised predose plasma concentration (Cpre,ss,norm) of nintedanib and of its metabolites BIBF 1202 and BIBF 1202 glucuronide evaluated at steady state based on course 2 and 3. If only one value was available and valid, then this value was used for calculation of Cpre,ss,norm.	Before the administration of nintedanib or placebo and between a window of 30 mins to an hour after administration of trial drug during Course 2 and between 1 and 3 hours after administration of trial drug during Course 3
Incidence and Intensity of Adverse Events	Incidence and intensity of adverse events according to the Common Terminology Criteria for Adverse Events (CTCAE) version 3.0. The worst CTCAE grade per patient is reported and MedDRA version 15.1 used. Serious signs and symptoms of progressive disease were reported as an adverse event in analysis of this endpoint.	From the first drug administration until 28 days after the last drug administration, up to 36 months

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim

Publications and helpful links

General Publications

• Lesaffre E, Edelman MJ, Hanna NH, Park K, Thatcher N, Willemsen S, Gaschler-Markefski B, Kaiser R, Manegold C. Statistical controversies in clinical research: futility analyses in oncology-lessons on potential pitfalls from a randomized controlled trial. Ann Oncol. 2017 Jul 1;28(7):1419-1426. doi: 10.1093/annonc/mdx042.

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start: December 1, 2008
• Primary Completion (Actual): June 1, 2011
• Study Completion (Actual): December 1, 2015

Study Registration Dates

• First Submitted: December 10, 2008
• First Submitted That Met QC Criteria: December 10, 2008
• First Posted (Estimate): December 11, 2008

Study Record Updates

• Last Update Posted (Estimate): February 2, 2017
• Last Update Submitted That Met QC Criteria: December 8, 2016
• Last Verified: December 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Micronutrients; Protein Kinase Inhibitors; Vitamins; Hematinics; Folic Acid Antagonists; Dexamethasone; Dexamethasone acetate; BB 1101; Nintedanib; Folic Acid; Vitamin B 12; Hydroxocobalamin; Vitamin B Complex; Pemetrexed
• Other Study ID Numbers: 1199.14; 2008-002072-10 (EudraCT Number: EudraCT)