Symptoms and General Pathology

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Neoplasms

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Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma, Bronchogenic

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Respiratory Tract Diseases

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Gastrointestinal Agents

All Drugs and Chemicals

Micronutrients

Hematinics

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Dexamethasone

Pemetrexed

Tin Fluorides

Dexamethasone acetate

Folic Acid

Vitamin B Complex

Vitamin B 12

Hydroxocobalamin

Nintedanib

BB 1101

Glucocorticoids

Hormones

Hormone Antagonists

Antineoplastic Agents, Hormonal

HIV Protease Inhibitors

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Folic Acid Antagonists

Trace Elements

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Folinic Acid

Folate

Vitamin B9

Vitamin B12

Cobalamin

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Methylcobalamin

nintedanib (BIBF1120) along with standard therapy of pemetrexed

nintedanib (BIBF1120) monotherapy only for patients who discontinue pemetrexed

pemetrexed monotherapy only for patients who discontinue nintedanib (BIBF1120) or placebo

placebo monotherapy only for patients who discontinue pemetrexed

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.

Nintedanib (BIBF1120)

500 mg/metre squared administered as an intravenous infusion over 10 minutes on Day 1 of each 21 day cycle.

pemetrexed

1000 ug IM injection starting a week before first pemetrexed infusion and every 9 weeks thereafter until discontinuation of pemetrexed

4 mg PO bid the day before, the day of and the day after each pemetrexed infusion

dexamethasone (or corticosteroid equivalent)

placebo

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.

Boehringer Ingelheim

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.

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

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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.

One patient in the nintedanib plus pemetrexed treatment arm reported a serious adverse event for which the preferred term was not yet coded until data cut-off (15 February 2013).

Nintedanib 200 mg twice daily administered orally in a form of a soft gelatin capsule on day2 to 21 of each 21-day treatment course plus pemetrexed 500 mg/m2 on Day1 of each 21-day treatment course administered via intravenous infusion. If required the dose of nitedanib could be redused to 150 mg twice daily (b.i.d.) or 100 mg b.i.d. and two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

Nintedanib Plus Pemetrexed

Placebo soft gelatin capsule matching that of nintedanib 2 times daily on day 2 to 21 of each 21-day treatment course administered orally plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion. If required two dose reductions for pemetrexed were allowed (according to the protocol-defined dose-reduction scheme). No dose increase was allowed after a dose reduction.

Placebo Plus Pemetrexed

Total

Age, Continuous

Gender

Randomised set uncut (RS): all patients who were randomised whether patients had received study treatment or not. Patients were allocated to the treatment groups as randomised, regardless of the actual medication taken.

Recruitment for the study was stopped early based on the results of a pre defined futility analysis.

Boehringer Ingelheim Call Center

HR, CI and p-value obtained from the proportional hazards model stratified by 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).

Progression Free Survival (PFS) as Assessed by Central Independent Review

HR, CI and p-value obtained from the prop. hazards model stratified by 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).

Overall Survival (Key Secondary Endpoint)

HR, CI and p-value obtained from the proportional hazards model stratified by 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)

Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Central Independent Review

Follow-up Analysis of Progression Free Survival (PFS) as Assessed by Investigator

Analysis based on the central independent review

Analysis based on the investigator's assessment

Central independent reviewer

Investigator assessment

Objective Tumor Response

central independent reviewer (N=32, 30)

Investigator assessment (N=53, 48)

Duration of Confirmed Objective Tumour Response

Central independent review (N=32, 30)

Time to Confirmed Objective Tumour Response

Analysis based on investigator's assessment

Central independent review (N=215, 192)

Investigator assessment (N=233, 217)

Disease Control

Duration of Disease Control

Central independent review (N=298, 305)

Investigator assessment (N=322, 325)

Change From Baseline in Tumour Size

Clinical Improvement.

Analysis evaluating the time to deterioration of cough. HR, CI and p-value obtained from the prop. hazards model stratified by 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)

Analysis evaluating the time to deterioration of dyspnoea. HR, CI and p-value obtained from the prop. hazards model stratified by 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).

Analysis evaluating the time to deterioration of pain. HR, CI and p-value obtained from the prop. hazards model stratified by 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).

Time to deterioration of cough

Time to deterioration of dyspnoea

Time to deterioration of pain

Quality of Life (QoL)

Nintedanib BIBF 1120 (N=188, 39)

Nintedanib BIBF 1202 (N=188, 40)

Nintedanib BIBF 1202 glucuronide (N=184, 39)

Nintedanib 150 mg twice daily administered orally in a form of a soft gelatin capsule plus pemetrexed 500 mg/m2 on Day 1 of each 21-day treatment course administered via intravenous infusion.

Nintedanib 150 mg Bid Plus Pemetrexed

Pharmacokinetic set- all patients in the treated set who were documented to have received at least 1 dose of nintedanib and who had at least 1 valid drug plasma concentration available

Dose Normalised Predose Plasma Concentration at Steady State (Cpre,ss,Norm) of Nintedanib and of Its Metabolites BIBF 1202 and BIBF 1202 Glucuronide

CTCAE grade 1

CTCAE grade 2

CTCAE grade 3

CTCAE grade 4

CTCAE grade 5

Treated set uncut - all randomised patients who were documented to have taken at least 1 dose of study medication . Patients were allocated to the treatment groups according to the treatment actually received.

Spots Global Cancer Trial Database for dexamethasone (or corticosteroid equivalent)