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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Nintedanib (BIBF1120)
* Drug: Pemetrexed
* Drug: pemetrexed
* Drug: B12
* Drug: dexamethasone (or corticosteroid equivalent)
* Drug: placebo
* Drug: dexamethasone (or corticosteroid equivalent)
* Drug: B12
* Drug: Folic Acid
* Drug: B12
* Drug: dexamethasone (or corticosteroid equivalent)
* Drug: Folic Acid
* Drug: placebo
* Drug: Folic Acid
* Drug: Nintedanib (BIBF1120)
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Male or female patient aged 18 years or older. Histologically or cytologically confirmed Stage IIIB, IV (according to AJCC) or recurrent non small cell lung cancer (NSCLC) (non squamous histologies) 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). 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. Life expectancy of at least three months. Eastern Cooperative Oncology Group (ECOG) score of 0 or 1. 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: Previous therapy with other vascular endothelial growth factor (VEGF) inhibitors (other than bevacizumab) or pemetrexed for treatment of NSCLC 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 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 Inability to stop intake of NSAIDS (non steroidal anti inflammatory drugs) for several days 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) Radiographic evidence of cavitary or necrotic tumors Centrally located tumors with radiographic evidence (CT or MRI) of local invasion of major blood vessels History of clinically significant haemoptysis within the past 3 months Therapeutic anticoagulation History of major thrombotic or clinically relevant major bleeding event in the past 6 months Significant cardiovascular diseases (i.e., hypertension not controlled by medical therapy, unstable angina, history of myocardial infarction within the past 6 months, Inadequate kidney, liver, blood clotting function Inadequate blood count Significant weight loss (> 10 %) within the past 6 weeks prior to treatment in the present trial Current peripheral neuropathy greater than or equal to Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 except due to trauma Pre-existing ascites (abdominal fluid collection) and/or clinically significant pleural effusion ( fluid collection between the lung and chest wall) Major injuries and/or surgery within the past ten days prior to start of study drug Incomplete wound healing Active or chronic hepatitis C and/or B infection Additional exclusion criteria apply

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: nintedanib (BIBF1120) plus pemetrexed<br>nintedanib (BIBF1120) along with standard therapy of pemetrexed | Drug: Nintedanib (BIBF1120)<br>* 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.<br>Drug: B12<br>* 1000 ug IM injection starting a week before first pemetrexed infusion and every 9 weeks thereafter until discontinuation of pemetrexed<br>Drug: dexamethasone (or corticosteroid equivalent)<br>* 4 mg PO bid the day before, the day of and the day after each pemetrexed infusion<br>Drug: Folic Acid<br>* 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.<br>Drug: Pemetrexed<br>* 500 mg/metre squared administered as an intravenous infusion over 10 minutes on Day 1 of each 21 day cycle.<br>|
| Placebo Comparator: Placebo plus pemetrexed<br>Pemetrexed standard therapy | Drug: pemetrexed<br>* 500 mg/metre squared administered as an intravenous infusion over 10 minutes on Day 1 of each 21 day cycle.<br>Drug: dexamethasone (or corticosteroid equivalent)<br>* 4 mg PO bid the day before, the day of and the day after each pemetrexed infusion<br>Drug: B12<br>* 1000 ug IM injection starting a week before first pemetrexed infusion and every 9 weeks thereafter until discontinuation of pemetrexed<br>Drug: placebo<br>* 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.<br>Drug: Folic Acid<br>* 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.<br>|
| Experimental: nintedanib (BIBF1120) monotherapy<br>nintedanib (BIBF1120) monotherapy only for patients who discontinue pemetrexed | Drug: Nintedanib (BIBF1120)<br>* 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.<br>|
| Active Comparator: pemetrexed monotherapy<br>pemetrexed monotherapy only for patients who discontinue nintedanib (BIBF1120) or placebo | Drug: Pemetrexed<br>* 500 mg/metre squared administered as an intravenous infusion over 10 minutes on Day 1 of each 21 day cycle.<br>Drug: B12<br>* 1000 ug IM injection starting a week before first pemetrexed infusion and every 9 weeks thereafter until discontinuation of pemetrexed<br>Drug: dexamethasone (or corticosteroid equivalent)<br>* 4 mg PO bid the day before, the day of and the day after each pemetrexed infusion<br>Drug: Folic Acid<br>* 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.<br>|
| Placebo Comparator: placebo monotherapy<br>placebo monotherapy only for patients who discontinue pemetrexed | Drug: placebo<br>* 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.<br>|

What is the study measuring?
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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 |