LUME-Lung 1: BIBF 1120 Plus Docetaxel as Compared to Placebo Plus Docetaxel in 2nd Line Non Small Cell Lung Cancer

Study Overview
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Brief Summary
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The present trial will be performed to evaluate whether BIBF 1120 in combination with standard therapy of docetaxel in patients with stage IIIB/IV or recurrent NSCLC is more effective as compared to placebo in combination with standard therapy of docetaxel. A secondary aim is to obtain safety information as well as information on quality of life of patients treated with BIBF 1120 in combination to standard therapy with docetaxel. In addition, blood will be collected for pharmacokinetic analysis.

Official Title
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Multicentre, Randomised, Double-blind, Phase III Trial to Investigate the Efficacy and Safety of Oral BIBF 1120 Plus Standard Docetaxel Therapy Compared to Placebo Plus Standard Docetaxel 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: placebo plus docetaxel
* Drug: BIBF 1120 plus docetaxel


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, locally advanced and/or metastatic NSCLC of stage IIIB or IV or recurrent NSCLC; relapse or failure of one first line prior chemotherapy; at least one target tumour lesion that has not been irradiated within the past three months and that can accurately be measured ; life expectancy of at least three months; Eastern Cooperative Oncology group (ECOG) score of 0 or 1; patient has given written informed consent Exclusion criteria: more than one prior chemotherapy regimen for advanced and/or metastatic or recurrent NSCLC; more than one chemotherapy treatment regimen (either neoadjuvant or adjuvant or neoadjuvant plus adjuvant) prior to first line chemotherapy; previous therapy with other VEGFR inhibitors (other than bevacizumab) or docetaxel for treatment of NSCLC; persistence of clinically relevant therapy related toxicities from previous chemotherapy and/or radiotherapy; treatment with other investigational drugs or other anti-cancer therapy or treatment in another clinical trial within the past four weeks before start of - therapy or concomitantly with this trial ; radiotherapy (except extremities and brain) within the past three months prior to baseline imaging; active brain metastases or leptomeningeal disease; radiographic evidence of cavitary or necrotic tumours; centrally located tumours 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 (except low dose heparin) or antiplatelet therapy; history of major thrombotic or clinically relevant major bleeding event in the past 6 months; known inherited predisposition to bleeding or thrombosis; significant cardiovascular diseases ; inadequate safety laboratory parameters; significant weight loss (> 10 %) within the past 6 weeks; current peripheral neuropathy greater than CTCAE grade 2 except due to trauma; preexisting ascites and/or clinically significant pleural effusion; major injuries and/or surgery within the past ten days prior to randomisation with incomplete wound healing; serious infections requiring systemic antibiotic therapy; decompensated diabetes mellitus or other contraindication to high dose corticosteroid therapy; gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug; active or chronic hepatitis C and/or B infection; serious illness or concomitant non-oncological disease or laboratory abnormality that may increase the risk associated with study participation or study drug administration; patients who are sexually active and unwilling to use a medically acceptable method of contraception during the trial and for at least twelve months after end of active therapy; pregnancy or breast feeding; psychological, familial, sociological or geographical factors potentially hampering compliance with the study protocol and follow-up schedule; patients unable to comply with the protocol; active alcohol or drug abuse; other malignancy within the past three years other than basal cell skin cancer, or carcinoma in situ of the cervix; any contraindications for therapy with docetaxel; history of severe hypersensitivity reactions to docetaxel or other drugs formulated with polysorbate 80 (Tween 80); hypersensitivity to BIBF 1120 and/or the excipients of the trial drugs; hypersensitivity to contrast media

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: BIBF 1120 plus docetaxel<br>BIBF 1120 2 times daily along with standard therapy of docetaxel | Drug: BIBF 1120 plus docetaxel<br>* BIBF 1120 2 times daily along with standard therapy of docetaxel<br>|
| Placebo Comparator: Placebo plus docetaxel<br>Placebo matching BIBF 1120 2 times daily along with standard therapy of docetaxel | Drug: placebo plus docetaxel<br>* placebo matching BIBF 1120 2 times daily along with standard therapy of docetaxel<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 Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) . 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 2 November 2010 (when 713 PFS events were observed) | 

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. A fixed-sequence-testing was implemented for key secondary endpoint if both the primary and the follow-up analysis showed a treatment benefit (P<0.05) of nintedanib over placebo. In this case, the OS would be tested using hierarchical testing of statistical hypotheses in (1) patients with adenocarcinoma and <9 months since start of first-line therapy, (2) patients with adenocarcinoma, and (3) all patients. Each hypothesis could be only tested at the pre-specified alpha level if the previous null hypothesis in the testing sequence had been. | From randomisation until cut-off date 15 February 2013 (approximately 48 months or 1151 deaths among all patients ) | 
| 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 cut-off date 15 February 2013 | 
| 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 cut-off date 15 February 2013 | 
| Objective Tumour 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. As per RECIST v1.0, Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. This endpoint was analysed based on the central independent reviewer as well as the investigator. | From randomisation until cut-off date 15 February 2013 | 
| 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. As per RECIST v1.0, Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions. 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 cut-off date 15 February 2013 | 
| 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 cut-off date 15 February 2013 | 
| 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. As per RECIST v1.0 for target lesions : Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression. This endpoint was analysed based on the central independent reviewer as well as the investigator. | From randomisation until cut-off date 15 February 2013 | 
| 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 cut-off date 15 February 2013 | 
| 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 (squamous vs non-squamous), 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 cut-off date 15 February 2013 | 
| 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 cut-off date 15 February 2013 | 
| Quality of Life (QoL) | Quality of life (QoL) was measured by standardised questionnaires (Health Status Self-Assessment Questionnaire (EQ-5D), EORTC Quality of life questionnaire - Core 30 (EORTC QLQ-C30), Quality of life questionnaire - lung cancer module (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 (EORTC 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 cut-off date 15 February 2013 | 
| 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 42 months |