E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stage IIIB/IV or recurrent non small cell lung cancer. non squamous histology |
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E.1.1.1 | Medical condition in easily understood language |
Advanced cancer of the lung of a certain type of cell-histology |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029522 |
E.1.2 | Term | Non-small cell lung cancer stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029521 |
E.1.2 | Term | Non-small cell lung cancer stage IIIB |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10029515 |
E.1.2 | Term | Non-small cell lung cancer recurrent |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The present trial will be performed to evaluate whether BIBF 1120 in combination with standard therapy pemetrexed in patients with Stage IIIB/IV or recurrent NSCLC is more effective compared to placebo in combination with standard therapy pemetrexed. The trial will be limited to non squamous histologies.
Changes related to Protocol Amendment 3, dated 08. August 2011: No further recruitment into this trial is permitted. All patients who were on active treatment as of June 18th, 2011 were unblinded and placebo was discontinued for all patients. All patients who decided to continue on their active active treatment based on an observed treatment benefit and after discussion with their treating physician receive either monotherapy with pemetrexed (standard of care treatment) or monotherapy with BIBF 1120 (investigational medicinal product) or combination therapy with pemetrexed + BIBF 1120 in case of an observed treatment benefit. |
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E.2.2 | Secondary objectives of the trial |
A secondary aim is to obtain safety information as well as information on quality of life of patients treated with BIBF 1120/pemetrexed compared to standard pemetrexed alone. In addition, blood will be collected for pharmacokinetic analysis. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Male or female patient aged 18 years or older - Histologically or cytologically confirmed Stage IIIB, IV (according to AJCC) or recurrent 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 ≥20 mm with conventional techniques or as ≥10 mm with spiral CT - Life expectancy of at least three months - 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 |
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E.4 | Principal exclusion criteria |
- More than one prior chemotherapy regimen for advanced and/or metastatic disease of NSCLC - More than one chemotherapy treatment regimen (either neoadjuvant or adjuvant or neoadjvant plus adjuvant) prior to first line chemotherapy of advanced, metastatic or recurrent NSCLC - Previous therapy with other VEGFR inhibitors (other than bevacizumab) or pemetrexed for treatment of NSCLC - Persistence of clinically relevant therapy related toxicities from previous chemotherapy and/or radiotherapy - 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 - Chemo-, hormone-, immunotherapy with monoclonal antibodies, treatment with tyrosine kinase inhibitors, or radiotherapy (except for 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. - Radiotherapy (except extremities and brain) within the past three months prior to baseline imaging - Patients taking NSAIDS with short half lives unable or unwilling to interrupt NSAIDsS for a five day period (2 days before pemetrexed, day of pemetrexed, 2 days after pemetrexed). Patients taking NSAIDS with long half lives must interrupt NSAID for 8 days (5 days before, day of and 2 days after treatment with pemetrexed) - 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) - leptomeningeal disease - 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 (more than one tea spoon of fresh blood per day) - Therapeutic anticoagulation (except low dose heparin and/or heparin flush as needed for maintenance of an indwelling intravenous device) or antiplatelet therapy (except for chronic low-dose therapy with acetylsalicylic acid ≤325mg per day) - 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 (i.e., hypertension not controlled by medical therapy, unstable angina, history of myocardial infarction within the past 6 months, congestive heart failure > NYHA II, serious cardiac arrhythmia, pericardial effusion) - Calculated creatinine clearance by Cockcroft Gault <45ml/min - Proteinuria CTCAE grade 2 or greater - Total bilirubin above the upper limit of normal - ALT and/or AST > 2.5 x upper limit of normal in the presence of live metastasis or ALT and/or AST >1.5 x upper limit of normal in patients without liver metastasis. - Prothrombin time and/or partial thromboplastin time greater than 50% deviation from normal limits - Absolute neutrophil count (ANC) < 1500 neutrophils /mm3 - Platelets < 100000 platelets/mm3 - Haemoglobin < 9.0 g/dL - Significant weight loss (> 10 %) within the past 6 weeks prior to treatment in the present trial Major injuries and/or surgery within the past ten days prior to randomisation with incomplete wound healing - Current peripheral neuropathy ≥CTCAE grade 2 except due to trauma - Preexisting ascites and/or clinically significant pleural effusion - Serious infections requiring systemic antibiotic (e.g antiviral, antimicrobial, antifungal) therapy - Gastrointestinal disorders or abnormalities that would interfere with absorption of the study drug - Active or chronic hepatitis C and/or B infection - Patients who are sexually active and unwilling to use a medically acceptable method of contraception (e.g. such as implants, injectables, combined oral contraceptives, some intrauterine devices or vasectomized partner for participating females, condoms for participating males) during the trial and for at least twelve months after end of active therapy - Pregnancy or breast feeding - 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 pemetrexed - History of severe hypersensitivity reactions to pemetrexed or other drugs formulated with mannitol - Hypersensitivity to BIBF 1120 and/or the excipients of the trial drugs - Hypersensitivity to contrast media
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E.5 End points |
E.5.1 | Primary end point(s) |
Progression free survival (imaging assessed by an independent central review according to the modified RECIST criteria) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Analysis will be performed when 713 centrally confirmed progression events have occured.
Changes related to Protocol Amendment 3, dated 08. August 2011: The analysis will be performed once the database for all treated patients (i.e. still blinded patients completed prior to the halt of the trial and patients unblinded after the halt of the trial) is locked. |
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E.5.2 | Secondary end point(s) |
• Overall survival (key secondary endpoint) • Tumor response according to the modified RECIST criteria (objective tumor response, disease control, duration of disease control) • Incidence and intensity of adverse events according to the common terminology criteria for adverse events (CTCAE version 3.0) • Clinical improvement • Changes in safety laboratory parameters • Quality of life measured by standardized questionnaires (EQ-5D, EORTC QLQ C-30, EORTC QLQ LC 13) • Pharmacokinetics of BIBF 1120 (and of clinical relevant metabolites, if feasible) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall survival will be analysed either after about 48 months or when 1151 death events have occured. The other end points will also be analysed at this point in time and already before at the time point of analysis of the primary PFS-endpoint.
Changes related to Protocol Amendment 3, dated 08. August 2011: The analysis will be performed once the database for all treated patients (i.e. still blinded patients completed prior to the halt of the trial and patients unblinded after the halt of the trial) is locked. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 161 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
European Union |
Argentina |
Australia |
Belarus |
Brazil |
Canada |
Chile |
Croatia |
Ecuador |
Hong Kong |
India |
Israel |
Korea, Republic of |
Macedonia, the former Yugoslav Republic of |
Malaysia |
Mexico |
Moldova, Republic of |
New Zealand |
Peru |
Russian Federation |
Serbia |
Singapore |
South Africa |
Taiwan |
Thailand |
Turkey |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The clinical trial will be considered completed as soon as the last patient has died or was lost to follow-up. In case patients would still be on treatment when the report of the trial is being performed, these patients will either be included in a follow-up trial or alterantively kept on treatment in this trial. Those patients will then be reported in an addendum to the report. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 2 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 6 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |