A Phase III, multi-center, placebo-controlled trial of Sorafenib (BAY 43-9006) in patients with relapsed or refractory advanced predominantly non squamous Non-Small Cell Lung Cancer (NSCLC) after 2 or 3 previous treatment regimens

•Ability to understand and willingness to sign a written Informed Consent. A signed Informed Consent must be obtained prior to performing any study specific procedures.
•Advanced relapsed or refractory predominantly non squamous NSCLC. The diagnosis must have been confirmed cyto-/ histologically (documentation of original cytology/ biopsy result is acceptable).
•Patients must have measurable or non-measurable disease as defined in Section 4.6.4.2. All sites of disease must be evaluated within 4 weeks prior to first dose of study medication.
•at least 2 but not more than 3 prior treatment regimens for advanced disease. (Adjuvant or neo-adjuvant anti-cancer treatments after which a relapse occurred within 1 year of therapy will be counted. Maintenance anti-cancer treament is counted as a separate regimen, if it was not administered as part of the immediate- past regimen).
o Prior therapy with bevacizumab (Avastin) permitted
o Prior therapy with standard EGFR inhibitors permitted. Every attempt should be made to enroll patient who have received an EGFR inhibitor in the geographic areas where this type of treatment is available.
•ECOG Performance Status of 0 or 1
•History of metastatic brain or meningeal tumors allowed, provided definitive therapy (surgery and/or radiation) has been administered before randomization , no further treatment of brain metastases is planned, and the subject is clinically and radiologically stable for at least 2 months prior to randomization. (Patients must be asymptomatic and off steroid treatment for at least 14 days prior to study entry (i.e. signature date of Study Informed Consent Form). Discontinuation of corticosteroid treatment must be done independent of study participation as per local standard of care and consent procedures).
•Male or female subjects >= 18 years of age (>= 20 for Japan) at the time of Informed Consent
•Life expectancy of at least 12 weeks
•Ability to swallow oral medication
•Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment (assessed centrally)
•Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and during the first 4 weeks after the completion of trial
•Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to start of the study drug:
o Haemoglobin > 9.0 g/dl
o Absolute neutrophil count (ANC) >1,500/mm3
o Platelet count * 100,000/µl
o Total bilirubin <= 1.5 x the upper limit of normal
o ALT < 2.5 x upper limit of normal (<= 5 x upper limit of normal in patients with liver metastases)
o AST < 2.5 x upper limit of normal (<= 5 x upper limit of normal in patients with liver metastases)
o Alkaline phosphatase < 4 x upper limit of normal (<= 5 x upper limit of normal in patients with liver metastases)
o PT-INR or PTT < 1.5 x upper limit of normal
o Serum creatinine < 1.5 x upper limit of normal
o Calculated creatinine clearance of >= 50 mL/min e.g.Cockroft-Gault, MDRD formula. (Measured creatinine clearance using EDTA, Inulin or 24 hours urine methods is recommended for patients with equivocal results or low body weight) NOTE: The central lab will use the Cockcroft-Gault calculation. Measured creatinine clearance will be done locally only if needed.

•NSCLC patients with predominantly squamous cell carcinoma histology
Excluded medical conditions:
•History of cardiac disease:
o Congestive heart failure >New York Heart Association (NYHA) class 2
o Active coronary artery disease (CAD), i.e. angina with onset in last 3 months or with symptoms at rest [myocardial infarction more than 6 months prior to study entry is allowed]
o Cardiac arrhythmias (>Grade 2 NCI-CTCAE vers. 3.0) which are poorly controlled with anti-arrhythmic therapy
o Uncontrolled hypertension [systolic blood pressure >= 150 mmHg or diastolic blood pressure >= 90 mmHg despite two anti-hypertensive medications]
o Any of the following:
- History of HIV infection
- Current chronic active or acute hepatitis B or C
•History of organ allograft
•Active clinically serious infections (> grade 2 NCI-CTCAE vers. 3.0)
•Patients with seizure disorder requiring medication (Patients who experienced seizures due to brain metastases prior to radical treatment of these metastases are allowed if the inclusion criterion related to brain metastases is adhered to - see section 4.2.1, inclusion criteria, for details).
•Patients with evidence or history of bleeding diathesis or coagulopathy
•Patients undergoing renal dialysis
•Pulmonary hemorrhage/ bleeding event >= CTCAE grade 2 within four weeks prior to the first dose of the study drug
•Any other hemorrhage/ bleeding event >= CTCAE grade 3 within four weeks prior to the first dose of the study drug
•Non-healing wound, ulcer or bone fracture
•Thrombotic or embolic venous or arterial events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months prior to the first dose of study drug
•Previously untreated or concurrent cancer that is distinct in primary site or histology from NSCLC, EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, superficial bladder tumors (Ta, Tis, T1). Any cancer curatively treated >3 years prior to entry is permitted. All treatments must be completed at least 3 years prior to the study entry (i.e. signature date of Study Informed Consent).
•Substance abuse, medical, psychological or social conditions that may interfere with the subject*s participation in the study or evaluation of the study results
•Known or suspected allergy or any other contraindication for sorafenib administration
•Pregnant or breast-feeding women. [Both men and women enrolled in this trial must use adequate barrier birth control measures during the course of the trial and during the first four weeks after the completion of trial].
•Any disease which could affect the evaluation of the study drug
•Any condition that is unstable or could jeopardize the safety of the subject and their compliance in the study
•Any condition which could affect the absorption or pharmacokinetics of the study drug including any type of gastrointestinal resection or surgery;Excluded therapies and medications, previous and concomitant:
•All prior anti-cancer drugs or device therapy for NSCLC including outside of this trial should be completed at least 3 weeks prior to first dose of study drug (Day 1, Cycle 1 [D1C1]).•Prior treatment with other VEGFR inhibitors (i.e. sunitinib, thalidomide, vandetanib and other experimental agents of this class). Bevacizumab (Avastin) is permitted.
•Radiotherapy during study or 3 weeks prior to Day 1, Cycle 1 (first dose of study drug. [Palliative radiotherapy will be allowed as described in the Prior and Concomitant Therapy section. If radiotherapy to the target lesion(s) during study is required, this will be regarded as progressive disease]. No previous irradiation to the only site of measurable or evaluable disease, unless that site had subsequent evidence of progression.
•Major surgery within 4 weeks prior to start of study (Informed Consent signature). Minimal invasive biopsy is allowed.
•Use of biologic response modifiers, such as G-CSF, within 3 week prior to study entry. [Therapeutic G-CSF and other hematopoietic growth factors may be used in the management of acute toxicity such as febrile neutropenia when clinically indicated or at the discretion of the investigator, however they may not be substituted for a required dose reduction].
•Any agents which could affect the absorption or pharmacokinetics of the study drug
•Prior exposure to the study drug
•Therapeutic anticoagulation with vitamin K antagonists such as warfarin, or with heparins or heparinoids. Prophylactic low dose warfarin (1 mg po qd) is permitted if the INR (International normalized ratio) is <= 1.5. Low-dose aspirin is permitted (80-100 mg daily).