A Phase III Randomized, Double-blind, Placebo Controlled Trial Comparing the Efficacy of Gemcitabine, Cisplatin and Sorafenib to Gemcitabine, Cisplatin and Placebo in First-Line Treatment of Patients With Stage IIIb With Effusion and Stage IV Non-Small Cell Lung Cancer (NSCLC)

A Phase III Randomized, Double-blind, Placebo Controlled Trial Comparing the Efficacy of Gemcitabine, Cisplatin and Sorafenib to Gemcitabine, Cisplatin and Placebo in First-Line Treatment of Patients With Stage IIIb With Effusion and Stage IV Non-Small Cell Lung Cancer (NSCLC)

Evaluation of gemcitabine and cisplatin in combination with either sorafenib or placebo for the treatment of patients with advanced Non-Small Cell Lung Cancer (NSCLC)

During follow-up, it was determined that there was one additional patient on placebo that was still receiving treatment as of 06 APR 2010 and therefore 10 patients' data are reported in the current CSR addendum, 6 in the sorafenib + GC group and 4 in the placebo + GC group, and as before all in the ITT (non-squamous) population.

Inclusion Criteria:

• Age > 18 years old
• Stage IIIB (with cytologically confirmed malignant pleural or pericardial effusion) or Stage IV histological or cytological confirmation of NSCLC of non-squamous cell carcinoma subtype. (thoracentesis or pericardiocentesis is not necessary if a biopsy of the original tumor is available to confirm diagnosis of NSCLC).
• Patients with at least one measurable lesion. Lesions must be measured by CT-scan or MRI (Magnetic resonance imaging) according to Response Evaluation Criteria in Solid Tumors (RECIST, see Appendix 10.3)
• Life expectancy of at least 12 weeks
• Adequate bone marrow, liver and renal function as assessed by the following laboratory requirements to be conducted within 7 days prior to start of first dose:
• Hemoglobin >/= 9.0 g/dl (>/= 5.6 mmol/l)
• Absolute neutrophil count (ANC) >/= 1,500/mm3
• Platelet count >/= 100,000/µl
• Total bilirubin </= 1.5 x upper limit of normal
• Alanine transaminase (ALT) and Aspartate transaminase (AST) </= 2.5 x upper limit of normal (</= 5 x upper limit of normal for patients with liver involvement of their cancer)
• Alkaline Phosphatase </= 4 x upper limit of normal
• PT-INR (Prothrombin Time - International Normalized Ratio) (international normalized ratio of PT) /PTT (Partial Thromboplastin Time) < 1.5 x upper limit of normal
• Serum Creatinine </= 1.5 times the upper limit of normal and Serum Creatinine Clearance >/= 70ml/min
• Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to performing any study specific procedures.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

Exclusion Criteria:

• Excluded medical conditions:

  • Cardiac disease: Congestive heart failure > class II NYHA (New York Heart Association). Patients must not have unstable angina (anginal symptoms at rest) or active coronary artery disease (CAD), or myocardial infarction within the past 6 months
  • Cardiac arrhythmias requiring anti-arrhythmic therapy
  • Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
  • History of HIV (Human immunodeficiency virus) infection or chronic hepatitis B or C
  • Active clinically serious infections (> grade 2 NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) version 3.0)
  • Patients with seizure disorder requiring medication (such as steroids or anti-epileptics)
  • Known brain metastasis. Patients with neurological symptoms should undergo a CT scan/MRI of the brain to exclude brain metastasis.
  • History of organ allograft
  • Patients with evidence or history of bleeding diathesis or coagulopathy
  • Patients undergoing renal dialysis
  • Cancer other than NSCLC within 5 years prior to start of study treatment EXCEPT cervical carcinoma in situ, treated basal cell carcinoma, or superficial bladder tumors [Ta (Noninvasive tumor), Tis (Carcinoma in situ) & T1 (Tumor invades lamina propria)]
  • Uncontrolled hypertension defined as systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg, despite optimal medical management.
  • Thrombotic or embolic events such as cerebrovascular accident including transient ischemic attacks within the past 6 months
  • Pulmonary hemorrhage/bleeding event > Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 within 4 weeks of first dose of study drug
  • Any other hemorrhage/bleeding event > CTCAE Grade 3 within 4 weeks of first dose of study drug
  • Serious, non-healing wound, ulcer, or bone fracture
  • Uncorrected dehydration
  • Pregnant or breast-feeding patients. Women of childbearing potential must have a negative pregnancy test performed within 7 days of the start of treatment. Both men and women enrolled in this trial must use adequate birth control measures during the course of the trial. The definition of effective contraception will be based on the judgment of the principal investigator or a designated associate.
  • Substance abuse, medical, psychological or social conditions that may interfere with the patient's participation in the study or evaluation of the study results
  • Known or suspected allergy to the investigational agent or any agent given in association with this trial
  • Any condition that is unstable or could jeopardize the safety of the patient and their compliance in the study
  • Patients unable to swallow oral medications
  • Any malabsorption condition
  • Patients with a hearing impairment (FOR GERMANY ONLY)
  • NSCLC patients with squamous cell carcinoma diagnosis documented either by cytology or biopsy.

• Excluded therapies and medications, previous and concomitant:

  • Any prior systemic anticancer therapy including cytotoxic therapy, targeted agents, experimental therapy, adjuvant, or neo-adjuvant therapy for NSCLC
  • Concomitant use of nephrotoxic drugs, ototoxic drugs, anticonvulsant, anti-gout treatment
  • Radiotherapy during study or within 3 weeks of start of study drug. (Palliative radiotherapy will be allowed as described in the Prior and Concomitant Therapy section)
  • Radiotherapy during study or within 4 weeks of start of study drug. (Palliative radiotherapy will be allowed as described in the Prior and Concomitant Therapy section) (FOR FRANCE ONLY)
  • Major surgery, open biopsy or significant traumatic injury within 4 weeks of first dose of study drug (bronchoscopy is allowed)
  • Granulocyte colony stimulating factor (GCSF) or Granulocyte macrophage colony stimulating factor (GMCSF), within 3 weeks of study entry (these growth factors may be used during the study thereafter).