A 3rd/4th Line Placebo-controlled Trial of Sorafenib in Patients With Predominantly Non Squamous Non-Small Cell Lung Cancer (NSCLC).

Phase 3

Completed

• Conditions: Non-Small-Cell Lung; Carcinoma
• Interventions: Drug: Sorafenib (Nexavar, BAY43-9006); Drug: Placebo

• Registration Number: NCT00863746
• Lead Sponsor: Bayer

Brief Summary

The purpose of the study is to see if sorafenib plus best supportive care (i.e. in addition to the non-cancer treatments patients would normally receive) is an effective treatment for lung cancer compared to best supportive care alone. The safety and tolerability of the two treatment groups will also be compared. The goal of the study is to test the ability of sorafenib to improve survival compared to best supportive care alone.

Detailed Description

Acronyms used in Adverse Events section: Disseminated intravascular coagulation (DIC), International normalized ratio (INR), Atrioventricular (AV), Gastrointestinal (GI), Not otherwise specified (NOS), Common Terminology Criteria for Adverse Events (CTCAE), Absolute neutrophil count (ANC), Central nervous system (CNS), Acute respiratory distress syndrome (ARDS), Alanine aminotransferase (ALT), Aspartate aminotransferase (AST).

Basic Information
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Recruitment & Eligibility
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Study & Design

Study Timeline

• Study First Submitted: 2009-03-17
• Study First Submitted QC: 2009-03-17
• Study First Posted: 2009-03-18
• Study Start: 2009-04
• Primary Completion: 2012-03
• Study Completion: 2013-04
• Results First Submitted: 2013-04-10
• Results First Submitted QC: 2013-06-23
• Results First Posted: 2013-07-30
• Status Verified: 2015-01
• Last Update Submitted: 2015-01-07
• Last Update Posted: 2015-01-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 703

Inclusion Criteria

• Ability to understand and willingness to sign a written Informed Consent

• Advanced relapsed or refractory predominantly non squamous NSCLC. The diagnosis must have been confirmed cyto-/ histologically

• Patients must have measurable or non-measurable disease

• At least two but not more than three prior standard treatment regimens for NSCLC

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• 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

• Both men and women using adequate barrier birth control measures during the course of the trial and 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:

  • Haemoglobin > 9.0 g/dl
  • Absolute neutrophil count (ANC) >1,500/mm3
  • Platelet count >/= 100,000/µl
  • Total bilirubin </=1.5 x the upper limit of normal
  • Alanine aminotransferase (ALT) < 2.5 x upper limit of normal (</= 5 x upper limit of normal in patients with liver metastases) Aspartate aminotransferase (AST) < 2.5 x upper limit of normal (</= 5 x upper limit of normal in patients with liver metastases)
  • Alkaline phosphatase < 4 x upper limit of normal (</= 5 x upper limit of normal in patients with liver metastases)
  • Prothrombin Time (PT)-International Normalized Ratio (INR) or Partial Thromboplastin Time (PTT) < 1.5 x upper limit of normal
  • Serum creatinine < 1.5 x upper limit of normal
  • Calculated creatinine clearance of >/= 50 mL/min

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Exclusion Criteria

• NSCLC patients with predominantly squamous cell carcinoma histology

Excluded medical conditions:

• History of cardiac disease: Congestive heart failure, Active coronary artery disease (CAD), Cardiac arrhythmias (>Grade 2 NCI-CTCAE [National Cancer Institute-Common Terminology Criteria for Adverse Events] vers. 3.0)
• Uncontrolled hypertension despite two anti-hypertensive medications
• History of Human immunodeficiency virus (HIV) infection or chronic 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 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
• Thrombotic or embolic venous or arterial events such as cerebrovascular accident
• Pregnant or breast-feeding women.
• Any condition which could affect the absorption or pharmacokinetics of the study drug
• Prior treatment with other Vascular Endothelial Growth Factor (VEGF) (R) inhibitors, including compounds that impact vascularity (i.e. sunitinib, thalidomide, vandetanib, vascular disrupting agents [VDA], VEGF-trap and other experimental agents of this class). Only bevacizumab (Avastin) is permitted.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sorafenib (Nexavar, BAY43-9006)	Sorafenib (Nexavar, BAY43-9006)	Participants received 2 tablets of Sorafenib (2×200 mg) orally twice daily (BID)
Placebo	Placebo	Participants received 2 tablets of placebo orally twice daily (BID)

Primary Outcome Measures

Name	Time	Method
Overall Survival	From randomization of the first subject until 36 months later	Overall survival (OS) was defined as the time from date of randomization to date of death due to any cause. Overall survival of subjects alive at the time of analysis will be censored at their last date of follow-up or database cut off date whichever came first.

Secondary Outcome Measures

Name	Time	Method
Progression-free Survival	From randomization of the first subject until 36 months later assessed every 6 weeks	Progression-free survival (PFS) was defined as the time from date of randomization to date of first observed disease progression (radiological or clinical, whichever is earlier) or death due to any cause, if death occurs before progression is documented. Progressive Disease (PD) is defined as at least a 20% increase in the sum of longest diameter (LD) of measured lesions taking as references the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. Appearance of new lesions will also constitute progressive disease. In exceptional circumstances unequivocal progression of a non-measured lesion may be accepted as evidence of disease progression.
Disease Control	From randomization of the first subject until 36 months later assessed every 6 weeks	Disease control (DC) was defined as the proportion of patients whose best response was Complete Response \[CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target)\] or Partial Response \[PR: at least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the baseline sum LD\] or Stable Disease \[SD: steady state of disease which was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for Progressive Disease (PD)\].
Objective Tumor Response	From randomization of the first subject until 36 months later assessed every 6 weeks	Objective tumor response was defined as the proportion of patients whose best response was Complete Response \[CR: disappearance of all clinical and radiological evidence of tumor (both target and non-target)\] or Partial Response \[PR: at least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference the baseline sum LD\] over the whole duration of study.
Time to Progression	From randomization of the first subject until 36 months later assessed every 6 weeks	Time to progression (TTP) was defined as the time from date of randomization to date of first observed disease progression (radiological or clinical, whichever is earlier).
Mean Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire for Palliative Care (EORTC QLQ-C15-PAL) - Global Health Status	Baseline and up to End of treatment (up to Cycle 41, 21 days per cycle)	The EORTC QLQ-C15-PAL is an abbreviated 15-item version of the EORTC core quality of life questionnaire (EORTC QLQ-C30) developed for use in palliative care. The 'Global Health status' subscale consists of question 15 of the questionnaire. The score of 'Global Health status' ranges from 0 (very poor) to 100 (excellent). The change of score ranges from -100 (maximum degree of worsening) to 100 (maximum degree of improvement).
Mean Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Lung Cancer Module (EORTC QLQ-LC13) - Dyspnea	Baseline and up to End of treatment (up to Cycle 41, 21 days per cycle)	A clinically valid 13-item tool for assessing disease- and treatment-specific symptoms in lung cancer patients in clinical trials. The dyspnea subscale uses questions 3, 4 and 5 of the questionnaire. The scale ranges from 0 to 100. Higher score means higher level of symptomatology/problems. The change of score ranges from -100 (decrease in level of symptomatology/problems) to 100 (increase in level of symptomatology/problems).
Mean Change From Baseline in European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire Lung Cancer Module (EORTC QLQ-LC13) - Coughing Subscale	Baseline and up to End of treatment (up to Cycle 41, 21 days per cycle)	A clinically valid 13-item tool for assessing disease- and treatment-specific symptoms in lung cancer patients in clinical trials. The coughing subscale uses question 1 of the questionnaire. The scale ranges from 0 to 100. Higher score means higher level of symptomatology/problems. The change of score ranges from -100 (decrease in level of symptomatology/problems) to 100 (increase in level of symptomatology/problems).
Mean Change From Baseline in EuroQol-5D (EQ-5D) - Index Score	Baseline and up to End of treatment (up to Cycle 41, 21 days per cycle)	The Euro-Qol 5D (EQ-5D) is a validated assessment tool of Health Related Quality of Life (HRQOL) and utilities consisting of 15 statements. Patients select those statements that best describe their current health state regarding mobility, self-care, usual activities, pain/discomfort, and anxiety/depression which is converted into a utility value. Range of scale is from -0.594 (worst possible health state) to 1 (perfect health) based on UK weights. The change of score ranges from -1.594 (high degree of worsening) to 1.594 (high degree of improvement).
Mean Change From Baseline in EuroQol-5D (EQ-5D) - VAS Score	Baseline and up to End of treatment (up to Cycle 41, 21 days per cycle)	A visual analogue scale (EQ VAS) used by patients to rate their current health state from 100 (best imaginable health state) to 0 (worst imaginable health state). The change of score ranges from -100 (high degree of worsening) to 100 (high degree of improvement)