A Trial Comparing Safety and Efficacy of Carboplatin and Paclitaxel Plus or Minus Sorafenib (BAY43-9006) in Chemonaive Patients With Stage IIIB-IV Non-Small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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The purpose of this study conducted in Asia-Pacific was to evaluate the efficacy and safety of Sorafenib in combination with paclitaxel and carboplatin versus placebo in combination with paclitaxel and carboplatin for chemonaive patients with unresectable stage IIIB (with effusion) or stage IV NSCLC. However, as indicated below, the study was terminated prematurely when the results from Study 11961 (NCT00300885), an earlier Phase 3 study of similar design in subjects with advanced NSCLC, showed an overall lack of efficacy and increased mortality in subjects with squamous subtype. The data available is presented as descriptive analyses, due to the limitations of implementing the statistical analysis plan.

Detailed Description
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The study was terminated early when the results from Study 11961 (NCT00300885), an earlier Phase 3 study evaluating the effects of Sorafenib in combination with paclitaxel and carboplatin in subjects with advanced NSCLC, showed an overall lack of efficacy of Sorafenib in combination with paclitaxel and carboplatin in NSCLC and increased mortality in subjects with squamous subtype.

Official Title
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A Randomized Controlled Trial Comparing Safety and Efficacy of Carboplatin and Paclitaxel Plus or Minus Sorafenib (BAY43-9006) in Chemonaive Patients With Stage IIIB-IV Non-Small Cell Lung Cancer (NSCLC)

Conditions
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Carcinoma, Non-Small-Cell Lung

Intervention / Treatment
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* Drug: Sorafenib + Paclitaxel + Carboplatin
* Drug: Placebo + Paclitaxel + Carboplatin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Stage IIIB (with cytologically confirmed malignant pleural or pericardial effusion) or Stage IV histological or cytological confirmation of NSCLC (thoracentesis or pericardiocentesis is not necessary if a biopsy of the original tumor is available to confirm diagnosis of NSCLC) Patients must have measurable disease according to response evaluation criteria in solid tumors (RECIST) criteria Prior local radiotherapy is allowed if it is completed at least 3 weeks prior to the first dose of study drug, but the lesion which undergo RECIST assessment should not be in the field of the prior radiation Prior surgery is allowed if it is performed at least 4 weeks prior to the first dose of study drug 18 years and above Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 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 Absolute neutrophil count (ANC) 1,500/mm3 Platelet count 100,000/mm3 Total bilirubin < 1.5 times the upper limit of normal alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 2.5 x upper limit of normal (< 5 x upper limit of normal for patients with liver involvement) international normalized ratio (INR) < 1.5 and activated or adjusted partial thromboplastin time (APTT) within normal limits (1.2 times the lower limit of normal (LLN) to 1.2 times the upper limit of normal (ULN)) Creatinine </= 1.5 times the upper limit of normal Ability to understand and the willingness to sign a written informed consent. A signed informed consent must be obtained prior to any study specific procedures Exclusion Criteria: Any prior systemic anticancer therapy including cytotoxic therapy, targeted agents, experimental therapy, adjuvant, or neo-adjuvant therapy for any current or prior diagnosis of NSCLC Cardiac disease: Congestive heart failure > class II New York Heart Association (NYHA). Patients must not have unstable angina (anginal symptoms at rest) or new-onset angina (began within the last 3 months) or myocardial infarction within the past 6 months Known brain metastasis. Patients with neurological symptoms should undergo at Computed Tomography (CT) scan/Magnetic Resonance Imaging (MRI) of the brain to exclude brain metastasis Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy Uncontrolled hypertension defined as systolic blood pressure > 150 mm Hg or diastolic pressure > 90 mm Hg, despite optimal medical management Known human immunodeficiency virus (HIV) infection Active clinically serious infections > Common Terminology Criteria for Adverse Events (CTCAE) Grade 2 Thrombotic or embolic events such as cerebrovascular accident including transient ischemic attacks within the past 6 months Pulmonary hemorrhage/bleeding event > 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 Evidence or history of bleeding diathesis or coagulopathy Major surgery, open biopsy or significant traumatic injury within 4 weeks of first dose of study drug Therapeutic anticoagulation with vitamin K antagonists such as warfarin, or with heparins or heparinoids. Low dose warfarin (1 mg daily, oral) is permitted if the INR remains < 1.5. Low-dose aspirin is permitted Known or suspected allergy to sorafenib or any agent given in the course of this trial Cancer other than NSCLC within 5 years prior to start of study treatment, EXCEPT cervical cancer in-situ, treated basal cell carcinoma, or superficial bladder tumors Concurrent cancer that is distinct in primary site or histology from NSCLC Substance abuse, medical, psychological or social conditions that may interfere with the patients participation in the study or evaluation of the study results Any condition that impairs patients ability to swallow whole pills Any malabsorption condition Women of childbearing potential must have a negative serum pregnancy test performed within 7 days prior to the start of treatment Women of childbearing potential and men must agree to use adequate contraception prior to study entry and for the duration of study participation, including the 30 days period after last study drug dosing. The investigator should advise the patient how to achieve an adequate contraception

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sorafenib + Paclitaxel + Carboplatin<br>Chemotherapy plus Multi Kinase Inhibitor: Sorafenib Group - Sorafenib (Nexavar, BAY43-9006), [400 mg, (2 tablets x 200 mg each) orally, twice daily] on Study Days 2-19 and paclitaxel (175 mg/m^2, intravenous (IV), over 2.5 to 4 hours) and carboplatin (area under the curve (AUC) =5, IV for 15 to 60 minutes) on Study Day 1. The cycle duration will be 21 days. | Drug: Sorafenib + Paclitaxel + Carboplatin<br>* Chemotherapy plus Multi Kinase Inhibitor: Sorafenib Group - Sorafenib (Nexavar, BAY43-9006), [400 mg, (2 tablets x 200 mg each) orally, twice daily] on Study Days 2-19 and paclitaxel (175 mg/m^2, intravenous (IV), over 2.5 to 4 hours) and carboplatin (area under the curve (AUC) =5, IV for 15 to 60 minutes) on Study Day 1. The cycle duration will be 21 days.<br>|
| Placebo Comparator: Placebo + Paclitaxel + Carboplatin<br>Chemotherapy + Placebo: Placebo Group - Placebo (2 tablets twice daily, orally) on Study Days 2-19 and paclitaxel (175 mg/m^2 IV, over 2.5 to 4 hours) and carboplatin (AUC=5 IV, for 15 to 60 minutes) on Study Day 1. The cycle duration will be 21 days | Drug: Placebo + Paclitaxel + Carboplatin<br>* Chemotherapy + Placebo: Placebo Group - Placebo (2 tablets twice daily, orally) on Study Days 2-19 and paclitaxel (175 mg/m^2 IV, over 2.5 to 4 hours) and carboplatin (AUC=5 IV, for 15 to 60 minutes) on Study Day 1. The cycle duration will be 21 days<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival | Progression free survival (PFS) is the time (days) from date of randomization to date of first observed disease progression (radiological or clinical, whichever was earlier) or death due to any cause, if death occurred before progression was documented. Since the study was terminated early and 89% of subjects' data were censored, only the number of PFS events (Failed [progressed or died before progression]) is reported, not the usual measure number of days. | Up to 5 months after randomization of the first patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall survival is the number of days from the date of randomization to the date of death due to any cause. Subjects alive at the time of analysis were censored at their last date of follow-up. Since the study was terminated early and 89% of subjects' data were censored, only the number of subjects who Failed (died) or were Censored is reported, not the usual measure number of days. | Up to 5 months after randomization of the first patient | 
| Best Tumor Response (Number of Responses Per Category) According to Response Evaluation Criteria in Solid Tumors (RECIST) | Complete response (CR): Disappearance of all target lesions (TL). Partial response (PR): At least 30% decrease in sum of the largest diameter (LD) of TLs, taking baseline sum as reference. Stable disease (SD): No change in tumor size. Progressive disease (PD): At least a 20% increase in the sum of the LD of TLs, taking as reference the smallest sum LD recorded since treatment started, or the appearance of 1 or more new lesions. | Best tumor response assessed every 6 weeks by investigator during treatment up to 5 months after randomization of the first patient. | 
| Duration of Response | Duration of response (PR or better) was defined as the time from the first documented objective PR or CR, whichever was noted earlier, to disease progression or death (if death occurred before progression was documented). Since only 4 subjects had a response, the duration of response was not calculated. | Time from first documented objective response (complete response or partial response) to disease progression or death, or to last tumor assessment if censored, up to 5 months after randomization of the first patient. | 
| Change From Baseline of Lung Cancer Symptoms (LCS) Score Assessed at Each Treatment Cycle (21 Days Per Cycle) Starting With Cycle 2 | The LCS is a validated instrument for determining treatment impact on lung symptoms. The LCS consists of 7 questions with 5 responses ranging from not at all to very much. The LCS total score ranges from 0 to 28. Lower scores reflect greater lung cancer symptoms. | Change from baseline of LCS score assessed at each treatment cycle starting with Cycle 2 (Cycles 2, 3, 4, 5, 6, 7; 21 days per cycle) up to 5 months after randomization of the first patient. | 
| Change From Baseline of Health-Related Quality of Life (HRQoL) Score Assessed at Treatment Cycle 3 and Cycle 5 | HRQoL was assessed with the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire, a validated instrument for determining lung cancer HRQoL. The 36-item questionnaire includes 4 domains: Physical, functional, emotional, and social/family well-being, and a lung cancer-specific subscale. The FACT-L total score ranges from 1 to 136. Lower scores demonstrate impaired HRQoL. | Change from baseline of HRQoL score assessed (at treatment Cycle 3 and Cycles 5 [21 days per cycle]) up to 5 months after randomization of the first patient. | 
| Change From Baseline of Health-Related Quality of Life (HRQoL) Score Assessed at Treatment Cycle 7 | HRQoL was assessed with the Functional Assessment of Cancer Therapy-Lung (FACT-L) questionnaire, a validated instrument for determining lung cancer HRQoL. The 36-item questionnaire includes 4 domains: Physical, functional, emotional, and social/family well-being, and a lung cancer-specific subscale. The FACT-L total score ranges from 1 to 136. Lower scores demonstrate impaired HRQoL. | Change from baseline of HRQoL score assessed (at treatment Cycle 7 [21 days per cycle]) up to 5 months after randomization of the first patient. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NSCLC