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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) (NEXUS)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Bayer
ClinicalTrials.gov Identifier:
NCT00449033
First received: March 16, 2007
Last updated: March 20, 2014
Last verified: March 2014
Results First Received: April 20, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Safety/Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Double Blind (Subject, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition: Carcinoma, Non-Small-Cell Lung
Interventions: Drug: Sorafenib (Nexavar, BAY43-9006)
Drug: Placebo
Drug: Gemcitabine
Drug: Cisplatin

  Participant Flow
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Recruitment Details
Key information relevant to the recruitment process for the overall study, such as dates of the recruitment period and locations
This study was conducted at 93 centers across 16 countries, which enrolled and randomized at least one patient. From a total of 1011 patients who were screened, 904 patients were randomized between 23 FEB 2007 and 03 MAR 2009.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
All 904 randomized patients were included in the intent to treat (ITT) population. A total of 901 patients received at least one dose of study medication and were included in the safety population. Study medication included administration of any one of the following treatments: gemcitabine, cisplatin, sorafenib or placebo.

Reporting Groups
  Description
Sorafenib (Nexavar, BAY43-9006) + GC Up to 6 cycles (21 days per cycle) of gemcitabine (G) and cisplatin (C) with sorafenib. Day 1: gemcitabine 1250 mg/ m^2 infusion (IV), followed by cisplatin 75 mg/ m^2 IV; Day 8: gemcitabine 1250 mg/ m^2 IV; Days 1-21: sorafenib 2 tablets (200 mg) taken orally (po) twice daily (bid). If the patient had radiological evidence of stable disease (SD) or better after completing up to 6 cycles in the Chemotherapy Phase, the patient could continue to Maintenance Phase, during which sorafenib was administered 400 mg bid until criteria for withdrawal were met.
Placebo + GC Up to 6 cycles (21 days per cycle) of gemcitabine (G) and cisplatin (C) with placebo. Day 1: gemcitabine 1250 mg/ m^2 infusion (IV), followed by cisplatin 75 mg/ m^2 IV; Day 8: gemcitabine 1250 mg/ m^2 IV; Days 1-21: placebo 2 tablets po bid. If the patient had radiological evidence of SD or better after completing up to 6 cycles in the Chemotherapy Phase, the patient could continue to Maintenance Phase, during which 2 placebo tablets were administered bid until criteria for withdrawal were met.

Participant Flow for 2 periods

Period 1:   Treatment Period
    Sorafenib (Nexavar, BAY43-9006) + GC     Placebo + GC  
STARTED     452     452 [1]
Received Treatment     452     449  
COMPLETED     0     0  
NOT COMPLETED     452     452  
Adverse Event                 117                 83  
Death                 21                 12  
Lost to Follow-up                 0                 2  
Physician Decision                 4                 5  
Protocol Violation                 8                 7  
Disease Progression                 231                 288  
Consent Withdrawn                 36                 20  
Amended Protocol Criteria                 22                 18  
Non-compliance                 7                 8  
Second Malignancy                 0                 1  
Reason Missing                 0                 4  
Treatment Ongoing                 6                 4  
[1] Reasons for not treated: Adverse event (N=1); Consent withdrawn (N=1); Reason missing (N=1)

Period 2:   Follow-up Period
    Sorafenib (Nexavar, BAY43-9006) + GC     Placebo + GC  
STARTED     425 [1]   434 [2]
COMPLETED     0     0  
NOT COMPLETED     425     434  
Death                 299                 311  
Lost to Follow-up                 6                 10  
Reason Missing                 120                 113  
[1] 425 entered, comprising 452 randomized less 21 deaths & 6 ongoing on treatment
[2] 434 entered, comprising 452 randomized less 12 deaths, 2 lost to follow-up & 4 ongoing on treatment



  Baseline Characteristics
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Population Description
Explanation of how the number of participants for analysis was determined. Includes whether analysis was per protocol, intention to treat, or another method. Also provides relevant details such as imputation technique, as appropriate.
No text entered.

Reporting Groups
  Description
Sorafenib (Nexavar, BAY43-9006) + GC Up to 6 cycles (21 days per cycle) of gemcitabine (G) and cisplatin (C) with sorafenib. Day 1: gemcitabine 1250 mg/ m^2 infusion (IV), followed by cisplatin 75 mg/ m^2 IV; Day 8: gemcitabine 1250 mg/ m^2 IV; Days 1-21: sorafenib 2 tablets (200 mg) taken orally (po) twice daily (bid). If the patient had radiological evidence of stable disease (SD) or better after completing up to 6 cycles in the Chemotherapy Phase, the patient could continue to Maintenance Phase, during which sorafenib was administered 400 mg bid until criteria for withdrawal were met.
Placebo + GC Up to 6 cycles (21 days per cycle) of gemcitabine (G) and cisplatin (C) with placebo. Day 1: gemcitabine 1250 mg/ m^2 infusion (IV), followed by cisplatin 75 mg/ m^2 IV; Day 8: gemcitabine 1250 mg/ m^2 IV; Days 1-21: placebo 2 tablets po bid. If the patient had radiological evidence of SD or better after completing up to 6 cycles in the Chemotherapy Phase, the patient could continue to Maintenance Phase, during which 2 placebo tablets were administered bid until criteria for withdrawal were met.
Total Total of all reporting groups

Baseline Measures
    Sorafenib (Nexavar, BAY43-9006) + GC     Placebo + GC     Total  
Number of Participants  
[units: participants]
  452     452     904  
Age  
[units: Years]
Median ( Full Range )
  60  
  ( 28 to 81 )  
  59  
  ( 22 to 82 )  
  59  
  ( 22 to 82 )  
Gender  
[units: Participants]
     
Female     168     155     323  
Male     284     297     581  
histology of the tumor  
[units: Participants]
     
Non-squamous     385     387     772  
Squamous     67     65     132  
Time since initial diagnosis  
[units: Weeks]
Median ( Full Range )
  2.6  
  ( 0 to 552 )  
  2.9  
  ( 0 to 924 )  
  2.7  
  ( 0 to 924 )  
Smoking history  
[units: Participants]
     
Non-smoker     111     107     218  
Passive smoker     2     3     5  
Past or present smoker     338     342     680  
Not available     1     0     1  
Tumor stage at randomization [1]
[units: Participants]
     
Stage III B     57     55     112  
Stage IV     395     397     792  
ECOG (Eastern Cooperative Oncology Group) Performance Status at randomization [2]
[units: Participants]
     
0     176     175     351  
1     276     277     553  
[1] Categorized information on tumor size, lymph node involvement and metastases. Stages I-IV. The higher the stage the more advanced cancer. Stage IIIB versus IV was a stratification factor for randomization. Stage IIIB (according to American Joint Committee on Cancer): primary tumor any stage, regional lymph node stage N3, no distant metastasis OR primary tumor stage T4, regional lymph node any stage, no distant metastasis. Stage IV: primary tumor any stage, regional lymph node any stage, distant metastasis present.
[2] ECOG 0 versus 1 was a stratification factor for randomization. ECOG Performance Status is a rating of daily living abilities, from 0 to 5: 0= fully active without restriction. 1= restricted in physically strenuous activity; 2= ambulatory, capable of all selfcare; 3= capable of limited selfcare; 4= completely disabled; 5= dead.



  Outcome Measures
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1.  Primary:   Overall Survival (OS) in the ITT (Non-squamous) Population   [ Time Frame: from randomization of the first patient until 38 months or date of death of any cause whichever came first ]

2.  Secondary:   OS in the ITT (Both Squamous and Non-squamous) Population   [ Time Frame: from randomization of the first patient until 38 months or date of death of any cause whichever came first ]

3.  Secondary:   OS in the ITT (Squamous) Population   [ Time Frame: from randomization of the first patient until 38 months or date of death of any cause whichever came first ]

4.  Secondary:   Progression-free Survival (PFS) in the ITT (Non-squamous) Population   [ Time Frame: from randomization of the first patient until 38 months or date of death or progression whichever came first, assessed until discontinuation every 6 weeks up to 9 months and then every 12 weeks ]

5.  Secondary:   Time to Progression (TTP) in the ITT (Non-squamous) Population   [ Time Frame: from randomization of the first patient until 38 months or date of death or progression whichever came first, assessed until discontinuation every 6 weeks up to 9 months and then every 12 weeks ]

6.  Secondary:   Percentage of Participants With Different Tumor Response in the ITT (Non-squamous) Population   [ Time Frame: from randomization of the first patient until 38 months or date of death or progression whichever came first, assessed until discontinuation every 6 weeks up to 9 months and then every 12 weeks ]

7.  Secondary:   Disease Control (DC) in the ITT (Non-squamous) Population   [ Time Frame: from randomization of the first patient until 38 months or date of death or progression whichever came first, assessed until discontinuation every 6 weeks up to 9 months and then every 12 weeks ]

8.  Secondary:   Duration of Response in the ITT (Non-squamous) Population   [ Time Frame: from randomization of the first patient until 38 months or date of death or progression whichever came first, assessed until discontinuation every 6 weeks up to 9 months and then every 12 weeks ]

9.  Secondary:   Duration of Stable Disease (SD) in the ITT (Non-squamous) Population   [ Time Frame: from randomization of the first patient until 38 months or date of death or progression whichever came first, assessed until discontinuation every 6 weeks up to 9 months and then every 12 weeks ]

10.  Secondary:   Time to Response (TTR) in the ITT (Non-squamous) Population   [ Time Frame: from randomization of the first patient until 38 months or date of death of any cause whichever came first ]

11.  Secondary:   Functional Assessment of Cancer Treatment-Lung (FACT-L) Scores in the ITT (Non-squamous) Population   [ Time Frame: from randomization of the first patient until 38 months ]

12.  Secondary:   Lung Cancer Subscale (LCS) Scores in the ITT (Non-squamous) Population   [ Time Frame: from randomization of the first patient to 38 months later or death whatever occurs first. ]

13.  Secondary:   Time to Symptomatic Deterioration (TSD) in the ITT (Non-squamous) Population   [ Time Frame: from randomization of the first patient to 38 months later or death whatever occurs first ]

14.  Secondary:   Euro Quality of Life - 5D (EQ-5D) Index Scores in the ITT (Non-squamous) Population   [ Time Frame: from randomization of the first patient until 38 months later or death whatever occurs first ]

15.  Secondary:   EQ-5D Visual Analog Scale (VAS) Scores in the ITT (Non-squamous) Population   [ Time Frame: from randomization of the first patient until 38 months later or death whatever occurs first ]


  Serious Adverse Events


  Other Adverse Events


  Limitations and Caveats
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Limitations of the study, such as early termination leading to small numbers of participants analyzed and technical problems with measurement leading to unreliable or uninterpretable data
Inclusion of squamous patients stopped in FEB 2008, as 11961 (NCT00558636) trial reported higher mortality for this subgroup. Squamous patients in 12006 (NCT00449033) trial discontinued drug as a precaution endorsed by Data Monitoring Committee.


  More Information
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Certain Agreements:  
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The agreement is:
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.
unchecked The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.


Results Point of Contact:  
Name/Title: Therapeutic Area Head
Organization: Bayer HealthCare AG
e-mail: clinical-trials-contact@bayerhealthcare.com


Publications of Results:

Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT00449033     History of Changes
Other Study ID Numbers: 12006, 2006-002688-26
Study First Received: March 16, 2007
Results First Received: April 20, 2011
Last Updated: March 20, 2014
Health Authority: Germany: Federal Institute for Drugs and Medical Devices
Austria: Federal Office for Safety in Health Care
Belgium: Federal Agency for Medicinal Products and Health Products
Brazil: National Health Surveillance Agency
China: Food and Drug Administration
Cyprus: Registrar of the Drugs Council
Finland: Finnish Medicines Agency
France: Afssaps - Agence française de sécurité sanitaire des produits de santé (Saint-Denis)
Greece: National Organization of Medicines
Ireland: Ministry of Health
Italy: Ministry of Health
Mexico: Federal Commission for Protection Against Health Risks
Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
Spain: Agencia Española de Medicamentos y Productos Sanitarios
Switzerland: Swissmedic
United Kingdom: Medicines and Healthcare Products Regulatory Agency