Study of Cisplatin/Vinorelbine +/- Cetuximab as First-line Treatment of Advanced Non Small Cell Lung Cancer (FLEX)

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Merck KGaA
ClinicalTrials.gov Identifier:
NCT00148798
First received: September 7, 2005
Last updated: June 13, 2014
Last verified: June 2014
Results First Received: August 24, 2011  
Study Type: Interventional
Study Design: Allocation: Randomized;   Endpoint Classification: Efficacy Study;   Intervention Model: Parallel Assignment;   Masking: Open Label;   Primary Purpose: Treatment
Condition: Non Small Cell Lung Cancer (NSCLC)
Interventions: Drug: cetuximab + cisplatin + vinorelbine
Drug: cisplatin + vinorelbine

  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
First/last subject (informed consent): October 2004/January 2006. Clinical data cut-off: 18 July 2007. Last subject completed 16 May 2012. Subjects randomized at 155 centers; Asia/Australia: 21; Europe: 120; South America: 14.

Pre-Assignment Details
Significant events and approaches for the overall study following participant enrollment, but prior to group assignment
Enrolled: 1,861 after consent to epidermal growth factor receptor (EGFR) assessment; 603 excluded (mainly non-fulfillment of inclusion or exclusion criteria). 1,258 screened for eligibility after consent for study procedures; 143 excluded (mainly non-fulfillment of inclusion or exclusion criteria). 1,125 subjects randomized.

Reporting Groups
  Description
Cetuximab Plus Chemotherapy

cetuximab given as an intravenous (i.v.) infusion every week (400mg/m^2 initial dose and 250mg/m^2 subsequent doses) until progressive disease (PD) + cisplatin 80mg/m^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m^2 i.v. infusion on days 1 and 8 of each 3-week cycle.

Safety population: includes all treated subjects.

Chemotherapy Alone

cisplatin 80mg/m^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m^2 i.v. infusion on days 1 and 8 of each 3-week cycle.

Safety population: includes all treated subjects.


Participant Flow:   Overall Study
    Cetuximab Plus Chemotherapy     Chemotherapy Alone  
STARTED     557 [1]   568 [2]
COMPLETED     557     568  
NOT COMPLETED     0     0  
[1] Intent To Treat (ITT) Population
[2] ITT Population



  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
Cetuximab Plus Chemotherapy

cetuximab given as an intravenous (i.v.) infusion every week (400mg/m^2 initial dose and 250mg/m^2 subsequent doses) until progressive disease (PD) + cisplatin 80mg/m^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m^2 i.v. infusion on days 1 and 8 of each 3-week cycle.

Safety population: includes all treated subjects.

Chemotherapy Alone

cisplatin 80mg/m^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m^2 i.v. infusion on days 1 and 8 of each 3-week cycle.

Safety population: includes all treated subjects.

Total Total of all reporting groups

Baseline Measures
    Cetuximab Plus Chemotherapy     Chemotherapy Alone     Total  
Number of Participants  
[units: participants]
  557     568     1125  
Age  
[units: years]
Median ( Full Range )
  59  
  ( 18 to 78 )  
  60  
  ( 20 to 83 )  
  59  
  ( 18 to 83 )  
Age, Customized  
[units: participants]
     
<18 years     0     0     0  
Between 18 and 65 years     385     389     774  
>=65 years     172     179     351  
Gender  
[units: participants]
     
Female     172     163     335  
Male     385     405     790  
Region of Enrollment  
[units: participants]
     
Australia     20     23     43  
Hong Kong     2     2     4  
Singapore     5     5     10  
Korea, Republic of     28     26     54  
Taiwan     21     22     43  
Austria     9     7     16  
Belgium     3     10     13  
Bulgaria     12     12     24  
Czech Republic     12     17     29  
France     25     25     50  
Germany     91     88     179  
Hungary     21     23     44  
Ireland     3     4     7  
Netherlands     10     10     20  
Poland     59     50     109  
Portugal     3     0     3  
Russian Federation     23     16     39  
Slovakia     8     12     20  
Spain     16     13     29  
Sweden     6     3     9  
Switzerland     10     6     16  
Turkey     1     2     3  
United Kingdom     23     21     44  
Ukraine     56     71     127  
Chile     10     16     26  
Italy     18     23     41  
Argentina     5     2     7  
Mexico     9     8     17  
Brazil     48     51     99  



  Outcome Measures
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1.  Primary:   Overall Survival Time (OS)   [ Time Frame: Time from randomisation to death or last day known to be alive, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]

2.  Secondary:   Progression-free Survival Time   [ Time Frame: Time from randomization to disease progression, death or last tumor assessment, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]

3.  Secondary:   Best Overall Response Rate   [ Time Frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]

4.  Secondary:   Disease Control Rate   [ Time Frame: Evaluations were performed every 6 weeks until progression, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]

5.  Secondary:   Quality of Life (QOL) Assessment European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 Global Health Status   [ Time Frame: at baseline, at cycle 3, at month 6, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]

6.  Secondary:   Quality of Life Assessment (EORTC QLQ-C30) Social Functioning   [ Time Frame: at baseline, at cycle 3, at month 6, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]

7.  Secondary:   A Population Pharmacokinetic (PK) Analysis for Cetuximab in Non-Small Cell Lung Cancer (NSCLC) - Serum Cetuximab Concentrations   [ Time Frame: Week 1, Day 1: baseline and end of infusion; Week 7, Day 43: within 12 h after cetuximab administration. ]

8.  Secondary:   Safety - Number of Patients Experiencing Any Adverse Event   [ Time Frame: time from first dose up to 30 after last dose of study treatment, reported between day of first patient randomised, Oct 2004, until cut-off date 18 Jul 2007 ]


  Serious Adverse Events


  Other Adverse Events
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Time Frame Time from first dose up to 30 days after the last dose of study treatment.
Additional Description Treatment-emergent adverse events were defined as those with onset occurring at or after the first dosing day of study medication and up to 30 days after the last administration of any study drug or the clinical cut-off date.

Frequency Threshold
Threshold above which other adverse events are reported   5%  

Reporting Groups
  Description
Cetuximab Plus Chemotherapy

cetuximab given as an intravenous (i.v.) infusion every week (400mg/m^2 initial dose and 250mg/m^2 subsequent doses) until progressive disease (PD) + cisplatin 80mg/m^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m^2 i.v. infusion on days 1 and 8 of each 3-week cycle.

Safety population: includes all treated subjects.

Chemotherapy Alone

cisplatin 80mg/m^2 i.v. infusion on day 1 of each 3-week cycle + vinorelbine 25mg/m^2 i.v. infusion on days 1 and 8 of each 3-week cycle.

Safety population: includes all treated subjects.


Other Adverse Events
    Cetuximab Plus Chemotherapy     Chemotherapy Alone  
Total, other (not including serious) adverse events      
# participants affected / at risk     532/548     537/562  
Blood and lymphatic system disorders      
Neutropenia † 1    
# participants affected / at risk     302/548 (55.11%)     324/562 (57.65%)  
Anaemia † 1    
# participants affected / at risk     226/548 (41.24%)     264/562 (46.98%)  
Leukopenia † 1    
# participants affected / at risk     176/548 (32.12%)     155/562 (27.58%)  
Febrile neutropenia † 1    
# participants affected / at risk     36/548 (6.57%)     32/562 (5.69%)  
Thrombocytopenia † 1    
# participants affected / at risk     23/548 (4.20%)     30/562 (5.34%)  
Ear and labyrinth disorders      
Tinnitus † 1    
# participants affected / at risk     49/548 (8.94%)     55/562 (9.79%)  
Eye disorders      
Conjunctivitis † 1    
# participants affected / at risk     33/548 (6.02%)     6/562 (1.07%)  
Gastrointestinal disorders      
Nausea † 1    
# participants affected / at risk     291/548 (53.10%)     303/562 (53.91%)  
Vomiting † 1    
# participants affected / at risk     214/548 (39.05%)     225/562 (40.04%)  
Constipation † 1    
# participants affected / at risk     204/548 (37.23%)     189/562 (33.63%)  
Diarrhoea † 1    
# participants affected / at risk     126/548 (22.99%)     103/562 (18.33%)  
Stomatitis † 1    
# participants affected / at risk     85/548 (15.51%)     27/562 (4.80%)  
Abdominal pain † 1    
# participants affected / at risk     72/548 (13.14%)     72/562 (12.81%)  
Dyspepsia † 1    
# participants affected / at risk     68/548 (12.41%)     55/562 (9.79%)  
Abdominal pain upper † 1    
# participants affected / at risk     45/548 (8.21%)     37/562 (6.58%)  
Dysphagia † 1    
# participants affected / at risk     31/548 (5.66%)     7/562 (1.25%)  
General disorders      
Fatigue † 1    
# participants affected / at risk     202/548 (36.86%)     181/562 (32.21%)  
Pyrexia † 1    
# participants affected / at risk     112/548 (20.44%)     80/562 (14.23%)  
Asthenia † 1    
# participants affected / at risk     90/548 (16.42%)     96/562 (17.08%)  
Chest pain † 1    
# participants affected / at risk     70/548 (12.77%)     70/562 (12.46%)  
Mucosal inflammation † 1    
# participants affected / at risk     56/548 (10.22%)     23/562 (4.09%)  
Chills † 1    
# participants affected / at risk     35/548 (6.39%)     19/562 (3.38%)  
Injection site reaction † 1    
# participants affected / at risk     33/548 (6.02%)     29/562 (5.16%)  
Oedema peripheral † 1    
# participants affected / at risk     29/548 (5.29%)     39/562 (6.94%)  
Infections and infestations      
Paronychia † 1    
# participants affected / at risk     46/548 (8.39%)     0/562 (0.00%)  
Nasopharyngitis † 1    
# participants affected / at risk     37/548 (6.75%)     16/562 (2.85%)  
Investigations      
Weight decreased † 1    
# participants affected / at risk     75/548 (13.69%)     50/562 (8.90%)  
Blood creatinine increased † 1    
# participants affected / at risk     47/548 (8.58%)     49/562 (8.72%)  
White blood cell count decreased † 1    
# participants affected / at risk     36/548 (6.57%)     26/562 (4.63%)  
Metabolism and nutrition disorders      
Anorexia † 1    
# participants affected / at risk     208/548 (37.96%)     202/562 (35.94%)  
Hypokalaemia † 1    
# participants affected / at risk     75/548 (13.69%)     49/562 (8.72%)  
Hypomagnesaemia † 1    
# participants affected / at risk     54/548 (9.85%)     27/562 (4.80%)  
Hypocalcaemia † 1    
# participants affected / at risk     31/548 (5.66%)     10/562 (1.78%)  
Musculoskeletal and connective tissue disorders      
Pain in extremity † 1    
# participants affected / at risk     53/548 (9.67%)     32/562 (5.69%)  
Back pain † 1    
# participants affected / at risk     39/548 (7.12%)     44/562 (7.83%)  
Myalgia † 1    
# participants affected / at risk     39/548 (7.12%)     37/562 (6.58%)  
Arthralgia † 1    
# participants affected / at risk     30/548 (5.47%)     22/562 (3.91%)  
Bone pain † 1    
# participants affected / at risk     29/548 (5.29%)     28/562 (4.98%)  
Nervous system disorders      
Dizziness † 1    
# participants affected / at risk     82/548 (14.96%)     57/562 (10.14%)  
Headache † 1    
# participants affected / at risk     79/548 (14.42%)     60/562 (10.68%)  
Peripheral sensory neuropathy † 1    
# participants affected / at risk     49/548 (8.94%)     46/562 (8.19%)  
Paraesthesia † 1    
# participants affected / at risk     40/548 (7.30%)     27/562 (4.80%)  
Dysgeusia † 1    
# participants affected / at risk     31/548 (5.66%)     33/562 (5.87%)  
Psychiatric disorders      
Insomnia † 1    
# participants affected / at risk     58/548 (10.58%)     49/562 (8.72%)  
Respiratory, thoracic and mediastinal disorders      
Dyspnoea † 1    
# participants affected / at risk     101/548 (18.43%)     95/562 (16.90%)  
Cough † 1    
# participants affected / at risk     97/548 (17.70%)     80/562 (14.23%)  
Haemoptysis † 1    
# participants affected / at risk     45/548 (8.21%)     24/562 (4.27%)  
Dysphonia † 1    
# participants affected / at risk     33/548 (6.02%)     14/562 (2.49%)  
Pharyngolaryngeal pain † 1    
# participants affected / at risk     31/548 (5.66%)     20/562 (3.56%)  
Epistaxis † 1    
# participants affected / at risk     30/548 (5.47%)     15/562 (2.67%)  
Skin and subcutaneous tissue disorders      
Rash † 1    
# participants affected / at risk     249/548 (45.44%)     17/562 (3.02%)  
Alopecia † 1    
# participants affected / at risk     107/548 (19.53%)     107/562 (19.04%)  
Dry skin † 1    
# participants affected / at risk     76/548 (13.87%)     9/562 (1.60%)  
Dermatitis acneiform † 1    
# participants affected / at risk     75/548 (13.69%)     1/562 (0.18%)  
Pruritus † 1    
# participants affected / at risk     64/548 (11.68%)     13/562 (2.31%)  
Acne † 1    
# participants affected / at risk     38/548 (6.93%)     2/562 (0.36%)  
Skin fissures † 1    
# participants affected / at risk     30/548 (5.47%)     0/562 (0.00%)  
Vascular disorders      
Phlebitis † 1    
# participants affected / at risk     48/548 (8.76%)     44/562 (7.83%)  
Hypertension † 1    
# participants affected / at risk     40/548 (7.30%)     27/562 (4.80%)  
Hypotension † 1    
# participants affected / at risk     39/548 (7.12%)     23/562 (4.09%)  
Events were collected by systematic assessment
1 Term from vocabulary, MedDRA (Unspecified)



  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
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