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Study of Cisplatin/Vinorelbine +/- Cetuximab as First-line Treatment of Advanced Non Small Cell Lung Cancer (FLEX) (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.
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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 
Overall Participants Analyzed 
[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 (97.08%)   537/562 (95.55%) 
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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