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

• ClinicalTrials.gov Identifier: NCT00148798
• Recruitment Status: Completed
• First Posted: September 8, 2005
• Results First Posted: October 4, 2011
• Last Update Posted: June 25, 2014
• Sponsor: Merck KGaA, Darmstadt, Germany
• Information provided by (Responsible Party): Merck KGaA, Darmstadt, Germany

Tracking Information

• First Submitted Date: September 7, 2005
• First Posted Date: September 8, 2005
• Results First Submitted Date: August 24, 2011
• Results First Posted Date: October 4, 2011
• Last Update Posted Date: June 25, 2014
• Study Start Date: October 2004
• Actual Primary Completion Date: July 2007 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: August 24, 2011)

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 ]

Time from randomization to death. Patients without event are censored at the last date known to be alive or at the clinical cut-off date, whatever is earlier.

• Original Primary Outcome Measures (submitted: September 7, 2005): Overall suvival time

Current Secondary Outcome Measures (submitted: August 24, 2011)

• 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 ]
  Duration from randomization until radiological progression (based on modified World Health Organisation (WHO) criteria) or death due to any cause. Only deaths within 60 days of last tumor assessment are considered. Patients without event are censored on the date of last tumor assessment.
• 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 ]
  The best overall response rate is defined as the proportion of subjects having achieved confirmed Complete Response + Partial Response as the best overall response according to radiological assessments (based on modified WHO criteria).
• 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 ]
  The disease control rate is defined as the proportion of subjects having achieved confirmed Complete Response + Partial Response + Stable Disease as best overall response according to radiological assessments (based on modified WHO criteria).
• 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 ]
  Mean global health status scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a better QoL.
• 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 ]
  Mean social functioning scores (EORTC QLQ-C30) against time for each treatment group. Scores were derived from mutually exclusive sets of items, with scale scores ranging from 0 to 100 after a linear transformation. Higher scores indicate a higher level of functioning.
• 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. ]
  Population PK analysis was conducted using non-linear mixed effects modeling (NONMEM) software, integrating the PK data from this study and the Phase II study EMR 62 202-011.
• 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 ]
  Please refer to Adverse Events section for further details

Original Secondary Outcome Measures (submitted: September 7, 2005)

• Progression-free suvival time
• Response rate
• Disease control rat
• Safety
• Quality of life
• Pharmacokinetics

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Cisplatin/Vinorelbine +/- Cetuximab as First-line Treatment of Advanced Non Small Cell Lung Cancer (FLEX)
• Official Title: Open, Randomized, Controlled, Multicenter Phase III Study Comparing Cisplatin/Vinorelbine Plus Cetuximab Versus Cisplatin/Vinorelbine as First-line Treatment for Patients With Epidermal Growth Factor Receptor Expressing (EGFR-expressing) Advanced NSCLC.
• Brief Summary: The purpose of this trial is to investigate the efficacy of cetuximab in combination with chemotherapy in comparison to chemotherapy alone in patients with advanced non small cell lung cancer who did not received prior chemotherapy. Overall survival will be taken as primary measure of efficacy.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Non Small Cell Lung Cancer (NSCLC)

Intervention

• Drug: cetuximab + cisplatin + vinorelbine
  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.
• Drug: cisplatin + vinorelbine
  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.

Study Arms

• Experimental: Cetuximab plus chemotherapy
  cetuximab + cisplatin + vinorelbine
  Intervention: Drug: cetuximab + cisplatin + vinorelbine
• Active Comparator: Chemotherapy alone
  cisplatin + vinorelbine alone
  Intervention: Drug: cisplatin + vinorelbine

Publications *

• Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Yu CT, Ganul V, Roh JK, Bajetta E, O'Byrne K, de Marinis F, Eberhardt W, Goddemeier T, Emig M, Gatzemeier U; FLEX Study Team. Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): an open-label randomised phase III trial. Lancet. 2009 May 2;373(9674):1525-31. doi: 10.1016/S0140-6736(09)60569-9.
• Pirker R, Pereira JR, Szczesna A, von Pawel J, Krzakowski M, Ramlau R, Vynnychenko I, Park K, Eberhardt WE, de Marinis F, Heeger S, Goddemeier T, O'Byrne KJ, Gatzemeier U. Prognostic factors in patients with advanced non-small cell lung cancer: data from the phase III FLEX study. Lung Cancer. 2012 Aug;77(2):376-82. doi: 10.1016/j.lungcan.2012.03.010. Epub 2012 Apr 11.
• Pirker R, Pereira JR, von Pawel J, Krzakowski M, Ramlau R, Park K, de Marinis F, Eberhardt WE, Paz-Ares L, Storkel S, Schumacher KM, von Heydebreck A, Celik I, O'Byrne KJ. EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: analysis of data from the phase 3 FLEX study. Lancet Oncol. 2012 Jan;13(1):33-42. doi: 10.1016/S1470-2045(11)70318-7. Epub 2011 Nov 4.
• O'Byrne KJ, Gatzemeier U, Bondarenko I, Barrios C, Eschbach C, Martens UM, Hotko Y, Kortsik C, Paz-Ares L, Pereira JR, von Pawel J, Ramlau R, Roh JK, Yu CT, Stroh C, Celik I, Schueler A, Pirker R. Molecular biomarkers in non-small-cell lung cancer: a retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol. 2011 Aug;12(8):795-805. doi: 10.1016/S1470-2045(11)70189-9. Epub 2011 Jul 22.
• Gatzemeier U, von Pawel J, Vynnychenko I, Zatloukal P, de Marinis F, Eberhardt WE, Paz-Ares L, Schumacher KM, Goddemeier T, O'Byrne KJ, Pirker R. First-cycle rash and survival in patients with advanced non-small-cell lung cancer receiving cetuximab in combination with first-line chemotherapy: a subgroup analysis of data from the FLEX phase 3 study. Lancet Oncol. 2011 Jan;12(1):30-7. doi: 10.1016/S1470-2045(10)70278-3. Epub 2010 Dec 17.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 24, 2011): 1861
• Original Enrollment (submitted: September 7, 2005): 1100
• Actual Study Completion Date: May 2012
• Actual Primary Completion Date: July 2007 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Diagnosis of histologically or cytologically confirmed NSCLC, stage IIIb with documented malignant pleural effusion or stage IV
• Immunohistochemical evidence of EGFR expression on tumor tissue
• Presence of at least 1 bi-dimensionally measurable index lesion, whereby index lesions must not lie in an irradiated area

Exclusion Criteria:

• Previous exposure to monoclonal antibodies, signal transduction inhibitors or EGFR-targeting therapy
• Previous chemotherapy for NSCLC
• Documented or symptomatic brain metastasis
• Superior vena cava syndrome contra-indicating hydration
• Previous malignancy in the last 5 years except basal cell carcinoma of the skin or pre-invasive carcinoma of the cervix

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Australia, Austria, Belgium, Brazil, Bulgaria, Chile, Czech Republic, France, Germany, Hong Kong, Hungary, Ireland, Italy, Korea, Republic of, Mexico, Netherlands, Poland, Russian Federation, Singapore, Slovakia, Spain, Sweden, Switzerland, Taiwan, Turkey, Ukraine, United Kingdom

Administrative Information

• NCT Number: NCT00148798
• Other Study ID Numbers: EMR 62202-046
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Merck KGaA, Darmstadt, Germany
• Original Responsible Party: Not Provided
• Current Study Sponsor: Merck KGaA, Darmstadt, Germany
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Robert Pirker, Professor; Universitätsklinik für Innere Medizin I, Wien

• PRS Account: Merck KGaA, Darmstadt, Germany
• Verification Date: June 2014