Trial With Cetuximab in Maintenance Therapy After Platinum Based Chemotherapy in First Line Treatment of Non-small Cell Lung Cancer (NSCLC)

Study Overview
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Brief Summary
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This open-label, randomized, multinational, non-comparative, phase IIIb trial with 2 parallel groups will screen about 1400 subjects with stage IIIB non-small cell lung cancer (NSCLC) with pleural effusion or stage IV NSCLC. It is expected that of approximately 1200 (85 percent) subjects who will be included, about 1000 will be Caucasian; about 120 Asian, and the remainder (about 80) will be of other ethnic origin (that is neither Caucasian nor Asian). Approximately 480 (40 percent) subjects are expected to be free of progression at the end of combination treatment with cetuximab and platinum-based chemotherapy. These subjects will be eligible for randomization to intravenous cetuximab maintenance therapy with either 500 milligram per square meter (mg/m^2) every 2 weeks or 250 mg/m^2 weekly (q1w); about 240 subjects are expected per group. The trial will be performed in a community practice setting, with approximately 230 centers participating in the trial worldwide (planned countries are Argentina, Australia, Austria, Belgium, Brazil, Chile, China, Colombia, Czech Republic, France, Germany, Greece, Hong Kong, Hungary, India, Ireland, Israel, Italy, Mexico, Netherlands, Poland, Portugal, Russia, Singapore, Slovakia, South Africa, South Korea, Spain, Switzerland, Taiwan, Turkey, United Kingdom and Venezuela). With noncompetitive enrollment, approximately 4 to 8 subjects are expected to be enrolled at each center. Enrollment in the individual centers is generally limited to a maximum of 8 subjects. If any of these subjects does not receive trial treatment for any reason or discontinue all trial treatment at the first visit, additional subjects may be enrolled until 8 subjects were treated. The primary endpoint of the trial will be overall survival time from inclusion into the trial to death. Additional secondary efficacy endpoints will be time to treatment failure, tumor response, and disease control rate. Other endpoints will include safety and toxicity, compliance with maintenance therapy, subject satisfaction and translational research (TR) (for subjects with tumor samples available).

Official Title
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Open, Randomized, Multinational Phase IIIb Trial Evaluating the Activity and Safety of Cetuximab as 250 mg/m^2 Weekly and 500 mg/m^2 Every Two Weeks Maintenance Therapy After Platinum-based Chemotherapy in Combination With Cetuximab as First-line Treatment for Subjects With Advanced Non-small Cell Lung Cancer (NSCLC)

Conditions
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Non-Small Cell Lung Cancer (NSCLC)

Intervention / Treatment
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* Drug: Cetuximab plus Platinum-based Doublet Chemotherapy
* Drug: Cetuximab 500 mg/m^2
* Drug: Cetuximab 250 mg/m^2


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject has given written informed consent before any trial-related activities are carried out Male or female, greater than or equal to (>=)18 years of age at the time of informed consent, inpatient or outpatient Diagnosis of histologically or cytologically confirmed NSCLC, stage IIIB NSCLC with pleural effusion or stage IV Presence of at least 1 uni-dimensionally measurable index lesion, whereby index lesions must not lie in a previously irradiated area Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1 at inclusion in the trial White blood count>= 3 * 10^9 per liter (/L) with neutrophils >= 1.5 * 10^9 /L , platelet count >=100 * 10^9 /L , and hemoglobin >= 5.6 millimole per liter (mmol/L) (9 gram per deciliter [g/dL]) Total bilirubin less than or equal to (=<)1.5 * upper limit of normal (ULN) range Aspartate aminotransferase (ASAT) and alanine aminotransferase (ALAT) =< 5 * ULN Glomerular filtration rate (GFR) >=60 milliliter per minute (mL/min). The creatinine clearance (CrCl) estimated based on the Cockroft-Gault formula is used as a surrogate for the GFR Effective contraception that is, barrier method (condoms, diaphragm), oral, injectable or implant birth control, for both male and female subjects during the whole trial period and for at least 6 months after the end of trial treatment, if the risk of conception exists Recovered from relevant toxicities prior to inclusion in the trial Exclusion Criteria: Previous exposure to Epidermal Growth Factor Receptor (EGFR)-targeting therapy Previous chemotherapy for NSCLC; neo-adjuvant or adjuvant (radio-)chemotherapy is allowed if it was finished 6 months prior to start of trial treatment Major surgery within 30 days prior to inclusion in the trial Prior chest irradiation within 90 days prior to inclusion in the trial (palliative radiation of bone lesions is allowed) Participation in another clinical trial or treatment with any investigational agent(s) within 30 days prior to inclusion in the trial Concurrent chronic systemic immune therapy, chemotherapy for disease other than cancer, or hormone therapy for the treatment of cancer not indicated in the trial protocol Documented or symptomatic brain metastasis Pre-existing ascites Grade >= 2 and/or pericardial effusion Grade >= 2 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 Active infection (infection requiring intravenous antibiotics), including active tuberculosis, known and declared human immunodeficiency virus (HIV) Myocardial infarction within 6 months prior to inclusion into the trial, uncontrolled congestive heart failure; or any current Grade 3 or 4 cardio-vascular disorder despite treatment Known hypersensitivity reaction to any of the components of trial treatments Symptomatic peripheral neuropathy National Cancer Institute-Common Toxicity Criteria (NCI-CTC) Grade >= 2 and/or ototoxicity Grade >= 2, except if due to trauma or mechanical impairment due to tumor mass History of significant neurologic or psychiatric disorders including dementia, seizures, bipolar disorder Medical or psychological condition that would not permit the subject to complete the trial or sign informed consent Legal incapacity or limited legal capacity Known drug abuse Pregnancy (absence to be confirmed by serum beta-human chorionic gonadotropin [beta-HCG test]) or lactation period

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cetuximab 250 mg/m^2 q1w + Platinum-based Doublet Chemotherapy<br> | Drug: Cetuximab plus Platinum-based Doublet Chemotherapy<br>* Single first dose of cetuximab 400 mg/m^2 infusion will be administered intravenously over 120 minutes (min) followed by cetuximab 250 mg/m^2 intravenous infusion over 60 min q1w with background platinum-based doublet chemotherapy up to maximum of 6 cycles, until progressive disease, unacceptable toxicity, or withdrawal of consent. Platinum based doublet chemotherapy will be administered as intravenous infusion as per study center included: vinorelbine 25 mg/m^2 on Day 1 (D1) and Day 8 (D8)+cisplatin 80 mg/m^2 on D1; or gemcitabine 1250 mg/m^2 on D1 and D8+cisplatin 75 mg/m^2 on D1; or gemcitabine 1000 mg/m^2 on D1 and D8+carboplatin at dose to reach area under curve (AUC)5 milligram*hour/milliliter (mg*hr/mL) on D1; or Docetaxel 75 mg/m^2 on D1+cisplatin 75 mg/m^2 on D1; or paclitaxel 175 mg/m^2 on D1+cisplatin 80 mg/m^2 on D1; or paclitaxel 200 mg/m^2 on D1+carboplatin at dose to reach AUC6 mg*hr/mL on D1, of each 3-week treatment cycle for a maximum of 6 cycles.<br>|
| Active Comparator: Cetuximab 500 mg/m^2 every 2 weeks<br> | Drug: Cetuximab 500 mg/m^2<br>* Subjects who will be free of disease progression at the end of combination therapy, will enter in the maintenance therapy period. In the maintenance period, subjects will be receive cetuximab 500 mg/m^2 as intravenous infusion every 2 weeks, until progressive disease (PD), unacceptable toxicity, or withdrawal of consent.<br>* Other names: Erbitux;|
| Active Comparator: Cetuximab 250 mg/m^2 weekly<br> | Drug: Cetuximab 250 mg/m^2<br>* Subjects who will free of disease progression at the end of combination therapy, will enter in the maintenance therapy period. In the maintenance period, subjects will be receive cetuximab 250 mg/m^2 as intravenous infusion weekly, until PD, unacceptable toxicity, or withdrawal of consent.<br>* Other names: Erbitux;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) Time | The OS time is defined as the time from trial inclusion to death. Participants without event are censored at the last date known to be alive or at the clinical cut-off date, whichever is earlier. | Time from trial inclusion to death or last day known to be alive, reported between day of first participant included, that is, Jan 2009 until cut-off date (17 Dec 2011) | 
| Percentage of Participants With 1-year Overall Survival | The OS time is defined as the time from trial inclusion to death. Participants without event are censored at the last date known to be alive or at the clinical cut-off date, whichever is earlier. Percentage of participants who were still alive until one year after the last participant was included (March 2010). | Time from trial inclusion to death or last day known to be alive, reported between day of first participant included, that is, Jan 2009 until one year after the last participant was included (March 2010) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) Time (From Randomization to Cetuximab Maintenance Regimen Until Death) | The OS time is defined as the time from randomization in cetuximab maintenance regimen to death. Participants without event are censored at the last date known to be alive or at the clinical cut-off date, whichever is earlier. | Time from randomization in cetuximab maintenance regimen to death or last day known to be alive, reported between day of first participant randomized, that is, May 2009 until cut-off date (17 Dec 2011) | 
| Time to Treatment Failure | Time to treatment failure is defined as the time from trial inclusion to date of either first occurrence of progression, discontinuation of treatment due to progression or adverse event, withdrawal of consent or lost to follow up, start of further anticancer therapy, or death, whichever is earlier. Participants without events are censored either at the time of their last drug intake, or on the day of inclusion (Day 1) if they received no study drug. | Time from trial inclusion to treatment failure or last drug intake, reported between day of first participant included, that is, Jan 2009 until cut-off date (17 Dec 2011) | 
| Time to Treatment Failure (From Randomization to Cetuximab Maintenance Regimen Until Death) | Time from randomization in cetuximab maintenance regimen to date of either first occurrence of progression, discontinuation of treatment due to progression or adverse event, withdrawal of consent or lost to follow up, start of further anticancer therapy, or death, whichever is earlier. Participants without events are censored either at the time of their last drug intake, or on the day of randomization (Day 1 of maintenance therapy) if they received no study drug. | Time from randomization in cetuximab maintenance regimen to treatment failure or last drug intake, reported between day of first participant randomized, that is, May 2009 until cut-off date (17 Dec 2011) | 
| Percentage of Participants With Best Unconfirmed Tumor Response in the Combination Therapy Phase | The response rate is defined as the percentage of participants having achieved complete response (CR) or partial response (PR) as the unconfirmed best overall response (BOR) according to centrally reviewed investigator assessments based on an independent review charter (IRC). As per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: CR = Disappearance of all target lesions; PR = at least 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Evaluations were performed every 2 cycles during combination therapy period until progression and at the end of combination therapy period, reported between day of first participant included, that is, Jan 2009, until cut-off date, (17 Dec 2011) | 
| Percentage of Participant With Best Unconfirmed Tumor Response for the Whole Study Period | The response rate is defined as the percentage of participants having achieved CR and PR as the BOR according to IRC assessment in combination therapy phase and radiological assessments (based on response evaluation criteria in solid tumors [RECIST] Version 1.0) in the maintenance therapy phase. As per RECIST v1.0 for target lesions and assessed by MRI: CR = Disappearance of all target lesions; PR = at least 30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR | Evaluations were performed every 2 cycles during combination therapy and 6-weekly during maintenance therapy period until progression and at end of both periods, reported between day of first participant included, Jan 2009 until cut-off date (17 Dec 2011) | 
| Percentage of Participants With Disease Control in the Combination Therapy Phase | The disease control rate is defined as the percentage of participants having achieved complete response or partial response or stable disease as the unconfirmed BOR according to IRC assessment. | Evaluations were performed every 2 cycles during combination therapy period until progression and at the end of combination therapy period, reported between day of first participant included, that is, Jan 2009, until cut-off date, (17 Dec 2011) | 
| Percentage of Participants With Disease Control for the Whole Study Period | The disease control rate is defined as the percentage of participants having achieved complete response or partial response or stable disease as the unconfirmed best overall response according to IRC assessment in combination therapy phase and radiological assessments (based on RECIST Version 1.0 criteria) in the maintenance therapy phase. | Evaluations were performed every 2 cycles during combination therapy and 6-weekly during maintenance therapy period until progression and at end of both periods, reported between day of first participant included, Jan 2009 until cut-off date (17 Dec 2011) |