A Study of Aflibercept Versus Placebo in Patients With Second-Line Docetaxel for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

Study Overview
=================
Brief Summary
-----------------
The primary objective of the study was to demonstrate overall survival improvement for aflibercept + docetaxel compared to docetaxel + placebo as second line treatment for participants with locally advanced or metastatic non-small cell lung cancer (NSCLC). The secondary objectives were to compare other efficacy parameters, to assess the overall safety of the two treatment arms, to assess the pharmacokinetics of intravenous (IV) aflibercept in this participant population and to determine immunogenicity of IV aflibercept in all participants.

Detailed Description
-----------------
The study included: A screening visit of up to 21 days prior to randomization Randomization at baseline (Treatment was initiated with 3 days of randomization) A treatment period with 3-week treatment cycles until the participant met the following discontinuation criteria: had progressive disease, had unacceptable toxicity, or refused further study treatment A post study treatment follow-up period (a visit was scheduled every 8 weeks until death or end of study)

Official Title
-----------------
A Multinational, Randomized, Double-Blind Study Comparing Aflibercept Versus Placebo in Patients Treated With Second-Line Docetaxel After Failure of One Platinum Based Therapy for Locally Advanced or Metastatic Non-Small-Cell Lung Cancer

Conditions
-----------------
Carcinoma, Non Small Cell Lung

Intervention / Treatment
-----------------
* Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
* Drug: Placebo
* Drug: Docetaxel (Taxotere®)
* Drug: Dexamethasone (pre- and post-medication for docetaxel)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Histological/cytological proven locally advanced or metastatic non-small cell lung cancer Disease progression during or after one, and only one, prior anticancer therapy which is platinum-based for advanced or metastatic disease Eastern Cooperative Oncology Group (ECOG) performance status 0, 1 or 2 Adequate renal, liver and bone marrow functions Exclusion Criteria: Squamous histology/cytology Less than 28 days elapsed from prior treatment with radiotherapy, surgery, or chemotherapy to the time of randomization Prior isotope therapy, whole pelvic radiotherapy, or radiotherapy to > 25% of bone marrow Prior docetaxel treatment Uncontrolled hypertension The above information was not intended to contain all considerations relevant to participation in a clinical trial.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Placebo/Docetaxel<br>Participants with Non-Small-Cell Lung Cancer (NSCLC) were administered Placebo immediately followed by Docetaxel every three weeks until disease progression, unacceptable toxicity, or participant's refusal. | Drug: Placebo<br>* Matching placebo to Aflibercept administered intravenously (IV) over 1 hour once on Day 1, every 3 weeks.<br>Drug: Docetaxel (Taxotere®)<br>* 75 mg/m² docetaxel in 250 mL dextrose 5% or NaCl 0.9% administered intravenously (IV) over 1 hour, on Day 1 every 3 weeks.<br>Drug: Dexamethasone (pre- and post-medication for docetaxel)<br>* As a pre- and post-medication for docetaxel, 8 mg dexamethasone was administered orally, the evening before Day 1, on Day 1 (early morning, 1 hour before docetaxel treatment, and evening) and on Day 2 (morning and evening).<br>|
| Placebo Comparator: Aflibercept/Docetaxel<br>Participants with Non-Small-Cell Lung Cancer (NSCLC) were administered Aflibercept immediately followed by Docetaxel every three weeks until disease progression, unacceptable toxicity, or participant's refusal. | Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)<br>* 6 mg/kg Aflibercept administered intravenously (IV) over 1 hour once on Day 1, every 3 weeks.<br>Drug: Docetaxel (Taxotere®)<br>* 75 mg/m² docetaxel in 250 mL dextrose 5% or NaCl 0.9% administered intravenously (IV) over 1 hour, on Day 1 every 3 weeks.<br>Drug: Dexamethasone (pre- and post-medication for docetaxel)<br>* As a pre- and post-medication for docetaxel, 8 mg dexamethasone was administered orally, the evening before Day 1, on Day 1 (early morning, 1 hour before docetaxel treatment, and evening) and on Day 2 (morning and evening).<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS was time interval from the date of randomization to the date of death due to any cause. If death was not observed during the study, overall survival time was censored at the last date the participant was known to be alive, or the study cutoff date, whichever was earlier. The cut-off date for the OS was date when 687 deaths were observed. OS was estimated from Kaplan-Meier Curves. | Baseline to the date when 687 deaths occurred (26 January 2011) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | PFS was defined as the time interval between the date of randomization and the time of occurrence of the first radiological tumor progression detected by a computer tomography (CT) scan and /or by Magnetic Resonance Imaging (MRI); or death due to any cause; whichever was earlier. Participants without disease progression were censored at the earliest date between their last valid tumour assessment and the data cutoff date. PFS was estimated from Kaplan-Meier Curves. | Baseline to data cut-off (26 January 2011) | 
| Overall Response (OR) Rate as Per Response Evaluation Criteria in Solid Tumours (RECIST) Criteria | Participants with OR were those who had a confirmed complete response [CR] or a confirmed partial response [PR], based on RECIST criteria, in which CR refected the disappearance of all tumor lesions (with no new tumors) PR reflected a pre-defined decrease in tumor burden - a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD OR was CR + PR The response rate was the percent of participants with a response. To determine a response, tumors were assessed by the investigators using Computerized Tomography (CT) scans or Magnetic Resonance Imaging (MRI) scans; and an observed response was confirmed by repeated imaging after 4 - 6 weeks. | Baseline to data cut-off (26 January 2011) | 
| Health Related Quality of Life (HRQL) Assessed by the Lung Cancer Symptom Scale (LCSS) | HRQL assessments were performed by participants using a self-administered LCSS questionnaire. LCSS is a 9-item questionnaire, six measuring major symptoms for lung malignancies (appetite, fatigue, cough, dyspnea, hemoptysis and pain), and 3 summation items related to total symptomatic distress, activity status and overall quality of life. Participant responses were measured using visual analogue scales (VAS) with 100-mm lines. The LCSS total score was defined as the mean of the 9 items of the scale, each scored between 0 (for best outcome) to 100 (for worst outcome). | Baseline (prior to first dose), at cycles 2 and 4 and at the end of study therapy. | 
| Health Related Quality of Life (HRQL) Assessed by the Average Symptom Burden Index (ASBI) | HRQL assessments were performed by participants using a self-administered LCSS questionnaire. LCSS is a 9-item questionnaire, six measuring major symptoms for lung malignancies, and 3 summation items related to total symptomatic distress, activity status and overall quality of life. Participant responses were measured using visual analogue scales (VAS) with 100-mm lines. ABSI was the mean score for the six major lung cancer symptoms (appetite, fatigue, cough, dyspnea, hemoptysis and pain), each scored between 0 (for best outcome) to 100 (for worst outcome). | Baseline (prior to first dose), at cycles 2 and 4 and at the end of study therapy. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
lung cancer, angiogenesis inhibitor, chemotherapy