Aflibercept Compared to Placebo in Term of Efficacy in Patients Treated With Gemcitabine for Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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The main objective of the study was to evaluate the effectiveness of aflibercept treatment by comparison to placebo in increasing the overall survival (OS) in participants with metastatic pancreatic cancer, treated with gemcitabine. The secondary objectives were to evaluate progression free survival, clinical benefit, overall response, safety and immunogenicity of aflibercept, in the two treatment arms (Arm 1: Aflibercept and Gemcitabine; Arm 2: Placebo and Gemcitabine). The study included an interim analysis of OS. In accordance with the study protocol, an interim analysis was performed for the purpose of futility and overwhelming efficacy. On the basis of the interim analysis, the Data Monitoring Committee (DMC) recommended that this study be terminated for futility based on predefined boundary rules.

Detailed Description
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The study included: A screening visit of up to 21 days prior to randomization Randomization at baseline A Treatment period (initiated within 3 days of randomization), which included 28-day treatment cycles in both arms until predefined treatment discontinuation criteria were met A follow-up visit 30 days after discontinuation of treatment, A post study treatment follow-up period until death or the study cutoff date. The criteria for treatment discontinuation were: Participant (or legal representative) chose to withdraw from treatment The investigator thought that continuation of the study would be detrimental to the participants well-being, such as: Disease progression Unacceptable AEs not manageable by symptomatic therapy, dose delay, or dose modification Intercurrent illness that prevented further administration of study treatment Noncompliance with the study protocol Participant was lost to follow-up Unblinding of the participant's investigational treatment

Official Title
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A Multinational, Randomized, Double-blind Study, Comparing the Efficacy of Aflibercept Once Every 2 Weeks Versus Placebo in Patients Treated With Gemcitabine for Metastatic Pancreatic Cancer

Conditions
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Pancreatic Neoplasm

Intervention / Treatment
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* Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
* Drug: Placebo
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cytologically or histologically confirmed evidence of epithelial cancer (adenocarcinoma) of the exocrine pancreas Metastatic disease No prior chemotherapy for pancreatic disease Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2 Adequate renal, liver and bone marrow functions Exclusion Criteria: Less than 42 days elapsed from prior major surgery (28 days from other prior surgery) to the time of randomization Prior treatment with anti-VEGF or VEGF-Receptor-inhibitors Uncontrolled hypertension Pregnancy or breastfeeding Participant with reproductive potential (M/F) without effective method of contraception The above information is not intended to contain all considerations relevant to potential participation in a clinical trial.

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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo and Gemcitabine<br>Participants with metastatic pancreatic cancer administered Placebo and 1000 mg/m^2 Gemcitabine. | Drug: Placebo<br>* 4 mg/kg was administered intravenously (IV) over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle<br>Drug: Gemcitabine<br>* 1000 mg/m^2 administered IV over 30 minutes on Days 1, 8, 15, and 22 of Cycle 1 (28 days), and then Days 1, 8, and 15 of subsequent 28-day cycles.<br>* Other names: Gemzar;|
| Experimental: Aflibercept and Gemcitabine<br>Participants with metastatic pancreatic cancer administered 4 mg/kg Aflibercept and 1000 mg/m^2 Gemcitabine. | Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)<br>* 4 mg/kg was administered intravenously (IV) over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.<br>Drug: Gemcitabine<br>* 1000 mg/m^2 administered IV over 30 minutes on Days 1, 8, 15, and 22 of Cycle 1 (28 days), and then Days 1, 8, and 15 of subsequent 28-day cycles.<br>* Other names: Gemzar;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | OS is the time interval from the date of randomization to the date of death due to any cause. If death was not observed during the study, data on OS were censored at the earlier of the last date participant was known to be alive, or the study data cutoff date (11 September 2009). OS time was estimated from Kaplan-Meier Plots. | From the first randomization until the end of study data cutoff date (approximately 2 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) Based on Response Evaluation Criteria in Solid Tumors [RECIST] Criteria | PFS was the time interval from the date of registration to the date of progression, or death from any cause if it occurs before tumor progression is documented. Tumor progression was assessed using RECIST criteria, by which progression was a pre-defined increase in the size of existing tumors or appearance of one or more new tumors. If a participant did not progress or die, the progression was censored to the date of the last valid tumor assessment or data cut-off, whichever was earlier. Median PFS time was estimated from Kaplan-Meier Plots. | From the first randomization until the end of study data cutoff date (approximately 2 years) | 
| Objective Response Rate (ORR) Assessed by the Investigators According to RECIST Criteria | Objective response (OR) included complete response [CR] and partial response [PR]. OR was to be assessed by the Investigators according to RECIST criteria, and confirmed by repeating tumor imaging at least 4 weeks after the first radiological documentation of response. CR would reflect the disappearance of all tumor lesions and PR would reflect a defined reduction of tumor burden. However, OR analysis was not performed, as the study was terminated due to futility. | From the first randomization until the end of the study data cutoff date (approximately 2 years) | 
| Clinical Benefit | Clinical benefit was to be assessed in all participants by time to symptom worsening (TTSW), evaluated from the time of randomization to symptom worsening, as well as by improvement in tumor related symptoms. However, this analysis was not performed, as the study was terminated due to futility. | From the first randomization until the end of the study data cutoff date (approximately 2 years) | 
| Safety-Number of Participants With Adverse Events (AE) | All AEs regardless of seriousness or relationship to study treatment, spanning from the signature of informed consent until 30 days after the last administration of study treatment, were recorded. The number of participants with all treatment emergent adverse events (TEAE), serious adverse events (SAE), TEAE leading to death, and TEAE leading to permanent treatment discontinuation are reported. | up to 30 days after treatment discontinuation. SAEs and related AEs were followed till resolved or stabilized. | 
| Number of Participants With Anti-drug Antibodies | Anti-drug antibodies in the participants blood sample were detected using a validated immunoassay. The validated lower limit of detection (LLOD) for the assay was about 5.4 ng/mL in the absence of aflibercept and about 25.2 ng/mL in the presence of 20 μg/mL of aflibercept. | Up to 90 days post last dose of study drug | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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metastatic pancreatic cancer, angiogenesis inhibitor, gemcitabine