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

Phase 3

Terminated

Conditions: Pancreatic Neoplasm

Interventions: Drug: Placebo
Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
Drug: Gemcitabine

Registration Number: NCT00574275

Lead Sponsor: Sanofi

Brief Summary: 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: 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

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 546

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo and Gemcitabine	Placebo	Participants with metastatic pancreatic cancer administered Placebo and 1000 mg/m\^2 Gemcitabine.
Aflibercept and Gemcitabine	Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)	Participants with metastatic pancreatic cancer administered 4 mg/kg Aflibercept and 1000 mg/m\^2 Gemcitabine.
Placebo and Gemcitabine	Gemcitabine	Participants with metastatic pancreatic cancer administered Placebo and 1000 mg/m\^2 Gemcitabine.
Aflibercept and Gemcitabine	Gemcitabine	Participants with metastatic pancreatic cancer administered 4 mg/kg Aflibercept and 1000 mg/m\^2 Gemcitabine.

Primary Outcome Measures

Name	Time	Method
Overall Survival (OS)	From the first randomization until the end of study data cutoff date (approximately 2 years)	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.

Secondary Outcome Measures

Name	Time	Method
Number of Participants With Anti-drug Antibodies	Up to 90 days post last dose of study drug	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.
Progression Free Survival (PFS) Based on Response Evaluation Criteria in Solid Tumors [RECIST] Criteria	From the first randomization until the end of study data cutoff date (approximately 2 years)	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.
Objective Response Rate (ORR) Assessed by the Investigators According to RECIST Criteria	From the first randomization until the end of the study data cutoff date (approximately 2 years)	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.
Clinical Benefit	From the first randomization until the end of the study data cutoff date (approximately 2 years)	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.
Safety-Number of Participants With Adverse Events (AE)	up to 30 days after treatment discontinuation. SAEs and related AEs were followed till resolved or stabilized.	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.