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

• ClinicalTrials.gov Identifier: NCT00574275
• Recruitment Status: Terminated
• First Posted: December 17, 2007
• Results First Posted: September 25, 2012
• Last Update Posted: June 7, 2016
• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Pancreatic Neoplasm	Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®); Drug: Placebo; Drug: Gemcitabine	Phase 3

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

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 546 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: December 2007
• Actual Primary Completion Date: October 2009
• Actual Study Completion Date: November 2010

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: Placebo and Gemcitabine; Participants with metastatic pancreatic cancer administered Placebo and 1000 mg/m^2 Gemcitabine.	Drug: Placebo; 4 mg/kg was administered intravenously (IV) over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle; Drug: Gemcitabine; 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.; Other Name: Gemzar
Experimental: Aflibercept and Gemcitabine; Participants with metastatic pancreatic cancer administered 4 mg/kg Aflibercept and 1000 mg/m^2 Gemcitabine.	Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®); 4 mg/kg was administered intravenously (IV) over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.; Drug: Gemcitabine; 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.; Other Name: Gemzar

Outcome Measures

Primary Outcome Measures :

1. Overall Survival (OS) [ Time Frame: 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 :

1. Progression Free Survival (PFS) Based on Response Evaluation Criteria in Solid Tumors [RECIST] Criteria [ Time Frame: 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.

2. Objective Response Rate (ORR) Assessed by the Investigators According to RECIST Criteria [ Time Frame: 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.

3. Clinical Benefit [ Time Frame: 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.

4. Safety-Number of Participants With Adverse Events (AE) [ Time Frame: 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.
5. Number of Participants With Anti-drug Antibodies [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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.

Contacts and Locations

Locations

United States, New Jersey

Sanofi-Aventis Administrative Office

Bridgewater, New Jersey, United States, 08807

Argentina

Sanofi-Aventis Administrative Office

Buenos Aires, Argentina

Austria

Sanofi-Aventis Administrative Office

Wien, Austria

Belgium

Sanofi-Aventis Administrative Office

Diegem, Belgium

Bulgaria

Sanofi-Aventis Administrative Office

Sofia, Bulgaria

Canada

Sanofi-Aventis Administrative Office

Laval, Canada

Chile

Sanofi-Aventis Administrative Office

Santiago, Chile

Colombia

Sanofi-Aventis Administrative Office

Santafe de Bogota, Colombia

Cyprus

Sanofi-Aventis Administrative Office

Nikosia, Cyprus

Czech Republic

Sanofi-Aventis Administrative Office

Praha, Czech Republic

France

Sanofi-Aventis Administrative Office

Paris, France

Germany

Sanofi-Aventis Administrative Office

Berlin, Germany

Greece

Sanofi-Aventis Administrative Office

Athens, Greece

Hungary

Sanofi-Aventis Administrative Office

Budapest, Hungary

India

Sanofi-Aventis Administrative Office

Mumbai, India

Italy

Sanofi-Aventis Administrative Office

Milano, Italy

Mexico

Sanofi-Aventis Administrative Office

Mexico, Mexico

Poland

Sanofi-Aventis Administrative Office

Warszawa, Poland

Puerto Rico

Sanofi-Aventis Administrative Office

Puerto Rico, Puerto Rico

Romania

Sanofi-Aventis Administrative Office

Bucuresti, Romania

Russian Federation

Sanofi-Aventis Administrative Office

Moscow, Russian Federation

Slovakia

Sanofi-Aventis Administrative Office

Brastislava, Slovakia

Spain

Sanofi-Aventis Administrative Office

Barcelona, Spain

Switzerland

Sanofi-Aventis Administrative Office

Geneva, Switzerland

Sponsors and Collaborators

Sanofi

Regeneron Pharmaceuticals

Investigators

• Study Director: Clinical Sciences & Operations; Sanofi

More Information

Publications of Results:

Rougier P, Riess H, Manges R, Karasek P, Humblet Y, Barone C, Santoro A, Assadourian S, Hatteville L, Philip PA. Randomised, placebo-controlled, double-blind, parallel-group phase III study evaluating aflibercept in patients receiving first-line treatment with gemcitabine for metastatic pancreatic cancer. Eur J Cancer. 2013 Aug;49(12):2633-42. doi: 10.1016/j.ejca.2013.04.002. Epub 2013 Apr 30.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT00574275
• Other Study ID Numbers: EFC10547; EudraCT 2007-003476-19
• First Posted: December 17, 2007
• Results First Posted: September 25, 2012
• Last Update Posted: June 7, 2016
• Last Verified: May 2016

Keywords provided by Sanofi:

metastatic pancreatic cancer; angiogenesis inhibitor; gemcitabine

Additional relevant MeSH terms:

Pancreatic Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Digestive System Diseases; Pancreatic Diseases; Endocrine System Diseases; Gemcitabine; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antiviral Agents; Anti-Infective Agents; Enzyme Inhibitors; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs