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

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ClinicalTrials.gov Identifier: NCT00574275
Recruitment Status : Terminated (Data Monitoring Committee concluded after a planned interim analysis that aflibercept added to gemcitabine would be unable to demonstrate improved survival)
First Posted : December 17, 2007
Results First Posted : September 25, 2012
Last Update Posted : June 7, 2016
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Triple (Participant, Care Provider, Investigator);   Primary Purpose: Treatment
Condition Pancreatic Neoplasm
Interventions Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
Drug: Placebo
Drug: Gemcitabine
Enrollment 546
Recruitment Details Between December 2007 and September 2009, a total of 546 participants were randomized in the study: 275 to the placebo group and 271 to the aflibercept group. 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.
Pre-assignment Details  
Arm/Group Title Placebo and Gemcitabine Aflibercept and Gemcitabine
Hide Arm/Group Description
  • Placebo: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
  • Aflibercept: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
Period Title: Overall Study
Started 275 271
TREATED 273 268
SAFETY POPULATION 271 [1] 270 [2]
Completed 0 [3] 0 [3]
Not Completed 275 271
Reason Not Completed
Randomized but not treated             2             3
Adverse Event             32             76
Disease progression             160             146
Lost to Follow-up             2             1
Study stopped based on DMC decision             62             23
Withdrawal by Subject             15             17
Error calculating tumor measurement             1             0
Physician Decision             1             1
Protocol Violation             0             1
Patient and Investigator decision             0             1
Insurance change             0             1
Operation for curative intent             0             1
[1]
Excludes 2 participants who received 1 dose of Aflibercept
[2]
Includes 2 participants from the Placebo and Gemcitabine arm who received 1 dose of Aflibercept
[3]
All participants stopped when they met treatment discontinuation criteria or by DMC recommendation
Arm/Group Title Placebo/Gemcitabine Aflibercept/Gemcitabine Total
Hide Arm/Group Description
  • Placebo: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
  • Aflibercept: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
Total of all reporting groups
Overall Number of Baseline Participants 275 271 546
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 275 participants 271 participants 546 participants
60.4  (10.0) 62.0  (9.4) 61.2  (9.7)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 275 participants 271 participants 546 participants
<65 years 179 161 340
>=65 but <75 years 77 90 167
>=75 years 19 20 39
Sex/Gender, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 275 participants 271 participants 546 participants
Male 157 160 317
Female 118 111 229
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 275 participants 271 participants 546 participants
Caucasian/White 267 256 523
Black 2 3 5
Asian/Oriental 3 7 10
Other 3 5 8
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 275 participants 271 participants 546 participants
ARGENTINA 3 0 3
AUSTRIA 6 2 8
BELGIUM 18 16 34
BULGARIA 12 11 23
CANADA 15 16 31
CHILE 8 8 16
CYPRUS 3 3 6
CZECH REPUBLIC 10 14 24
FRANCE 11 13 24
GERMANY 15 10 25
GREECE 5 7 12
HUNGARY 7 10 17
INDIA 3 3 6
ITALY 17 24 41
MEXICO 1 2 3
POLAND 12 11 23
PUERTO RICO 1 0 1
ROMANIA 13 8 21
RUSSIAN FEDERATION 19 19 38
SLOVAKIA 5 3 8
SPAIN 13 14 27
SWITZERLAND 8 9 17
UNITED STATES 70 68 138
Eastern Cooperative Oncology Group (ECOG) Performance Status Score   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 275 participants 271 participants 546 participants
Participants with ECOG Score = 0 102 102 204
Participants with ECOG Score = 1 154 152 306
Participants with ECOG Score = 2 19 17 36
[1]
Measure Description: The ECOG score assesses how the disease affects a participant's daily living abilities. It ranges from 0-5, with 0 being the best and 5 being the worst outcome. "0" reflects a fully active participant, able to carry on all pre-disease performance without restriction. "1" reflects a participant restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature. "2" reflects an ambulatory participant, who is up and about more than 50% of waking hours, and capable of all self-care but unable to carry out any work activities.
Primary tumor resection   [1] 
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 275 participants 271 participants 546 participants
Yes 40 39 79
No 235 232 467
[1]
Measure Description: Whether the participant had prior pancreatectomy.
1.Primary Outcome
Title Overall Survival (OS)
Hide Description

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.

Time Frame From the first randomization until the end of study data cutoff date (approximately 2 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) population, which included all randomized participants.
Arm/Group Title Placebo and Gemcitabine Aflibercept and Gemcitabine
Hide Arm/Group Description:
  • Placebo: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
  • Aflibercept: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
Overall Number of Participants Analyzed 275 271
Overall Number of Units Analyzed
Type of Units Analyzed: OS Event (Death)
142 142
Median (95% Confidence Interval)
Unit of Measure: months
7.75
(6.768 to 8.575)
6.54
(5.552 to 7.852)
2.Secondary Outcome
Title Progression Free Survival (PFS) Based on Response Evaluation Criteria in Solid Tumors [RECIST] Criteria
Hide Description

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.

Time Frame From the first randomization until the end of study data cutoff date (approximately 2 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Intent-to-treat (ITT) population, which included all randomized participants.
Arm/Group Title Placebo and Gemcitabine Aflibercept and Gemcitabine
Hide Arm/Group Description:
  • Placebo: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
  • Aflibercept: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
Overall Number of Participants Analyzed 275 271
Overall Number of Units Analyzed
Type of Units Analyzed: PFS Events
189 182
Median (95% Confidence Interval)
Unit of Measure: months
3.71
(3.515 to 4.567)
3.71
(3.450 to 4.468)
3.Secondary Outcome
Title Objective Response Rate (ORR) Assessed by the Investigators According to RECIST Criteria
Hide Description

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.

Time Frame From the first randomization until the end of the study data cutoff date (approximately 2 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Since the study was terminated due to futility, this analysis was not performed.
Arm/Group Title Placebo and Gemcitabine Aflibercept and Gemcitabine
Hide Arm/Group Description:
  • Placebo: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
  • Aflibercept: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
4.Secondary Outcome
Title Clinical Benefit
Hide Description

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.

Time Frame From the first randomization until the end of the study data cutoff date (approximately 2 years)
Hide Outcome Measure Data
Hide Analysis Population Description
Since the study was terminated due to futility, analysis for this endpoint was not performed.
Arm/Group Title Placebo and Gemcitabine Aflibercept and Gemcitabine
Hide Arm/Group Description:
  • Placebo: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
  • Aflibercept: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
Overall Number of Participants Analyzed 0 0
No data displayed because Outcome Measure has zero total analyzed.
5.Secondary Outcome
Title Safety-Number of Participants With Adverse Events (AE)
Hide Description 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.
Time Frame up to 30 days after treatment discontinuation. SAEs and related AEs were followed till resolved or stabilized.
Hide Outcome Measure Data
Hide Analysis Population Description
The safety population included all randomized participants who were administered at least 1 dose of study medications (placebo, aflibercept, or gemcitabine). For safety analyses, participants were analyzed according to the treatment received.
Arm/Group Title Placebo and Gemcitabine Aflibercept and Gemcitabine
Hide Arm/Group Description:
  • Placebo: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
  • Aflibercept: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
Overall Number of Participants Analyzed 271 270
Measure Type: Number
Unit of Measure: participants
Treatment Emergent Adverse Event (TEAE) 257 266
Treatment Emergent Serious Adverse Event 122 148
TEAE leading to death 43 55
TEAE leading to permanent discontinuation 32 76
6.Secondary Outcome
Title Number of Participants With Anti-drug Antibodies
Hide Description 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.
Time Frame Up to 90 days post last dose of study drug
Hide Outcome Measure Data
Hide Analysis Population Description
Safety population with samples available for analysis
Arm/Group Title Placebo and Gemcitabine Aflibercept and Gemcitabine
Hide Arm/Group Description:
  • Placebo: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
  • Aflibercept: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
Overall Number of Participants Analyzed 202 201
Measure Type: Number
Unit of Measure: participants
5 5
Time Frame From treatment initiation up to November 26, 2010
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo and Gemcitabine Aflibercept and Gemcitabine
Hide Arm/Group Description
  • Placebo: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
  • Aflibercept: 4 mg/kg was administered IV over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
  • 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.
All-Cause Mortality
Placebo and Gemcitabine Aflibercept and Gemcitabine
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Placebo and Gemcitabine Aflibercept and Gemcitabine
Affected / at Risk (%) Affected / at Risk (%)
Total   122/271 (45.02%)   148/270 (54.81%) 
Blood and lymphatic system disorders     
Neutropenia  1  0/271 (0.00%)  2/270 (0.74%) 
Thrombocytopenia  1  1/271 (0.37%)  2/270 (0.74%) 
Anaemia  1  2/271 (0.74%)  4/270 (1.48%) 
Febrile neutropenia  1  1/271 (0.37%)  1/270 (0.37%) 
Splenic vein thrombosis  1  1/271 (0.37%)  1/270 (0.37%) 
Anaemia of malignant disease  1  1/271 (0.37%)  1/270 (0.37%) 
Splenic infarction  1  1/271 (0.37%)  0/270 (0.00%) 
Disseminated intravascular coagulation  1  1/271 (0.37%)  0/270 (0.00%) 
Cardiac disorders     
Atrial fibrillation  1  0/271 (0.00%)  2/270 (0.74%) 
Cardiac failure  1  0/271 (0.00%)  2/270 (0.74%) 
Acute myocardial infarction  1  1/271 (0.37%)  1/270 (0.37%) 
Atrial flutter  1  0/271 (0.00%)  1/270 (0.37%) 
Cardiac failure congestive  1  0/271 (0.00%)  1/270 (0.37%) 
Extrasystoles  1  0/271 (0.00%)  1/270 (0.37%) 
Left ventricular failure  1  0/271 (0.00%)  1/270 (0.37%) 
Myocardial ischaemia  1  0/271 (0.00%)  1/270 (0.37%) 
Ventricular extrasystoles  1  1/271 (0.37%)  0/270 (0.00%) 
Sinus bradycardia  1  1/271 (0.37%)  0/270 (0.00%) 
Ventricular fibrillation  1  1/271 (0.37%)  0/270 (0.00%) 
Endocrine disorders     
Inappropriate antidiuretic hormone secretion  1  0/271 (0.00%)  1/270 (0.37%) 
Gastrointestinal disorders     
Nausea  1  3/271 (1.11%)  3/270 (1.11%) 
Vomiting  1  6/271 (2.21%)  10/270 (3.70%) 
Diarrhoea  1  2/271 (0.74%)  1/270 (0.37%) 
Constipation  1  1/271 (0.37%)  0/270 (0.00%) 
Abdominal pain  1  11/271 (4.06%)  6/270 (2.22%) 
Stomatitis  1  0/271 (0.00%)  1/270 (0.37%) 
Abdominal pain upper  1  0/271 (0.00%)  2/270 (0.74%) 
Ascites  1  2/271 (0.74%)  4/270 (1.48%) 
Abdominal distension  1  1/271 (0.37%)  1/270 (0.37%) 
Intestinal obstruction  1  4/271 (1.48%)  4/270 (1.48%) 
Dysphagia  1  1/271 (0.37%)  0/270 (0.00%) 
Gastrointestinal haemorrhage  1  1/271 (0.37%)  4/270 (1.48%) 
Haematemesis  1  1/271 (0.37%)  0/270 (0.00%) 
Duodenal obstruction  1  1/271 (0.37%)  3/270 (1.11%) 
Duodenal stenosis  1  1/271 (0.37%)  3/270 (1.11%) 
Gastrointestinal obstruction  1  1/271 (0.37%)  1/270 (0.37%) 
Melaena  1  0/271 (0.00%)  2/270 (0.74%) 
Ileus  1  3/271 (1.11%)  1/270 (0.37%) 
Small intestinal obstruction  1  1/271 (0.37%)  1/270 (0.37%) 
Upper gastrointestinal haemorrhage  1  0/271 (0.00%)  1/270 (0.37%) 
Duodenal ulcer haemorrhage  1  0/271 (0.00%)  1/270 (0.37%) 
Enteritis  1  0/271 (0.00%)  1/270 (0.37%) 
Enterocutaneous fistula  1  0/271 (0.00%)  1/270 (0.37%) 
Gastric ulcer haemorrhage  1  0/271 (0.00%)  1/270 (0.37%) 
Ileus paralytic  1  0/271 (0.00%)  1/270 (0.37%) 
Intestinal perforation  1  0/271 (0.00%)  1/270 (0.37%) 
Oesophageal stenosis  1  0/271 (0.00%)  1/270 (0.37%) 
Pancreatitis chronic  1  0/271 (0.00%)  1/270 (0.37%) 
Peritonitis  1  0/271 (0.00%)  1/270 (0.37%) 
Colonic obstruction  1  1/271 (0.37%)  0/270 (0.00%) 
Gastrointestinal ischaemia  1  1/271 (0.37%)  0/270 (0.00%) 
Gastrointestinal oedema  1  1/271 (0.37%)  0/270 (0.00%) 
Oesophagitis haemorrhagic  1  1/271 (0.37%)  0/270 (0.00%) 
Pancreatitis  1  1/271 (0.37%)  0/270 (0.00%) 
Thrombosis mesenteric vessel  1  1/271 (0.37%)  0/270 (0.00%) 
General disorders     
Fatigue  1  5/271 (1.85%)  1/270 (0.37%) 
Pyrexia  1  5/271 (1.85%)  3/270 (1.11%) 
Asthenia  1  1/271 (0.37%)  3/270 (1.11%) 
Disease progression  1  25/271 (9.23%)  38/270 (14.07%) 
Pain  1  1/271 (0.37%)  0/270 (0.00%) 
Device occlusion  1  2/271 (0.74%)  3/270 (1.11%) 
Performance status decreased  1  0/271 (0.00%)  1/270 (0.37%) 
Malaise  1  0/271 (0.00%)  1/270 (0.37%) 
Non-cardiac chest pain  1  1/271 (0.37%)  1/270 (0.37%) 
Device dislocation  1  0/271 (0.00%)  1/270 (0.37%) 
Sudden death  1  0/271 (0.00%)  1/270 (0.37%) 
Death  1  4/271 (1.48%)  0/270 (0.00%) 
Hepatobiliary disorders     
Jaundice  1  2/271 (0.74%)  3/270 (1.11%) 
Hyperbilirubinaemia  1  2/271 (0.74%)  3/270 (1.11%) 
Cholangitis  1  4/271 (1.48%)  5/270 (1.85%) 
Bile duct obstruction  1  1/271 (0.37%)  2/270 (0.74%) 
Bile duct stenosis  1  0/271 (0.00%)  2/270 (0.74%) 
Portal vein thrombosis  1  0/271 (0.00%)  2/270 (0.74%) 
Cholangitis acute  1  1/271 (0.37%)  1/270 (0.37%) 
Cholecystitis acute  1  0/271 (0.00%)  1/270 (0.37%) 
Jaundice cholestatic  1  2/271 (0.74%)  0/270 (0.00%) 
Hepatic failure  1  2/271 (0.74%)  0/270 (0.00%) 
Portal hypertension  1  1/271 (0.37%)  0/270 (0.00%) 
Infections and infestations     
Urinary tract infection  1  3/271 (1.11%)  0/270 (0.00%) 
Pneumonia  1  3/271 (1.11%)  2/270 (0.74%) 
Pharyngitis  1  0/271 (0.00%)  1/270 (0.37%) 
Influenza  1  0/271 (0.00%)  1/270 (0.37%) 
Sepsis  1  2/271 (0.74%)  2/270 (0.74%) 
Abdominal abscess  1  1/271 (0.37%)  1/270 (0.37%) 
Bronchopneumonia  1  0/271 (0.00%)  1/270 (0.37%) 
Bacterascites  1  0/271 (0.00%)  2/270 (0.74%) 
Escherichia urinary tract infection  1  0/271 (0.00%)  1/270 (0.37%) 
Skin infection  1  0/271 (0.00%)  1/270 (0.37%) 
Cellulitis  1  1/271 (0.37%)  0/270 (0.00%) 
Device related infection  1  3/271 (1.11%)  0/270 (0.00%) 
Biliary sepsis  1  2/271 (0.74%)  1/270 (0.37%) 
Clostridium difficile colitis  1  0/271 (0.00%)  1/270 (0.37%) 
Enterocolitis infectious  1  0/271 (0.00%)  1/270 (0.37%) 
Febrile infection  1  0/271 (0.00%)  1/270 (0.37%) 
Liver abscess  1  0/271 (0.00%)  1/270 (0.37%) 
Peritoneal infection  1  0/271 (0.00%)  1/270 (0.37%) 
Subdiaphragmatic abscess  1  0/271 (0.00%)  1/270 (0.37%) 
Escherichia sepsis  1  2/271 (0.74%)  0/270 (0.00%) 
Anal abscess  1  1/271 (0.37%)  0/270 (0.00%) 
Cholecystitis infective  1  1/271 (0.37%)  0/270 (0.00%) 
Fungal oesophagitis  1  1/271 (0.37%)  0/270 (0.00%) 
Pyelonephritis  1  1/271 (0.37%)  0/270 (0.00%) 
Urosepsis  1  1/271 (0.37%)  0/270 (0.00%) 
Injury, poisoning and procedural complications     
Fall  1  0/271 (0.00%)  1/270 (0.37%) 
Anastomotic leak  1  0/271 (0.00%)  1/270 (0.37%) 
Hip fracture  1  0/271 (0.00%)  1/270 (0.37%) 
Therapeutic agent toxicity  1  0/271 (0.00%)  1/270 (0.37%) 
Investigations     
Weight decreased  1  1/271 (0.37%)  0/270 (0.00%) 
Hepatic enzyme increased  1  0/271 (0.00%)  1/270 (0.37%) 
Ejection fraction decreased  1  0/271 (0.00%)  1/270 (0.37%) 
Blood glucose fluctuation  1  1/271 (0.37%)  0/270 (0.00%) 
Gamma-glutamyltransferase increased  1  1/271 (0.37%)  0/270 (0.00%) 
Metabolism and nutrition disorders     
Decreased appetite  1  2/271 (0.74%)  1/270 (0.37%) 
Dehydration  1  5/271 (1.85%)  5/270 (1.85%) 
Diabetes mellitus  1  0/271 (0.00%)  1/270 (0.37%) 
Hyponatraemia  1  1/271 (0.37%)  1/270 (0.37%) 
Hyperglycaemia  1  0/271 (0.00%)  1/270 (0.37%) 
Failure to thrive  1  0/271 (0.00%)  1/270 (0.37%) 
Hyperkalaemia  1  0/271 (0.00%)  1/270 (0.37%) 
Hypoalbuminaemia  1  0/271 (0.00%)  1/270 (0.37%) 
Hypoglycaemia  1  2/271 (0.74%)  0/270 (0.00%) 
Musculoskeletal and connective tissue disorders     
Pain in extremity  1  1/271 (0.37%)  0/270 (0.00%) 
Musculoskeletal pain  1  0/271 (0.00%)  1/270 (0.37%) 
Musculoskeletal chest pain  1  0/271 (0.00%)  1/270 (0.37%) 
Bone pain  1  0/271 (0.00%)  1/270 (0.37%) 
Groin pain  1  0/271 (0.00%)  1/270 (0.37%) 
Myositis  1  2/271 (0.74%)  0/270 (0.00%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Tumour pain  1  2/271 (0.74%)  1/270 (0.37%) 
Cancer pain  1  1/271 (0.37%)  2/270 (0.74%) 
Malignant ascites  1  2/271 (0.74%)  0/270 (0.00%) 
Bladder neoplasm  1  0/271 (0.00%)  1/270 (0.37%) 
Tumour associated fever  1  2/271 (0.74%)  0/270 (0.00%) 
Paraneoplastic syndrome  1  1/271 (0.37%)  0/270 (0.00%) 
Tumour haemorrhage  1  1/271 (0.37%)  0/270 (0.00%) 
Nervous system disorders     
Syncope  1  0/271 (0.00%)  1/270 (0.37%) 
Ischaemic stroke  1  2/271 (0.74%)  1/270 (0.37%) 
Cerebellar syndrome  1  0/271 (0.00%)  1/270 (0.37%) 
Cerebral haemorrhage  1  0/271 (0.00%)  1/270 (0.37%) 
Cerebral infarction  1  0/271 (0.00%)  1/270 (0.37%) 
Diabetic ketoacidotic hyperglycaemic coma  1  0/271 (0.00%)  1/270 (0.37%) 
Convulsion  1  1/271 (0.37%)  0/270 (0.00%) 
Hepatic encephalopathy  1  1/271 (0.37%)  0/270 (0.00%) 
Intracranial pressure increased  1  1/271 (0.37%)  0/270 (0.00%) 
Monoplegia  1  1/271 (0.37%)  0/270 (0.00%) 
Spinal cord compression  1  1/271 (0.37%)  0/270 (0.00%) 
Psychiatric disorders     
Confusional state  1  0/271 (0.00%)  2/270 (0.74%) 
Completed suicide  1  0/271 (0.00%)  1/270 (0.37%) 
Mental status changes  1  2/271 (0.74%)  0/270 (0.00%) 
Renal and urinary disorders     
Proteinuria  1  0/271 (0.00%)  1/270 (0.37%) 
Haematuria  1  0/271 (0.00%)  1/270 (0.37%) 
Nephrotic syndrome  1  0/271 (0.00%)  2/270 (0.74%) 
Renal failure  1  0/271 (0.00%)  1/270 (0.37%) 
Renal failure acute  1  1/271 (0.37%)  1/270 (0.37%) 
Reproductive system and breast disorders     
Epididymitis  1  0/271 (0.00%)  1/270 (0.37%) 
Respiratory, thoracic and mediastinal disorders     
Epistaxis  1  0/271 (0.00%)  2/270 (0.74%) 
Dyspnoea  1  3/271 (1.11%)  2/270 (0.74%) 
Pulmonary embolism  1  11/271 (4.06%)  4/270 (1.48%) 
Pleural effusion  1  0/271 (0.00%)  2/270 (0.74%) 
Chronic obstructive pulmonary disease  1  0/271 (0.00%)  1/270 (0.37%) 
Interstitial lung disease  1  2/271 (0.74%)  1/270 (0.37%) 
Pneumonia aspiration  1  1/271 (0.37%)  1/270 (0.37%) 
Pneumothorax  1  0/271 (0.00%)  1/270 (0.37%) 
Tachypnoea  1  0/271 (0.00%)  1/270 (0.37%) 
Hypoxia  1  1/271 (0.37%)  0/270 (0.00%) 
Pleuritic pain  1  1/271 (0.37%)  0/270 (0.00%) 
Respiratory failure  1  1/271 (0.37%)  0/270 (0.00%) 
Skin and subcutaneous tissue disorders     
Dermatitis  1  0/271 (0.00%)  1/270 (0.37%) 
Urticaria  1  0/271 (0.00%)  1/270 (0.37%) 
Skin ulcer  1  0/271 (0.00%)  1/270 (0.37%) 
Vascular disorders     
Hypertension  1  0/271 (0.00%)  4/270 (1.48%) 
Deep vein thrombosis  1  2/271 (0.74%)  3/270 (1.11%) 
Thrombophlebitis superficial  1  1/271 (0.37%)  1/270 (0.37%) 
Jugular vein thrombosis  1  0/271 (0.00%)  1/270 (0.37%) 
Hypertensive crisis  1  0/271 (0.00%)  2/270 (0.74%) 
Embolism arterial  1  0/271 (0.00%)  1/270 (0.37%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo and Gemcitabine Aflibercept and Gemcitabine
Affected / at Risk (%) Affected / at Risk (%)
Total   239/271 (88.19%)   249/270 (92.22%) 
Blood and lymphatic system disorders     
Neutropenia  1  71/271 (26.20%)  85/270 (31.48%) 
Thrombocytopenia  1  17/271 (6.27%)  47/270 (17.41%) 
Gastrointestinal disorders     
Nausea  1  124/271 (45.76%)  102/270 (37.78%) 
Vomiting  1  77/271 (28.41%)  82/270 (30.37%) 
Diarrhoea  1  57/271 (21.03%)  65/270 (24.07%) 
Constipation  1  73/271 (26.94%)  64/270 (23.70%) 
Abdominal pain  1  61/271 (22.51%)  54/270 (20.00%) 
Stomatitis  1  16/271 (5.90%)  43/270 (15.93%) 
Abdominal pain upper  1  28/271 (10.33%)  33/270 (12.22%) 
General disorders     
Fatigue  1  103/271 (38.01%)  97/270 (35.93%) 
Pyrexia  1  47/271 (17.34%)  51/270 (18.89%) 
Asthenia  1  42/271 (15.50%)  51/270 (18.89%) 
Oedema peripheral  1  43/271 (15.87%)  33/270 (12.22%) 
Infections and infestations     
Urinary tract infection  1  17/271 (6.27%)  16/270 (5.93%) 
Investigations     
Weight decreased  1  43/271 (15.87%)  81/270 (30.00%) 
Metabolism and nutrition disorders     
Decreased appetite  1  72/271 (26.57%)  78/270 (28.89%) 
Musculoskeletal and connective tissue disorders     
Back pain  1  23/271 (8.49%)  27/270 (10.00%) 
Arthralgia  1  10/271 (3.69%)  15/270 (5.56%) 
Pain in extremity  1  4/271 (1.48%)  14/270 (5.19%) 
Nervous system disorders     
Headache  1  19/271 (7.01%)  51/270 (18.89%) 
Dysgeusia  1  8/271 (2.95%)  15/270 (5.56%) 
Psychiatric disorders     
Insomnia  1  18/271 (6.64%)  28/270 (10.37%) 
Depression  1  8/271 (2.95%)  19/270 (7.04%) 
Anxiety  1  13/271 (4.80%)  16/270 (5.93%) 
Renal and urinary disorders     
Proteinuria  1  6/271 (2.21%)  30/270 (11.11%) 
Respiratory, thoracic and mediastinal disorders     
Dysphonia  1  6/271 (2.21%)  40/270 (14.81%) 
Epistaxis  1  5/271 (1.85%)  37/270 (13.70%) 
Dyspnoea  1  16/271 (5.90%)  26/270 (9.63%) 
Cough  1  14/271 (5.17%)  14/270 (5.19%) 
Skin and subcutaneous tissue disorders     
Rash  1  19/271 (7.01%)  17/270 (6.30%) 
Vascular disorders     
Hypertension  1  17/271 (6.27%)  96/270 (35.56%) 
Deep vein thrombosis  1  16/271 (5.90%)  9/270 (3.33%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 13.1

As the study was terminated due to futility, some changes were made to the planned analyses, and the analyses for the following outcome measures were not performed:

  • Objective Response Rate (ORR)
  • Clinical Benefit
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The investigator shall have the right to independently publish study results from his site after a multicenter publication, or 12 months after the completion of the study by all sites. He must provide the sponsor a copy of any such publication derived from the study for review and comment at least 45 days (20 days for abstracts) in advance of any submission, and delay publication till the approval of the publication is given in writing by the Sponsor (not to exceed ninety days).
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: International Clinical Development Study Director
Organization: Sanofi
EMail: Contact-Us@sanofi.com
Layout table for additonal information
Responsible Party: Sanofi
ClinicalTrials.gov Identifier: NCT00574275     History of Changes
Other Study ID Numbers: EFC10547
EudraCT 2007-003476-19
First Submitted: December 14, 2007
First Posted: December 17, 2007
Results First Submitted: August 17, 2012
Results First Posted: September 25, 2012
Last Update Posted: June 7, 2016