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VELOUR: Aflibercept Versus Placebo in Combination With Irinotecan and 5-FU in the Treatment of Patients With Metastatic Colorectal Cancer After Failure of an Oxaliplatin Based Regimen

Sponsor
Sanofi (Industry)
Overall Status
Completed
CT.gov ID
NCT00561470
Collaborator
Regeneron Pharmaceuticals (Industry), NSABP Foundation Inc (Other)
1,226
Enrollment
221
Locations
2
Arms
55
Duration (Months)
5.5
Patients Per Site
0.1
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

The main objective of the study was to evaluate the effectiveness of aflibercept (versus placebo) in increasing the overall survival in participants with metastatic colorectal cancer treated with FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) and that have previously failed an oxaliplatin based treatment for metastatic disease.

The secondary objectives were to compare progression-free survival, to evaluate overall response rate, to evaluate the safety profile, to assess immunogenicity of intravenous (IV) aflibercept, and to assess pharmacokinetics of IV aflibercept in both treatment arms.

Condition or Disease Intervention/Treatment Phase
  • Drug: Placebo
  • Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
  • Drug: FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)
  • Drug: FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)
 Phase 3

Detailed Description

Participants were

  • randomized at baseline (treatment was initiated with 3 days of randomization)

  • administered treatment in cycles of 14-days till a study withdrawal criterion was met

  • followed up 30 days after discontinuation of treatment, and every 8 weeks until death or end of study.

The criteria for discontinuation of study treatment for a participant are:

  • 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 due to

  • disease progression

  • unacceptable AEs

  • intercurrent illnesses

  • non-compliance to the study protocol

  • participant was lost to follow-up

  • participant was unblinded for the investigational treatment

Study Design

Study Type:
Interventional
Actual Enrollment :
1226 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 With Metastatic Colorectal Cancer (MCRC) Treated With Irinotecan / 5-FU Combination (FOLFIRI) After Failure of an Oxaliplatin Based Regimen
Study Start Date :
Nov 1, 2007
Actual Primary Completion Date :
Feb 1, 2011
Actual Study Completion Date :
Jun 1, 2012

Arms and Interventions

Arm Intervention/Treatment
Placebo Comparator: Placebo/FOLFIRI

Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) starting on Day 1 of a 2-week cycle until a treatment discontinuation criterion was met

Drug: Placebo
4 mg/kg of sterile aqueous buffered vehicle (pH 6.0) was administered intra venously (IV) over 1 hour on Day 1, every 2 weeks

Drug: FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)
The FOLFIRI regimen was initiated immediately after Placebo administration on Day 1 The FOLFIRI regimen included: 180 mg/m² Irinotecan (Campto®, Camptosar®) IV infusion over 90 minutes and dl leucovorin 400 mg/m² (200 mg/m² for the l-isomer form) IV infusion over 2 hours, followed by: 5-FU 400 mg/m² IV bolus given over 2-4 minutes, followed by: 5-FU 2400 mg/m² continuous IV infusion over 46-hours
Experimental: Aflibercept/FOLFIRI

Participants with Metastatic Colorectal Cancer administered Aflibercept followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) starting on Day 1 of a 2-week cycle until a treatment discontinuation criterion was met

Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
4 mg/kg of Aflibercept was administered IV over 1 hour on Day 1, every 2 weeks.

Drug: FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)
The FOLFIRI regimen was initiated immediately after Aflibercept administration on Day 1 The FOLFIRI regimen included: 180 mg/m² Irinotecan (Campto®, Camptosar®) IV infusion over 90 minutes and dl leucovorin 400 mg/m² (200 mg/m² for the l-isomer form) IV infusion over 2 hours, followed by: 5-FU 400 mg/m² IV bolus given over 2-4 minutes, followed by: 5-FU 2400 mg/m² continuous IV infusion over 46-hours

Outcome Measures

Primary Outcome Measures

  1. Overall Survival (OS) [From the date of the first randomization until the study data cut-off date, 07 February 2011 (approximately three years)]

    Overall Survival was the time interval from the date of randomization to the date of death due to any cause. Once disease progression was documented, participants were followed every 2 months for survival status, until death or until the study cutoff date, whichever came first. The final data cutoff date for the analysis of OS was the date when 863 deaths had occurred (07 February 2011). OS was estimated using the Kaplan-Meier method, and the Hazard Ratio was estimated using the Cox Proportional Hazard Model.

Secondary Outcome Measures

  1. Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC) [From the date of the first randomization until the occurrence of 561 OS events, 06 May 2010 (approximately 30 months)]

    PFS was the time interval from the date of randomization to the date of progression, or death from any cause if it occurs before tumor progression is documented. To evaluate disease progression, copies of all tumor imaging sets were systematically collected and assessed by the IRC. PFS was analyzed using the Kaplan-Meier method, and the Hazard Ratio was estimated using the Cox Proportional Hazard Model. The analysis for PFS was performed as planned when 561 deaths (OS events) had occurred.

  2. Overall Objective Response Rate (ORR) Based on the Tumor Assessment by the Independent Review Committee (IRC) as Per Response Evaluation Criteria in Solid Tumours (RECIST) Criteria [From the date of the first randomization until the study data cut-off date, 06 May 2010 (approximately 30 months)]

    The overall ORR was the percentage of evaluable participants who achieved complete response [CR] or partial response [PR] according to RECIST criteria version 1.0. CR reflected the disappearance of all tumor lesions (with no new tumors) PR reflected a pre-defined reduction in tumor burden Tumors were assessed by the IRC using Computerized Tomography (CT) scans or Magnetic Resonance Imaging (MRI) scans; and an observed response was confirmed by repeated imaging after 4 - 6 weeks.

  3. Number of Participants With Adverse Events (AE) [From the date of the first randomization up to 30 days after the treatment discontinuation or until TEAE was resolved or stabilized]

    All AEs regardless of seriousness or relationship to study treatment, spanning from the first administration of study treatment until 30 days after the last administration of study treatment, were recorded, and followed until resolution or stabilization. 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.

  4. Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay [Baseline, every other treatment cycle, 30 days and 90 days after the last infusion of aflibercept/placebo]

    Serum samples for immunogenicity assessment were analyzed using a bridging immunoassay to detect ADA. Positive samples in the ADA assay were further analyzed in the NAb assay using a validated, non-quantitative ligand binding assay.

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No

Participants who met the following main selection criteria were included in the study.

Inclusion Criteria:

  • Histologically or cytologically proven adenocarcinoma of the colon or rectum

  • Metastatic disease that is not amenable to potentially curative treatment

  • One and only one prior line of treatment for metastatic disease. This prior line should be an oxaliplatin based chemotherapy (participants who relapse within 6 months of completion of oxaliplatin based adjuvant chemotherapy are eligible)

  • Prior treatment with bevacizumab is permitted.

Exclusion Criteria:

  • Prior therapy with irinotecan

  • Eastern Cooperative Oncology Group performance status >2

The above information is not intended to contain all considerations relevant to participation in a clinical trial.

Contacts and Locations

Locations

Site City State Country Postal Code
1 Sanofi-Aventis Investigational Site Number 840119 Birmingham Alabama United States 35203
2 Sanofi-Aventis Investigational Site Number 840074 Muscle Shoals Alabama United States 35661
3 Sanofi-Aventis Investigational Site Number 840093 Hot Springs Arizona United States 71913
4 Sanofi-Aventis Investigational Site Number 840080 Anaheim California United States 92801
5 Sanofi-Aventis Investigational Site Number 840076 Fountain Valley California United States 92708
6 Sanofi-Aventis Investigational Site Number 840120 Fountain Valley California United States 92708
7 Sanofi-Aventis Investigational Site Number 840073 Greenbrae California United States 94904-2007
8 Sanofi-Aventis Investigational Site Number 840101 Hayward California United States 94545
9 Sanofi-Aventis Investigational Site Number 840046 La Jolla California United States 92037
10 Sanofi-Aventis Investigational Site Number 840116 Loma Linda California United States 92354
11 Sanofi-Aventis Investigational Site Number 840048 Long Beach California United States 90813
12 Sanofi-Aventis Investigational Site Number 840201 Oakland California United States 94611
13 Sanofi-Aventis Investigational Site Number 840901 Roseville California United States 95678
14 Sanofi-Aventis Investigational Site Number 840042 Sacramento California United States 95816
15 Sanofi-Aventis Investigational Site Number 840301 Sacramento California United States 95825
16 Sanofi-Aventis Investigational Site Number 840112 Salinas California United States 93901-3906
17 Sanofi-Aventis Investigational Site Number 840006 San Diego California United States 92102
18 Sanofi-Aventis Investigational Site Number 840106 San Diego California United States 92102
19 Sanofi-Aventis Investigational Site Number 840206 San Diego California United States 92102
20 Sanofi-Aventis Investigational Site Number 840306 San Diego California United States 92102
21 Sanofi-Aventis Investigational Site Number 840406 San Diego California United States 92102
22 Sanofi-Aventis Investigational Site Number 840506 San Diego California United States 92102
23 Sanofi-Aventis Investigational Site Number 840606 San Diego California United States 92102
24 Sanofi-Aventis Investigational Site Number 840706 San Diego California United States 92102
25 Sanofi-Aventis Investigational Site Number 840806 San Diego California United States 92102
26 Sanofi-Aventis Investigational Site Number 840906 San Diego California United States 92102
27 Sanofi-Aventis Investigational Site Number 840401 San Francisco California United States 94115
28 Sanofi-Aventis Investigational Site Number 840601 San Jose California United States 95119
29 Sanofi-Aventis Investigational Site Number 840501 Santa Clara California United States 95051
30 Sanofi-Aventis Investigational Site Number 840801 South San Francisco California United States 94080
31 Sanofi-Aventis Investigational Site Number 840001 Vallejo California United States 94589
32 Sanofi-Aventis Investigational Site Number 840701 Walnut Creek California United States 94596
33 Sanofi-Aventis Investigational Site Number 840071 Stamford Connecticut United States 06902
34 Sanofi-Aventis Investigational Site Number 840014 Newark Delaware United States 19718
35 Sanofi-Aventis Investigational Site Number 840089 Boynton Beach Florida United States 33435
36 Sanofi-Aventis Investigational Site Number 840041 Gainesville Florida United States 32608
37 Sanofi-Aventis Investigational Site Number 840031 Gainesville Florida United States 32610
38 Sanofi-Aventis Investigational Site Number 840122 Miami Florida United States 33176
39 Sanofi-Aventis Investigational Site Number 840079 The Villages Florida United States 32159
40 Sanofi-Aventis Investigational Site Number 840087 Chicago Illinois United States 60616
41 Sanofi-Aventis Investigational Site Number 840019 Decatur Illinois United States 62526
42 Sanofi-Aventis Investigational Site Number 840115 Elk Grove Village Illinois United States 60007
43 Sanofi-Aventis Investigational Site Number 840010 Naperville Illinois United States 60540
44 Sanofi-Aventis Investigational Site Number 840113 Quincy Illinois United States 62301
45 Sanofi-Aventis Investigational Site Number 840072 Indianapolis Indiana United States 46254
46 Sanofi-Aventis Investigational Site Number 840047 Indianapolis Indiana United States 46260
47 Sanofi-Aventis Investigational Site Number 840034 Munster Indiana United States 46321
48 Sanofi-Aventis Investigational Site Number 840088 Louisville Kentucky United States 40202
49 Sanofi-Aventis Investigational Site Number 840096 Paducah Kentucky United States 42003
50 Sanofi-Aventis Investigational Site Number 840043 Baton Rouge Louisiana United States 70809
51 Sanofi-Aventis Investigational Site Number 840084 Metairie Louisiana United States 70006
52 Sanofi-Aventis Investigational Site Number 840015 New Orleans Louisiana United States 70121
53 Sanofi-Aventis Investigational Site Number 840070 Rockville Maryland United States 20850
54 Sanofi-Aventis Investigational Site Number 840029 Salisbury Maryland United States 21801
55 Sanofi-Aventis Investigational Site Number 840053 Pontiac Michigan United States 48341
56 Sanofi-Aventis Investigational Site Number 840021 St Louis Park Minnesota United States 55416
57 Sanofi-Aventis Investigational Site Number 840081 Kansas City Missouri United States 64128
58 Sanofi-Aventis Investigational Site Number 840052 St Louis Missouri United States 63104
59 Sanofi-Aventis Investigational Site Number 840114 St. Louis Missouri United States 63136
60 Sanofi-Aventis Investigational Site Number 840049 Las Vegas Nevada United States 89106
61 Sanofi-Aventis Investigational Site Number 840044 Albuquerque New Mexico United States 87131
62 Sanofi-Aventis Investigational Site Number 840036 Albany New York United States 12206
63 Sanofi-Aventis Investigational Site Number 840094 Lake Success New York United States 11042
64 Sanofi-Aventis Investigational Site Number 840017 Syracuse New York United States 13210
65 Sanofi-Aventis Investigational Site Number 840097 Syracuse New York United States 13210
66 Sanofi-Aventis Investigational Site Number 840035 Burlington North Carolina United States 27215
67 Sanofi-Aventis Investigational Site Number 840024 Charlotte North Carolina United States 28204
68 Sanofi-Aventis Investigational Site Number 840026 Charlotte North Carolina United States 28262
69 Sanofi-Aventis Investigational Site Number 840005 Goldsboro North Carolina United States 27534
70 Sanofi-Aventis Investigational Site Number 840004 Hendersonville North Carolina United States 28791
71 Sanofi-Aventis Investigational Site Number 840075 Winston-Salem North Carolina United States 27103
72 Sanofi-Aventis Investigational Site Number 840098 Cincinnati Ohio United States 45219
73 Sanofi-Aventis Investigational Site Number 840011 Kettering Ohio United States 45429
74 Sanofi-Aventis Investigational Site Number 840086 Middletown Ohio United States 45042
75 Sanofi-Aventis Investigational Site Number 840008 Toledo Ohio United States 43623
76 Sanofi-Aventis Investigational Site Number 840039 Portland Oregon United States 97227
77 Sanofi-Aventis Investigational Site Number 840118 Bethlehem Pennsylvania United States 18015
78 Sanofi-Aventis Investigational Site Number 840033 Philadelphia Pennsylvania United States 19107
79 Sanofi-Aventis Investigational Site Number 840012 Pittsburgh Pennsylvania United States 15212
80 Sanofi-Aventis Investigational Site Number 840082 Pawtucket Rhode Island United States 02860
81 Sanofi-Aventis Investigational Site Number 840095 Woonsocket Rhode Island United States 02895
82 Sanofi-Aventis Investigational Site Number 840085 Charleston South Carolina United States 29403
83 Sanofi-Aventis Investigational Site Number 840037 Spartanburg South Carolina United States 29303
84 Sanofi-Aventis Investigational Site Number 840078 Corpus Christi Texas United States 78405
85 Sanofi-Aventis Investigational Site Number 840117 Temple Texas United States 76508
86 Sanofi-Aventis Investigational Site Number 840099 Seattle Washington United States 98115
87 Sanofi-Aventis Investigational Site Number 840002 Marshfield Wisconsin United States 54449
88 Sanofi-Aventis Investigational Site Number 032003 Bahia Blanca Argentina 8000
89 Sanofi-Aventis Investigational Site Number 032006 Buenos Aires Argentina 1426ANZ
90 Sanofi-Aventis Investigational Site Number 032005 Ciudad De Buenos Aires Argentina C1426BOR
91 Sanofi-Aventis Investigational Site Number 032007 Salta Argentina 4400
92 Sanofi-Aventis Investigational Site Number 036004 Hornsby Australia 2077
93 Sanofi-Aventis Investigational Site Number 036001 Kingswood Australia 2747
94 Sanofi-Aventis Investigational Site Number 036002 Kurralta Park Australia 5037
95 Sanofi-Aventis Investigational Site Number 036005 Melbourne Australia 3050
96 Sanofi-Aventis Investigational Site Number 036003 Melbourne Australia 3128
97 Sanofi-Aventis Investigational Site Number 036007 Nedlands Australia 6009
98 Sanofi-Aventis Investigational Site Number 036006 Subiaco Australia 6008
99 Sanofi-Aventis Investigational Site Number 040001 Wien Austria 1090
100 Sanofi-Aventis Investigational Site Number 056006 Bonheiden Belgium 2820
101 Sanofi-Aventis Investigational Site Number 056007 Bruxelles Belgium 1000
102 Sanofi-Aventis Investigational Site Number 056002 Bruxelles Belgium 1070
103 Sanofi-Aventis Investigational Site Number 056004 Bruxelles Belgium 1200
104 Sanofi-Aventis Investigational Site Number 056001 Gent Belgium 9000
105 Sanofi-Aventis Investigational Site Number 056005 Haine-Saint-Paul Belgium 7100
106 Sanofi-Aventis Investigational Site Number 056003 Leuven Belgium 3000
107 Sanofi-Aventis Investigational Site Number 076004 Porto Alegre Brazil 90035-003
108 Sanofi-Aventis Investigational Site Number 076005 Porto Alegre Brazil 90110-270
109 Sanofi-Aventis Investigational Site Number 076002 Porto Alegre Brazil 90430090
110 Sanofi-Aventis Investigational Site Number 076008 Rio De Janeiro Brazil 20231-050
111 Sanofi-Aventis Investigational Site Number 076003 Rio De Janeiro Brazil 22260-020
112 Sanofi-Aventis Investigational Site Number 076001 Santo Andre Brazil 09050-360
113 Sanofi-Aventis Investigational Site Number 076007 Sao Paulo Brazil 01246-000
114 Sanofi-Aventis Investigational Site Number 076006 Sao Paulo Brazil 01308050
115 Sanofi-Aventis Investigational Site Number 152002 Santiago Chile 7510032
116 Sanofi-Aventis Investigational Site Number 152003 Santiago Chile 7650635
117 Sanofi-Aventis Investigational Site Number 152001 Santiago Chile 8380455
118 Sanofi-Aventis Investigational Site Number 152005 Santiago Chile 8380456
119 Sanofi-Aventis Investigational Site Number 152004 Viña Del Mar Chile 2540364
120 Sanofi-Aventis Investigational Site Number 203002 Brno Czech Republic 62500
121 Sanofi-Aventis Investigational Site Number 203001 Brno Czech Republic 65653
122 Sanofi-Aventis Investigational Site Number 203004 Praha 5 Czech Republic 15006
123 Sanofi-Aventis Investigational Site Number 208001 Odense C Denmark 5000
124 Sanofi-Aventis Investigational Site Number 208003 Ålborg Denmark 9100
125 Sanofi-Aventis Investigational Site Number 233002 Tallinn Estonia 13419
126 Sanofi-Aventis Investigational Site Number 233001 Tartu Estonia 50406
127 Sanofi-Aventis Investigational Site Number 250002 Brest France 29200
128 Sanofi-Aventis Investigational Site Number 250004 Clichy Cx France 92118
129 Sanofi-Aventis Investigational Site Number 250005 La Roche Sur Yon France 85925
130 Sanofi-Aventis Investigational Site Number 250001 Lyon Cedex 03 France 69437
131 Sanofi-Aventis Investigational Site Number 250003 Paris France 75013
132 Sanofi-Aventis Investigational Site Number 276003 Aschaffenburg Germany 63739
133 Sanofi-Aventis Investigational Site Number 276002 Essen Germany 45147
134 Sanofi-Aventis Investigational Site Number 276001 Halle / Saale Germany 06120
135 Sanofi-Aventis Investigational Site Number 276005 Magdeburg Germany 39104
136 Sanofi-Aventis Investigational Site Number 276004 Magdeburg Germany 39130
137 Sanofi-Aventis Investigational Site Number 276006 München Germany 81737
138 Sanofi-Aventis Investigational Site Number 300005 Athens Greece 11522
139 Sanofi-Aventis Investigational Site Number 300004 Athens Greece 11527
140 Sanofi-Aventis Investigational Site Number 300001 Heraklion Greece 71110
141 Sanofi-Aventis Investigational Site Number 300002 Ilion, Athens Greece
142 Sanofi-Aventis Investigational Site Number 300003 Patras Greece 26500
143 Sanofi-Aventis Investigational Site Number 380007 Ancona Italy 60032
144 Sanofi-Aventis Investigational Site Number 380005 Aviano Italy 33081
145 Sanofi-Aventis Investigational Site Number 380004 Candiolo Italy 10060
146 Sanofi-Aventis Investigational Site Number 380003 Genova Italy 16128
147 Sanofi-Aventis Investigational Site Number 380001 Milano Italy 20133
148 Sanofi-Aventis Investigational Site Number 380002 Milano Italy 20141
149 Sanofi-Aventis Investigational Site Number 380008 Rozzano Italy 20089
150 Sanofi-Aventis Investigational Site Number 380006 San Giovanni Rotondo Italy 71013
151 Sanofi-Aventis Investigational Site Number 410001 Goyang Korea, Republic of 410-760
152 Sanofi-Aventis Investigational Site Number 410003 Seoul Korea, Republic of 110-744
153 Sanofi-Aventis Investigational Site Number 410005 Seoul Korea, Republic of 120-752
154 Sanofi-Aventis Investigational Site Number 410002 Seoul Korea, Republic of 135-710
155 Sanofi-Aventis Investigational Site Number 410004 Seoul Korea, Republic of 138-736
156 Sanofi-Aventis Investigational Site Number 528004 Amsterdam Netherlands 1091 HA
157 Sanofi-Aventis Investigational Site Number 528001 Blaricum Netherlands 1261 AN
158 Sanofi-Aventis Investigational Site Number 528005 Breda Netherlands 4819 EV
159 Sanofi-Aventis Investigational Site Number 528002 Rotterdam Netherlands 3007 AC
160 Sanofi-Aventis Investigational Site Number 528003 Sittard-Geleen Netherlands 6162 BG
161 Sanofi-Aventis Investigational Site Number 554009 Auckland New Zealand 1023
162 Sanofi-Aventis Investigational Site Number 554010 Christchurch New Zealand
163 Sanofi-Aventis Investigational Site Number 578002 Bergen Norway 5021
164 Sanofi-Aventis Investigational Site Number 578001 Oslo Norway 0407
165 Sanofi-Aventis Investigational Site Number 578003 Stavanger Norway 4011
166 Sanofi-Aventis Investigational Site Number 616005 Czestochowa Poland 42-200
167 Sanofi-Aventis Investigational Site Number 616004 Elblag Poland 82-300
168 Sanofi-Aventis Investigational Site Number 616007 Krakow Poland 31-826
169 Sanofi-Aventis Investigational Site Number 616003 Lodz Poland 93-509
170 Sanofi-Aventis Investigational Site Number 616002 Poznan Poland 61-485
171 Sanofi-Aventis Investigational Site Number 616006 Rybnik Poland 44-200
172 Sanofi-Aventis Investigational Site Number 616001 Wroclaw Poland 53-413
173 Sanofi-Aventis Investigational Site Number 630001 San Juan Puerto Rico 00927
174 Sanofi-Aventis Investigational Site Number 642004 Alba Iulia Romania 510077
175 Sanofi-Aventis Investigational Site Number 642007 Bucharest Romania 050098
176 Sanofi-Aventis Investigational Site Number 642001 Bucuresti Romania 022328
177 Sanofi-Aventis Investigational Site Number 642002 Bucuresti Romania 022328
178 Sanofi-Aventis Investigational Site Number 642003 Cluj Napoca Romania 400015
179 Sanofi-Aventis Investigational Site Number 642006 Iasi Romania 700106
180 Sanofi-Aventis Investigational Site Number 642005 Suceava Romania 720237
181 Sanofi-Aventis Investigational Site Number 643001 Moscow Russian Federation 115478
182 Sanofi-Aventis Investigational Site Number 643006 Moscow Russian Federation 115478
183 Sanofi-Aventis Investigational Site Number 643002 Moscow Russian Federation 129128
184 Sanofi-Aventis Investigational Site Number 643003 Saint-Petersburg Russian Federation 197758
185 Sanofi-Aventis Investigational Site Number 643004 St-Petersburg Russian Federation 191104
186 Sanofi-Aventis Investigational Site Number 643007 St-Petersburg Russian Federation 197758
187 Sanofi-Aventis Investigational Site Number 710004 Cape Town South Africa 7506
188 Sanofi-Aventis Investigational Site Number 710005 Durban South Africa 4001
189 Sanofi-Aventis Investigational Site Number 710008 Durban South Africa 4062
190 Sanofi-Aventis Investigational Site Number 710001 Parktown South Africa 2193
191 Sanofi-Aventis Investigational Site Number 710006 Port Elizabeth South Africa 6001
192 Sanofi-Aventis Investigational Site Number 710007 Pretoria South Africa 0001
193 Sanofi-Aventis Investigational Site Number 710003 Pretoria South Africa 0181
194 Sanofi-Aventis Investigational Site Number 724002 Barakaldo Spain 48903
195 Sanofi-Aventis Investigational Site Number 724005 Barcelona Spain 08003
196 Sanofi-Aventis Investigational Site Number 724001 Barcelona Spain 08035
197 Sanofi-Aventis Investigational Site Number 724006 Madrid Spain 28035
198 Sanofi-Aventis Investigational Site Number 724003 Madrid Spain 28041
199 Sanofi-Aventis Investigational Site Number 724007 Reus Spain 43201
200 Sanofi-Aventis Investigational Site Number 752002 Stockholm Sweden 171 76
201 Sanofi-Aventis Investigational Site Number 752003 Sundsvall Sweden 851 86
202 Sanofi-Aventis Investigational Site Number 752001 Uppsala Sweden 751 85
203 Sanofi-Aventis Investigational Site Number 792005 Adana Turkey 01120
204 Sanofi-Aventis Investigational Site Number 792004 Ankara Turkey 06100
205 Sanofi-Aventis Investigational Site Number 792001 Ankara Turkey 06500
206 Sanofi-Aventis Investigational Site Number 792002 Izmir Turkey 35340
207 Sanofi-Aventis Investigational Site Number 792003 Kayseri Turkey 38039
208 Sanofi-Aventis Investigational Site Number 804005 Dnipropetrovsk Ukraine
209 Sanofi-Aventis Investigational Site Number 804004 Donetsk Ukraine 83092
210 Sanofi-Aventis Investigational Site Number 804006 Kharkiv Ukraine 61037
211 Sanofi-Aventis Investigational Site Number 804002 Kharkov Ukraine 61070
212 Sanofi-Aventis Investigational Site Number 826001 Aberdeen United Kingdom AB25 2ZD
213 Sanofi-Aventis Investigational Site Number 826010 Bournemouth United Kingdom BH7 7DW
214 Sanofi-Aventis Investigational Site Number 826009 Dudley United Kingdom DY1 2HQ
215 Sanofi-Aventis Investigational Site Number 826008 London United Kingdom EC1A 7BE
216 Sanofi-Aventis Investigational Site Number 826004 London United Kingdom N18 1QX
217 Sanofi-Aventis Investigational Site Number 826007 London United Kingdom SE1 7EH
218 Sanofi-Aventis Investigational Site Number 826011 London United Kingdom SW3 6JJ
219 Sanofi-Aventis Investigational Site Number 826002 Manchester United Kingdom M20 4BX
220 Sanofi-Aventis Investigational Site Number 826003 Northwood United Kingdom HA6 2RN
221 Sanofi-Aventis Investigational Site Number 826005 Sutton United Kingdom SM2 5PT

Sponsors and Collaborators

  • Sanofi
  • Regeneron Pharmaceuticals
  • NSABP Foundation Inc

Investigators

  • Study Director: Clinical Sciences & Operations, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Sanofi
ClinicalTrials.gov Identifier:
NCT00561470
Other Study ID Numbers:
  • EFC10262
  • EudraCT 2007-000820-42
First Posted:
Nov 21, 2007
Last Update Posted:
Sep 28, 2012
Last Verified:
Mar 1, 2012
Keywords provided by Sanofi
colorectal cancer
metastatic
anti-angiogenic
irinotecan
5-FU
FOLFIRI
Additional relevant MeSH terms:
Neoplasms
Colorectal Neoplasms
Neoplasm Metastasis
Leucovorin
Fluorouracil
Irinotecan
Aflibercept
Levoleucovorin

Study Results

Participant Flow

Recruitment Details Between 19 November 2007 and 16 March 2010, 614 participants were randomized to the placebo arm and 612 participants were randomized to the aflibercept arm.
Pre-assignment Detail
Arm/Group Title Placebo/FOLFIRI Aflibercept/FOLFIRI
Arm/Group Description Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Period Title: Overall Study
STARTED 614 612
TREATED 609 607
SAFETY POPULATION 605 611
ONGOING TREATMENT 11 14
COMPLETED 0 0
NOT COMPLETED 614 612

Baseline Characteristics

Arm/Group Title Placebo/Folfiri Aflibercept/Folfiri Total
Arm/Group Description Participants with Metastatic Colorectal Cancer administered Placebo and FOLFIRI (Irinotecan, 5- Fluorouracil, and Leucovorin) Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept and FOLFIRI (Irinotecan, 5- Fluorouracil, and Leucovorin) Total of all reporting groups
Overall Participants 614 612 1226
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]
60.2
(10.8)
59.5
(10.5)
59.8
(10.7)
Age, Customized (participants) [Number]
<65 years
376
61.2%
407
66.5%
783
63.9%
>=65 but <75 years
199
32.4%
172
28.1%
371
30.3%
>=75 years
39
6.4%
33
5.4%
72
5.9%
Sex/Gender, Customized (participants) [Number]
Male
353
57.5%
365
59.6%
718
58.6%
Female
261
42.5%
247
40.4%
508
41.4%
Race/Ethnicity, Customized (participants) [Number]
Caucasian/White
523
85.2%
548
89.5%
1071
87.4%
Black
27
4.4%
16
2.6%
43
3.5%
Asian/Oriental
51
8.3%
35
5.7%
86
7%
Other
13
2.1%
13
2.1%
26
2.1%
Region of Enrollment (participants) [Number]
ARGENTINA
4
0.7%
2
0.3%
6
0.5%
AUSTRALIA
42
6.8%
54
8.8%
96
7.8%
AUSTRIA
3
0.5%
4
0.7%
7
0.6%
BELGIUM
37
6%
45
7.4%
82
6.7%
BRAZIL
21
3.4%
27
4.4%
48
3.9%
CHILE
31
5%
33
5.4%
64
5.2%
CZECH REPUBLIC
30
4.9%
47
7.7%
77
6.3%
DENMARK
9
1.5%
6
1%
15
1.2%
ESTONIA
7
1.1%
3
0.5%
10
0.8%
FRANCE
1
0.2%
1
0.2%
2
0.2%
GERMANY
23
3.7%
12
2%
35
2.9%
GREECE
9
1.5%
10
1.6%
19
1.5%
ITALY
26
4.2%
23
3.8%
49
4%
KOREA, REPUBLIC OF
39
6.4%
26
4.2%
65
5.3%
NETHERLANDS
20
3.3%
14
2.3%
34
2.8%
NEW ZEALAND
13
2.1%
7
1.1%
20
1.6%
NORWAY
14
2.3%
19
3.1%
33
2.7%
POLAND
24
3.9%
32
5.2%
56
4.6%
PUERTO RICO
4
0.7%
2
0.3%
6
0.5%
ROMANIA
16
2.6%
16
2.6%
32
2.6%
RUSSIAN FEDERATION
35
5.7%
40
6.5%
75
6.1%
SOUTH AFRICA
36
5.9%
31
5.1%
67
5.5%
SPAIN
27
4.4%
28
4.6%
55
4.5%
SWEDEN
10
1.6%
4
0.7%
14
1.1%
TURKEY
4
0.7%
2
0.3%
6
0.5%
UKRAINE
11
1.8%
11
1.8%
22
1.8%
UNITED KINGDOM
47
7.7%
52
8.5%
99
8.1%
UNITED STATES
71
11.6%
61
10%
132
10.8%
Eastern Cooperative Oncology Group (ECOG) performance status score (participants) [Number]
Participants with ECOG Score = 0
350
57%
349
57%
699
57%
Participants with ECOG Score = 1
250
40.7%
250
40.8%
500
40.8%
Participants with ECOG Score = 2
14
2.3%
13
2.1%
27
2.2%
Prior Bevacizumab (participants) [Number]
Yes
187
30.5%
186
30.4%
373
30.4%
No
427
69.5%
426
69.6%
853
69.6%

Outcome Measures

1. Primary Outcome
Title Overall Survival (OS)
Description Overall Survival was the time interval from the date of randomization to the date of death due to any cause. Once disease progression was documented, participants were followed every 2 months for survival status, until death or until the study cutoff date, whichever came first. The final data cutoff date for the analysis of OS was the date when 863 deaths had occurred (07 February 2011). OS was estimated using the Kaplan-Meier method, and the Hazard Ratio was estimated using the Cox Proportional Hazard Model.
Time Frame From the date of the first randomization until the study data cut-off date, 07 February 2011 (approximately three years)

Outcome Measure Data

Analysis Population Description
Intent-to-treat population (ITT) - all participants who gave informed consent and were randomized.
Arm/Group Title Placebo/FOLFIRI Aflibercept/FOLFIRI
Arm/Group Description Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Measure Participants 614 612
Measure Events (Death) 460 403
Median (Inter-Quartile Range) [months]
12.06
13.50
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/FOLFIRI, Aflibercept/FOLFIRI
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0032
Comments Stratified Log-Rank test p-value. Stratified on ECOG Performance Status and prior Bevacizumab according to IVRS using the Cox Proportional Hazard Model. Significance threshold was set to 0.0466 using the O'Brien-Fleming alpha spending function.
Method Stratified Log-Rank test
Comments
Method of Estimation Estimation Parameter Stratified Hazard Ratio
Estimated Value 0.817
Confidence Interval (2-Sided) 95.34%
0.713 to 0.937
Parameter Dispersion Type:
Value:
Estimation Comments Stratified on ECOG Performance Status (0 vs 1 vs 2) and prior Bevacizumab (yes vs no) according to IVRS using the Cox Proportional Hazard Model. Significance threshold was set to 0.0466 using the O'Brien-Fleming alpha spending function.
2. Secondary Outcome
Title Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC)
Description PFS was the time interval from the date of randomization to the date of progression, or death from any cause if it occurs before tumor progression is documented. To evaluate disease progression, copies of all tumor imaging sets were systematically collected and assessed by the IRC. PFS was analyzed using the Kaplan-Meier method, and the Hazard Ratio was estimated using the Cox Proportional Hazard Model. The analysis for PFS was performed as planned when 561 deaths (OS events) had occurred.
Time Frame From the date of the first randomization until the occurrence of 561 OS events, 06 May 2010 (approximately 30 months)

Outcome Measure Data

Analysis Population Description
Intent to Treat (ITT) population included all participants who gave informed consent and were randomized.
Arm/Group Title Placebo/FOLFIRI Aflibercept/FOLFIRI
Arm/Group Description Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Measure Participants 614 612
Measure First PFS Events 454 393
Median (Inter-Quartile Range) [months]
4.67
6.90
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/FOLFIRI, Aflibercept/FOLFIRI
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.00007
Comments Stratified on ECOG Performance Status (0 vs 1 vs 2) and prior Bevacizumab (yes vs no) according to IVRS
Method Stratified Log-Rank test
Comments
Method of Estimation Estimation Parameter Stratified Hazard ratio
Estimated Value 0.758
Confidence Interval (2-Sided) 99.99%
0.578 to 0.995
Parameter Dispersion Type:
Value:
Estimation Comments Stratified on ECOG Performance Status (0 vs 1 vs 2) and prior Bevacizumab (yes vs no) according to IVRS using the Cox Proportional Hazard Model.
3. Secondary Outcome
Title Overall Objective Response Rate (ORR) Based on the Tumor Assessment by the Independent Review Committee (IRC) as Per Response Evaluation Criteria in Solid Tumours (RECIST) Criteria
Description The overall ORR was the percentage of evaluable participants who achieved complete response [CR] or partial response [PR] according to RECIST criteria version 1.0. CR reflected the disappearance of all tumor lesions (with no new tumors) PR reflected a pre-defined reduction in tumor burden Tumors were assessed by the IRC using Computerized Tomography (CT) scans or Magnetic Resonance Imaging (MRI) scans; and an observed response was confirmed by repeated imaging after 4 - 6 weeks.
Time Frame From the date of the first randomization until the study data cut-off date, 06 May 2010 (approximately 30 months)

Outcome Measure Data

Analysis Population Description
The evaluable patient population (EPP) for tumor response included all randomized participants with measurable disease at study entry, as per IRC evaluation, and with at least one valid post-baseline tumor evaluation.
Arm/Group Title Placebo/FOLFIRI Aflibercept/FOLFIRI
Arm/Group Description Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Measure Participants 530 531
Number (95% Confidence Interval) [percentage of participants]
11.1
1.8%
19.8
3.2%
Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo/FOLFIRI, Aflibercept/FOLFIRI
Comments
Type of Statistical Test Superiority or Other
Comments
Statistical Test of Hypothesis p-Value 0.0001
Comments
Method Stratified Cochran-Mantel-Haenszel
Comments Stratified on ECOG Performance Status (0 vs 1 vs 2) and Prior Bevacizumab (yes vs no) according to IVRS.
4. Secondary Outcome
Title Number of Participants With Adverse Events (AE)
Description All AEs regardless of seriousness or relationship to study treatment, spanning from the first administration of study treatment until 30 days after the last administration of study treatment, were recorded, and followed until resolution or stabilization. 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 From the date of the first randomization up to 30 days after the treatment discontinuation or until TEAE was resolved or stabilized

Outcome Measure Data

Analysis Population Description
The safety population was the subset of the ITT population that took at least one dose of study treatment. Analyses was based on the treatment actually received (any participant who received at least one dose of aflibercept, even when receiving the rest of study treatment with placebo, was counted in the aflibercept treatment arm).
Arm/Group Title Placebo/FOLFIRI Aflibercept/FOLFIRI
Arm/Group Description Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Measure Participants 605 611
Treatment-Emergent Adverse Event (TEAE)
592
96.4%
606
99%
Serious TEAE
198
32.2%
294
48%
TEAE leading to Death
29
4.7%
37
6%
TEAE causing permanent treatment discontinuation
73
11.9%
164
26.8%
5. Secondary Outcome
Title Immunogenicity Assessment: Number of Participants With Positive Sample(s) in the Anti-drug Antibodies (ADA) Assay and in the Neutralizing Anti-drug Antibodies (NAb) Assay
Description Serum samples for immunogenicity assessment were analyzed using a bridging immunoassay to detect ADA. Positive samples in the ADA assay were further analyzed in the NAb assay using a validated, non-quantitative ligand binding assay.
Time Frame Baseline, every other treatment cycle, 30 days and 90 days after the last infusion of aflibercept/placebo

Outcome Measure Data

Analysis Population Description
Immunogenicity population included all participants who were treated and tested for immunogenicity at least once post-baseline.
Arm/Group Title Placebo/FOLFIRI Aflibercept/FOLFIRI
Arm/Group Description Participants with Metastatic Colorectal Cancer administered Placebo and FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) Participants with Metastatic Colorectal Cancer administered Aflibercept and FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin)
Measure Participants 526 521
At least one positive sample in the ADA assay
18
2.9%
8
1.3%
At least one positive sample in the NAb assay
2
0.3%
1
0.2%

Adverse Events

Time Frame From treatment initiation to 7 February, 2011
Adverse Event Reporting Description
Arm/Group Title Placebo/FOLFIRI Aflibercept/FOLFIRI
Arm/Group Description Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
All Cause Mortality
Placebo/FOLFIRI Aflibercept/FOLFIRI
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total / (NaN) / (NaN)
Serious Adverse Events
Placebo/FOLFIRI Aflibercept/FOLFIRI
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 198/605 (32.7%) 294/611 (48.1%)
Blood and lymphatic system disorders
Neutropenia 4/605 (0.7%) 11/611 (1.8%)
Thrombocytopenia 3/605 (0.5%) 2/611 (0.3%)
Anaemia 3/605 (0.5%) 7/611 (1.1%)
Febrile neutropenia 6/605 (1%) 19/611 (3.1%)
Coagulopathy 0/605 (0%) 2/611 (0.3%)
Pancytopenia 0/605 (0%) 2/611 (0.3%)
Thrombotic microangiopathy 0/605 (0%) 1/611 (0.2%)
Cardiac disorders
Angina pectoris 0/605 (0%) 1/611 (0.2%)
Atrial fibrillation 2/605 (0.3%) 3/611 (0.5%)
Sinus bradycardia 0/605 (0%) 1/611 (0.2%)
Acute myocardial infarction 0/605 (0%) 2/611 (0.3%)
Myocardial ischaemia 1/605 (0.2%) 0/611 (0%)
Cardiac failure congestive 0/605 (0%) 1/611 (0.2%)
Intracardiac thrombus 0/605 (0%) 1/611 (0.2%)
Myocardial infarction 0/605 (0%) 1/611 (0.2%)
Pericarditis 1/605 (0.2%) 0/611 (0%)
Endocrine disorders
Hypercalcaemia of malignancy 1/605 (0.2%) 0/611 (0%)
Eye disorders
Periorbital oedema 0/605 (0%) 1/611 (0.2%)
Gastrointestinal disorders
Diarrhoea 14/605 (2.3%) 44/611 (7.2%)
Nausea 3/605 (0.5%) 4/611 (0.7%)
Stomatitis 0/605 (0%) 8/611 (1.3%)
Vomiting 7/605 (1.2%) 10/611 (1.6%)
Abdominal pain 7/605 (1.2%) 12/611 (2%)
Constipation 4/605 (0.7%) 6/611 (1%)
Abdominal pain upper 3/605 (0.5%) 4/611 (0.7%)
Haemorrhoids 0/605 (0%) 2/611 (0.3%)
Rectal haemorrhage 4/605 (0.7%) 6/611 (1%)
Aphthous stomatitis 0/605 (0%) 1/611 (0.2%)
Proctalgia 0/605 (0%) 3/611 (0.5%)
Ascites 4/605 (0.7%) 3/611 (0.5%)
Gastrooesophageal reflux disease 0/605 (0%) 1/611 (0.2%)
Intestinal obstruction 11/605 (1.8%) 10/611 (1.6%)
Abdominal pain lower 1/605 (0.2%) 1/611 (0.2%)
Gastritis 0/605 (0%) 1/611 (0.2%)
Enteritis 1/605 (0.2%) 2/611 (0.3%)
Gingivitis 0/605 (0%) 1/611 (0.2%)
Ileus 5/605 (0.8%) 4/611 (0.7%)
Colitis 1/605 (0.2%) 4/611 (0.7%)
Small intestinal obstruction 2/605 (0.3%) 5/611 (0.8%)
Anal haemorrhage 1/605 (0.2%) 0/611 (0%)
Faecal incontinence 1/605 (0.2%) 0/611 (0%)
Gastrointestinal haemorrhage 0/605 (0%) 3/611 (0.5%)
Gastrointestinal inflammation 0/605 (0%) 3/611 (0.5%)
Periodontitis 0/605 (0%) 1/611 (0.2%)
Gastrointestinal obstruction 2/605 (0.3%) 1/611 (0.2%)
Haematemesis 2/605 (0.3%) 0/611 (0%)
Mechanical ileus 2/605 (0.3%) 1/611 (0.2%)
Colitis ischaemic 0/605 (0%) 1/611 (0.2%)
Colonic obstruction 0/605 (0%) 2/611 (0.3%)
Duodenal ulcer perforation 1/605 (0.2%) 1/611 (0.2%)
Peritonitis 1/605 (0.2%) 1/611 (0.2%)
Small intestinal perforation 1/605 (0.2%) 1/611 (0.2%)
Subileus 0/605 (0%) 2/611 (0.3%)
Colonic fistula 1/605 (0.2%) 0/611 (0%)
Duodenal obstruction 1/605 (0.2%) 0/611 (0%)
Duodenal ulcer haemorrhage 0/605 (0%) 1/611 (0.2%)
Enterocolitis 0/605 (0%) 1/611 (0.2%)
Enterocutaneous fistula 0/605 (0%) 1/611 (0.2%)
Gastrointestinal hypomotility 1/605 (0.2%) 0/611 (0%)
Gastrointestinal perforation 1/605 (0.2%) 0/611 (0%)
Ileal perforation 0/605 (0%) 1/611 (0.2%)
Ileitis 0/605 (0%) 1/611 (0.2%)
Large intestinal haemorrhage 0/605 (0%) 1/611 (0.2%)
Large intestinal obstruction 0/605 (0%) 1/611 (0.2%)
Lower gastrointestinal haemorrhage 0/605 (0%) 1/611 (0.2%)
Mallory-weiss syndrome 0/605 (0%) 1/611 (0.2%)
Mesenteric vein thrombosis 0/605 (0%) 1/611 (0.2%)
Neutropenic colitis 0/605 (0%) 1/611 (0.2%)
Pancreatitis 1/605 (0.2%) 0/611 (0%)
Rectal obstruction 0/605 (0%) 1/611 (0.2%)
Rectal stenosis 1/605 (0.2%) 0/611 (0%)
General disorders
Fatigue 3/605 (0.5%) 2/611 (0.3%)
Asthenia 4/605 (0.7%) 5/611 (0.8%)
Pyrexia 15/605 (2.5%) 10/611 (1.6%)
Oedema peripheral 3/605 (0.5%) 0/611 (0%)
Disease progression 14/605 (2.3%) 16/611 (2.6%)
Pain 1/605 (0.2%) 2/611 (0.3%)
Non-cardiac chest pain 1/605 (0.2%) 2/611 (0.3%)
Malaise 0/605 (0%) 1/611 (0.2%)
Thrombosis in device 0/605 (0%) 2/611 (0.3%)
General physical health deterioration 1/605 (0.2%) 1/611 (0.2%)
Medical device complication 0/605 (0%) 1/611 (0.2%)
Death 1/605 (0.2%) 2/611 (0.3%)
Suprapubic pain 1/605 (0.2%) 0/611 (0%)
Mucosal inflammation 0/605 (0%) 1/611 (0.2%)
Sudden death 1/605 (0.2%) 0/611 (0%)
Hepatobiliary disorders
Hyperbilirubinaemia 4/605 (0.7%) 2/611 (0.3%)
Cholecystitis 1/605 (0.2%) 4/611 (0.7%)
Biliary colic 1/605 (0.2%) 0/611 (0%)
Cholangitis 1/605 (0.2%) 1/611 (0.2%)
Hepatic function abnormal 1/605 (0.2%) 0/611 (0%)
Jaundice cholestatic 1/605 (0.2%) 0/611 (0%)
Bile duct obstruction 0/605 (0%) 1/611 (0.2%)
Hepatic haemorrhage 0/605 (0%) 1/611 (0.2%)
Hepatitis 1/605 (0.2%) 0/611 (0%)
Hepatotoxicity 1/605 (0.2%) 0/611 (0%)
Immune system disorders
Hypersensitivity 2/605 (0.3%) 0/611 (0%)
Infections and infestations
Urinary tract infection 3/605 (0.5%) 8/611 (1.3%)
Upper respiratory tract infection 0/605 (0%) 1/611 (0.2%)
Pneumonia 5/605 (0.8%) 11/611 (1.8%)
Lower respiratory tract infection 2/605 (0.3%) 1/611 (0.2%)
Device related infection 6/605 (1%) 5/611 (0.8%)
Bronchitis 0/605 (0%) 1/611 (0.2%)
Cystitis 1/605 (0.2%) 0/611 (0%)
Oral candidiasis 0/605 (0%) 1/611 (0.2%)
Neutropenic infection 5/605 (0.8%) 4/611 (0.7%)
Sinusitis 0/605 (0%) 1/611 (0.2%)
Viral infection 1/605 (0.2%) 0/611 (0%)
Pharyngitis 0/605 (0%) 1/611 (0.2%)
Respiratory tract infection 0/605 (0%) 1/611 (0.2%)
Sepsis 5/605 (0.8%) 8/611 (1.3%)
Gastroenteritis 2/605 (0.3%) 1/611 (0.2%)
Catheter site infection 0/605 (0%) 3/611 (0.5%)
Infection 1/605 (0.2%) 1/611 (0.2%)
Lobar pneumonia 5/605 (0.8%) 0/611 (0%)
Lung infection 1/605 (0.2%) 1/611 (0.2%)
Anal abscess 1/605 (0.2%) 1/611 (0.2%)
Diverticulitis 0/605 (0%) 1/611 (0.2%)
Neutropenic sepsis 0/605 (0%) 3/611 (0.5%)
Perirectal abscess 0/605 (0%) 3/611 (0.5%)
Subcutaneous abscess 0/605 (0%) 1/611 (0.2%)
Abscess jaw 0/605 (0%) 1/611 (0.2%)
Clostridial infection 0/605 (0%) 1/611 (0.2%)
Oesophageal candidiasis 0/605 (0%) 1/611 (0.2%)
Septic shock 0/605 (0%) 2/611 (0.3%)
Appendicitis 0/605 (0%) 1/611 (0.2%)
Bacterial sepsis 0/605 (0%) 1/611 (0.2%)
Beta haemolytic streptococcal infection 0/605 (0%) 1/611 (0.2%)
Bronchopneumonia 1/605 (0.2%) 0/611 (0%)
Device related sepsis 0/605 (0%) 1/611 (0.2%)
Emphysematous cystitis 0/605 (0%) 1/611 (0.2%)
Enterocolitis infectious 0/605 (0%) 1/611 (0.2%)
Escherichia infection 1/605 (0.2%) 0/611 (0%)
Pelvic abscess 0/605 (0%) 1/611 (0.2%)
Perinephric abscess 0/605 (0%) 1/611 (0.2%)
Peritonitis bacterial 0/605 (0%) 1/611 (0.2%)
Pneumonia streptococcal 0/605 (0%) 1/611 (0.2%)
Rectal abscess 0/605 (0%) 1/611 (0.2%)
Staphylococcal sepsis 0/605 (0%) 1/611 (0.2%)
Viral diarrhoea 1/605 (0.2%) 0/611 (0%)
Injury, poisoning and procedural complications
Fall 1/605 (0.2%) 0/611 (0%)
Post procedural haemorrhage 1/605 (0.2%) 2/611 (0.3%)
Skin laceration 1/605 (0.2%) 0/611 (0%)
Gastrointestinal stoma complication 0/605 (0%) 3/611 (0.5%)
Head injury 1/605 (0.2%) 0/611 (0%)
Incisional hernia 0/605 (0%) 1/611 (0.2%)
Wound dehiscence 1/605 (0.2%) 0/611 (0%)
Ankle fracture 0/605 (0%) 1/611 (0.2%)
Femoral neck fracture 1/605 (0.2%) 0/611 (0%)
Femur fracture 1/605 (0.2%) 0/611 (0%)
Limb traumatic amputation 0/605 (0%) 1/611 (0.2%)
Pneumothorax traumatic 1/605 (0.2%) 0/611 (0%)
Subdural haematoma 0/605 (0%) 1/611 (0.2%)
Investigations
Neutrophil count decreased 0/605 (0%) 1/611 (0.2%)
Blood creatinine increased 2/605 (0.3%) 2/611 (0.3%)
Blood bilirubin increased 1/605 (0.2%) 0/611 (0%)
Haemoglobin decreased 0/605 (0%) 1/611 (0.2%)
International normalised ratio increased 0/605 (0%) 1/611 (0.2%)
Blood creatine increased 0/605 (0%) 1/611 (0.2%)
C-reactive protein increased 1/605 (0.2%) 0/611 (0%)
Hepatic enzyme increased 0/605 (0%) 1/611 (0.2%)
Metabolism and nutrition disorders
Decreased appetite 2/605 (0.3%) 3/611 (0.5%)
Dehydration 7/605 (1.2%) 24/611 (3.9%)
Diabetes mellitus 0/605 (0%) 1/611 (0.2%)
Hypoglycaemia 0/605 (0%) 2/611 (0.3%)
Hyponatraemia 0/605 (0%) 2/611 (0.3%)
Failure to thrive 1/605 (0.2%) 0/611 (0%)
Hypoproteinaemia 1/605 (0.2%) 0/611 (0%)
Musculoskeletal and connective tissue disorders
Back pain 4/605 (0.7%) 3/611 (0.5%)
Bone pain 1/605 (0.2%) 1/611 (0.2%)
Musculoskeletal chest pain 2/605 (0.3%) 0/611 (0%)
Bursitis 1/605 (0.2%) 0/611 (0%)
Osteonecrosis of jaw 0/605 (0%) 1/611 (0.2%)
Pathological fracture 1/605 (0.2%) 0/611 (0%)
Fistula 0/605 (0%) 1/611 (0.2%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastatic pain 3/605 (0.5%) 2/611 (0.3%)
Cancer pain 1/605 (0.2%) 1/611 (0.2%)
Tumour pain 1/605 (0.2%) 1/611 (0.2%)
Metastases to central nervous system 1/605 (0.2%) 1/611 (0.2%)
Benign neoplasm of cervix uteri 0/605 (0%) 1/611 (0.2%)
Bladder cancer 0/605 (0%) 1/611 (0.2%)
Tumour associated fever 0/605 (0%) 1/611 (0.2%)
Nervous system disorders
Headache 1/605 (0.2%) 3/611 (0.5%)
Peripheral sensory neuropathy 0/605 (0%) 1/611 (0.2%)
Syncope 3/605 (0.5%) 1/611 (0.2%)
Presyncope 0/605 (0%) 1/611 (0.2%)
Transient ischaemic attack 0/605 (0%) 2/611 (0.3%)
Migraine 0/605 (0%) 1/611 (0.2%)
Spinal cord compression 1/605 (0.2%) 0/611 (0%)
Aphasia 1/605 (0.2%) 0/611 (0%)
Brachial plexopathy 1/605 (0.2%) 0/611 (0%)
Cerebrovascular accident 0/605 (0%) 1/611 (0.2%)
Coma 0/605 (0%) 1/611 (0.2%)
Convulsion 0/605 (0%) 1/611 (0.2%)
Disturbance in attention 1/605 (0.2%) 0/611 (0%)
Haemorrhage intracranial 1/605 (0.2%) 0/611 (0%)
Metabolic encephalopathy 0/605 (0%) 1/611 (0.2%)
Psychiatric disorders
Anxiety 0/605 (0%) 1/611 (0.2%)
Depression 0/605 (0%) 1/611 (0.2%)
Confusional state 2/605 (0.3%) 2/611 (0.3%)
Hallucination 0/605 (0%) 1/611 (0.2%)
Mental status changes 0/605 (0%) 1/611 (0.2%)
Renal and urinary disorders
Proteinuria 0/605 (0%) 1/611 (0.2%)
Haematuria 2/605 (0.3%) 1/611 (0.2%)
Urinary retention 1/605 (0.2%) 4/611 (0.7%)
Urinary incontinence 1/605 (0.2%) 0/611 (0%)
Hydronephrosis 3/605 (0.5%) 1/611 (0.2%)
Renal failure acute 0/605 (0%) 2/611 (0.3%)
Renal impairment 0/605 (0%) 2/611 (0.3%)
Renal vein thrombosis 0/605 (0%) 1/611 (0.2%)
Bladder neck obstruction 0/605 (0%) 1/611 (0.2%)
Nephrotic syndrome 0/605 (0%) 1/611 (0.2%)
Renal failure 1/605 (0.2%) 1/611 (0.2%)
Cystitis haemorrhagic 0/605 (0%) 1/611 (0.2%)
Nephrolithiasis 1/605 (0.2%) 0/611 (0%)
Obstructive uropathy 1/605 (0.2%) 0/611 (0%)
Urinary tract obstruction 1/605 (0.2%) 0/611 (0%)
Reproductive system and breast disorders
Pelvic pain 1/605 (0.2%) 0/611 (0%)
Balanitis 0/605 (0%) 1/611 (0.2%)
Respiratory, thoracic and mediastinal disorders
Epistaxis 0/605 (0%) 2/611 (0.3%)
Cough 0/605 (0%) 1/611 (0.2%)
Dyspnoea 3/605 (0.5%) 3/611 (0.5%)
Oropharyngeal pain 0/605 (0%) 1/611 (0.2%)
Pulmonary embolism 12/605 (2%) 19/611 (3.1%)
Pleural effusion 0/605 (0%) 1/611 (0.2%)
Pleuritic pain 0/605 (0%) 1/611 (0.2%)
Atelectasis 0/605 (0%) 1/611 (0.2%)
Interstitial lung disease 2/605 (0.3%) 0/611 (0%)
Pneumonitis 1/605 (0.2%) 1/611 (0.2%)
Pneumothorax 0/605 (0%) 2/611 (0.3%)
Acute pulmonary oedema 0/605 (0%) 1/611 (0.2%)
Acute respiratory distress syndrome 0/605 (0%) 1/611 (0.2%)
Acute respiratory failure 0/605 (0%) 1/611 (0.2%)
Pneumomediastinum 0/605 (0%) 1/611 (0.2%)
Pneumonia aspiration 0/605 (0%) 1/611 (0.2%)
Pulmonary artery thrombosis 0/605 (0%) 1/611 (0.2%)
Pulmonary hypertension 0/605 (0%) 1/611 (0.2%)
Skin and subcutaneous tissue disorders
Rash maculo-papular 0/605 (0%) 1/611 (0.2%)
Vascular disorders
Hypertension 0/605 (0%) 10/611 (1.6%)
Deep vein thrombosis 7/605 (1.2%) 7/611 (1.1%)
Hypotension 0/605 (0%) 1/611 (0.2%)
Jugular vein thrombosis 2/605 (0.3%) 0/611 (0%)
Vena cava thrombosis 2/605 (0.3%) 2/611 (0.3%)
Pelvic venous thrombosis 2/605 (0.3%) 0/611 (0%)
Orthostatic hypotension 0/605 (0%) 1/611 (0.2%)
Subclavian vein thrombosis 2/605 (0.3%) 1/611 (0.2%)
Circulatory collapse 1/605 (0.2%) 1/611 (0.2%)
Thrombophlebitis 1/605 (0.2%) 0/611 (0%)
Arterial thrombosis limb 1/605 (0.2%) 0/611 (0%)
Embolism arterial 0/605 (0%) 1/611 (0.2%)
Hypovolaemic shock 0/605 (0%) 1/611 (0.2%)
Superior vena caval occlusion 0/605 (0%) 1/611 (0.2%)
Other (Not Including Serious) Adverse Events
Placebo/FOLFIRI Aflibercept/FOLFIRI
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total 575/605 (95%) 599/611 (98%)
Blood and lymphatic system disorders
Neutropenia 202/605 (33.4%) 229/611 (37.5%)
Gastrointestinal disorders
Diarrhoea 335/605 (55.4%) 411/611 (67.3%)
Nausea 327/605 (54%) 322/611 (52.7%)
Stomatitis 199/605 (32.9%) 304/611 (49.8%)
Vomiting 199/605 (32.9%) 194/611 (31.8%)
Abdominal pain 141/605 (23.3%) 158/611 (25.9%)
Constipation 146/605 (24.1%) 135/611 (22.1%)
Abdominal pain upper 46/605 (7.6%) 63/611 (10.3%)
Dyspepsia 56/605 (9.3%) 50/611 (8.2%)
Haemorrhoids 13/605 (2.1%) 34/611 (5.6%)
Proctalgia 11/605 (1.8%) 32/611 (5.2%)
General disorders
Fatigue 234/605 (38.7%) 292/611 (47.8%)
Asthenia 77/605 (12.7%) 109/611 (17.8%)
Pyrexia 73/605 (12.1%) 77/611 (12.6%)
Oedema peripheral 42/605 (6.9%) 52/611 (8.5%)
Infections and infestations
Urinary tract infection 35/605 (5.8%) 51/611 (8.3%)
Investigations
Weight decreased 87/605 (14.4%) 195/611 (31.9%)
Metabolism and nutrition disorders
Decreased appetite 143/605 (23.6%) 195/611 (31.9%)
Dehydration 12/605 (2%) 33/611 (5.4%)
Musculoskeletal and connective tissue disorders
Back pain 69/605 (11.4%) 72/611 (11.8%)
Arthralgia 40/605 (6.6%) 31/611 (5.1%)
Pain in extremity 33/605 (5.5%) 34/611 (5.6%)
Nervous system disorders
Headache 53/605 (8.8%) 136/611 (22.3%)
Dizziness 53/605 (8.8%) 36/611 (5.9%)
Dysgeusia 32/605 (5.3%) 42/611 (6.9%)
Neuropathy peripheral 30/605 (5%) 34/611 (5.6%)
Lethargy 28/605 (4.6%) 33/611 (5.4%)
Psychiatric disorders
Insomnia 45/605 (7.4%) 47/611 (7.7%)
Renal and urinary disorders
Proteinuria 9/605 (1.5%) 63/611 (10.3%)
Respiratory, thoracic and mediastinal disorders
Epistaxis 45/605 (7.4%) 168/611 (27.5%)
Dysphonia 20/605 (3.3%) 155/611 (25.4%)
Cough 58/605 (9.6%) 67/611 (11%)
Dyspnoea 51/605 (8.4%) 69/611 (11.3%)
Oropharyngeal pain 19/605 (3.1%) 45/611 (7.4%)
Rhinorrhoea 11/605 (1.8%) 38/611 (6.2%)
Skin and subcutaneous tissue disorders
Alopecia 182/605 (30.1%) 164/611 (26.8%)
Palmar-plantar erythrodysaesthesia syndrome 26/605 (4.3%) 67/611 (11%)
Rash 35/605 (5.8%) 41/611 (6.7%)
Skin hyperpigmentation 17/605 (2.8%) 50/611 (8.2%)
Hyperhidrosis 33/605 (5.5%) 17/611 (2.8%)
Vascular disorders
Hypertension 65/605 (10.7%) 250/611 (40.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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

Name/Title International Clinical Development Study Director
Organization sanofi-aventis
Phone
Email contact-us@sanofi.com
Responsible Party:
Sanofi
ClinicalTrials.gov Identifier:
NCT00561470
Other Study ID Numbers:
  • EFC10262
  • EudraCT 2007-000820-42
First Posted:
Nov 21, 2007
Last Update Posted:
Sep 28, 2012
Last Verified:
Mar 1, 2012