Trial Outcomes & Findings for 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 (NCT NCT00561470)

Last Updated: 2012-09-28

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1226 participants

Primary outcome timeframe

From the date of the first randomization until the study data cut-off date, 07 February 2011 (approximately three years)

Results posted on

2012-09-28

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Placebo/FOLFIRI Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks	Aflibercept/FOLFIRI Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Overall Study STARTED	614	612
Overall Study TREATED	609	607
Overall Study SAFETY POPULATION	605	611
Overall Study ONGOING TREATMENT	11	14
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	614	612

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo/FOLFIRI Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks	Aflibercept/FOLFIRI Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Overall Study Adverse Event	74	163
Overall Study Disease progression	437	305
Overall Study poor compliance to protocol	4	4
Overall Study Lost to Follow-up	2	0
Overall Study Physician Decision	21	20
Overall Study Consent Withdrawn	2	6
Overall Study Subject request	43	77
Overall Study Metastatic surgery	10	12
Overall Study Unauthorized procedure	3	1
Overall Study Randomized but not treated	5	5
Overall Study Missed visit window	1	4
Overall Study Planning surgery	1	1
Overall Study Ongoing Treatment	11	14

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo/Folfiri n=614 Participants Participants with Metastatic Colorectal Cancer administered Placebo and FOLFIRI (Irinotecan, 5- Fluorouracil, and Leucovorin)	Aflibercept/Folfiri n=612 Participants Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept and FOLFIRI (Irinotecan, 5- Fluorouracil, and Leucovorin)	Total n=1226 Participants Total of all reporting groups
Age Continuous	60.2 years STANDARD_DEVIATION 10.8 • n=5 Participants	59.5 years STANDARD_DEVIATION 10.5 • n=7 Participants	59.8 years STANDARD_DEVIATION 10.7 • n=5 Participants
Age, Customized <65 years	376 participants n=5 Participants	407 participants n=7 Participants	783 participants n=5 Participants
Age, Customized >=65 but <75 years	199 participants n=5 Participants	172 participants n=7 Participants	371 participants n=5 Participants
Age, Customized >=75 years	39 participants n=5 Participants	33 participants n=7 Participants	72 participants n=5 Participants
Sex/Gender, Customized Male	353 participants n=5 Participants	365 participants n=7 Participants	718 participants n=5 Participants
Sex/Gender, Customized Female	261 participants n=5 Participants	247 participants n=7 Participants	508 participants n=5 Participants
Race/Ethnicity, Customized Caucasian/White	523 participants n=5 Participants	548 participants n=7 Participants	1071 participants n=5 Participants
Race/Ethnicity, Customized Black	27 participants n=5 Participants	16 participants n=7 Participants	43 participants n=5 Participants
Race/Ethnicity, Customized Asian/Oriental	51 participants n=5 Participants	35 participants n=7 Participants	86 participants n=5 Participants
Race/Ethnicity, Customized Other	13 participants n=5 Participants	13 participants n=7 Participants	26 participants n=5 Participants
Region of Enrollment ARGENTINA	4 participants n=5 Participants	2 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment AUSTRALIA	42 participants n=5 Participants	54 participants n=7 Participants	96 participants n=5 Participants
Region of Enrollment AUSTRIA	3 participants n=5 Participants	4 participants n=7 Participants	7 participants n=5 Participants
Region of Enrollment BELGIUM	37 participants n=5 Participants	45 participants n=7 Participants	82 participants n=5 Participants
Region of Enrollment BRAZIL	21 participants n=5 Participants	27 participants n=7 Participants	48 participants n=5 Participants
Region of Enrollment CHILE	31 participants n=5 Participants	33 participants n=7 Participants	64 participants n=5 Participants
Region of Enrollment CZECH REPUBLIC	30 participants n=5 Participants	47 participants n=7 Participants	77 participants n=5 Participants
Region of Enrollment DENMARK	9 participants n=5 Participants	6 participants n=7 Participants	15 participants n=5 Participants
Region of Enrollment ESTONIA	7 participants n=5 Participants	3 participants n=7 Participants	10 participants n=5 Participants
Region of Enrollment FRANCE	1 participants n=5 Participants	1 participants n=7 Participants	2 participants n=5 Participants
Region of Enrollment GERMANY	23 participants n=5 Participants	12 participants n=7 Participants	35 participants n=5 Participants
Region of Enrollment GREECE	9 participants n=5 Participants	10 participants n=7 Participants	19 participants n=5 Participants
Region of Enrollment ITALY	26 participants n=5 Participants	23 participants n=7 Participants	49 participants n=5 Participants
Region of Enrollment KOREA, REPUBLIC OF	39 participants n=5 Participants	26 participants n=7 Participants	65 participants n=5 Participants
Region of Enrollment NETHERLANDS	20 participants n=5 Participants	14 participants n=7 Participants	34 participants n=5 Participants
Region of Enrollment NEW ZEALAND	13 participants n=5 Participants	7 participants n=7 Participants	20 participants n=5 Participants
Region of Enrollment NORWAY	14 participants n=5 Participants	19 participants n=7 Participants	33 participants n=5 Participants
Region of Enrollment POLAND	24 participants n=5 Participants	32 participants n=7 Participants	56 participants n=5 Participants
Region of Enrollment PUERTO RICO	4 participants n=5 Participants	2 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment ROMANIA	16 participants n=5 Participants	16 participants n=7 Participants	32 participants n=5 Participants
Region of Enrollment RUSSIAN FEDERATION	35 participants n=5 Participants	40 participants n=7 Participants	75 participants n=5 Participants
Region of Enrollment SOUTH AFRICA	36 participants n=5 Participants	31 participants n=7 Participants	67 participants n=5 Participants
Region of Enrollment SPAIN	27 participants n=5 Participants	28 participants n=7 Participants	55 participants n=5 Participants
Region of Enrollment SWEDEN	10 participants n=5 Participants	4 participants n=7 Participants	14 participants n=5 Participants
Region of Enrollment TURKEY	4 participants n=5 Participants	2 participants n=7 Participants	6 participants n=5 Participants
Region of Enrollment UKRAINE	11 participants n=5 Participants	11 participants n=7 Participants	22 participants n=5 Participants
Region of Enrollment UNITED KINGDOM	47 participants n=5 Participants	52 participants n=7 Participants	99 participants n=5 Participants
Region of Enrollment UNITED STATES	71 participants n=5 Participants	61 participants n=7 Participants	132 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) performance status score Participants with ECOG Score = 0	350 participants n=5 Participants	349 participants n=7 Participants	699 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) performance status score Participants with ECOG Score = 1	250 participants n=5 Participants	250 participants n=7 Participants	500 participants n=5 Participants
Eastern Cooperative Oncology Group (ECOG) performance status score Participants with ECOG Score = 2	14 participants n=5 Participants	13 participants n=7 Participants	27 participants n=5 Participants
Prior Bevacizumab Yes	187 participants n=5 Participants	186 participants n=7 Participants	373 participants n=5 Participants
Prior Bevacizumab No	427 participants n=5 Participants	426 participants n=7 Participants	853 participants n=5 Participants

PRIMARY outcome

Timeframe: From the date of the first randomization until the study data cut-off date, 07 February 2011 (approximately three years)

Population: Intent-to-treat population (ITT) - all participants who gave informed consent and were randomized.

Outcome measures

Outcome measures
Measure	Placebo/FOLFIRI n=460 Events (Death) Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks	Aflibercept/FOLFIRI n=403 Events (Death) Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Overall Survival (OS)	12.06 months Interval 6.83 to 21.03	13.50 months Interval 7.62 to 25.59

SECONDARY outcome

Timeframe: From the date of the first randomization until the occurrence of 561 OS events, 06 May 2010 (approximately 30 months)

Population: Intent to Treat (ITT) population included all participants who gave informed consent and were randomized.

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.

Outcome measures

Outcome measures
Measure	Placebo/FOLFIRI n=454 First PFS Events Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks	Aflibercept/FOLFIRI n=393 First PFS Events Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Progression-free Survival (PFS) Assessed by Independent Review Committee (IRC)	4.67 months Interval 2.6 to 9.1	6.90 months Interval 3.84 to 10.05

SECONDARY outcome

Timeframe: From the date of the first randomization until the study data cut-off date, 06 May 2010 (approximately 30 months)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo/FOLFIRI n=530 Participants Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks	Aflibercept/FOLFIRI n=531 Participants Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
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	11.1 percentage of participants Interval 8.5 to 13.8	19.8 percentage of participants Interval 16.4 to 23.2

SECONDARY outcome

Timeframe: From the date of the first randomization up to 30 days after the treatment discontinuation or until TEAE was resolved or stabilized

Population: 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).

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.

Outcome measures

Outcome measures
Measure	Placebo/FOLFIRI n=605 Participants Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks	Aflibercept/FOLFIRI n=611 Participants Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Number of Participants With Adverse Events (AE) Treatment-Emergent Adverse Event (TEAE)	592 participants	606 participants
Number of Participants With Adverse Events (AE) Serious TEAE	198 participants	294 participants
Number of Participants With Adverse Events (AE) TEAE leading to Death	29 participants	37 participants
Number of Participants With Adverse Events (AE) TEAE causing permanent treatment discontinuation	73 participants	164 participants

SECONDARY outcome

Timeframe: Baseline, every other treatment cycle, 30 days and 90 days after the last infusion of aflibercept/placebo

Population: Immunogenicity population included all participants who were treated and tested for immunogenicity at least once post-baseline.

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.

Outcome measures

Outcome measures
Measure	Placebo/FOLFIRI n=526 Participants Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks	Aflibercept/FOLFIRI n=521 Participants Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
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 At least one positive sample in the ADA assay	18 participants	8 participants
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 At least one positive sample in the NAb assay	2 participants	1 participants

Adverse Events

Placebo/FOLFIRI

Serious events: 198 serious events

Other events: 575 other events

Deaths: 0 deaths

Aflibercept/FOLFIRI

Serious events: 294 serious events

Other events: 599 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

International Clinical Development Study Director

sanofi-aventis

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee 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).
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo/FOLFIRI n=605 participants at risk Participants with Metastatic Colorectal Cancer administered Placebo followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks	Aflibercept/FOLFIRI n=611 participants at risk Participants with Metastatic Colorectal Cancer administered 4 mg/kg of Aflibercept, followed by FOLFIRI (Irinotecan, 5-Fluorouracil, and Leucovorin) every two weeks
Infections and infestations Urinary tract infection	5.8% 35/605 • From treatment initiation to 7 February, 2011	8.3% 51/611 • From treatment initiation to 7 February, 2011
Blood and lymphatic system disorders Neutropenia	33.4% 202/605 • From treatment initiation to 7 February, 2011	37.5% 229/611 • From treatment initiation to 7 February, 2011
Metabolism and nutrition disorders Decreased appetite	23.6% 143/605 • From treatment initiation to 7 February, 2011	31.9% 195/611 • From treatment initiation to 7 February, 2011
Metabolism and nutrition disorders Dehydration	2.0% 12/605 • From treatment initiation to 7 February, 2011	5.4% 33/611 • From treatment initiation to 7 February, 2011
Psychiatric disorders Insomnia	7.4% 45/605 • From treatment initiation to 7 February, 2011	7.7% 47/611 • From treatment initiation to 7 February, 2011
Nervous system disorders Headache	8.8% 53/605 • From treatment initiation to 7 February, 2011	22.3% 136/611 • From treatment initiation to 7 February, 2011
Nervous system disorders Dizziness	8.8% 53/605 • From treatment initiation to 7 February, 2011	5.9% 36/611 • From treatment initiation to 7 February, 2011
Nervous system disorders Dysgeusia	5.3% 32/605 • From treatment initiation to 7 February, 2011	6.9% 42/611 • From treatment initiation to 7 February, 2011
Nervous system disorders Neuropathy peripheral	5.0% 30/605 • From treatment initiation to 7 February, 2011	5.6% 34/611 • From treatment initiation to 7 February, 2011
Nervous system disorders Lethargy	4.6% 28/605 • From treatment initiation to 7 February, 2011	5.4% 33/611 • From treatment initiation to 7 February, 2011
Vascular disorders Hypertension	10.7% 65/605 • From treatment initiation to 7 February, 2011	40.9% 250/611 • From treatment initiation to 7 February, 2011
Respiratory, thoracic and mediastinal disorders Epistaxis	7.4% 45/605 • From treatment initiation to 7 February, 2011	27.5% 168/611 • From treatment initiation to 7 February, 2011
Respiratory, thoracic and mediastinal disorders Dysphonia	3.3% 20/605 • From treatment initiation to 7 February, 2011	25.4% 155/611 • From treatment initiation to 7 February, 2011
Respiratory, thoracic and mediastinal disorders Cough	9.6% 58/605 • From treatment initiation to 7 February, 2011	11.0% 67/611 • From treatment initiation to 7 February, 2011
Respiratory, thoracic and mediastinal disorders Dyspnoea	8.4% 51/605 • From treatment initiation to 7 February, 2011	11.3% 69/611 • From treatment initiation to 7 February, 2011
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	3.1% 19/605 • From treatment initiation to 7 February, 2011	7.4% 45/611 • From treatment initiation to 7 February, 2011
Respiratory, thoracic and mediastinal disorders Rhinorrhoea	1.8% 11/605 • From treatment initiation to 7 February, 2011	6.2% 38/611 • From treatment initiation to 7 February, 2011
Gastrointestinal disorders Diarrhoea	55.4% 335/605 • From treatment initiation to 7 February, 2011	67.3% 411/611 • From treatment initiation to 7 February, 2011
Gastrointestinal disorders Nausea	54.0% 327/605 • From treatment initiation to 7 February, 2011	52.7% 322/611 • From treatment initiation to 7 February, 2011
Gastrointestinal disorders Stomatitis	32.9% 199/605 • From treatment initiation to 7 February, 2011	49.8% 304/611 • From treatment initiation to 7 February, 2011
Gastrointestinal disorders Vomiting	32.9% 199/605 • From treatment initiation to 7 February, 2011	31.8% 194/611 • From treatment initiation to 7 February, 2011
Gastrointestinal disorders Abdominal pain	23.3% 141/605 • From treatment initiation to 7 February, 2011	25.9% 158/611 • From treatment initiation to 7 February, 2011
Gastrointestinal disorders Constipation	24.1% 146/605 • From treatment initiation to 7 February, 2011	22.1% 135/611 • From treatment initiation to 7 February, 2011
Gastrointestinal disorders Abdominal pain upper	7.6% 46/605 • From treatment initiation to 7 February, 2011	10.3% 63/611 • From treatment initiation to 7 February, 2011
Gastrointestinal disorders Dyspepsia	9.3% 56/605 • From treatment initiation to 7 February, 2011	8.2% 50/611 • From treatment initiation to 7 February, 2011
Gastrointestinal disorders Haemorrhoids	2.1% 13/605 • From treatment initiation to 7 February, 2011	5.6% 34/611 • From treatment initiation to 7 February, 2011
Gastrointestinal disorders Proctalgia	1.8% 11/605 • From treatment initiation to 7 February, 2011	5.2% 32/611 • From treatment initiation to 7 February, 2011
Skin and subcutaneous tissue disorders Alopecia	30.1% 182/605 • From treatment initiation to 7 February, 2011	26.8% 164/611 • From treatment initiation to 7 February, 2011
Skin and subcutaneous tissue disorders Palmar-plantar erythrodysaesthesia syndrome	4.3% 26/605 • From treatment initiation to 7 February, 2011	11.0% 67/611 • From treatment initiation to 7 February, 2011
Skin and subcutaneous tissue disorders Rash	5.8% 35/605 • From treatment initiation to 7 February, 2011	6.7% 41/611 • From treatment initiation to 7 February, 2011
Skin and subcutaneous tissue disorders Skin hyperpigmentation	2.8% 17/605 • From treatment initiation to 7 February, 2011	8.2% 50/611 • From treatment initiation to 7 February, 2011
Skin and subcutaneous tissue disorders Hyperhidrosis	5.5% 33/605 • From treatment initiation to 7 February, 2011	2.8% 17/611 • From treatment initiation to 7 February, 2011
Musculoskeletal and connective tissue disorders Back pain	11.4% 69/605 • From treatment initiation to 7 February, 2011	11.8% 72/611 • From treatment initiation to 7 February, 2011
Musculoskeletal and connective tissue disorders Arthralgia	6.6% 40/605 • From treatment initiation to 7 February, 2011	5.1% 31/611 • From treatment initiation to 7 February, 2011
Musculoskeletal and connective tissue disorders Pain in extremity	5.5% 33/605 • From treatment initiation to 7 February, 2011	5.6% 34/611 • From treatment initiation to 7 February, 2011
Renal and urinary disorders Proteinuria	1.5% 9/605 • From treatment initiation to 7 February, 2011	10.3% 63/611 • From treatment initiation to 7 February, 2011
General disorders Fatigue	38.7% 234/605 • From treatment initiation to 7 February, 2011	47.8% 292/611 • From treatment initiation to 7 February, 2011
General disorders Asthenia	12.7% 77/605 • From treatment initiation to 7 February, 2011	17.8% 109/611 • From treatment initiation to 7 February, 2011
General disorders Pyrexia	12.1% 73/605 • From treatment initiation to 7 February, 2011	12.6% 77/611 • From treatment initiation to 7 February, 2011
General disorders Oedema peripheral	6.9% 42/605 • From treatment initiation to 7 February, 2011	8.5% 52/611 • From treatment initiation to 7 February, 2011
Investigations Weight decreased	14.4% 87/605 • From treatment initiation to 7 February, 2011	31.9% 195/611 • From treatment initiation to 7 February, 2011