Trial Outcomes & Findings for Aflibercept Compared to Placebo in Term of Efficacy in Patients Treated With Gemcitabine for Metastatic Pancreatic Cancer (NCT NCT00574275)

Last Updated: 2016-06-07

Results Overview

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.

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

546 participants

Primary outcome timeframe

From the first randomization until the end of study data cutoff date (approximately 2 years)

Results posted on

2016-06-07

Participant Flow

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.

Participant milestones

Participant milestones
Measure	Placebo and Gemcitabine * 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 and Gemcitabine * 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 Study STARTED	275	271
Overall Study TREATED	273	268
Overall Study SAFETY POPULATION	271	270
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	275	271

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo and Gemcitabine * 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 and Gemcitabine * 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 Study Randomized but not treated	2	3
Overall Study Adverse Event	32	76
Overall Study Disease progression	160	146
Overall Study Lost to Follow-up	2	1
Overall Study Study stopped based on DMC decision	62	23
Overall Study Withdrawal by Subject	15	17
Overall Study Error calculating tumor measurement	1	0
Overall Study Physician Decision	1	1
Overall Study Protocol Violation	0	1
Overall Study Patient and Investigator decision	0	1
Overall Study Insurance change	0	1
Overall Study Operation for curative intent	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo/Gemcitabine n=275 Participants * 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/Gemcitabine n=271 Participants * 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 n=546 Participants Total of all reporting groups
Age, Continuous	60.4 Years STANDARD_DEVIATION 10.0 • n=93 Participants	62.0 Years STANDARD_DEVIATION 9.4 • n=4 Participants	61.2 Years STANDARD_DEVIATION 9.7 • n=27 Participants
Age, Customized <65 years	179 participants n=93 Participants	161 participants n=4 Participants	340 participants n=27 Participants
Age, Customized >=65 but <75 years	77 participants n=93 Participants	90 participants n=4 Participants	167 participants n=27 Participants
Age, Customized >=75 years	19 participants n=93 Participants	20 participants n=4 Participants	39 participants n=27 Participants
Sex/Gender, Customized Male	157 participants n=93 Participants	160 participants n=4 Participants	317 participants n=27 Participants
Sex/Gender, Customized Female	118 participants n=93 Participants	111 participants n=4 Participants	229 participants n=27 Participants
Race/Ethnicity, Customized Caucasian/White	267 participants n=93 Participants	256 participants n=4 Participants	523 participants n=27 Participants
Race/Ethnicity, Customized Black	2 participants n=93 Participants	3 participants n=4 Participants	5 participants n=27 Participants
Race/Ethnicity, Customized Asian/Oriental	3 participants n=93 Participants	7 participants n=4 Participants	10 participants n=27 Participants
Race/Ethnicity, Customized Other	3 participants n=93 Participants	5 participants n=4 Participants	8 participants n=27 Participants
Region of Enrollment ARGENTINA	3 participants n=93 Participants	0 participants n=4 Participants	3 participants n=27 Participants
Region of Enrollment AUSTRIA	6 participants n=93 Participants	2 participants n=4 Participants	8 participants n=27 Participants
Region of Enrollment BELGIUM	18 participants n=93 Participants	16 participants n=4 Participants	34 participants n=27 Participants
Region of Enrollment BULGARIA	12 participants n=93 Participants	11 participants n=4 Participants	23 participants n=27 Participants
Region of Enrollment CANADA	15 participants n=93 Participants	16 participants n=4 Participants	31 participants n=27 Participants
Region of Enrollment CHILE	8 participants n=93 Participants	8 participants n=4 Participants	16 participants n=27 Participants
Region of Enrollment CYPRUS	3 participants n=93 Participants	3 participants n=4 Participants	6 participants n=27 Participants
Region of Enrollment CZECH REPUBLIC	10 participants n=93 Participants	14 participants n=4 Participants	24 participants n=27 Participants
Region of Enrollment FRANCE	11 participants n=93 Participants	13 participants n=4 Participants	24 participants n=27 Participants
Region of Enrollment GERMANY	15 participants n=93 Participants	10 participants n=4 Participants	25 participants n=27 Participants
Region of Enrollment GREECE	5 participants n=93 Participants	7 participants n=4 Participants	12 participants n=27 Participants
Region of Enrollment HUNGARY	7 participants n=93 Participants	10 participants n=4 Participants	17 participants n=27 Participants
Region of Enrollment INDIA	3 participants n=93 Participants	3 participants n=4 Participants	6 participants n=27 Participants
Region of Enrollment ITALY	17 participants n=93 Participants	24 participants n=4 Participants	41 participants n=27 Participants
Region of Enrollment MEXICO	1 participants n=93 Participants	2 participants n=4 Participants	3 participants n=27 Participants
Region of Enrollment POLAND	12 participants n=93 Participants	11 participants n=4 Participants	23 participants n=27 Participants
Region of Enrollment PUERTO RICO	1 participants n=93 Participants	0 participants n=4 Participants	1 participants n=27 Participants
Region of Enrollment ROMANIA	13 participants n=93 Participants	8 participants n=4 Participants	21 participants n=27 Participants
Region of Enrollment RUSSIAN FEDERATION	19 participants n=93 Participants	19 participants n=4 Participants	38 participants n=27 Participants
Region of Enrollment SLOVAKIA	5 participants n=93 Participants	3 participants n=4 Participants	8 participants n=27 Participants
Region of Enrollment SPAIN	13 participants n=93 Participants	14 participants n=4 Participants	27 participants n=27 Participants
Region of Enrollment SWITZERLAND	8 participants n=93 Participants	9 participants n=4 Participants	17 participants n=27 Participants
Region of Enrollment UNITED STATES	70 participants n=93 Participants	68 participants n=4 Participants	138 participants n=27 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Score Participants with ECOG Score = 0	102 participants n=93 Participants	102 participants n=4 Participants	204 participants n=27 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Score Participants with ECOG Score = 1	154 participants n=93 Participants	152 participants n=4 Participants	306 participants n=27 Participants
Eastern Cooperative Oncology Group (ECOG) Performance Status Score Participants with ECOG Score = 2	19 participants n=93 Participants	17 participants n=4 Participants	36 participants n=27 Participants
Primary tumor resection Yes	40 participants n=93 Participants	39 participants n=4 Participants	79 participants n=27 Participants
Primary tumor resection No	235 participants n=93 Participants	232 participants n=4 Participants	467 participants n=27 Participants

PRIMARY outcome

Timeframe: From the first randomization until the end of study data cutoff date (approximately 2 years)

Population: Intent-to-treat (ITT) population, which included all randomized participants.

Outcome measures

Outcome measures
Measure	Placebo and Gemcitabine n=142 OS Event (Death) * 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 and Gemcitabine n=142 OS Event (Death) * 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 Survival (OS)	7.75 months Interval 6.768 to 8.575	6.54 months Interval 5.552 to 7.852

SECONDARY outcome

Timeframe: From the first randomization until the end of study data cutoff date (approximately 2 years)

Population: Intent-to-treat (ITT) population, which included all randomized participants.

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.

Outcome measures

Outcome measures
Measure	Placebo and Gemcitabine n=189 PFS Events * 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 and Gemcitabine n=182 PFS Events * 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.
Progression Free Survival (PFS) Based on Response Evaluation Criteria in Solid Tumors [RECIST] Criteria	3.71 months Interval 3.515 to 4.567	3.71 months Interval 3.45 to 4.468

SECONDARY outcome

Timeframe: From the first randomization until the end of the study data cutoff date (approximately 2 years)

Population: Since the study was terminated due to futility, this analysis was not performed.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: From the first randomization until the end of the study data cutoff date (approximately 2 years)

Population: Since the study was terminated due to futility, analysis for this endpoint was not performed.

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.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: up to 30 days after treatment discontinuation. SAEs and related AEs were followed till resolved or stabilized.

Population: 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.

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.

Outcome measures

Outcome measures
Measure	Placebo and Gemcitabine n=271 Participants * 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 and Gemcitabine n=270 Participants * 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.
Safety-Number of Participants With Adverse Events (AE) Treatment Emergent Adverse Event (TEAE)	257 participants	266 participants
Safety-Number of Participants With Adverse Events (AE) Treatment Emergent Serious Adverse Event	122 participants	148 participants
Safety-Number of Participants With Adverse Events (AE) TEAE leading to death	43 participants	55 participants
Safety-Number of Participants With Adverse Events (AE) TEAE leading to permanent discontinuation	32 participants	76 participants

SECONDARY outcome

Timeframe: Up to 90 days post last dose of study drug

Population: Safety population with samples available for analysis

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.

Outcome measures

Outcome measures
Measure	Placebo and Gemcitabine n=202 Participants * 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 and Gemcitabine n=201 Participants * 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.
Number of Participants With Anti-drug Antibodies	5 participants	5 participants

Adverse Events

Placebo and Gemcitabine

Serious events: 122 serious events

Other events: 239 other events

Deaths: 0 deaths

Aflibercept and Gemcitabine

Serious events: 148 serious events

Other events: 249 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

International Clinical Development Study Director

Sanofi

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 and Gemcitabine n=271 participants at risk * 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 and Gemcitabine n=270 participants at risk * 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.
Infections and infestations Urinary tract infection	6.3% 17/271 • From treatment initiation up to November 26, 2010	5.9% 16/270 • From treatment initiation up to November 26, 2010
Blood and lymphatic system disorders Neutropenia	26.2% 71/271 • From treatment initiation up to November 26, 2010	31.5% 85/270 • From treatment initiation up to November 26, 2010
Blood and lymphatic system disorders Thrombocytopenia	6.3% 17/271 • From treatment initiation up to November 26, 2010	17.4% 47/270 • From treatment initiation up to November 26, 2010
Metabolism and nutrition disorders Decreased appetite	26.6% 72/271 • From treatment initiation up to November 26, 2010	28.9% 78/270 • From treatment initiation up to November 26, 2010
Psychiatric disorders Insomnia	6.6% 18/271 • From treatment initiation up to November 26, 2010	10.4% 28/270 • From treatment initiation up to November 26, 2010
Psychiatric disorders Depression	3.0% 8/271 • From treatment initiation up to November 26, 2010	7.0% 19/270 • From treatment initiation up to November 26, 2010
Psychiatric disorders Anxiety	4.8% 13/271 • From treatment initiation up to November 26, 2010	5.9% 16/270 • From treatment initiation up to November 26, 2010
Nervous system disorders Headache	7.0% 19/271 • From treatment initiation up to November 26, 2010	18.9% 51/270 • From treatment initiation up to November 26, 2010
Nervous system disorders Dysgeusia	3.0% 8/271 • From treatment initiation up to November 26, 2010	5.6% 15/270 • From treatment initiation up to November 26, 2010
Vascular disorders Hypertension	6.3% 17/271 • From treatment initiation up to November 26, 2010	35.6% 96/270 • From treatment initiation up to November 26, 2010
Vascular disorders Deep vein thrombosis	5.9% 16/271 • From treatment initiation up to November 26, 2010	3.3% 9/270 • From treatment initiation up to November 26, 2010
Respiratory, thoracic and mediastinal disorders Dysphonia	2.2% 6/271 • From treatment initiation up to November 26, 2010	14.8% 40/270 • From treatment initiation up to November 26, 2010
Respiratory, thoracic and mediastinal disorders Epistaxis	1.8% 5/271 • From treatment initiation up to November 26, 2010	13.7% 37/270 • From treatment initiation up to November 26, 2010
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.9% 16/271 • From treatment initiation up to November 26, 2010	9.6% 26/270 • From treatment initiation up to November 26, 2010
Respiratory, thoracic and mediastinal disorders Cough	5.2% 14/271 • From treatment initiation up to November 26, 2010	5.2% 14/270 • From treatment initiation up to November 26, 2010
Gastrointestinal disorders Nausea	45.8% 124/271 • From treatment initiation up to November 26, 2010	37.8% 102/270 • From treatment initiation up to November 26, 2010
Gastrointestinal disorders Vomiting	28.4% 77/271 • From treatment initiation up to November 26, 2010	30.4% 82/270 • From treatment initiation up to November 26, 2010
Gastrointestinal disorders Diarrhoea	21.0% 57/271 • From treatment initiation up to November 26, 2010	24.1% 65/270 • From treatment initiation up to November 26, 2010
Gastrointestinal disorders Constipation	26.9% 73/271 • From treatment initiation up to November 26, 2010	23.7% 64/270 • From treatment initiation up to November 26, 2010
Gastrointestinal disorders Abdominal pain	22.5% 61/271 • From treatment initiation up to November 26, 2010	20.0% 54/270 • From treatment initiation up to November 26, 2010
Gastrointestinal disorders Stomatitis	5.9% 16/271 • From treatment initiation up to November 26, 2010	15.9% 43/270 • From treatment initiation up to November 26, 2010
Gastrointestinal disorders Abdominal pain upper	10.3% 28/271 • From treatment initiation up to November 26, 2010	12.2% 33/270 • From treatment initiation up to November 26, 2010
Skin and subcutaneous tissue disorders Rash	7.0% 19/271 • From treatment initiation up to November 26, 2010	6.3% 17/270 • From treatment initiation up to November 26, 2010
Musculoskeletal and connective tissue disorders Back pain	8.5% 23/271 • From treatment initiation up to November 26, 2010	10.0% 27/270 • From treatment initiation up to November 26, 2010
Musculoskeletal and connective tissue disorders Arthralgia	3.7% 10/271 • From treatment initiation up to November 26, 2010	5.6% 15/270 • From treatment initiation up to November 26, 2010
Musculoskeletal and connective tissue disorders Pain in extremity	1.5% 4/271 • From treatment initiation up to November 26, 2010	5.2% 14/270 • From treatment initiation up to November 26, 2010
Renal and urinary disorders Proteinuria	2.2% 6/271 • From treatment initiation up to November 26, 2010	11.1% 30/270 • From treatment initiation up to November 26, 2010
General disorders Fatigue	38.0% 103/271 • From treatment initiation up to November 26, 2010	35.9% 97/270 • From treatment initiation up to November 26, 2010
General disorders Pyrexia	17.3% 47/271 • From treatment initiation up to November 26, 2010	18.9% 51/270 • From treatment initiation up to November 26, 2010
General disorders Asthenia	15.5% 42/271 • From treatment initiation up to November 26, 2010	18.9% 51/270 • From treatment initiation up to November 26, 2010
General disorders Oedema peripheral	15.9% 43/271 • From treatment initiation up to November 26, 2010	12.2% 33/270 • From treatment initiation up to November 26, 2010
Investigations Weight decreased	15.9% 43/271 • From treatment initiation up to November 26, 2010	30.0% 81/270 • From treatment initiation up to November 26, 2010