Pancreatic Neoplasm
Conditions
Keywords
metastatic pancreatic cancer, angiogenesis inhibitor, gemcitabine
Brief summary
The main objective of the study was to evaluate the effectiveness of aflibercept treatment by comparison to placebo in increasing the overall survival (OS) in participants with metastatic pancreatic cancer, treated with gemcitabine. The secondary objectives were to evaluate progression free survival, clinical benefit, overall response, safety and immunogenicity of aflibercept, in the two treatment arms (Arm 1: Aflibercept and Gemcitabine; Arm 2: Placebo and Gemcitabine). The study included an interim analysis of OS. In accordance with the study protocol, an interim analysis was performed for the purpose of futility and overwhelming efficacy. On the basis of the interim analysis, the Data Monitoring Committee (DMC) recommended that this study be terminated for futility based on predefined boundary rules.
Detailed description
The study included: * A screening visit of up to 21 days prior to randomization * Randomization at baseline * A Treatment period (initiated within 3 days of randomization), which included 28-day treatment cycles in both arms until predefined treatment discontinuation criteria were met * A follow-up visit 30 days after discontinuation of treatment, * A post study treatment follow-up period until death or the study cutoff date. The criteria for treatment discontinuation were: * Participant (or legal representative) chose to withdraw from treatment * The investigator thought that continuation of the study would be detrimental to the participants well-being, such as: * Disease progression * Unacceptable AEs not manageable by symptomatic therapy, dose delay, or dose modification * Intercurrent illness that prevented further administration of study treatment * Noncompliance with the study protocol * Participant was lost to follow-up * Unblinding of the participant's investigational treatment
Interventions
4 mg/kg was administered intravenously (IV) over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle.
DRUGPlacebo
4 mg/kg was administered intravenously (IV) over 1 hour once every 2 weeks, on Days 1 and 15 of each 28-day cycle
DRUGGemcitabine
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.
Sponsors
Regeneron Pharmaceuticals
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Cytologically or histologically confirmed evidence of epithelial cancer (adenocarcinoma) of the exocrine pancreas * Metastatic disease * No prior chemotherapy for pancreatic disease * Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2 * Adequate renal, liver and bone marrow functions
Exclusion criteria
* Less than 42 days elapsed from prior major surgery (28 days from other prior surgery) to the time of randomization * Prior treatment with anti-VEGF or VEGF-Receptor-inhibitors * Uncontrolled hypertension * Pregnancy or breastfeeding * Participant with reproductive potential (M/F) without effective method of contraception The above information is not intended to contain all considerations relevant to potential participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | From the first randomization until the end of study data cutoff date (approximately 2 years) | OS is the time interval from the date of randomization to the date of death due to any cause. If death was not observed during the study, data on OS were censored at the earlier of the last date participant was known to be alive, or the study data cutoff date (11 September 2009). OS time was estimated from Kaplan-Meier Plots. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Progression Free Survival (PFS) Based on Response Evaluation Criteria in Solid Tumors [RECIST] Criteria | From the first randomization until the end of study data cutoff date (approximately 2 years) | PFS was the time interval from the date of registration to the date of progression, or death from any cause if it occurs before tumor progression is documented. Tumor progression was assessed using RECIST criteria, by which progression was a pre-defined increase in the size of existing tumors or appearance of one or more new tumors. If a participant did not progress or die, the progression was censored to the date of the last valid tumor assessment or data cut-off, whichever was earlier. Median PFS time was estimated from Kaplan-Meier Plots. |
| Objective Response Rate (ORR) Assessed by the Investigators According to RECIST Criteria | From the first randomization until the end of the study data cutoff date (approximately 2 years) | Objective response (OR) included complete response \[CR\] and partial response \[PR\]. OR was to be assessed by the Investigators according to RECIST criteria, and confirmed by repeating tumor imaging at least 4 weeks after the first radiological documentation of response. CR would reflect the disappearance of all tumor lesions and PR would reflect a defined reduction of tumor burden. However, OR analysis was not performed, as the study was terminated due to futility. |
| Clinical Benefit | From the first randomization until the end of the study data cutoff date (approximately 2 years) | Clinical benefit was to be assessed in all participants by time to symptom worsening (TTSW), evaluated from the time of randomization to symptom worsening, as well as by improvement in tumor related symptoms. However, this analysis was not performed, as the study was terminated due to futility. |
| Safety-Number of Participants With Adverse Events (AE) | up to 30 days after treatment discontinuation. SAEs and related AEs were followed till resolved or stabilized. | All AEs regardless of seriousness or relationship to study treatment, spanning from the signature of informed consent until 30 days after the last administration of study treatment, were recorded. The number of participants with all treatment emergent adverse events (TEAE), serious adverse events (SAE), TEAE leading to death, and TEAE leading to permanent treatment discontinuation are reported. |
| Number of Participants With Anti-drug Antibodies | Up to 90 days post last dose of study drug | Anti-drug antibodies in the participants blood sample were detected using a validated immunoassay. The validated lower limit of detection (LLOD) for the assay was about 5.4 ng/mL in the absence of aflibercept and about 25.2 ng/mL in the presence of 20 μg/mL of aflibercept. |
Countries
Argentina, Austria, Belgium, Bulgaria, Canada, Chile, Colombia, Cyprus, Czechia, France, Germany, Greece, Hungary, India, Italy, Mexico, Poland, Puerto Rico, Romania, Russia, Slovakia, Spain, Switzerland, United States
Participant flow
Recruitment details
Between December 2007 and September 2009, a total of 546 participants were randomized in the study: 275 to the placebo group and 271 to the aflibercept group. On the basis of the interim analysis, the Data Monitoring Committee (DMC) recommended that this study be terminated for futility based on predefined boundary rules.
Participants by arm
| Arm | Count |
|---|---|
| Placebo/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. | 275 |
| Aflibercept/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. | 271 |
| Total | 546 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 32 | 76 |
| Overall Study | Disease progression | 160 | 146 |
| Overall Study | Error calculating tumor measurement | 1 | 0 |
| Overall Study | Insurance change | 0 | 1 |
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Operation for curative intent | 0 | 1 |
| Overall Study | Patient and Investigator decision | 0 | 1 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Violation | 0 | 1 |
| Overall Study | Randomized but not treated | 2 | 3 |
| Overall Study | Study stopped based on DMC decision | 62 | 23 |
| Overall Study | Withdrawal by Subject | 15 | 17 |
Baseline characteristics
| Characteristic | Aflibercept/Gemcitabine | Total | Placebo/Gemcitabine |
|---|---|---|---|
| Age, Continuous | 62.0 Years STANDARD_DEVIATION 9.4 | 61.2 Years STANDARD_DEVIATION 9.7 | 60.4 Years STANDARD_DEVIATION 10 |
| Age, Customized >=65 but <75 years | 90 participants | 167 participants | 77 participants |
| Age, Customized <65 years | 161 participants | 340 participants | 179 participants |
| Age, Customized >=75 years | 20 participants | 39 participants | 19 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Score Participants with ECOG Score = 0 | 102 participants | 204 participants | 102 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Score Participants with ECOG Score = 1 | 152 participants | 306 participants | 154 participants |
| Eastern Cooperative Oncology Group (ECOG) Performance Status Score Participants with ECOG Score = 2 | 17 participants | 36 participants | 19 participants |
| Primary tumor resection No | 232 participants | 467 participants | 235 participants |
| Primary tumor resection Yes | 39 participants | 79 participants | 40 participants |
| Race/Ethnicity, Customized Asian/Oriental | 7 participants | 10 participants | 3 participants |
| Race/Ethnicity, Customized Black | 3 participants | 5 participants | 2 participants |
| Race/Ethnicity, Customized Caucasian/White | 256 participants | 523 participants | 267 participants |
| Race/Ethnicity, Customized Other | 5 participants | 8 participants | 3 participants |
| Region of Enrollment ARGENTINA | 0 participants | 3 participants | 3 participants |
| Region of Enrollment AUSTRIA | 2 participants | 8 participants | 6 participants |
| Region of Enrollment BELGIUM | 16 participants | 34 participants | 18 participants |
| Region of Enrollment BULGARIA | 11 participants | 23 participants | 12 participants |
| Region of Enrollment CANADA | 16 participants | 31 participants | 15 participants |
| Region of Enrollment CHILE | 8 participants | 16 participants | 8 participants |
| Region of Enrollment CYPRUS | 3 participants | 6 participants | 3 participants |
| Region of Enrollment CZECH REPUBLIC | 14 participants | 24 participants | 10 participants |
| Region of Enrollment FRANCE | 13 participants | 24 participants | 11 participants |
| Region of Enrollment GERMANY | 10 participants | 25 participants | 15 participants |
| Region of Enrollment GREECE | 7 participants | 12 participants | 5 participants |
| Region of Enrollment HUNGARY | 10 participants | 17 participants | 7 participants |
| Region of Enrollment INDIA | 3 participants | 6 participants | 3 participants |
| Region of Enrollment ITALY | 24 participants | 41 participants | 17 participants |
| Region of Enrollment MEXICO | 2 participants | 3 participants | 1 participants |
| Region of Enrollment POLAND | 11 participants | 23 participants | 12 participants |
| Region of Enrollment PUERTO RICO | 0 participants | 1 participants | 1 participants |
| Region of Enrollment ROMANIA | 8 participants | 21 participants | 13 participants |
| Region of Enrollment RUSSIAN FEDERATION | 19 participants | 38 participants | 19 participants |
| Region of Enrollment SLOVAKIA | 3 participants | 8 participants | 5 participants |
| Region of Enrollment SPAIN | 14 participants | 27 participants | 13 participants |
| Region of Enrollment SWITZERLAND | 9 participants | 17 participants | 8 participants |
| Region of Enrollment UNITED STATES | 68 participants | 138 participants | 70 participants |
| Sex/Gender, Customized Female | 111 participants | 229 participants | 118 participants |
| Sex/Gender, Customized Male | 160 participants | 317 participants | 157 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 239 / 271 | 249 / 270 |
| serious Total, serious adverse events | 122 / 271 | 148 / 270 |
Outcome results
Primary
Overall Survival (OS)
OS is the time interval from the date of randomization to the date of death due to any cause. If death was not observed during the study, data on OS were censored at the earlier of the last date participant was known to be alive, or the study data cutoff date (11 September 2009). OS time was estimated from Kaplan-Meier Plots.
Time frame: From the first randomization until the end of study data cutoff date (approximately 2 years)
Population: Intent-to-treat (ITT) population, which included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo and Gemcitabine | Overall Survival (OS) | 7.75 months |
| Aflibercept and Gemcitabine | Overall Survival (OS) | 6.54 months |
Secondary
Clinical Benefit
Clinical benefit was to be assessed in all participants by time to symptom worsening (TTSW), evaluated from the time of randomization to symptom worsening, as well as by improvement in tumor related symptoms. However, this analysis was not performed, as the study was terminated due to futility.
Time frame: From the first randomization until the end of the study data cutoff date (approximately 2 years)
Population: Since the study was terminated due to futility, analysis for this endpoint was not performed.
Secondary
Number of Participants With Anti-drug Antibodies
Anti-drug antibodies in the participants blood sample were detected using a validated immunoassay. The validated lower limit of detection (LLOD) for the assay was about 5.4 ng/mL in the absence of aflibercept and about 25.2 ng/mL in the presence of 20 μg/mL of aflibercept.
Time frame: Up to 90 days post last dose of study drug
Population: Safety population with samples available for analysis
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo and Gemcitabine | Number of Participants With Anti-drug Antibodies | 5 participants |
| Aflibercept and Gemcitabine | Number of Participants With Anti-drug Antibodies | 5 participants |
Secondary
Objective Response Rate (ORR) Assessed by the Investigators According to RECIST Criteria
Objective response (OR) included complete response \[CR\] and partial response \[PR\]. OR was to be assessed by the Investigators according to RECIST criteria, and confirmed by repeating tumor imaging at least 4 weeks after the first radiological documentation of response. CR would reflect the disappearance of all tumor lesions and PR would reflect a defined reduction of tumor burden. However, OR analysis was not performed, as the study was terminated due to futility.
Time frame: From the first randomization until the end of the study data cutoff date (approximately 2 years)
Population: Since the study was terminated due to futility, this analysis was not performed.
Secondary
Progression Free Survival (PFS) Based on Response Evaluation Criteria in Solid Tumors [RECIST] Criteria
PFS was the time interval from the date of registration to the date of progression, or death from any cause if it occurs before tumor progression is documented. Tumor progression was assessed using RECIST criteria, by which progression was a pre-defined increase in the size of existing tumors or appearance of one or more new tumors. If a participant did not progress or die, the progression was censored to the date of the last valid tumor assessment or data cut-off, whichever was earlier. Median PFS time was estimated from Kaplan-Meier Plots.
Time frame: From the first randomization until the end of study data cutoff date (approximately 2 years)
Population: Intent-to-treat (ITT) population, which included all randomized participants.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo and Gemcitabine | Progression Free Survival (PFS) Based on Response Evaluation Criteria in Solid Tumors [RECIST] Criteria | 3.71 months |
| Aflibercept and Gemcitabine | Progression Free Survival (PFS) Based on Response Evaluation Criteria in Solid Tumors [RECIST] Criteria | 3.71 months |
Secondary
Safety-Number of Participants With Adverse Events (AE)
All AEs regardless of seriousness or relationship to study treatment, spanning from the signature of informed consent until 30 days after the last administration of study treatment, were recorded. The number of participants with all treatment emergent adverse events (TEAE), serious adverse events (SAE), TEAE leading to death, and TEAE leading to permanent treatment discontinuation are reported.
Time frame: up to 30 days after treatment discontinuation. SAEs and related AEs were followed till resolved or stabilized.
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.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo and Gemcitabine | Safety-Number of Participants With Adverse Events (AE) | TEAE leading to permanent discontinuation | 32 participants |
| Placebo and Gemcitabine | Safety-Number of Participants With Adverse Events (AE) | Treatment Emergent Adverse Event (TEAE) | 257 participants |
| Placebo and Gemcitabine | Safety-Number of Participants With Adverse Events (AE) | Treatment Emergent Serious Adverse Event | 122 participants |
| Placebo and Gemcitabine | Safety-Number of Participants With Adverse Events (AE) | TEAE leading to death | 43 participants |
| Aflibercept and Gemcitabine | Safety-Number of Participants With Adverse Events (AE) | TEAE leading to death | 55 participants |
| Aflibercept and Gemcitabine | Safety-Number of Participants With Adverse Events (AE) | TEAE leading to permanent discontinuation | 76 participants |
| Aflibercept and Gemcitabine | Safety-Number of Participants With Adverse Events (AE) | Treatment Emergent Serious Adverse Event | 148 participants |
| Aflibercept and Gemcitabine | Safety-Number of Participants With Adverse Events (AE) | Treatment Emergent Adverse Event (TEAE) | 266 participants |