Ovarian Neoplasms, Ascites
Conditions
Keywords
Ovarian neoplasm, Ascites, Angiogenesis inhibitor, Vascular Endothelial Growth Factor A, Recombinant fusion protein
Brief summary
This study was designed to characterize the effect of aflibercept in participants with advanced chemoresistant ovarian cancer. Primary objective: Compare the effect of aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®) to placebo treatment on repeat paracentesis in symptomatic malignant ascites in participants with advanced ovarian cancer Secondary objectives: Safety, tolerability, paracentesis-related parameters, participant-reported outcome.
Detailed description
The study included: * A Thirty (30)-day screening phase * The double blind treatment period for a minimum of 60 days. Day 1 of the double-blind treatment period was defined as the date of the qualifying paracentesis (ie, withdrawal of \>= 1 Liter of ascitic fluid). Participants were randomized after adequate recovery from the qualifying paracentesis (The first dose was administered on Day 1 or Day 2). * The optional open-label extension (until treatment discontinuation criteria were met) * A posttreatment follow-up phase lasting 60 days. Criteria for discontinuation included: 1. Participant or his legally authorized representative request discontinuation 2. In the Investigator's opinion, continuation of treatment would be detrimental to the participant's well being, such as disease progression, unacceptable toxicity, noncompliance, or logistical considerations 3. Sponsor request 4. Intercurrent illness that prevented further administration of investigational product(IP) 5. More than 2 IP dose reductions 6. Unacceptable adverse events (AE) not manageable by symptomatic therapy, dose delay, or dose modification 7. Arterial thromboembolic events, including cerebrovascular accidents, myocardial infarctions, transient ischemic attacks, new onset or worsening of preexisting angina 8. Radiographic evidence of intestinal obstruction (for example, dilated loops of bowel accompanied by air-fluid levels) or gastrointestinal perforation (for example, presence of extraluminal gas) requiring surgical intervention
Interventions
4.0 mg/kg aflibercept was administered intravenously (IV) over 1 hour once every 2 weeks in the DB period.
DRUGPlacebo
Placebo was administered intravenously (IV) over 1 hour once every 2 weeks in the DB period.
Sponsors
Regeneron Pharmaceuticals
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Participants who met the following criteria were eligible to participate in this study. Inclusion Criteria: * Advanced ovarian epithelial cancer, treated with paracentesis * Platinum-resistant, and topotecan-resistant and/or liposomal doxorubicin-resistant disease; * Eastern Cooperative Oncology Group (ECOG) performance status =\< 2.
Exclusion criteria
* Pseudomyxoma peritonei or peritoneal mesothelioma; * Transudative ascites; * Peritoneovenous or other shunt placed for malignant ascites management; * Recent (\<6 months) cardiovascular event (pulmonary embolus, myocardial infarction, stroke) or gastrointestinal disease (ulcer, hepatic cirrhosis); * Known brain metastases; * Uncontrolled hypertension; * Recent treatment with chemotherapy, surgery or radiotherapy; * Prior treatment with VEGF or VEGFR inhibitor. The above information is not intended to contain all considerations relevant to participation in a clinical trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to Repeat Paracentesis (TRP) | From Day 1 up to 6 months from randomization | TRP was defined as the number of days between the date of randomization and the date of the first post-randomization paracentesis. For participants who did not undergo a postrandomization paracentesis on study, TRP was calculated from randomization to the end of the double-blind treatment period. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Curve (AUC) for Participant Assessed Ascites Impact Measure (AIM) | From Day 1 up to 60 days from randomization to the first postrandomization paracentesis | AIM 4 symptoms (abdominal discomfort, abdominal bloating, abdominal pain, and ability to move normally) are scored from 0 to 5, where higher scores represent worst outcomes. An AIM total score ranges from 0-20. A plot for (The AIM questionnaire total score - Baseline score) versus time were generated. AIM AUC represents the overall improvement (scored positive) if the area is below the baseline value or worsening (scored negative) if the area is above the baseline. AIM AUC for a participant is the sum of individual areas representing improvement (+) or worsening (-). |
| 60-Day Frequency of Paracentesis (FOP) | From Day 1 up to 60 days from randomization | 60-Day FOP was defined as the total number of paracenteses performed within the first 60 days after randomization during the double blind treatment period. |
| Plasma Levels of Free and VEGF-bound Aflibercept | Following every biweekly treatment administration up to 60 days after treatment discontinuation | Free aflibercept and VEGF-bound aflibercept plasma concentrations were measured by separate enzyme-linked immunosorbent assay (ELISA). The limit of quantitation of free aflibercept was 15.6 ng/mL, and of VEGF-bound aflibercept was 43.9 ng/mL. Peak free aflibercept was estimated at the end of Cycle 1 (C1) administration. The median free and VEGF-bound trough concentrations were determined for each participant beyond Cycle 3 (C3), then mean values were estimated from these median values. |
Countries
Austria, Belgium, Canada, Hungary, India, Israel, Spain, United Kingdom, United States
Participant flow
Recruitment details
Fifty-eight (58) participants from a total of 23 sites in 7 countries were enrolled in the study.
Pre-assignment details
55 were randomized (started population). 3 participants were not randomized but they were treated, and permanently withdrawn from the study due to disease progression (1 participant), fatal disease progression (1 participant) and a treatment emergent adverse event (1 participant).
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants with advanced ovarian cancer administered placebo intravenously, once every two weeks in the DB period and 4.0 mg/kg aflibercept intravenously, once every two weeks in the OL period. | 26 |
| Aflibercept Participants with advanced ovarian cancer administered 4.0 mg/kg aflibercept intravenously, once every two weeks in the DB period and the OL period. | 29 |
| Total | 55 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Double Blind Treatment (DB) Period | Adverse Event | 5 | 5 |
| Double Blind Treatment (DB) Period | Disease progression | 10 | 13 |
| Double Blind Treatment (DB) Period | Subject request | 0 | 1 |
| Double Blind Treatment (DB) Period | Withdrew DB and continued to OL | 11 | 10 |
| Open Label Treatment (OL) Period | Adverse Event | 2 | 2 |
| Open Label Treatment (OL) Period | Disease progression | 8 | 7 |
| Open Label Treatment (OL) Period | Ongoing Treatment | 1 | 0 |
| Open Label Treatment (OL) Period | Worsening dyspnea | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | Aflibercept | Total |
|---|---|---|---|
| Age, Customized >=35 to <45 years | 5 participants | 1 participants | 6 participants |
| Age, Customized < 35 years | 0 participants | 1 participants | 1 participants |
| Age, Customized >=45 to <55 years | 10 participants | 7 participants | 17 participants |
| Age, Customized >=55 to <65 years | 4 participants | 11 participants | 15 participants |
| Age, Customized >=65 to <75 years | 6 participants | 7 participants | 13 participants |
| Age, Customized >=75 years | 1 participants | 2 participants | 3 participants |
| Race/Ethnicity, Customized Asian, Oriental | 6 participants | 7 participants | 13 participants |
| Race/Ethnicity, Customized Black | 1 participants | 0 participants | 1 participants |
| Race/Ethnicity, Customized Caucasian | 19 participants | 22 participants | 41 participants |
| Sex: Female, Male Female | 26 Participants | 29 Participants | 55 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 25 | 28 / 30 |
| serious Total, serious adverse events | 18 / 25 | 27 / 30 |
Outcome results
Primary
Time to Repeat Paracentesis (TRP)
TRP was defined as the number of days between the date of randomization and the date of the first post-randomization paracentesis. For participants who did not undergo a postrandomization paracentesis on study, TRP was calculated from randomization to the end of the double-blind treatment period.
Time frame: From Day 1 up to 6 months from randomization
Population: The intent-to-treat (ITT) population - all participants who were randomized in the study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Time to Repeat Paracentesis (TRP) | 23.3 days | Standard Error 7.7 |
| Aflibercept | Time to Repeat Paracentesis (TRP) | 55.1 days | Standard Error 7.25 |
p-value: 0.001995% CI: [10.56, 53.05]ANOVA
Secondary
60-Day Frequency of Paracentesis (FOP)
60-Day FOP was defined as the total number of paracenteses performed within the first 60 days after randomization during the double blind treatment period.
Time frame: From Day 1 up to 60 days from randomization
Population: The intent-to-treat (ITT) population - all participants who were randomized in the study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | 60-Day Frequency of Paracentesis (FOP) | 5.1 paracentesis | Standard Error 0.69 |
| Aflibercept | 60-Day Frequency of Paracentesis (FOP) | 2.7 paracentesis | Standard Error 0.65 |
p-value: 0.003595% CI: [-4.33, -0.54]ANOVA
Secondary
Area Under the Curve (AUC) for Participant Assessed Ascites Impact Measure (AIM)
AIM 4 symptoms (abdominal discomfort, abdominal bloating, abdominal pain, and ability to move normally) are scored from 0 to 5, where higher scores represent worst outcomes. An AIM total score ranges from 0-20. A plot for (The AIM questionnaire total score - Baseline score) versus time were generated. AIM AUC represents the overall improvement (scored positive) if the area is below the baseline value or worsening (scored negative) if the area is above the baseline. AIM AUC for a participant is the sum of individual areas representing improvement (+) or worsening (-).
Time frame: From Day 1 up to 60 days from randomization to the first postrandomization paracentesis
Population: The intent-to-treat (ITT) population - all participants who were randomized in the study, and had evaluable AIM scores.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Area Under the Curve (AUC) for Participant Assessed Ascites Impact Measure (AIM) | 29.8 (units on a 4-symptom scale)*day | Standard Error 148.07 |
| Aflibercept | Area Under the Curve (AUC) for Participant Assessed Ascites Impact Measure (AIM) | 405.3 (units on a 4-symptom scale)*day | Standard Error 143.21 |
p-value: 0.01695% CI: [-46.48, 797.42]ANOVA
Secondary
Plasma Levels of Free and VEGF-bound Aflibercept
Free aflibercept and VEGF-bound aflibercept plasma concentrations were measured by separate enzyme-linked immunosorbent assay (ELISA). The limit of quantitation of free aflibercept was 15.6 ng/mL, and of VEGF-bound aflibercept was 43.9 ng/mL. Peak free aflibercept was estimated at the end of Cycle 1 (C1) administration. The median free and VEGF-bound trough concentrations were determined for each participant beyond Cycle 3 (C3), then mean values were estimated from these median values.
Time frame: Following every biweekly treatment administration up to 60 days after treatment discontinuation
Population: The analysis was performed using the safety population with evaluable blood samples. 42 participants were evaluated.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Placebo | Plasma Levels of Free and VEGF-bound Aflibercept | Peak Free Aflibercept (C1) (N=20, N=15) | 69.8 μg/mL | Standard Deviation 29.7 |
| Placebo | Plasma Levels of Free and VEGF-bound Aflibercept | Trough Free Aflibercept (Beyond C3) (N=15, N=19) | 5.33 μg/mL | Standard Deviation 3.67 |
| Placebo | Plasma Levels of Free and VEGF-bound Aflibercept | Trough Bound Aflibercept (Beyond C3) (N=16, N=17) | 3.02 μg/mL | Standard Deviation 1.29 |
| Aflibercept | Plasma Levels of Free and VEGF-bound Aflibercept | Peak Free Aflibercept (C1) (N=20, N=15) | 62.1 μg/mL | Standard Deviation 29.5 |
| Aflibercept | Plasma Levels of Free and VEGF-bound Aflibercept | Trough Free Aflibercept (Beyond C3) (N=15, N=19) | 5.10 μg/mL | Standard Deviation 5.29 |
| Aflibercept | Plasma Levels of Free and VEGF-bound Aflibercept | Trough Bound Aflibercept (Beyond C3) (N=16, N=17) | 3.49 μg/mL | Standard Deviation 1.48 |