Study of the Effect of Intravenous AVE0005 (VEGF Trap) in Advanced Ovarian Cancer Patients With Recurrent Symptomatic Malignant Ascites

• ClinicalTrials.gov Identifier: NCT00327444
• Recruitment Status: Completed
• First Posted: May 18, 2006
• Results First Posted: January 1, 2013
• Last Update Posted: January 1, 2013
• Sponsor: Sanofi
• Collaborator: Regeneron Pharmaceuticals
• Information provided by (Responsible Party): Sanofi

Tracking Information

• First Submitted Date: May 16, 2006
• First Posted Date: May 18, 2006
• Results First Submitted Date: August 17, 2012
• Results First Posted Date: January 1, 2013
• Last Update Posted Date: January 1, 2013
• Study Start Date: July 2006
• Actual Primary Completion Date: October 2009 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 30, 2012)

Time to Repeat Paracentesis (TRP) [ Time Frame: 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.

• Original Primary Outcome Measures (submitted: May 16, 2006): Time to Repeat Paracentesis

Current Secondary Outcome Measures (submitted: November 30, 2012)

• Area Under the Curve (AUC) for Participant Assessed Ascites Impact Measure (AIM) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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.

• Original Secondary Outcome Measures (submitted: May 16, 2006): Ascites Impact Measure (patient questionnaire)60-Day Frequency of Paracentesis, Safety, tolerability, Tumor assessments, Quality of life
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of the Effect of Intravenous AVE0005 (VEGF Trap) in Advanced Ovarian Cancer Patients With Recurrent Symptomatic Malignant Ascites
• Official Title: A Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-arm Study of the Effect of Intravenous Aflibercept Administered Every 2 Weeks in Advanced Ovarian Cancer Patients With Recurrent Symptomatic Malignant Ascites

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

• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment

Condition

• Ovarian Neoplasms
• Ascites

Intervention

• Drug: aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
  4.0 mg/kg aflibercept was administered intravenously (IV) over 1 hour once every 2 weeks in the DB period.
• Drug: Placebo
  Placebo was administered intravenously (IV) over 1 hour once every 2 weeks in the DB period.
• Drug: aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
  4.0 mg/kg aflibercept was administered intravenously (IV) over 1 hour once every 2 weeks in the OL period.

Study Arms

• Placebo Comparator: Placebo

  Participants with advanced ovarian cancer administered placebo in the double-blind (DB) period.

  In the open-label (OL) period, participants had the option to receive aflibercept or be withdrawn from the study.

  Interventions:

  • Drug: Placebo
  • Drug: aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
• Experimental: Aflibercept

  Participants with advanced ovarian cancer administered aflibercept in the double-blind (DB) period.

  In the open-label (OL) period, participants had the option to continue to receive aflibercept or be withdrawn from the study.

  Interventions:

  • Drug: aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
  • Drug: aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)

• Publications *: Gotlieb WH, Amant F, Advani S, Goswami C, Hirte H, Provencher D, Somani N, Yamada SD, Tamby JF, Vergote I. Intravenous aflibercept for treatment of recurrent symptomatic malignant ascites in patients with advanced ovarian cancer: a phase 2, randomised, double-blind, placebo-controlled study. Lancet Oncol. 2012 Feb;13(2):154-62. doi: 10.1016/S1470-2045(11)70338-2. Epub 2011 Dec 20.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 3, 2010): 58
• Original Enrollment (submitted: May 16, 2006): 54
• Actual Study Completion Date: October 2009
• Actual Primary Completion Date: October 2009 (Final data collection date for primary outcome measure)

Eligibility 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.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Austria, Belgium, Canada, Hungary, India, Israel, Spain, United Kingdom, United States
• Removed Location Countries: Switzerland

Administrative Information

• NCT Number: NCT00327444
• Other Study ID Numbers: EFC6125; EudraCT : 2005-005026-31; AVE0005A /3001
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Sanofi
• Original Responsible Party: Not Provided
• Current Study Sponsor: Sanofi
• Original Study Sponsor: Same as current
• Collaborators: Regeneron Pharmaceuticals

Investigators

• Principal Investigator: Walter GOTLIEB; Director of Gynecologic Oncology and Colposcopy Associate Professor of Oncology, McGill University - Montreal - Quebec Canada

• PRS Account: Sanofi
• Verification Date: July 2011