Study of AVE0005 (VEGF Trap) in Patients With Chemoresistant Advanced Ovarian Cancer

Neoplasms Clinical Trial

Official title:

A Multicenter, Randomized, Double-blind, Parallel-arm, Two-stage Study of the Efficacy and Safety of AVE0005 (VEGF Trap) Administered Intravenously Every 2 Weeks in Patients With Platinum-resistant and topotecan-and/or Liposomal Doxorubicin-resistant Advanced Ovarian Cancer

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00327171
• Other study ID #: ARD6122
• Secondary ID: AVE0005
• Status: Completed
• Phase: Phase 2
• First received: May 16, 2006
• Last updated: September 17, 2012
• Start date: May 2006
• Est. completion date: March 2010

Study information

• Verified date: September 2011
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug AdministrationSpain: Ministry of HealthSweden: Medical Products Agency
• Study type: Interventional

Clinical Trial Summary

This study evaluated outcomes in participants with advanced ovarian epithelial adenocarcinoma receiving aflibercept.

The primary objective was to compare the objective response rate of Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®) 4.0 mg/kg and 2.0 mg/kg, administered intravenously (IV) every 2 weeks with historical control in participants with advanced ovarian epithelial (including fallopian tube and primary peritoneal) adenocarcinoma resistant to platinum and topotecan and/or liposomal doxorubicin.

The secondary objectives was to further assess efficacy, safety, pharmacokinetics, potential biological and pharmacogenomic markers of study drug activity, and health-related quality of life.

This study employed an Independent Review Committee (IRC) for radiological tumor assessments. For all tumor assessment-related efficacy variables, two analyses were performed: the primary analysis was based on Independent Review Committee (IRC) reviewed data and the secondary analysis was based on Investigator evaluation. If an endpoint was evaluated by the IRC, the IRC reviewed data is reported for this study.

Description:

The study included:

• A screening period for 21 days

• Randomization at baseline (Treatment was initiated with 5 days of randomization)

• A treatment period with 14-day study treatment cycles until a study withdrawal criterion was met

• A follow-up period up to 60 days after the end of treatment

Withdrawal criteria that led to treatment discontinuation were:

• The participant or their legally authorized representative requested to withdraw

• In the investigator's opinion, continuation of the study would be detrimental to the participant's well being, due to reasons such as disease progression, unacceptable toxicity, noncompliance, or logistical considerations.

• A specific request by the Sponsor

• Participant had intercurrent illness that prevented further administration of study treatment

• Participant had more than 2 aflibercept dose reductions

• Participant had arterial thromboembolic events, including cerebrovascular accidents, myocardial infarctions, transient ischemic attacks, new onset or worsening of pre-existing angina

• Participant had radiographic evidence of intestinal obstruction (e.g., dilated loops of bowel accompanied by air-fluid levels) or gastrointestinal perforation (e.g., presence of extraluminal gas) requiring surgical intervention

• Participant was lost to follow-up

After discontinuing treatment, participants remained on the study until the last post-treatment visit or until recovery of drug related toxicities, whichever was later.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 218
• Est. completion date: March 2010
• Est. primary completion date: April 2008
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

Participants who met the following criteria were eligible for the study.

Inclusion Criteria:

• Histologically-confirmed ovarian epithelial (including fallopian tube and primary peritoneal) adenocarcinoma.

• Prior treatment with at least 2 treatment regimens in the advanced disease treatment setting

• Platinum-resistant disease defined by relapse or progression of disease during or after treatment, or drug intolerance

• Topotecan- and/or liposomal doxorubicin-resistant disease defined by relapse or progression of disease during or after treatment, or drug intolerance

• Evidence of at least one unidimensional measurable tumor lesion by computed tomography (CT) or magnetic resonance imaging (MRI) scan according to Response Evaluation Criteria in Solid Tumors (RECIST) that has not been treated with surgery or radiation therapy

Exclusion Criteria:

• Diagnosis of any second malignancy within the last 5 years, except for adequately treated basal cell or squamous cell skin cancer, or for in situ carcinoma of the cervix uteri

• Prior treatment with a vascular endothelial growth factor (VEGF) or VEGF receptor inhibitor

• More than 3 chemotherapy regimens in the advanced disease treatment setting

• Uncontrolled hypertension

The above information is not intended to contain all considerations relevant to potential participation in a clinical trial.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Cancer of the Ovary
• Neoplasms
• Ovarian Neoplasms

Intervention

Drug:
• Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
Aflibercept 4.0 mg/kg administered intravenously (IV) over 1 hour once every 2 weeks. Aflibercept could be reduced by 1 dose level ( to 2.0 mg/kg) or 2 dose levels (to 1.0 mg/kg) in case of uncontrolled hypertension or urinary protein >3.5 g/24 hours. Intrapatient dose escalation was not to be permitted. Participants requiring more than 2 dose level reductions would be withdrawn from study treatment.
• Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)
Aflibercept 2.0 mg/kg administered intravenously (IV) over 1 hour once every 2 weeks. Aflibercept could be reduced by 1 dose level (to 1.0 mg/kg) or 2 dose levels (to 0.5 mg/kg) in case of uncontrolled hypertension or urinary protein >3.5 g/24 hours. Intrapatient dose escalation was not to be permitted. Participants requiring more than 2 dose level reductions would be withdrawn from study treatment.

Locations

Country	Name	City	State
Australia	Sanofi-Aventis Administrative Office	Macquarie Park
Canada	Sanofi-Aventis Administrative Office	Laval
France	Sanofi-Aventis Administrative Office	Paris
Germany	Sanofi-Aventis Administrative Office	Berlin
Italy	Sanofi-Aventis Administrative Office	Milano
Netherlands	Sanofi-Aventis Administrative Office	Gouda
Portugal	Sanofi-Aventis Administrative Office	Porto Salvo
Spain	Sanofi-Aventis Administrative Office	Barcelona
Sweden	Sanofi-Aventis Administrative Office	Bromma
Switzerland	Sanofi-Aventis Administrative Office	Geneva
United States	Sanofi-Aventis Administrative Office	Bridgewater	New Jersey

Sponsors (2)

Lead Sponsor	Collaborator
Sanofi	Regeneron Pharmaceuticals

Countries where clinical trial is conducted

United States,  Australia,  Canada,  France,  Germany,  Italy,  Netherlands,  Portugal,  Spain,  Sweden,  Switzerland, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Number of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Based on the Analysis by an Independent Review Committee (IRC) - Simon's Cohort	OR included Complete Response (CR) and Partial Response (PR). Per RECIST, CR was disappearance of all target or non-target lesions, or normalization of tumor marker levels (for non-target lesions) and PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, with baseline sum LD as reference.; Tumors were assessed by an independent third-party core imaging laboratory evaluating the chest, abdomen, and pelvis by Computerized Tomography (CT) scans or Magnetic Resonance Imaging (MRI) scans; and responses were confirmed by repeat tumor imaging 4-6 weeks later.	From enrollment to efficacy cut-off date, 18 January 2008 (approximately 20 months)	No
Primary	Number of Participants With Confirmed Objective Response (OR) as Per Response Evaluation Criteria in Solid Tumors (RECIST) Based on the Analysis by the IRC - Efficacy Evaluable Population	OR included Complete Response (CR) and Partial Response (PR). Per RECIST, CR was disappearance of all target or non-target lesions, or normalization of tumor marker levels (for non-target lesions) and PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, with baseline sum LD as reference.; Tumors were assessed by an independent third-party core imaging laboratory evaluating the chest, abdomen, and pelvis by Computerized Tomography (CT) scans or Magnetic Resonance Imaging (MRI) scans; and responses were confirmed by repeat tumor imaging 4-6 weeks later.	From enrollment to efficacy cut-off date, 18 January 2008 (approximately 20 months)	No
Secondary	Number of Participants With a Clinical Benefit Response (CBR) as Per RECIST Based on the Analysis by the IRC	CBR was defined as having a Stable disease (SD) for >= 6 months or a confirmed OR (PR or CR). Based on RECIST: SD was neither a sufficient shrinkage of the target lesions to qualify for PR nor sufficient increase to qualify for Progressive disease (PD), the persistence of non-target lesions or the maintenance of tumor marker level above the normal limits (for non-target lesions); CR was the disappearance of all target or non-target lesions; and PR was at least a 30% decrease in the sum of the longest diameter (LD) of target lesions, with reference to the baseline sum LD.	From enrollment to efficacy cut-off date, 18 January 2008 (approximately 20 months)	No
Secondary	Duration of Response (DR) Based on the Analysis by an Independent Review Committee (IRC)	DR was defined as the time interval from the first documentation of CR or PR to the date of tumor progression (or disease progression) as determined by RECIST, or death from any cause, whichever was earlier.; Based on RECIST, progressive disease was at least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started, the appearance of one or more new target or non-target lesions, or the unequivocal progression of existing non-target lesions.	From enrollment to efficacy cut-off date, 18 January 2008 (approximately 20 months)	No
Secondary	Tumor Marker Response Rate (TMRR) Based on the Gynecologic Cancer Intergroup (GCIG) Definition	TMRR was the proportion of evaluable participants achieving a cancer antigen -125 (CA-125) response based on GCIG definition. A response to CA-125 occurred if after two elevated levels before therapy there was at least a 50% decrease in a post-treatment serum sample, which was confirmed by an independent sample collected 21 days or later that was =< 110% of the post-treatment serum sample.	From enrollment to efficacy cut-off date, 18 January 2008 (approximately 20 months)	No
Secondary	Time to Tumor Progression (TTP) as Per RECIST Based on the Analysis by the IRC	TTP was defined as the time interval measured from the date of randomization to the date of tumor progression as determined by RECIST. TTP was estimated from Kaplan-Meier curves.; For a participant who did not reach tumor progression during study, the censoring date was the date of the last valid tumor burden assessment or the date of study cut-off, whichever was earlier. If the participant had no valid post-baseline tumor burden assessment due to early termination, the censoring date was the date of randomization.	From enrollment to efficacy cut-off date, 18 January 2008 (approximately 20 months)	No
Secondary	Time to Tumor Marker (CA-125) Progression (TTMP)	TTMP was the time interval from the date of randomization to the date of tumor marker progression as was defined by GCIG for the evaluable participants. TTMP was estimated using Kaplan-Meier curves.; For a participant who did not reach tumor marker progression (TMP) during study, the censoring date was the date of the last valid tumor burden assessment or the date of study cut-off, whichever was earlier. If the participant had no valid post-baseline tumor burden assessment due to early termination, the censoring date was the date of randomization.	From enrollment to efficacy cut-off date, 18 January 2008 (approximately 20 months)	No
Secondary	Number of Participants With Disease Progression Events for Progression-free Survival (PFS) Analysis by the IRC.	PFS was as the time interval measured from the date of randomization to the date of tumor progression as determined by RECIST or death from any cause, whichever was earlier.; The number of participants with tumor/disease progression are reported. Participants who did not reach tumor progression during study, or had no valid post-baseline tumor burden assessment due to early termination, were censored in the PFS analysis.	From enrollment to efficacy cut-off date, 18 January 2008 (approximately 20 months)	No
Secondary	Progression-free Survival (PFS) Time Based on Analysis by the IRC	PFS was as the time interval measured from the date of randomization to the date of tumor progression as determined by RECIST or death from any cause, whichever was earlier. PFS was estimated using Kaplan-Meier curves.; For a participant who did not reach tumor progression during study, the censoring date was the date of the last valid tumor burden assessment or the date of study cut-off, whichever was earlier. If the participant had no valid post-baseline tumor burden assessment due to early termination, the censoring date was the date of randomization.	From enrollment to efficacy cut-off date, 18 January 2008 (approximately 20 months)	No
Secondary	Overall Survival (OS) Time	OS was the time interval between randomization and the date of death from any cause. OS was estimated using Kaplan-Meier curves; A participant was censored for the OS analysis if the participant were alive during the study. The censoring date was either at the date that the participant was last known to be alive or the date of study cut-off, whichever was earlier.	From enrollment to efficacy cut-off date, 18 January 2008 (approximately 20 months)	No
Secondary	Overall Safety - Number of Participants With Adverse Events (AE)	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.	up to 30+/-5 days after treatment discontinuation, or up to recovery or stabilization of a followed-up adverse event	Yes
Secondary	Participant's Assessment of Health Related Quality of Life (HRQL) Using a by Using the Functional Assessment of Cancer Therapy-Ovarian (FACT-O) Questionnaire	The FACT-O questionnaire consists of 38 scored questions (scored from 0-4) that address physical well-being, social/family well-being, emotional well-being, functional well-being and some additional concerns which relate specifically to ovarian cancer symptoms. For each question, higher scores reflect a better quality of life. The total FACT-O score ranges from 0-152, with 152 indicating the best outcome.	On Day 1 of Cycle 1 (baseline) , and after Day 14 of Cycle 2	No