AVE0005 (VEGF Trap) in Patients With Recurrent Symptomatic Malignant Ascites

• Sponsor: Sanofi (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00396591
• Collaborator: Regeneron Pharmaceuticals (Industry)
• Enrollment: 16
• Locations: 3
• Arm: 1
• Duration (Months): 25
• Patients Per Site: 5.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The primary objective of this study was to compare the time between paracenteses before and after administration of Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®) in ovarian cancer participants with symptomatic malignant ascites.

The secondary objectives were to further assess efficacy and safety of Aflibercept treatment, and the exploratory objectives were to assess pharmacokinetics, immunogenicity and health-related quality of life.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Neoplasms	Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®)	Phase 2

Detailed Description

The study consisted of:

• A 30-day screening phase prior to Day 1

• Day 1 registration and pre-treatment paracentesis

• Aflibercept administration within 1-day of registration

• Two-week study treatment cycles (for efficacy data, the cut-off date was 6 months post-registration

• A 60-day post-treatment follow-up phase

During the study, participants were treated with Aflibercept study treatment through the duration of the study unless they met one the following criteria for discontinuation:

• Participant (or legal representative) chose to withdraw from treatment

• The investigator or sponsor thought that continuation of the study would be detrimental to the participants well-being

• Participant had intercurrent illness that prevented further administration of investigational product (IP)

• Participant had more than 2 IP dose reductions

• Participant had unacceptable adverse events (AEs)

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

• Participant required surgical intervention for intestinal obstruction or gastrointestinal perforation

Study Design

• Study Type: Interventional
• Actual Enrollment: 16 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicenter, Open-label, Single-arm Study of the Efficacy and Safety of Intravenous AVE0005 (VEGF Trap) Administered Every 2 Weeks in Advanced Ovarian Cancer Patients With Recurrent Symptomatic Malignant Ascites
• Study Start Date: Oct 1, 2006
• Actual Primary Completion Date: Nov 1, 2008
• Actual Study Completion Date: Nov 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Aflibercept Participants with advanced ovarian epithelial cancer (including fallopian tube and primary peritoneal adenocarcinoma) treated with Aflibercept every 2 weeks until a criterion for treatment discontinuation was met	Drug: Aflibercept (ziv-aflibercept, AVE0005, VEGF trap, ZALTRAP®); 4.0 mg/kg administered intravenously (IV) once every 2 weeks

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With a Repeat Paracentesis Response (RPR) [up to 2 years post-registration]

   RPR was defined as at least a two-fold increase in the time to repeat paracentesis (TRP) as compared to the average duration of the 2 intervals between the 3 most recent paracenteses prior to study registration (ie, the baseline interval of paracentesis). Percentage of participants with a repeat paracentesis response were the number of participants with RPR / number of total participants * 100.

Secondary Outcome Measures

1. Time to Repeat Paracentesis (TRP) [up to 6 months from registration]

   TRP is the number of days between the date of registration and the date of the first postregistration paracentesis. Median TRP was estimated from Kaplan-Meier curves. For participants who did not undergo a postregistration paracentesis while on study, TRP was censored at the end of the treatment period (last dose + 1 cycle), at the last visit known without repeat paracentesis, at 6 months postregistration, or at death, whichever was earlier.

2. 60-day Frequency of Paracentesis (FOP) [up to 60 days post-registration]

   FOP was the total number of paracenteses performed within the first 60 days postregistration. For participants who had withdrawn after registration but prior to the 60-day cutoff date, the withdrawal would have been regarded as a paracentesis event and the 60-day FOP normalized and calculated as the nearest integer of the value corresponding to 60 × number of paracenteses / x, where x represents the number of days on study.

3. Progression-free Survival (PFS) Time [up to 6 months post-registration]

   According to the Response Evaluation Criteria in Solid Tumors [RECIST], progression was at least a 20% increase in the sum of the longest diameter (LD) of tumors, compared to smallest sum LD recorded since treatment started, or the appearance of one or more new tumors. PFS time was interval from the date of registration to the date of tumor progression or death from any cause, whichever was earlier. Median PFS time was estimated from Kaplan-Meier Plots. If participants were alive and progression-free at 6 months postregistration, they were censored for PFS.

4. Overall Survival (OS) Time [up to 6 months post-registration]

   OS time was the time interval between the date of registration to the date of death from any cause. Median OS was estimated from Kaplan-Meier curves. Participants who died after efficacy data cutoff date (6 months postregistration) were censored at the data cutoff date.

5. Number of Participants With a Positive Anti-drug Antibody Response [up to 60 days after the last dose of treatment]

   Anti-drug antibodies in participant's serum were measured using 2 different methods an Enzyme Linked Immunosorbent Assay (ELISA) in which the lower limit of detection (LLOD) was 238.4 ng/mL; and an Electrochemiluminescence-based, Bridging Assay in which the validated LLOD 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. Participants with detectable anti-drug antibodies by either method were considered to have a positive anti-drug antibody response.

6. Safety - Number of Participants With Adverse Events (AE) [up to 60 days after last dose of treatment (approximately 2 years), or until TEAE was resolved or stabilized]

   All AEs regardless of seriousness or relationship to study treatment, spanning from the first administration of study treatment until 60 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Participants that met the following criteria were eligible.

Inclusion Criteria:

• Symptomatic malignant ascites resulting from advanced ovarian epithelial cancer (including fallopian tube and primary peritoneal adenocarcinoma) that required at least 3 previous therapeutic paracenteses at a frequency of 1 to 4 paracenteses per month for management.

• 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.

Exclusion Criteria:

• Peritoneovenous or other type of shunt that was placed for the management of ascites

• Prior treatment with a VEGF or VEGF receptor inhibitor

• Uncontrolled hypertension

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sanofi-Aventis Administrative Office	Bridgewater	New Jersey	United States	08807
2	Sanofi-Aventis Administrative Office	Milano		Italy
3	Sanofi-Aventis Administrative Office	Bromma		Sweden

Sponsors and Collaborators

• Sanofi
• Regeneron Pharmaceuticals

Investigators

• Study Director: ICD, Sanofi

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Sanofi
• ClinicalTrials.gov Identifier: NCT00396591
• Other Study ID Numbers: ARD6772; EUDRACT: 2006-000604-16
• First Posted: Nov 7, 2006
• Last Update Posted: Jan 10, 2013
• Last Verified: Jul 1, 2011

• Keywords provided by Sanofi: Ovarian cancer; malignant ascites; angiogenesis; angiogenesis inhibition; VEGF-Trap fusion recombinant protein
• Additional relevant MeSH terms: Ovarian Neoplasms; Ascites; Aflibercept

Study Results

Participant Flow

Recruitment Details	17 participants were screened for this study, of which 16 participants were enrolled.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants with advanced ovarian epithelial cancer treated with 4.0 mg/kg Aflibercept every 2 weeks until a criterion for treatment discontinuation was met
Period Title: Overall Study
STARTED	16
COMPLETED	0
NOT COMPLETED	16

Baseline Characteristics

Arm/Group Title	Aflibercept
Arm/Group Description	Participants with advanced ovarian epithelial cancer treated with 4.0 mg/kg Aflibercept every 2 weeks until a criterion for treatment discontinuation was met
Overall Participants	16
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.3 (8.9)
Age, Customized (participants) [Number]
<65 years	11 68.8%
>=65 years	5 31.3%
Sex: Female, Male (Count of Participants)
Female	16 100%
Male	0 0%
Race/Ethnicity, Customized (Number) [Number]
Caucasian	16 100%
Primary tumor site - Ovaries (Number) [Number]
Number [Participants]	16 100%
Time since initial cancer diagnosis (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	2.8 (1.7)
Histology (Number) [Number]
Serous	9 56.3%
Endometrioid	3 18.8%
Clear cell (mesonephroid)	1 6.3%
Other	1 6.3%
Missing data	2 12.5%
Histology grade (Number) [Number]
Unknown	5 31.3%
Moderately differentiated	1 6.3%
Poorly differentiated	10 62.5%
Prior anticancer surgeries, (Number) [Number]
No	1 6.3%
Yes	15 93.8%
Baseline interval of paracentesis (days) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [days]	16.5 (7.8)
Eastern Cooperative Oncology Group (ECOG) performance status score (participants) [Number]
ECOG Score = 0	3 18.8%
ECOG Score = 1	10 62.5%
ECOG Score = 2	3 18.8%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With a Repeat Paracentesis Response (RPR)
Description	RPR was defined as at least a two-fold increase in the time to repeat paracentesis (TRP) as compared to the average duration of the 2 intervals between the 3 most recent paracenteses prior to study registration (ie, the baseline interval of paracentesis). Percentage of participants with a repeat paracentesis response were the number of participants with RPR / number of total participants * 100.
Time Frame	up to 2 years post-registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Participants with advanced ovarian epithelial cancer treated with 4.0 mg/kg Aflibercept every 2 weeks until a criterion for treatment discontinuation was met
Measure Participants	16
Number (95% Confidence Interval) [percentage of participants]	62.5 390.6%

2. Secondary Outcome

Title	Time to Repeat Paracentesis (TRP)
Description	TRP is the number of days between the date of registration and the date of the first postregistration paracentesis. Median TRP was estimated from Kaplan-Meier curves. For participants who did not undergo a postregistration paracentesis while on study, TRP was censored at the end of the treatment period (last dose + 1 cycle), at the last visit known without repeat paracentesis, at 6 months postregistration, or at death, whichever was earlier.
Time Frame	up to 6 months from registration

Outcome Measure Data

Analysis Population Description

All participants were analyzed. 8 had one or more paracentesis events. Participants with no paracentesis events were censored at the end of the treatment period (last dose + 1 cycle).

Arm/Group Title	Aflibercept
Arm/Group Description	Participants with advanced ovarian epithelial cancer treated with 4.0 mg/kg Aflibercept every 2 weeks until a criterion for treatment discontinuation was met
Measure Participants	16
Measure Paracentesis (>/= 1 per participant)	8
Median (95% Confidence Interval) [days]	76.0

3. Secondary Outcome

Title	60-day Frequency of Paracentesis (FOP)
Description	FOP was the total number of paracenteses performed within the first 60 days postregistration. For participants who had withdrawn after registration but prior to the 60-day cutoff date, the withdrawal would have been regarded as a paracentesis event and the 60-day FOP normalized and calculated as the nearest integer of the value corresponding to 60 × number of paracenteses / x, where x represents the number of days on study.
Time Frame	up to 60 days post-registration

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Aflibercept
Arm/Group Description	Participants with advanced ovarian epithelial cancer treated with 4.0 mg/kg Aflibercept every 2 weeks until a criterion for treatment discontinuation was met
Measure Participants	16
Mean (Standard Deviation) [paracenteses]	1.5 (1.6)

4. Secondary Outcome

Title	Progression-free Survival (PFS) Time
Description	According to the Response Evaluation Criteria in Solid Tumors [RECIST], progression was at least a 20% increase in the sum of the longest diameter (LD) of tumors, compared to smallest sum LD recorded since treatment started, or the appearance of one or more new tumors. PFS time was interval from the date of registration to the date of tumor progression or death from any cause, whichever was earlier. Median PFS time was estimated from Kaplan-Meier Plots. If participants were alive and progression-free at 6 months postregistration, they were censored for PFS.
Time Frame	up to 6 months post-registration

Outcome Measure Data

Analysis Population Description

Participants with a PFS event (tumor progression or death) were analyzed.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants with advanced ovarian epithelial cancer treated with 4.0 mg/kg Aflibercept every 2 weeks until a criterion for treatment discontinuation was met
Measure Participants	12
Median (95% Confidence Interval) [days]	59.5

5. Secondary Outcome

Title	Overall Survival (OS) Time
Description	OS time was the time interval between the date of registration to the date of death from any cause. Median OS was estimated from Kaplan-Meier curves. Participants who died after efficacy data cutoff date (6 months postregistration) were censored at the data cutoff date.
Time Frame	up to 6 months post-registration

Outcome Measure Data

Analysis Population Description

All participants were analyzed. 5 participants who died after efficacy data cutoff date (6 months postregistration) were censored at the data cutoff date.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants with advanced ovarian epithelial cancer treated with 4.0 mg/kg Aflibercept every 2 weeks until a criterion for treatment discontinuation was met
Measure Participants	16
Measure Events (Death)	11
Median (95% Confidence Interval) [days]	92.0

6. Secondary Outcome

Title	Number of Participants With a Positive Anti-drug Antibody Response
Description	Anti-drug antibodies in participant's serum were measured using 2 different methods an Enzyme Linked Immunosorbent Assay (ELISA) in which the lower limit of detection (LLOD) was 238.4 ng/mL; and an Electrochemiluminescence-based, Bridging Assay in which the validated LLOD 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. Participants with detectable anti-drug antibodies by either method were considered to have a positive anti-drug antibody response.
Time Frame	up to 60 days after the last dose of treatment

Outcome Measure Data

Analysis Population Description

Participants who received at least part of 1 dose of aflibercept and had evaluable blood samples

Arm/Group Title	Aflibercept
Arm/Group Description	Participants with advanced ovarian epithelial cancer treated with 4.0 mg/kg Aflibercept every 2 weeks until a criterion for treatment discontinuation was met
Measure Participants	11
Number [participants]	0 0%

7. Secondary Outcome

Title	Safety - Number of Participants With Adverse Events (AE)
Description	All AEs regardless of seriousness or relationship to study treatment, spanning from the first administration of study treatment until 60 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.
Time Frame	up to 60 days after last dose of treatment (approximately 2 years), or until TEAE was resolved or stabilized

Outcome Measure Data

Analysis Population Description

All participants who received at least part of 1 dose of the study treatment.

Arm/Group Title	Aflibercept
Arm/Group Description	Participants with advanced ovarian epithelial cancer treated with 4.0 mg/kg Aflibercept every 2 weeks until a criterion for treatment discontinuation was met
Measure Participants	16
With at least one TEAE	16 100%
With at least one serious TEAE	15 93.8%
With a TEAE leading to death	8 50%
With a TEAE resulting in discontinuation	2 12.5%

Adverse Events

Time Frame	From treatment initiation to January 30, 2009
Arm/Group Title	Aflibercept
Arm/Group Description	Participants with advanced ovarian epithelial cancer treated with 4.0 mg/kg Aflibercept every 2 weeks until a criterion for treatment discontinuation was met
All Cause Mortality
	Aflibercept
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Aflibercept
	Affected / at Risk (%)	# Events
Total	15/16 (93.8%)
Blood and lymphatic system disorders
Anaemia	1/16 (6.3%)
Cardiac disorders
Tachyarrhythmia	1/16 (6.3%)
Gastrointestinal disorders
Abdominal pain	1/16 (6.3%)
Intestinal obstruction	5/16 (31.3%)
Intestinal perforation	1/16 (6.3%)
Large intestinal obstruction	1/16 (6.3%)
Nausea	2/16 (12.5%)
Small intestinal obstruction	1/16 (6.3%)
Vomiting	4/16 (25%)
General disorders
Disease progression	4/16 (25%)
General physical health deterioration	1/16 (6.3%)
Infections and infestations
Gastroenteritis	1/16 (6.3%)
Metabolism and nutrition disorders
Dehydration	1/16 (6.3%)
Nervous system disorders
Cognitive disorder	1/16 (6.3%)
Respiratory, thoracic and mediastinal disorders
Hydropneumothorax	1/16 (6.3%)
Other (Not Including Serious) Adverse Events
	Aflibercept
	Affected / at Risk (%)	# Events
Total	16/16 (100%)
Blood and lymphatic system disorders
Anaemia	1/16 (6.3%)
Lymphadenitis	1/16 (6.3%)
Cardiac disorders
Tachyarrhythmia	1/16 (6.3%)
Eye disorders
Conjunctivitis	1/16 (6.3%)
Gastrointestinal disorders
Abdominal distension	2/16 (12.5%)
Abdominal pain	6/16 (37.5%)
Abdominal pain upper	2/16 (12.5%)
Colitis	1/16 (6.3%)
Constipation	3/16 (18.8%)
Diarrhoea	2/16 (12.5%)
Dyspepsia	1/16 (6.3%)
Gastritis	1/16 (6.3%)
Gastrooesophageal reflux disease	1/16 (6.3%)
Intestinal obstruction	1/16 (6.3%)
Intestinal perforation	1/16 (6.3%)
Nausea	6/16 (37.5%)
Oesophagitis	1/16 (6.3%)
Subileus	1/16 (6.3%)
Toothache	1/16 (6.3%)
Vomiting	8/16 (50%)
General disorders
Asthenia	5/16 (31.3%)
Disease progression	5/16 (31.3%)
Early satiety	2/16 (12.5%)
Fatigue	4/16 (25%)
General physical health deterioration	1/16 (6.3%)
Mucosal inflammation	1/16 (6.3%)
Oedema peripheral	3/16 (18.8%)
Pain	2/16 (12.5%)
Pyrexia	1/16 (6.3%)
Hepatobiliary disorders
Hepatic failure	1/16 (6.3%)
Infections and infestations
Gastroenteritis	2/16 (12.5%)
Nasopharyngitis	1/16 (6.3%)
Rhinitis	1/16 (6.3%)
Tooth infection	1/16 (6.3%)
Urinary tract infection	1/16 (6.3%)
Investigations
Cardiac murmur	1/16 (6.3%)
Urine output decreased	1/16 (6.3%)
Urine output increased	1/16 (6.3%)
Weight decreased	2/16 (12.5%)
Metabolism and nutrition disorders
Anorexia	5/16 (31.3%)
Decreased appetite	1/16 (6.3%)
Dehydration	2/16 (12.5%)
Hypokalaemia	1/16 (6.3%)
Hyponatraemia	2/16 (12.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	2/16 (12.5%)
Back pain	3/16 (18.8%)
Musculoskeletal pain	1/16 (6.3%)
Neck pain	1/16 (6.3%)
Nervous system disorders
Dizziness	1/16 (6.3%)
Dysgeusia	1/16 (6.3%)
Headache	3/16 (18.8%)
Neuropathy peripheral	1/16 (6.3%)
Peripheral sensory neuropathy	1/16 (6.3%)
Psychiatric disorders
Insomnia	2/16 (12.5%)
Respiratory, thoracic and mediastinal disorders
Cough	1/16 (6.3%)
Dysphonia	3/16 (18.8%)
Pleural effusion	1/16 (6.3%)
Sinus congestion	1/16 (6.3%)
Skin and subcutaneous tissue disorders
Alopecia	1/16 (6.3%)
Hyperhidrosis	1/16 (6.3%)
Palmar-plantar erythrodysaesthesia syndrome	1/16 (6.3%)
Rash	2/16 (12.5%)
Skin exfoliation	1/16 (6.3%)
Vascular disorders
Hypertension	7/16 (43.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The investigator has 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 for abstracts) in advance of any submission for publication. The Sponsor may request for the publication to be delayed for a limited time, not to exceed 90 days to preserve its proprietary rights.