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Aflibercept in Combination With Docetaxel in Metastatic Androgen Independent Prostate Cancer (VENICE)

Primary Purpose

Prostatic Neoplasms, Neoplasm Metastasis

Status
Completed
Phase
Phase 3
Locations
International
Study Type
Interventional
Intervention
Aflibercept
Placebo (for aflibercept)
Docetaxel
Prednisone or Prednisolone
Sponsored by
Sanofi
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Prostatic Neoplasms focused on measuring metastatic, prostate, cancer

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  • Histologically- or cytologically-confirmed prostate adenocarcinoma;
  • Metastatic disease;
  • Progressive disease while receiving hormonal therapy or after surgical castration;
  • Effective castration.

Exclusion Criteria:

  • Prior cytotoxic chemotherapy for prostate cancer, except estramustine and except adjuvant/neoadjuvant treatment completed >3 years ago;
  • Prior treatment with Vascular Endothelial Growth Factor (VEGF) inhibitors or VEGF receptor inhibitors;
  • Eastern Cooperative Oncology Group (ECOG) performance status >2.

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

Sites / Locations

  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office
  • Sanofi-Aventis Administrative Office

Arms of the Study

Arm 1

Arm 2

Arm Type

Placebo Comparator

Experimental

Arm Label

Placebo

Aflibercept

Arm Description

Placebo added to standard chemotherapy with docetaxel plus prednisone or prednisolone

Aflibercept added to standard chemotherapy with docetaxel plus prednisone or prednisolone

Outcomes

Primary Outcome Measures

Overall Survival Time
Overall survival (OS) time was measured as the time from date of randomization to the date of death due to any cause. The median OS time and its 95.6% confidence interval were estimated using the Kaplan-Meier method. In the absence of confirmation of death, the participant was censored at the last date he/she was known to be alive or the study cut-off date (when 873 deaths have occurred), whichever was earlier.

Secondary Outcome Measures

Prostate Specific Antigen Response Rate
Prostate specific antigen (PSA) response was defined as ≥50% decrease from baseline in serum PSA levels, confirmed at least 3 weeks later. Increases of any magnitude during the first 12 weeks were ignored in determining PSA response.
Time to Skeletal Related Events
Skeletal Related Events (SRE) included pathological fractures and/or spinal cord compression, need for bone irradiation, including radioisotopes or bone surgery, change in antineoplastic therapy to treat bone pain. Time to SRE was defined as the time from the date of randomization to the date of occurence of the first event defining a SRE or death due to any cause, whichever occurred first. The median time to SRE and its 95% confidence interval were estimated using the Kaplan-Meier method. In the absence of SRE, the participant was censored at the last date he/she was known to be alive or the study cut-off date, whichever was earlier.
Progression Free Survival Time
Disease progression was defined as a composite of: Radiological tumor progression (≥20% increase in target lesions, or appearance of at least 2 new bone lesions); PSA progression (≥25% increase in PSA level confirmed 3 weeks later); Pain progression (increase in pain intensity or in analgesic consumption for cancer related pain confirmed 3 weeks later); Radiotherapy for cancer related symptoms; Occurence of Skeletal related events (SRE). Progression Free survival (PFS) time was measured as the time from the date of randomization up to the date of occurrence of the first event defining a disease progression or death due to any cause, whichever occurred first. The median PFS time and its 95% confidence interval were estimated using the Kaplan-Meier method. In the absence of disease progression, the participant was censored at the the date of last assessment without evidence of progression or the study cut-off date, whichever was earlier.
Tumor Response Rate in Participants With Measurable Disease
Tumor response was defined as either a Complete Response (disappearance of all target lesions) or a Partial Response (≥30% decrease from baseline in target lesions) as assessed by Response Evaluation Criteria In Solid Tumors (RECIST)version 1.0.
Prostate Specific Antigen Progression-free Survival Time
Prostate specific antigen (PSA) progression was defined as ≥25% increase in PSA level confirmed 3 weeks later, above the nadir in participants who had achieved a PSA response, or above the baseline in participants who hadn't achieved a PSA response. PSA progression-free survival (PFS) time was defined as the time from the date of randomization up to the date of the first documented PSA progression or death due to any cause, whichever occurred first. The median PSA-PFS time and its 95% confidence interval were estimated using the Kaplan-Meier method. In the absence of PSA progression or death, the participant was censored at the the date of last assessment without evidence of progression or the study cut-off date, whichever was earlier.
Pain Progression-free Survival Time
Pain progression was defined as either ≥1-point increase in Present Pain Intensity (PPI) score or ≥25% increase in Analgesics Score (AS) confirmed at least 3 weeks later, or requirement for palliative radiotherapy. PPI scale is a self-report 0-5 scale to assess pain intensity - a score 0 reflects no pain, a score 5 reflects excruciating pain. AS is a scoring method to assess analgesics consumption. Each analgesic is scored 1 or 4 depending on the analgesic type and dose. AS is the sum of the analgesic scores. Pain progression-free survival (PFS) time was measured as the time from the date of randomization up to the date of first pain progression or death due to any cause, whichever occurred first. The median pain-PFS and its 95% confidence interval were estimated using the Kaplan-Meier method. In the absence of event, the participant was censored at the the date of last assessment without evidence of pain progression or the study cut-off date, whichever was earlier.
Pain Response Rate
Pain response was defined as either a ≥2-point decrease from baseline in Present Pain Intensity (PPI) score without increase in Analgesics Score (AS), or a ≥50% decrease from baseline in AS without increase in the PPI score confirmed at least 3 weeks later. Increases in PPI or AS during the first 12 weeks were ignored in determining pain response.
Change From Baseline in Functional Assessment of Cancer Therapy-Prostate Total Score as a Measure of Health Related Quality of Life
Functional Assessment of Cancer Therapy-Prostate (FACT-P) is a 39-item participant questionnaire that measures the concerns of patients with prostate cancer. It consists of 5 subscales assessing physical well-being, social/family well-being, emotional well-being, functional well-being, and prostate-specific concerns. FACT-P total score is the sum of the 5 subscores. It ranges from 0 to 156 with higher score indicating better quality of life.
Number of Participants With Adverse Events as a Measure of Safety
Adverse Events (AE) are any unfavorable and unintended sign, symptom, syndrome or illness observed by the investigator or reported by the participant during the study. AE were collected at regular intervals throughout the study then graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.3.0).
Number of Participants With Positive Anti-aflibercept Antibody Levels as a Measure of Immunogenicity of Aflibercept
Serum for detection of anti-drug antibodies (ADA) was collected in patients treated in selected centers only. Samples were analyzed using a titer-based, bridging immunoassay developed and validated to detect ADAs in human serum. Samples with positive antibody levels were further analyzed using a validated, non-quantitative ligand binding assay to detect neutralizing antibodies Ab). A participant was considered to have positive antibody levels if antibodies were detected above the quantification limits.

Full Information

First Posted
August 21, 2007
Last Updated
June 21, 2016
Sponsor
Sanofi
Collaborators
Regeneron Pharmaceuticals
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1. Study Identification

Unique Protocol Identification Number
NCT00519285
Brief Title
Aflibercept in Combination With Docetaxel in Metastatic Androgen Independent Prostate Cancer
Acronym
VENICE
Official Title
A Multicenter, Randomized, Double Blind Study Comparing the Efficacy and Safety of Aflibercept Versus Placebo Administered Every 3 Weeks in Patients Treated With Docetaxel/ Prednisone for Metastatic Androgen-independent Prostate Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
June 2016
Overall Recruitment Status
Completed
Study Start Date
August 2007 (undefined)
Primary Completion Date
April 2012 (Actual)
Study Completion Date
April 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sanofi
Collaborators
Regeneron Pharmaceuticals

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Primary objective was to demonstrate overall survival improvement with aflibercept compared to placebo in patients receiving docetaxel / prednisone for metastatic androgen-independent prostate cancer (MAIPC). The secondary objectives were: To assess the efficacy of aflibercept compared to placebo on other parameters such prostate-specific antigen (PSA) level, cancer related pain, progression free survival (PFS), tumor-based and skeletal events and health-related quality of life (HRQL); To assess the overall safety in both treatment arms; To determine the pharmacokinetics of intravenous (IV) aflibercept in this population; to determine immunogenicity of IV aflibercept.
Detailed Description
The study consisted in 3-week treatment cycles until progressive disease, unacceptable toxicity, or participant's refusal of further study treatment. After disease progression, participants were to be followed every 3 months until death or the study cutoff date, whichever came first. The study cut-off date was event-driven and was defined as the date when 873 deaths had occurred.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Prostatic Neoplasms, Neoplasm Metastasis
Keywords
metastatic, prostate, cancer

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
1224 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
Placebo added to standard chemotherapy with docetaxel plus prednisone or prednisolone
Arm Title
Aflibercept
Arm Type
Experimental
Arm Description
Aflibercept added to standard chemotherapy with docetaxel plus prednisone or prednisolone
Intervention Type
Drug
Intervention Name(s)
Aflibercept
Other Intervention Name(s)
AVE0005, ZALTRAP®)
Intervention Description
25 mg/ml solution 6 mg/kg, 1-hour IV on Day 1 of each 3-Week cycle
Intervention Type
Drug
Intervention Name(s)
Placebo (for aflibercept)
Intervention Description
Sterile aqueous buffered solution identical to aflibercept 1-hour IV on Day 1 of each 3-Week cycle
Intervention Type
Drug
Intervention Name(s)
Docetaxel
Other Intervention Name(s)
Taxotere®
Intervention Description
Marketed formulation 75 mg/m², 1 hour IV on Day 1 of each 3-week cycle (immediately after Aflibercept or placebo)
Intervention Type
Drug
Intervention Name(s)
Prednisone or Prednisolone
Intervention Description
Marketed formulation 5 mg twice daily PO from day 1 continuously
Primary Outcome Measure Information:
Title
Overall Survival Time
Description
Overall survival (OS) time was measured as the time from date of randomization to the date of death due to any cause. The median OS time and its 95.6% confidence interval were estimated using the Kaplan-Meier method. In the absence of confirmation of death, the participant was censored at the last date he/she was known to be alive or the study cut-off date (when 873 deaths have occurred), whichever was earlier.
Time Frame
From randomization up to the cut-off date (median follow-up of 35.4 months)
Secondary Outcome Measure Information:
Title
Prostate Specific Antigen Response Rate
Description
Prostate specific antigen (PSA) response was defined as ≥50% decrease from baseline in serum PSA levels, confirmed at least 3 weeks later. Increases of any magnitude during the first 12 weeks were ignored in determining PSA response.
Time Frame
Before randomization (baseline) then every 3 weeks up to PSA progression (≥25% increase) or the cut-off date, whichever occurred first
Title
Time to Skeletal Related Events
Description
Skeletal Related Events (SRE) included pathological fractures and/or spinal cord compression, need for bone irradiation, including radioisotopes or bone surgery, change in antineoplastic therapy to treat bone pain. Time to SRE was defined as the time from the date of randomization to the date of occurence of the first event defining a SRE or death due to any cause, whichever occurred first. The median time to SRE and its 95% confidence interval were estimated using the Kaplan-Meier method. In the absence of SRE, the participant was censored at the last date he/she was known to be alive or the study cut-off date, whichever was earlier.
Time Frame
From randomization up to the cut-off date (median follow-up of 35.4 months)
Title
Progression Free Survival Time
Description
Disease progression was defined as a composite of: Radiological tumor progression (≥20% increase in target lesions, or appearance of at least 2 new bone lesions); PSA progression (≥25% increase in PSA level confirmed 3 weeks later); Pain progression (increase in pain intensity or in analgesic consumption for cancer related pain confirmed 3 weeks later); Radiotherapy for cancer related symptoms; Occurence of Skeletal related events (SRE). Progression Free survival (PFS) time was measured as the time from the date of randomization up to the date of occurrence of the first event defining a disease progression or death due to any cause, whichever occurred first. The median PFS time and its 95% confidence interval were estimated using the Kaplan-Meier method. In the absence of disease progression, the participant was censored at the the date of last assessment without evidence of progression or the study cut-off date, whichever was earlier.
Time Frame
From randomization up to the cut-off date (median follow-up of 35.4 months)
Title
Tumor Response Rate in Participants With Measurable Disease
Description
Tumor response was defined as either a Complete Response (disappearance of all target lesions) or a Partial Response (≥30% decrease from baseline in target lesions) as assessed by Response Evaluation Criteria In Solid Tumors (RECIST)version 1.0.
Time Frame
Before randomization (baseline) then every 3 months up to tumor progression (≥25% increase) or the cut-off date, whichever occurred first
Title
Prostate Specific Antigen Progression-free Survival Time
Description
Prostate specific antigen (PSA) progression was defined as ≥25% increase in PSA level confirmed 3 weeks later, above the nadir in participants who had achieved a PSA response, or above the baseline in participants who hadn't achieved a PSA response. PSA progression-free survival (PFS) time was defined as the time from the date of randomization up to the date of the first documented PSA progression or death due to any cause, whichever occurred first. The median PSA-PFS time and its 95% confidence interval were estimated using the Kaplan-Meier method. In the absence of PSA progression or death, the participant was censored at the the date of last assessment without evidence of progression or the study cut-off date, whichever was earlier.
Time Frame
From randomization up to the cut-off date (median follow-up of 35.4 months)
Title
Pain Progression-free Survival Time
Description
Pain progression was defined as either ≥1-point increase in Present Pain Intensity (PPI) score or ≥25% increase in Analgesics Score (AS) confirmed at least 3 weeks later, or requirement for palliative radiotherapy. PPI scale is a self-report 0-5 scale to assess pain intensity - a score 0 reflects no pain, a score 5 reflects excruciating pain. AS is a scoring method to assess analgesics consumption. Each analgesic is scored 1 or 4 depending on the analgesic type and dose. AS is the sum of the analgesic scores. Pain progression-free survival (PFS) time was measured as the time from the date of randomization up to the date of first pain progression or death due to any cause, whichever occurred first. The median pain-PFS and its 95% confidence interval were estimated using the Kaplan-Meier method. In the absence of event, the participant was censored at the the date of last assessment without evidence of pain progression or the study cut-off date, whichever was earlier.
Time Frame
From randomization up to the cut-off date (median follow-up of 35.4 months)
Title
Pain Response Rate
Description
Pain response was defined as either a ≥2-point decrease from baseline in Present Pain Intensity (PPI) score without increase in Analgesics Score (AS), or a ≥50% decrease from baseline in AS without increase in the PPI score confirmed at least 3 weeks later. Increases in PPI or AS during the first 12 weeks were ignored in determining pain response.
Time Frame
Before randomization (baseline) then every 3 weeks up to pain progression or the cut-off date, whichever occurred first
Title
Change From Baseline in Functional Assessment of Cancer Therapy-Prostate Total Score as a Measure of Health Related Quality of Life
Description
Functional Assessment of Cancer Therapy-Prostate (FACT-P) is a 39-item participant questionnaire that measures the concerns of patients with prostate cancer. It consists of 5 subscales assessing physical well-being, social/family well-being, emotional well-being, functional well-being, and prostate-specific concerns. FACT-P total score is the sum of the 5 subscores. It ranges from 0 to 156 with higher score indicating better quality of life.
Time Frame
Before randomization (baseline) then every 3 weeks until disease progression or administration of further antitumor therapy, whichever came first
Title
Number of Participants With Adverse Events as a Measure of Safety
Description
Adverse Events (AE) are any unfavorable and unintended sign, symptom, syndrome or illness observed by the investigator or reported by the participant during the study. AE were collected at regular intervals throughout the study then graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v.3.0).
Time Frame
From first dose of study treatment (aflibercept/placebo or docetaxel whichever came first) to last dose of study treatment (aflibercept/placebo or docetaxel whichever came last) + 30 days
Title
Number of Participants With Positive Anti-aflibercept Antibody Levels as a Measure of Immunogenicity of Aflibercept
Description
Serum for detection of anti-drug antibodies (ADA) was collected in patients treated in selected centers only. Samples were analyzed using a titer-based, bridging immunoassay developed and validated to detect ADAs in human serum. Samples with positive antibody levels were further analyzed using a validated, non-quantitative ligand binding assay to detect neutralizing antibodies Ab). A participant was considered to have positive antibody levels if antibodies were detected above the quantification limits.
Time Frame
Pre-dose of cycle 1 (baseline), pre-dose of each every other cycle, then 30 and 90 days after the last administration of the study drug

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Histologically- or cytologically-confirmed prostate adenocarcinoma; Metastatic disease; Progressive disease while receiving hormonal therapy or after surgical castration; Effective castration. Exclusion Criteria: Prior cytotoxic chemotherapy for prostate cancer, except estramustine and except adjuvant/neoadjuvant treatment completed >3 years ago; Prior treatment with Vascular Endothelial Growth Factor (VEGF) inhibitors or VEGF receptor inhibitors; Eastern Cooperative Oncology Group (ECOG) performance status >2. The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Clinical Sciences & Operations
Organizational Affiliation
Sanofi
Official's Role
Study Director
Facility Information:
Facility Name
Sanofi-Aventis Administrative Office
City
Bridgewater
State/Province
New Jersey
ZIP/Postal Code
08807
Country
United States
Facility Name
Sanofi-Aventis Administrative Office
City
Buenos Aires
Country
Argentina
Facility Name
Sanofi-Aventis Administrative Office
City
Macquarie Park
Country
Australia
Facility Name
Sanofi-Aventis Administrative Office
City
Diegem
Country
Belgium
Facility Name
Sanofi-Aventis Administrative Office
City
Sao Paulo
Country
Brazil
Facility Name
Sanofi-Aventis Administrative Office
City
Laval
Country
Canada
Facility Name
Sanofi-Aventis Administrative Office
City
Providencia Santiago
Country
Chile
Facility Name
Sanofi-Aventis Administrative Office
City
City of Zagreb
Country
Croatia
Facility Name
Sanofi-Aventis Administrative Office
City
Praha
Country
Czech Republic
Facility Name
Sanofi-Aventis Administrative Office
City
Horsholm
Country
Denmark
Facility Name
Sanofi-Aventis Administrative Office
City
Tallinn
Country
Estonia
Facility Name
Sanofi-Aventis Administrative Office
City
Paris
Country
France
Facility Name
Sanofi-Aventis Administrative Office
City
Frankfurt
Country
Germany
Facility Name
Sanofi-Aventis Administrative Office
City
Hong Kong
Country
Hong Kong
Facility Name
Sanofi-Aventis Administrative Office
City
Budapest
Country
Hungary
Facility Name
Sanofi-Aventis Administrative Office
City
Natanya
Country
Israel
Facility Name
Sanofi-Aventis Administrative Office
City
Milan
Country
Italy
Facility Name
Sanofi-Aventis Administrative Office
City
Seoul
Country
Korea, Republic of
Facility Name
Sanofi-Aventis Administrative Office
City
Gouda
Country
Netherlands
Facility Name
Sanofi-Aventis Administrative Office
City
Warsaw
Country
Poland
Facility Name
Sanofi-Aventis Administrative Office
City
Porto Salvo
Country
Portugal
Facility Name
Sanofi-Aventis Administrative Office
City
Moscow
Country
Russian Federation
Facility Name
Sanofi-Aventis Administrative Office
City
Singapore
Country
Singapore
Facility Name
Sanofi-Aventis Administrative Office
City
Gauteng
Country
South Africa
Facility Name
Sanofi-Aventis Administrative Office
City
Barcelona
Country
Spain
Facility Name
Sanofi-Aventis Administrative Office
City
Bromma
Country
Sweden
Facility Name
Sanofi-Aventis Administrative Office
City
Geneva
Country
Switzerland
Facility Name
Sanofi-Aventis Administrative Office
City
Taipei
Country
Taiwan
Facility Name
Sanofi-Aventis Administrative Office
City
Istanbul
Country
Turkey
Facility Name
Sanofi-Aventis Administrative Office
City
Kiev
Country
Ukraine
Facility Name
Sanofi-Aventis Administrative Office
City
Guildford Surrey
Country
United Kingdom

12. IPD Sharing Statement

Citations:
PubMed Identifier
23742877
Citation
Tannock IF, Fizazi K, Ivanov S, Karlsson CT, Flechon A, Skoneczna I, Orlandi F, Gravis G, Matveev V, Bavbek S, Gil T, Viana L, Aren O, Karyakin O, Elliott T, Birtle A, Magherini E, Hatteville L, Petrylak D, Tombal B, Rosenthal M; VENICE investigators. Aflibercept versus placebo in combination with docetaxel and prednisone for treatment of men with metastatic castration-resistant prostate cancer (VENICE): a phase 3, double-blind randomised trial. Lancet Oncol. 2013 Jul;14(8):760-8. doi: 10.1016/S1470-2045(13)70184-0. Epub 2013 Jun 4.
Results Reference
result
PubMed Identifier
25515657
Citation
van Soest RJ, Templeton AJ, Vera-Badillo FE, Mercier F, Sonpavde G, Amir E, Tombal B, Rosenthal M, Eisenberger MA, Tannock IF, de Wit R. Neutrophil-to-lymphocyte ratio as a prognostic biomarker for men with metastatic castration-resistant prostate cancer receiving first-line chemotherapy: data from two randomized phase III trials. Ann Oncol. 2015 Apr;26(4):743-749. doi: 10.1093/annonc/mdu569. Epub 2014 Dec 15.
Results Reference
derived
PubMed Identifier
24722180
Citation
de Liano AG, Reig O, Mellado B, Martin C, Rull EU, Maroto JP. Prognostic and predictive value of plasma testosterone levels in patients receiving first-line chemotherapy for metastatic castrate-resistant prostate cancer. Br J Cancer. 2014 Apr 29;110(9):2201-8. doi: 10.1038/bjc.2014.189. Epub 2014 Apr 10.
Results Reference
derived

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Aflibercept in Combination With Docetaxel in Metastatic Androgen Independent Prostate Cancer

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