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

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

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.

Study Overview

• Status: Completed
• Conditions: Prostatic Neoplasms; Neoplasm Metastasis
• Intervention / Treatment: Drug: Placebo (for aflibercept); Drug: Docetaxel; Drug: Prednisone or Prednisolone; Drug: 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.

• Study Type: Interventional
• Enrollment (Actual): 1224
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Sanofi-Aventis Administrative Office
• Australia
  • Macquarie Park, Australia
    • Sanofi-Aventis Administrative Office
• Belgium
  • Diegem, Belgium
    • Sanofi-Aventis Administrative Office
• Brazil
  • Sao Paulo, Brazil
    • Sanofi-Aventis Administrative Office
• Canada
  • Laval, Canada
    • Sanofi-Aventis Administrative Office
• Chile
  • Providencia Santiago, Chile
    • Sanofi-Aventis Administrative Office
• Croatia
  • City of Zagreb, Croatia
    • Sanofi-Aventis Administrative Office
• Czech Republic
  • Praha, Czech Republic
    • Sanofi-Aventis Administrative Office
• Denmark
  • Horsholm, Denmark
    • Sanofi-Aventis Administrative Office
• Estonia
  • Tallinn, Estonia
    • Sanofi-Aventis Administrative Office
• France
  • Paris, France
    • Sanofi-Aventis Administrative Office
• Germany
  • Frankfurt, Germany
    • Sanofi-Aventis Administrative Office
• Hong Kong
  • Hong Kong, Hong Kong
    • Sanofi-Aventis Administrative Office
• Hungary
  • Budapest, Hungary
    • Sanofi-Aventis Administrative Office
• Israel
  • Natanya, Israel
    • Sanofi-Aventis Administrative Office
• Italy
  • Milan, Italy
    • Sanofi-Aventis Administrative Office
• Korea, Republic of
  • Seoul, Korea, Republic of
    • Sanofi-Aventis Administrative Office
• Netherlands
  • Gouda, Netherlands
    • Sanofi-Aventis Administrative Office
• Poland
  • Warsaw, Poland
    • Sanofi-Aventis Administrative Office
• Portugal
  • Porto Salvo, Portugal
    • Sanofi-Aventis Administrative Office
• Russian Federation
  • Moscow, Russian Federation
    • Sanofi-Aventis Administrative Office
• Singapore
  • Singapore, Singapore
    • Sanofi-Aventis Administrative Office
• South Africa
  • Gauteng, South Africa
    • Sanofi-Aventis Administrative Office
• Spain
  • Barcelona, Spain
    • Sanofi-Aventis Administrative Office
• Sweden
  • Bromma, Sweden
    • Sanofi-Aventis Administrative Office
• Switzerland
  • Geneva, Switzerland
    • Sanofi-Aventis Administrative Office
• Taiwan
  • Taipei, Taiwan
    • Sanofi-Aventis Administrative Office
• Turkey
  • Istanbul, Turkey
    • Sanofi-Aventis Administrative Office
• Ukraine
  • Kiev, Ukraine
    • Sanofi-Aventis Administrative Office
• United Kingdom
  • Guildford Surrey, United Kingdom
    • Sanofi-Aventis Administrative Office
• United States
  • New Jersey
    • Bridgewater, New Jersey, United States, 08807
      • Sanofi-Aventis Administrative Office

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo added to standard chemotherapy with docetaxel plus prednisone or prednisolone	Drug: Placebo (for aflibercept); Sterile aqueous buffered solution identical to aflibercept 1-hour IV on Day 1 of each 3-Week cycle; Drug: Docetaxel; Marketed formulation 75 mg/m², 1 hour IV on Day 1 of each 3-week cycle (immediately after Aflibercept or placebo); Other Names: Taxotere®; Drug: Prednisone or Prednisolone; Marketed formulation 5 mg twice daily PO from day 1 continuously
Experimental: Aflibercept; Aflibercept added to standard chemotherapy with docetaxel plus prednisone or prednisolone	Drug: Docetaxel; Marketed formulation 75 mg/m², 1 hour IV on Day 1 of each 3-week cycle (immediately after Aflibercept or placebo); Other Names: Taxotere®; Drug: Prednisone or Prednisolone; Marketed formulation 5 mg twice daily PO from day 1 continuously; Drug: Aflibercept; 25 mg/ml solution 6 mg/kg, 1-hour IV on Day 1 of each 3-Week cycle; Other Names: AVE0005; ZALTRAP®)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	From randomization up to the cut-off date (median follow-up of 35.4 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Before randomization (baseline) then every 3 weeks up to PSA progression (≥25% increase) or the cut-off date, whichever occurred first
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.	From randomization up to the cut-off date (median follow-up of 35.4 months)
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.	From randomization up to the cut-off date (median follow-up of 35.4 months)
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.	Before randomization (baseline) then every 3 months up to tumor progression (≥25% increase) or the cut-off date, whichever occurred first
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.	From randomization up to the cut-off date (median follow-up of 35.4 months)
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.	From randomization up to the cut-off date (median follow-up of 35.4 months)
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.	Before randomization (baseline) then every 3 weeks up to pain progression or the cut-off date, whichever occurred first
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.	Before randomization (baseline) then every 3 weeks until disease progression or administration of further antitumor therapy, whichever came first
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).	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
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.	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

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: August 1, 2007
• Primary Completion (Actual): April 1, 2012
• Study Completion (Actual): April 1, 2012

Study Registration Dates

• First Submitted: August 21, 2007
• First Submitted That Met QC Criteria: August 21, 2007
• First Posted (Estimate): August 22, 2007

Study Record Updates

• Last Update Posted (Estimate): July 22, 2016
• Last Update Submitted That Met QC Criteria: June 21, 2016
• Last Verified: June 1, 2016

More Information

Terms related to this study

• Keywords: cancer; metastatic; prostate
• Additional Relevant MeSH Terms: Pathologic Processes; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Neoplastic Processes; Neoplasms; Prostatic Neoplasms; Neoplasm Metastasis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Inflammatory Agents; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Docetaxel; Prednisolone; Prednisone; Aflibercept
• Other Study ID Numbers: EFC6546; 2006-004756-20 (EudraCT Number)