Aflibercept in Combination With Docetaxel in Metastatic Androgen Independent Prostate Cancer

Prostatic Neoplasms Clinical Trial

— 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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00519285
• Other study ID #: EFC6546
• Secondary ID: 2006-004756-20
• Status: Completed
• Phase: Phase 3
• First received: August 21, 2007
• Last updated: August 2, 2013
• Start date: August 2007
• Est. completion date: April 2012

Study information

• Verified date: August 2013
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 1224
• Est. completion date: April 2012
• Est. primary completion date: February 2012
• Accepts healthy volunteers: No
• Gender: Male
• Age group: 18 Years and older

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Neoplasm Metastasis
• Neoplasms
• Prostatic Neoplasms

Intervention

Drug:
• Aflibercept
25 mg/ml solution 6 mg/kg, 1-hour IV on Day 1 of each 3-Week cycle
• Placebo (for aflibercept)
Sterile aqueous buffered solution identical to aflibercept 1-hour IV on Day 1 of each 3-Week cycle
• Docetaxel
Marketed formulation 75 mg/m², 1 hour IV on Day 1 of each 3-week cycle (immediately after Aflibercept or placebo)
• Prednisone or Prednisolone
Marketed formulation 5 mg twice daily PO from day 1 continuously

Locations

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

References & Publications (1)

Tannock IF, Fizazi K, Ivanov S, Karlsson CT, Fléchon A, Skoneczna I, Orlandi F, Gravis G, Matveev V, Bavbek S, Gil T, Viana L, Arén O, Karyakin O, Elliott T, Birtle A, Magherini E, Hatteville L, Petrylak D, Tombal B, Rosenthal M; VENICE investigators. Afl — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)	No
Secondary	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	No
Secondary	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)	No
Secondary	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)	No
Secondary	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	No
Secondary	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)	No
Secondary	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)	No
Secondary	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	No
Secondary	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	No
Secondary	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	Yes
Secondary	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	No