Trial Outcomes & Findings for Aflibercept in Combination With Docetaxel in Metastatic Androgen Independent Prostate Cancer (NCT NCT00519285)

NCT ID: NCT00519285

Last Updated: 2016-07-22

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1224 participants

Primary outcome timeframe

From randomization up to the cut-off date (median follow-up of 35.4 months)

Results posted on

2016-07-22

Participant Flow

Between August 2007 and February 2010, a total of 1548 patients gave informed consent for this study.

Amongst these patients, a total of 324 were screening failures (primarily due to non-compliance with exclusion criteria) and did not get randomized.

Participant milestones

Participant milestones
Measure	Placebo Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Study STARTED	612	612
Overall Study TREATED	604	605
Overall Study Still Treated at Cut-off Date	1	2
Overall Study COMPLETED	0	0
Overall Study NOT COMPLETED	612	612

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Study Adverse Event	127	266
Overall Study Disease progression	334	186
Overall Study Physician Decision	75	47
Overall Study Participant's request	53	84
Overall Study Consent withdrawn	4	5
Overall Study Poor compliance to protocol	5	7
Overall Study Reason unspecified	5	8
Overall Study Not treated	8	7
Overall Study Treatment ongoing	1	2

Baseline Characteristics

Aflibercept in Combination With Docetaxel in Metastatic Androgen Independent Prostate Cancer

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=612 Participants Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept n=612 Participants Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Total n=1224 Participants Total of all reporting groups
Age, Continuous	67.6 Years STANDARD_DEVIATION 8.0 • n=5 Participants	67.9 Years STANDARD_DEVIATION 7.8 • n=7 Participants	67.8 Years STANDARD_DEVIATION 7.9 • n=5 Participants
Age, Customized <65 years	225 participants n=5 Participants	195 participants n=7 Participants	420 participants n=5 Participants
Age, Customized 65-74 years	259 participants n=5 Participants	283 participants n=7 Participants	542 participants n=5 Participants
Age, Customized ≥75 years	128 participants n=5 Participants	134 participants n=7 Participants	262 participants n=5 Participants
Sex/Gender, Customized Male	612 participants n=5 Participants	612 participants n=7 Participants	1224 participants n=5 Participants
Race/Ethnicity, Customized Caucasian/White	552 participants n=5 Participants	560 participants n=7 Participants	1112 participants n=5 Participants
Race/Ethnicity, Customized Black	17 participants n=5 Participants	15 participants n=7 Participants	32 participants n=5 Participants
Race/Ethnicity, Customized Asian/Oriental	36 participants n=5 Participants	32 participants n=7 Participants	68 participants n=5 Participants
Race/Ethnicity, Customized Other	7 participants n=5 Participants	5 participants n=7 Participants	12 participants n=5 Participants
Region of Enrollment Western Europe	219 Participants n=5 Participants	227 Participants n=7 Participants	446 Participants n=5 Participants
Region of Enrollment Eastern Europe	131 Participants n=5 Participants	132 Participants n=7 Participants	263 Participants n=5 Participants
Region of Enrollment North America	81 Participants n=5 Participants	95 Participants n=7 Participants	176 Participants n=5 Participants
Region of Enrollment South America	88 Participants n=5 Participants	71 Participants n=7 Participants	159 Participants n=5 Participants
Region of Enrollment Other region	93 Participants n=5 Participants	87 Participants n=7 Participants	180 Participants n=5 Participants
Body Surface Area (BSA)	2.0 m² STANDARD_DEVIATION 0.2 • n=5 Participants	2.0 m² STANDARD_DEVIATION 0.2 • n=7 Participants	2.0 m² STANDARD_DEVIATION 0.2 • n=5 Participants
Eastern Co-operative Group (ECOG) performance status ECOG 0	285 participants n=5 Participants	283 participants n=7 Participants	568 participants n=5 Participants
Eastern Co-operative Group (ECOG) performance status ECOG 1	299 participants n=5 Participants	303 participants n=7 Participants	602 participants n=5 Participants
Eastern Co-operative Group (ECOG) performance status ECOG 2	28 participants n=5 Participants	26 participants n=7 Participants	54 participants n=5 Participants

PRIMARY outcome

Timeframe: From randomization up to the cut-off date (median follow-up of 35.4 months)

Population: The analysis was performed on the Intent-to-treat (ITT) population (i.e all randomized participants according to the treatment assigned regardless of the drug actually received). At the cut-off date, 873 deaths had occurred, 445 in the Placebo group and 428 in the Aflibercept group.

Outcome measures

Outcome measures
Measure	Placebo n=612 Participants Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept n=612 Participants Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Overall Survival Time	21.22 months Interval 19.614 to 23.754	22.14 months Interval 20.304 to 24.082

SECONDARY outcome

Timeframe: Before randomization (baseline) then every 3 weeks up to PSA progression (≥25% increase) or the cut-off date, whichever occurred first

Population: The analysis was performed on the ITT population evaluable for PSA response (i.e. with a baseline PSA ≥10 ng/mL).

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.

Outcome measures

Outcome measures
Measure	Placebo n=559 Participants Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept n=560 Participants Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Prostate Specific Antigen Response Rate	63.5 percentage of participants Interval 59.5 to 67.5	68.6 percentage of participants Interval 64.7 to 72.4

SECONDARY outcome

Timeframe: From randomization up to the cut-off date (median follow-up of 35.4 months)

Population: The analysis was performed on the ITT population. At the cut-off date, SRE or death had occurred in 1013 participants, 516 in the Placebo group and 497 in the Aflibercept group.

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.

Outcome measures

Outcome measures
Measure	Placebo n=612 Participants Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept n=612 Participants Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Time to Skeletal Related Events	14.98 months Interval 13.733 to 16.427	15.31 months Interval 14.127 to 16.657

SECONDARY outcome

Timeframe: From randomization up to the cut-off date (median follow-up of 35.4 months)

Population: The analysis was performed on the ITT population. At the cut-off date, disease progression or death had occurred in 1184 participants, 592 in each treatment group.

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.

Outcome measures

Outcome measures
Measure	Placebo n=612 Participants Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept n=612 Participants Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Progression Free Survival Time	6.24 months Interval 5.585 to 6.899	6.90 months Interval 6.209 to 7.359

SECONDARY outcome

Timeframe: Before randomization (baseline) then every 3 months up to tumor progression (≥25% increase) or the cut-off date, whichever occurred first

Population: The analysis was performed on the ITT population evaluable for tumor response (i.e. received at least one dose of study drugs (aflibercept/placebo or docetaxel), had no important deviations to protocol and was evaluable for response as per RECIST version 1.0).

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.

Outcome measures

Outcome measures
Measure	Placebo n=320 Participants Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept n=323 Participants Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Tumor Response Rate in Participants With Measurable Disease	28.1 percentage of participants Interval 23.2 to 33.1	38.7 percentage of participants Interval 33.4 to 44.0

SECONDARY outcome

Timeframe: From randomization up to the cut-off date (median follow-up of 35.4 months)

Population: The analysis was performed in the ITT population evaluable for PSA progression (i.e. with an evaluable baseline PSA). At the cut-off date, PSA progression or death had occurred in 1138 participants, 571 in the Placebo group and 567 in the Aflibercept group.

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.

Outcome measures

Outcome measures
Measure	Placebo n=606 Participants Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept n=608 Participants Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Prostate Specific Antigen Progression-free Survival Time	8.11 months Interval 7.622 to 8.575	8.25 months Interval 7.819 to 8.772

SECONDARY outcome

Timeframe: From randomization up to the cut-off date (median follow-up of 35.4 months)

Population: The analysis was performed on the ITT population evaluable for pain progression (i.e. with no pain or with stable pain at baseline). At the cut-off date, pain progression or death had occurred in 507 participants, 263 in the Placebo group and 244 in the Aflibercept group.

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.

Outcome measures

Outcome measures
Measure	Placebo n=301 Participants Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept n=287 Participants Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Pain Progression-free Survival Time	9.72 months Interval 8.509 to 11.499	9.20 months Interval 8.181 to 10.448

SECONDARY outcome

Timeframe: Before randomization (baseline) then every 3 weeks up to pain progression or the cut-off date, whichever occurred first

Population: The analysis was performed in the ITT population evaluable for pain response (i.e. stable analgesia at baseline and, baseline PPI ≥2 and/or baseline AS ≥10 points).

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.

Outcome measures

Outcome measures
Measure	Placebo n=67 Participants Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept n=67 Participants Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Pain Response Rate	46.3 percentage of participants Interval 34.3 to 58.2	35.8 percentage of participants Interval 24.3 to 47.3

SECONDARY outcome

Timeframe: Before randomization (baseline) then every 3 weeks until disease progression or administration of further antitumor therapy, whichever came first

Population: The analysis was performed on the ITT population evaluable for Health related quality of life (i.e. with baseline and at least one post-baseline evaluable FACT-P questionnaire).

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.

Outcome measures

Outcome measures
Measure	Placebo n=574 Participants Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept n=568 Participants Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Change From Baseline in Functional Assessment of Cancer Therapy-Prostate Total Score as a Measure of Health Related Quality of Life Change from baseline at cycle 1 (n =493, 461)	5.08 units on a scale Standard Deviation 12.73	1.30 units on a scale Standard Deviation 15.70
Change From Baseline in Functional Assessment of Cancer Therapy-Prostate Total Score as a Measure of Health Related Quality of Life Change from baseline at cycle 2 (n =467, 437)	6.22 units on a scale Standard Deviation 14.50	-0.03 units on a scale Standard Deviation 17.99
Change From Baseline in Functional Assessment of Cancer Therapy-Prostate Total Score as a Measure of Health Related Quality of Life Change from baseline at cycle 6 (n =293, 224)	5.50 units on a scale Standard Deviation 16.38	-1.00 units on a scale Standard Deviation 16.85
Change From Baseline in Functional Assessment of Cancer Therapy-Prostate Total Score as a Measure of Health Related Quality of Life Change from baseline at cycle 10 (n =158, 117)	6.61 units on a scale Standard Deviation 16.35	-1.60 units on a scale Standard Deviation 15.41

SECONDARY outcome

Timeframe: 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

Population: The analysis was performed on the safety population (i.e. all randomized and treated participants according to the treatment actually received). Six participants in the Placebo group who received at least one dose of aflibercept in error were considered in the Aflibercept group.

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).

Outcome measures

Outcome measures
Measure	Placebo n=598 Participants Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept n=611 Participants Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Number of Participants With Adverse Events as a Measure of Safety Any Adverse Event	585 participants	607 participants
Number of Participants With Adverse Events as a Measure of Safety - Grade 3-4 AE	290 participants	470 participants
Number of Participants With Adverse Events as a Measure of Safety - Serious AE	184 participants	331 participants
Number of Participants With Adverse Events as a Measure of Safety - AE leading to death	23 participants	46 participants
Number of Participants With Adverse Events as a Measure of Safety --- Related AE leading to death	8 participants	19 participants
Number of Participants With Adverse Events as a Measure of Safety - AE leading to permanent discontinuation	125 participants	268 participants
Number of Participants With Adverse Events as a Measure of Safety - AE leading to premature discontinuation	73 participants	116 participants

SECONDARY outcome

Timeframe: 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

Population: The analysis was performed on the safety population evaluable for immunogenicity (i.e. exposed to aflibercept with serum samples evaluable for immunogenicity).

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.

Outcome measures

Outcome measures
Measure	Placebo n=149 Participants Placebo, 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily	Aflibercept n=179 Participants Aflibercept, 6 mg/kg 1 hour IV, immediately followed by docetaxel, 75 mg/m² 1 hour IV, every 3 weeks in combination with oral prednisone or prednisolone, 5 mg PO twice daily
Number of Participants With Positive Anti-aflibercept Antibody Levels as a Measure of Immunogenicity of Aflibercept At baseline	0 participants	2 participants
Number of Participants With Positive Anti-aflibercept Antibody Levels as a Measure of Immunogenicity of Aflibercept At any time post-baseline	4 participants	9 participants
Number of Participants With Positive Anti-aflibercept Antibody Levels as a Measure of Immunogenicity of Aflibercept - Neutralizing Ab	0 participants	2 participants
Number of Participants With Positive Anti-aflibercept Antibody Levels as a Measure of Immunogenicity of Aflibercept - Not neutralizing Ab	2 participants	5 participants
Number of Participants With Positive Anti-aflibercept Antibody Levels as a Measure of Immunogenicity of Aflibercept - Neutralizing potential not evaluated	2 participants	2 participants

Adverse Events

Placebo

Serious events: 184 serious events

Other events: 551 other events

Deaths: 0 deaths

Aflibercept

Serious events: 331 serious events

Other events: 573 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Trial Transparency Team

Sanofi

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The investigator shall have 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 days for abstracts) in advance of any submission to a journal, and delay publication till the approval of the publication is given in writing by the Sponsor (not to exceed ninety days).
Publication restrictions are in place

Restriction type: OTHER