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TROPIC: XRP6258 Plus Prednisone Compared to Mitoxantrone Plus Prednisone in Hormone Refractory Metastatic Prostate Cancer

Sponsor
Sanofi (Industry)
Overall Status
Completed
CT.gov ID
NCT00417079
Collaborator
(none)
755
Enrollment
26
Locations
2
Arms
32
Duration (Months)
29
Patients Per Site
0.9
Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This is a randomized, open-label, multi-center study comparing the safety and efficacy of XRP6258 plus prednisone to mitoxantrone plus prednisone in the treatment of hormone refractory metastatic prostate cancer previously treated with a Taxotere®-containing regimen. The primary objective is overall survival. Secondary objectives include progression free survival, overall response rate, prostate-specific antigen (PSA) response/progression, pain response/progression, overall safety, and pharmacokinetics. Patients will be treated until disease progression, death, unacceptable toxicity, or for a maximum of 10 cycles. Patients will have long-term follow-up for a maximum of up to 2 years.

Condition or Disease Intervention/Treatment Phase
Phase 3

Study Design

Study Type:
Interventional
Actual Enrollment :
755 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Randomized, Open Label Multi-Center Study of XRP6258 at 25 mg/m^2 in Combination With Prednisone Every 3 Weeks Compared to Mitoxantrone in Combination With Prednisone For The Treatment of Hormone Refractory Metastatic Prostate Cancer Previously Treated With A Taxotere®-Containing Regimen
Study Start Date :
Jan 1, 2007
Actual Primary Completion Date :
Sep 1, 2009
Actual Study Completion Date :
Sep 1, 2009

Arms and Interventions

Arm Intervention/Treatment
Active Comparator: Mitoxantrone + Prednisone

Mitoxantrone + Prednisone

Drug: mitoxantrone
12 mg/m^2 administered by intravenous (IV) route over 15-30 minutes on day 1 of each 21-day cycle

Drug: prednisone
10 mg daily administered by oral route
Experimental: Cabazitaxel + Prednisone

Cabazitaxel + Prednisone

Drug: cabazitaxel (XRP6258) (RPR116258)
25 mg/m^2 administered by intravenous (IV) route over 1 hour on day 1 of each 21-day cycle
Other Names:
  • Jevtana

    • Drug: prednisone
    10 mg daily administered by oral route

    Outcome Measures

    Primary Outcome Measures

    1. Overall Survival [From the date of randomization up to 104 weeks (study cut-off)]

      Overall survival was defined as the time interval from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, the survival time was censored at the last date patient was known to be alive or at the cut-off date, whichever had come first.

    Secondary Outcome Measures

    1. Time to Progression Free Survival (PFS) [From the date of randomization up to 104 weeks (study cut-off)]

      Progression free survival was defined as a composite endpoint evaluated from the date of randomization to the date of tumor progression, PSA progression, pain progression, or death due to any cause, whichever occurred first

    2. Overall Tumor Response [From the date of randomization up to 104 weeks (study cut-off)]

      Tumor Overall Response Rate (ORR) (only in patients with measurable disease): Objective responses (Complete Response and Partial Response) for measurable disease as assessed by investigators according to RECIST criteria. Complete Response (CR) is defined as: Disappearance of all target lesions. Partial Response (PR) is defined as: At least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference baseline sum LD. Confirmation of objective responses will be performed by repeat tumor imaging (CT scans, MRI, bone scans) after the first documentation of response.

    3. Time to Tumor Progression [From the date of randomization up to 104 weeks (study cut-off)]

      Time to tumor progression is defined as the number of months from randomization until evidence of progressive disease (RECIST)

    4. Time to Prostatic Specific Antigen (PSA) Progression [at screening, day 1 of every treatment cycle, up to 104 weeks (study cut-off)]

      In PSA non-responders, progression will be defined as a 25% increase over nadir and increase in the absolute value PSA level by at least 5 ng/ml and confirmed by a second value at least 4 weeks later. In PSA responders and in patients not evaluable for PSA response at baseline, progression will be defined as a ≥50% increase over nadir, provided that the increase is a minimum of 5 ng/ml and confirmed by a second value at least 1 week later.

    5. PSA (Prostate-Specific Antigen) Response [from baseline up to 104 weeks (study cut-off)]

      PSA response was defined as a ≥ 50% reduction in serum PSA, determined only for patients with a serum PSA ≥ 20ng/mL at baseline, confirmed by a repeat PSA ≥ 3 weeks later.

    6. Time to Pain Progression [from baseline up to 104 weeks (study cut-off)]

      Pain Progression is defined as an increase of ≥1 point in the median Personal Pain Intensity (PPI) from its nadir noted on 2 consecutive 3-week-apart visits or ≥25 % increase in the mean analgesic score compared with the baseline score & noted on 2 consecutive 3-week-apart visits or requirement for local palliative radiotherapy. Evaluation of the PPI & analgesic scores are based on the short-form McGill Pain Questionnaire which consists of 15 descriptors (11 sensory; 4 affective) which are rated on an intensity scale as 0=none (best) 1=mild 2=moderate 3=severe (worst) (TOTAL: 0=best 45=worst)

    7. Pain Response [from baseline up to 104 weeks (study cut-off)]

      Pain Response was defined as a two-point or greater reduction from baseline median Present Pain Intensity (PPI) score without an increased Analgesic Score (AS) or a decrease of ≥50% in the AS without an increase in the PPI score, maintained for at least 3 weeks.

    Eligibility Criteria

    Criteria

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

    Inclusion Criteria

    1. Histologically or cytologically confirmed adenocarcinoma of the prostate that is refractory to hormone therapy and previously treated with a Taxotere®-containing regimen.

    2. Documented progression of disease (demonstrating at least one visceral or soft tissue metastatic lesion, including a new lesion). Patients with non-measurable disease must have documented rising prostate-specific antigen (PSA) levels or appearance of new lesion.

    3. Surgical or hormone-induced castration

    4. Life expectancy > 2 months

    5. Eastern Cooperative Oncology Group (ECOG) performance status 0 - 2

    Exclusion criteria

    1. Previous treatment with mitoxantrone

    2. Previous treatment with <225 mg/m^2 cumulative dose of Taxotere (or docetaxel)

    3. Prior radiotherapy to ≥ 40% of bone marrow

    4. Surgery, radiation, chemotherapy, or other anti-cancer therapy within 4 weeks prior to enrollment in the study

    5. Other prior malignancy, except for adequately treated superficial basal cell skin cancer, or any other cancer from which the patient has been disease-free for less than 5 years

    6. Known brain or leptomeningeal involvement

    7. Other concurrent serious illness or medical conditions

    8. Inadequate organ function evidenced by unacceptable laboratory results

    The investigator will evaluate whether there are other reasons why a patient may not participate.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 sanofi-aventis US Bridgewater New Jersey United States 08807
    2 sanofi-aventis Argentina Buenos Aires Argentina
    3 sanofi-aventis Belgium Diegem Belgium
    4 sanofi-aventis Brazil Sao Paulo Brazil
    5 sanofi-aventis Canada Laval Quebec Canada
    6 sanofi-aventis Chile Santiago Chile
    7 sanofi-aventis Czech Republic Praha Czech Republic
    8 sanofi-aventis Denmark Horsholm Denmark
    9 sanofi-aventis Finland Helsinki Finland
    10 sanofi-aventis France Paris France
    11 sanofi-aventis Germany Berlin Germany
    12 Sanofi-Aventis Hungaria Budapest Hungary
    13 sanofi-aventis India Mumbai India
    14 sanofi-aventis Italy Milano Italy
    15 sanofi-aventis South Korea Seoul Korea, Republic of
    16 sanofi-aventis Mexico Mexico Mexico
    17 sanofi-aventis Netherlands Gouda Netherlands
    18 sanofi-aventis Russia Moscow Russian Federation
    19 sanofi-aventis Singapore Singapore Singapore
    20 sanofi-aventis Slovakia Bratislava Slovakia
    21 sanofi-aventis South Africa Midrand South Africa
    22 sanofi-aventis Spain Barcelona Spain
    23 sanofi-aventis Sweden Bromma Sweden
    24 sanofi-aventis Taiwan Taipei Taiwan
    25 sanofi-aventis Turkey Istanbul Turkey
    26 sanofi-aventis UK Guildford Surrey United Kingdom

    Sponsors and Collaborators

    • Sanofi

    Investigators

    • Study Director: ICD, Sanofi

    Study Documents (Full-Text)

    None provided.

    More Information

    Publications

    None provided.
    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00417079
    Other Study ID Numbers:
    • EFC6193
    First Posted:
    Dec 29, 2006
    Last Update Posted:
    Mar 10, 2011
    Last Verified:
    Mar 1, 2011
    Keywords provided by , ,
    Cancer
    Prostate
    Additional relevant MeSH terms:
    Prostatic Neoplasms
    Neoplasms
    Prednisone
    Mitoxantrone

    Study Results

    Participant Flow

    Recruitment Details Multicenter study: 146 actives sites from 26 countries in Europe, USA, South America and Asia Pacific region. Study initiation date: January 2nd, 2007; study completion date/study cut off date: September 25th, 2009.
    Pre-assignment Detail 165 patients signed informed consent but were not randomized and considered as screen failure. Intention to Treat Population (ITT or randomized patients): 755 patients (377 mitoxantrone, 378 cabazitaxel). Safety population (treated patients): 742 patients (371 mitoxantrone, 371 cabazitaxel) (Patients not treated: 6 mitoxantrone, 7 cabazitaxel).
    Arm/Group Title Mitoxantrone + Prednisone Cabazitaxel + Prednisone
    Arm/Group Description mitoxantrone 12 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily cabazitaxel 25 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily
    Period Title: Overall Study
    STARTED 377 378
    COMPLETED 46 105
    NOT COMPLETED 331 273

    Baseline Characteristics

    Arm/Group Title Mitoxantrone + Prednisone Cabazitaxel + Prednisone Total
    Arm/Group Description mitoxantrone 12 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily cabazitaxel 25 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily Total of all reporting groups
    Overall Participants 377 378 755
    Age (years) [Median (Full Range) ]
    Median (Full Range) [years]
    67.0
    68.0
    67
    Sex/Gender, Customized (participants) [Number]
    Male
    377
    100%
    378
    100%
    755
    100%
    Region of Enrollment (participants) [Number]
    United States
    106
    28.1%
    97
    25.7%
    203
    26.9%
    Taiwan
    4
    1.1%
    7
    1.9%
    11
    1.5%
    Slovakia
    1
    0.3%
    1
    0.3%
    2
    0.3%
    Spain
    10
    2.7%
    9
    2.4%
    19
    2.5%
    Chile
    9
    2.4%
    12
    3.2%
    21
    2.8%
    Russian Federation
    6
    1.6%
    4
    1.1%
    10
    1.3%
    Italy
    17
    4.5%
    18
    4.8%
    35
    4.6%
    India
    11
    2.9%
    9
    2.4%
    20
    2.6%
    France
    44
    11.7%
    46
    12.2%
    90
    11.9%
    Denmark
    19
    5%
    26
    6.9%
    45
    6%
    South Africa
    7
    1.9%
    9
    2.4%
    16
    2.1%
    Netherlands
    8
    2.1%
    9
    2.4%
    17
    2.3%
    Korea, Republic of
    8
    2.1%
    7
    1.9%
    15
    2%
    Finland
    4
    1.1%
    1
    0.3%
    5
    0.7%
    Turkey
    17
    4.5%
    19
    5%
    36
    4.8%
    United Kingdom
    17
    4.5%
    20
    5.3%
    37
    4.9%
    Hungary
    8
    2.1%
    7
    1.9%
    15
    2%
    Czech Republic
    10
    2.7%
    12
    3.2%
    22
    2.9%
    Mexico
    2
    0.5%
    3
    0.8%
    5
    0.7%
    Canada
    16
    4.2%
    16
    4.2%
    32
    4.2%
    Argentina
    7
    1.9%
    3
    0.8%
    10
    1.3%
    Brazil
    7
    1.9%
    4
    1.1%
    11
    1.5%
    Belgium
    16
    4.2%
    15
    4%
    31
    4.1%
    Singapore
    6
    1.6%
    3
    0.8%
    9
    1.2%
    Germany
    6
    1.6%
    11
    2.9%
    17
    2.3%
    Sweden
    11
    2.9%
    10
    2.6%
    21
    2.8%
    Eastern Cooperative Oncology Group (ECOG) Performance Status (Number) [Number]
    0 - Fully Active
    120
    31.8%
    141
    37.3%
    261
    34.6%
    1 - Ambulatory, Restricted Activity
    224
    59.4%
    209
    55.3%
    433
    57.4%
    2 - Ambulatory, No Work Activities
    33
    8.8%
    28
    7.4%
    61
    8.1%
    Prostatic Specific Antigen PSA (ng/mL) [Median (Full Range) ]
    Median (Full Range) [ng/mL]
    127.5
    143.9
    135.00
    Measurable disease (Number) [Number]
    Measurable disease
    204
    54.1%
    201
    53.2%
    405
    53.6%
    Not Measurable disease
    173
    45.9%
    177
    46.8%
    350
    46.4%
    Extent of disease (Number) [Number]
    Metastatic
    356
    94.4%
    364
    96.3%
    720
    95.4%
    Locoregional Recurrence
    20
    5.3%
    14
    3.7%
    34
    4.5%
    Missing
    1
    0.3%
    0
    0%
    1
    0.1%
    Tumor Location: number of sites involved (Number) [Number]
    1
    134
    35.5%
    146
    38.6%
    280
    37.1%
    2
    117
    31%
    112
    29.6%
    229
    30.3%
    3
    78
    20.7%
    73
    19.3%
    151
    20%
    4 or more
    43
    11.4%
    44
    11.6%
    87
    11.5%
    Missing
    5
    1.3%
    3
    0.8%
    8
    1.1%

    Outcome Measures

    1. Primary Outcome
    Title Overall Survival
    Description Overall survival was defined as the time interval from the date of randomization to the date of death due to any cause. In the absence of confirmation of death, the survival time was censored at the last date patient was known to be alive or at the cut-off date, whichever had come first.
    Time Frame From the date of randomization up to 104 weeks (study cut-off)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on the intention To Treat (ITT) population. The ITT population is composed of all randomized patients (i.e. patients assigned to a treatment group by the randomization, regardless of whether patients received any study drug or received a different study drug from which they were randomized).
    Arm/Group Title Mitoxantrone + Prednisone Cabazitaxel + Prednisone
    Arm/Group Description mitoxantrone 12 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily cabazitaxel 25 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily
    Measure Participants 377 378
    Median (95% Confidence Interval) [Months]
    12.7
    15.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Mitoxantrone + Prednisone, Cabazitaxel + Prednisone
    Comments The study required an estimated sample size of 720 patients (360 per arm) in order to detect a 25% reduction in the hazard ratio for death in the cabazitaxel group relative to the mitoxantrone group with 90% power. The final analysis was planned for when 511 deaths had occurred.
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments A 2-sided significance level of 0.0452 was used for the final analysis based on an interim analysis performed after 307 events with an adjusted significance level of 0.016 based on the O'Brien-Fleming type 1 error spending function.
    Method Log Rank
    Comments Analysis was performed by using a log-rank comparisons stratified according to disease measurability and ECOG performance status (0-1 versus 2)
    2. Secondary Outcome
    Title Time to Progression Free Survival (PFS)
    Description Progression free survival was defined as a composite endpoint evaluated from the date of randomization to the date of tumor progression, PSA progression, pain progression, or death due to any cause, whichever occurred first
    Time Frame From the date of randomization up to 104 weeks (study cut-off)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on the intention To Treat (ITT) population. The ITT population is composed of all randomized patients (i.e. patients assigned to a treatment group by the randomization, regardless of whether patients received any study drug or received a different study drug from which they were randomized).
    Arm/Group Title Mitoxantrone + Prednisone Cabazitaxel + Prednisone
    Arm/Group Description mitoxantrone 12 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily cabazitaxel 25 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily
    Measure Participants 377 378
    Median (95% Confidence Interval) [Months]
    1.4
    2.8
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Mitoxantrone + Prednisone, Cabazitaxel + Prednisone
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Log Rank
    Comments
    3. Secondary Outcome
    Title Overall Tumor Response
    Description Tumor Overall Response Rate (ORR) (only in patients with measurable disease): Objective responses (Complete Response and Partial Response) for measurable disease as assessed by investigators according to RECIST criteria. Complete Response (CR) is defined as: Disappearance of all target lesions. Partial Response (PR) is defined as: At least a 30% decrease in the sum of longest diameter (LD) of target lesions taking as reference baseline sum LD. Confirmation of objective responses will be performed by repeat tumor imaging (CT scans, MRI, bone scans) after the first documentation of response.
    Time Frame From the date of randomization up to 104 weeks (study cut-off)

    Outcome Measure Data

    Analysis Population Description
    Tumor response rate was evaluated only for patients, in the Intention-To-Treat (ITT) population, with measurable disease by Response Evaluation Criteria in Solid Tumor (RECIST).
    Arm/Group Title Mitoxantrone + Prednisone Cabazitaxel + Prednisone
    Arm/Group Description mitoxantrone 12 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily cabazitaxel 25 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily
    Measure Participants 204 201
    Number (95% Confidence Interval) [percentage of participants]
    4.4
    1.2%
    14.4
    3.8%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Mitoxantrone + Prednisone, Cabazitaxel + Prednisone
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0005
    Comments
    Method Chi-squared
    Comments
    4. Secondary Outcome
    Title Time to Tumor Progression
    Description Time to tumor progression is defined as the number of months from randomization until evidence of progressive disease (RECIST)
    Time Frame From the date of randomization up to 104 weeks (study cut-off)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on the intention To Treat (ITT) population. The ITT population is composed of all randomized patients (i.e. patients assigned to a treatment group by the randomization, regardless of whether patients received any study drug or received a different study drug from which they were randomized).
    Arm/Group Title Mitoxantrone + Prednisone Cabazitaxel + Prednisone
    Arm/Group Description mitoxantrone 12 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily cabazitaxel 25 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily
    Measure Participants 377 378
    Median (95% Confidence Interval) [Months]
    5.4
    8.8
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Mitoxantrone + Prednisone, Cabazitaxel + Prednisone
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value <0.0001
    Comments
    Method Log Rank
    Comments Log-rank comparisons stratified according to disease measurability and ECOG performance status.
    Method of Estimation Estimation Parameter Cox Proportional Hazard
    Estimated Value 0.61
    Confidence Interval (2-Sided) 95%
    0.49 to 0.76
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio (HR) < 1 favours the cabazitaxel group and > 1 favours the mitoxantrone group.
    5. Secondary Outcome
    Title Time to Prostatic Specific Antigen (PSA) Progression
    Description In PSA non-responders, progression will be defined as a 25% increase over nadir and increase in the absolute value PSA level by at least 5 ng/ml and confirmed by a second value at least 4 weeks later. In PSA responders and in patients not evaluable for PSA response at baseline, progression will be defined as a ≥50% increase over nadir, provided that the increase is a minimum of 5 ng/ml and confirmed by a second value at least 1 week later.
    Time Frame at screening, day 1 of every treatment cycle, up to 104 weeks (study cut-off)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on the intention To Treat (ITT) population. The ITT population is composed of all randomized patients (i.e. patients assigned to a treatment group by the randomization, regardless of whether patients received any study drug or received a different study drug from which they were randomized).
    Arm/Group Title Mitoxantrone + Prednisone Cabazitaxel + Prednisone
    Arm/Group Description mitoxantrone 12 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily cabazitaxel 25 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily
    Measure Participants 377 378
    Median (95% Confidence Interval) [Months]
    3.1
    6.4
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Mitoxantrone + Prednisone, Cabazitaxel + Prednisone
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0010
    Comments
    Method Log Rank
    Comments Log-rank comparisons stratified according to disease measurability and ECOG performance status.
    Method of Estimation Estimation Parameter Cox Proportional Hazard
    Estimated Value 0.75
    Confidence Interval (2-Sided) 95%
    0.63 to 0.90
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio (HR) < 1 favours the cabazitaxel group and > 1 favours the mitoxantrone group.
    6. Secondary Outcome
    Title PSA (Prostate-Specific Antigen) Response
    Description PSA response was defined as a ≥ 50% reduction in serum PSA, determined only for patients with a serum PSA ≥ 20ng/mL at baseline, confirmed by a repeat PSA ≥ 3 weeks later.
    Time Frame from baseline up to 104 weeks (study cut-off)

    Outcome Measure Data

    Analysis Population Description
    Prostate Specific Antigen (PSA) response was evaluated only in patients, in the Intention-To-Treat population, with a baseline PSA >20ng/mL.
    Arm/Group Title Mitoxantrone + Prednisone Cabazitaxel + Prednisone
    Arm/Group Description mitoxantrone 12 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily cabazitaxel 25 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily
    Measure Participants 325 329
    Number (95% Confidence Interval) [Percentage of participants]
    17.8
    4.7%
    39.2
    10.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Mitoxantrone + Prednisone, Cabazitaxel + Prednisone
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.0002
    Comments
    Method Chi-squared
    Comments
    7. Secondary Outcome
    Title Time to Pain Progression
    Description Pain Progression is defined as an increase of ≥1 point in the median Personal Pain Intensity (PPI) from its nadir noted on 2 consecutive 3-week-apart visits or ≥25 % increase in the mean analgesic score compared with the baseline score & noted on 2 consecutive 3-week-apart visits or requirement for local palliative radiotherapy. Evaluation of the PPI & analgesic scores are based on the short-form McGill Pain Questionnaire which consists of 15 descriptors (11 sensory; 4 affective) which are rated on an intensity scale as 0=none (best) 1=mild 2=moderate 3=severe (worst) (TOTAL: 0=best 45=worst)
    Time Frame from baseline up to 104 weeks (study cut-off)

    Outcome Measure Data

    Analysis Population Description
    Analysis was performed on the intention To Treat (ITT) population. Data from 265 and 279 patients in the cabazitaxel and mitoxantrone groups, respectively, were censored as a results of > 2 PPI and/or AS assessments being missed during the same week (unless a complete evaluation of ≥5 values showed pain progression).
    Arm/Group Title Mitoxantrone + Prednisone Cabazitaxel + Prednisone
    Arm/Group Description mitoxantrone 12 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily cabazitaxel 25 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily
    Measure Participants 377 378
    Median (95% Confidence Interval) [Months]
    NA
    11.1
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Mitoxantrone + Prednisone, Cabazitaxel + Prednisone
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.5192
    Comments
    Method Log Rank
    Comments Log-rank comparisons stratified according to disease measurability and ECOG performance status.
    Method of Estimation Estimation Parameter Cox Proportional Hazard
    Estimated Value 0.91
    Confidence Interval (2-Sided) 95%
    0.69 to 1.19
    Parameter Dispersion Type:
    Value:
    Estimation Comments Hazard ratio (HR) < 1 favours the cabazitaxel group and > 1 favours the mitoxantrone group.
    8. Secondary Outcome
    Title Pain Response
    Description Pain Response was defined as a two-point or greater reduction from baseline median Present Pain Intensity (PPI) score without an increased Analgesic Score (AS) or a decrease of ≥50% in the AS without an increase in the PPI score, maintained for at least 3 weeks.
    Time Frame from baseline up to 104 weeks (study cut-off)

    Outcome Measure Data

    Analysis Population Description
    Pain Response (applies only to patients, in the Intention-To-Treat (ITT) population, with median PPI ≥2 on McGill-Melzack scale and/or mean Analgesic Score ≥10 points at baseline)
    Arm/Group Title Mitoxantrone + Prednisone Cabazitaxel + Prednisone
    Arm/Group Description mitoxantrone 12 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily cabazitaxel 25 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily
    Measure Participants 168 174
    Number (95% Confidence Interval) [Percentage of participants]
    7.7
    2%
    9.2
    2.4%
    Statistical Analysis 1
    Statistical Analysis Overview Comparison Group Selection Mitoxantrone + Prednisone, Cabazitaxel + Prednisone
    Comments
    Type of Statistical Test Superiority or Other
    Comments
    Statistical Test of Hypothesis p-Value 0.6286
    Comments
    Method Chi-squared
    Comments

    Adverse Events

    Time Frame Adverse events are collected from the time to the first patient signed an informed consent form until 30 days after the administration of the last cycle of the study treatment to the last patient (i.e. 104 weeks).
    Adverse Event Reporting Description The safety analyses are performed on the safety population which includes all randomized patients who received at least part of one dose of the study drug.
    Arm/Group Title Mitoxantrone + Prednisone Cabazitaxel + Prednisone
    Arm/Group Description mitoxantrone 12 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily cabazitaxel 25 mg/m^2 (Day 1) by intravenous (IV) every 3 weeks, and prednisone 10 mg orally given daily
    All Cause Mortality
    Mitoxantrone + Prednisone Cabazitaxel + Prednisone
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total / (NaN) / (NaN)
    Serious Adverse Events
    Mitoxantrone + Prednisone Cabazitaxel + Prednisone
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 77/371 (20.8%) 145/371 (39.1%)
    Blood and lymphatic system disorders
    Febrile neutropenia 4/371 (1.1%) 25/371 (6.7%)
    Neutropenia 3/371 (0.8%) 18/371 (4.9%)
    Leukopenia 0/371 (0%) 3/371 (0.8%)
    Anaemia 2/371 (0.5%) 2/371 (0.5%)
    Thrombocytopenia 0/371 (0%) 2/371 (0.5%)
    Pancytopenia 1/371 (0.3%) 0/371 (0%)
    Cardiac disorders
    Atrial fibrillation 1/371 (0.3%) 2/371 (0.5%)
    Cardiac arrest 0/371 (0%) 2/371 (0.5%)
    Cardiac failure 0/371 (0%) 2/371 (0.5%)
    Ventricular fibrillation 0/371 (0%) 1/371 (0.3%)
    Cardiotoxicity 1/371 (0.3%) 0/371 (0%)
    Myocardial infarction 1/371 (0.3%) 0/371 (0%)
    Gastrointestinal disorders
    Diarrhoea 0/371 (0%) 9/371 (2.4%)
    Vomiting 2/371 (0.5%) 6/371 (1.6%)
    Abdominal pain 0/371 (0%) 6/371 (1.6%)
    Constipation 1/371 (0.3%) 3/371 (0.8%)
    Nausea 1/371 (0.3%) 3/371 (0.8%)
    Intestinal obstruction 0/371 (0%) 3/371 (0.8%)
    Rectal haemorrhage 0/371 (0%) 2/371 (0.5%)
    Abdominal pain lower 0/371 (0%) 1/371 (0.3%)
    Caecitis 0/371 (0%) 1/371 (0.3%)
    Duodenal ulcer perforation 0/371 (0%) 1/371 (0.3%)
    Dysphagia 0/371 (0%) 1/371 (0.3%)
    Enterocolitis 0/371 (0%) 1/371 (0.3%)
    Enterovesical fistula 0/371 (0%) 1/371 (0.3%)
    Gastric ulcer 0/371 (0%) 1/371 (0.3%)
    Haemorrhoidal haemorrhage 0/371 (0%) 1/371 (0.3%)
    Mesenteric vein thrombosis 0/371 (0%) 1/371 (0.3%)
    Oesophageal ulcer 0/371 (0%) 1/371 (0.3%)
    Haematemesis 2/371 (0.5%) 0/371 (0%)
    Pancreatic mass 1/371 (0.3%) 0/371 (0%)
    Pancreatitis 1/371 (0.3%) 0/371 (0%)
    Proctalgia 1/371 (0.3%) 0/371 (0%)
    General disorders
    Pyrexia 1/371 (0.3%) 6/371 (1.6%)
    Asthenia 0/371 (0%) 2/371 (0.5%)
    Chest pain 0/371 (0%) 2/371 (0.5%)
    Disease progression 11/371 (3%) 1/371 (0.3%)
    Fatigue 0/371 (0%) 1/371 (0.3%)
    Influenza like illness 0/371 (0%) 1/371 (0.3%)
    Oedema peripheral 0/371 (0%) 1/371 (0.3%)
    Pain 0/371 (0%) 1/371 (0.3%)
    Sudden death 0/371 (0%) 1/371 (0.3%)
    Hepatobiliary disorders
    Bile duct stone 0/371 (0%) 1/371 (0.3%)
    Biliary colic 0/371 (0%) 1/371 (0.3%)
    Cholecystitis 0/371 (0%) 1/371 (0.3%)
    Cholangitis 1/371 (0.3%) 0/371 (0%)
    Hepatic failure 1/371 (0.3%) 0/371 (0%)
    Immune system disorders
    Anaphylactic shock 0/371 (0%) 1/371 (0.3%)
    Infections and infestations
    Pneumonia 2/371 (0.5%) 6/371 (1.6%)
    Urinary tract infection 3/371 (0.8%) 4/371 (1.1%)
    Sepsis 0/371 (0%) 4/371 (1.1%)
    Septic shock 0/371 (0%) 4/371 (1.1%)
    Neutropenic sepsis 1/371 (0.3%) 3/371 (0.8%)
    Infection 2/371 (0.5%) 2/371 (0.5%)
    Neutropenic infection 0/371 (0%) 2/371 (0.5%)
    Salmonellosis 0/371 (0%) 2/371 (0.5%)
    Cellulitis 2/371 (0.5%) 1/371 (0.3%)
    Urosepsis 2/371 (0.5%) 1/371 (0.3%)
    Cystitis 1/371 (0.3%) 1/371 (0.3%)
    Lobar pneumonia 1/371 (0.3%) 1/371 (0.3%)
    Bacteraemia 0/371 (0%) 1/371 (0.3%)
    Bronchopneumonia 0/371 (0%) 1/371 (0.3%)
    Campylobacter infection 0/371 (0%) 1/371 (0.3%)
    Fungal sepsis 0/371 (0%) 1/371 (0.3%)
    Groin abscess 0/371 (0%) 1/371 (0.3%)
    Implant site cellulitis 0/371 (0%) 1/371 (0.3%)
    Oesophageal candidiasis 0/371 (0%) 1/371 (0.3%)
    Pneumonia klebsiella 0/371 (0%) 1/371 (0.3%)
    Urinary tract infection enterococcal 0/371 (0%) 1/371 (0.3%)
    Urinary tract infection fungal 0/371 (0%) 1/371 (0.3%)
    Bacterial sepsis 1/371 (0.3%) 0/371 (0%)
    Febrile infection 1/371 (0.3%) 0/371 (0%)
    Pneumococcal sepsis 1/371 (0.3%) 0/371 (0%)
    Injury, poisoning and procedural complications
    Hip fracture 1/371 (0.3%) 2/371 (0.5%)
    Ankle fracture 0/371 (0%) 1/371 (0.3%)
    Femur fracture 0/371 (0%) 1/371 (0.3%)
    Accidental overdose 1/371 (0.3%) 0/371 (0%)
    Alcohol poisoning 1/371 (0.3%) 0/371 (0%)
    Fracture 1/371 (0.3%) 0/371 (0%)
    Multiple fractures 1/371 (0.3%) 0/371 (0%)
    Tibia fracture 1/371 (0.3%) 0/371 (0%)
    Investigations
    Eastern cooperative oncology group performance status worsened 0/371 (0%) 1/371 (0.3%)
    Metabolism and nutrition disorders
    Dehydration 1/371 (0.3%) 4/371 (1.1%)
    Electrolyte imbalance 0/371 (0%) 1/371 (0.3%)
    Hyperglycaemia 0/371 (0%) 1/371 (0.3%)
    Hyperkalaemia 0/371 (0%) 1/371 (0.3%)
    Hypoalbuminaemia 0/371 (0%) 1/371 (0.3%)
    Musculoskeletal and connective tissue disorders
    Back pain 4/371 (1.1%) 3/371 (0.8%)
    Pain in extremity 2/371 (0.5%) 2/371 (0.5%)
    Osteonecrosis 2/371 (0.5%) 1/371 (0.3%)
    Flank pain 0/371 (0%) 1/371 (0.3%)
    Arthralgia 1/371 (0.3%) 0/371 (0%)
    Spinal column stenosis 1/371 (0.3%) 0/371 (0%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain 1/371 (0.3%) 1/371 (0.3%)
    Metastatic pain 1/371 (0.3%) 1/371 (0.3%)
    Gastric cancer 1/371 (0.3%) 0/371 (0%)
    Metastases to meninges 1/371 (0.3%) 0/371 (0%)
    Metastases to spine 1/371 (0.3%) 0/371 (0%)
    Prostate cancer metastatic 1/371 (0.3%) 0/371 (0%)
    Nervous system disorders
    Spinal cord compression 3/371 (0.8%) 4/371 (1.1%)
    Syncope 1/371 (0.3%) 2/371 (0.5%)
    Cerebral haemorrhage 0/371 (0%) 1/371 (0.3%)
    Grand mal convulsion 0/371 (0%) 1/371 (0.3%)
    Metabolic encephalopathy 0/371 (0%) 1/371 (0.3%)
    Neuropathy peripheral 0/371 (0%) 1/371 (0.3%)
    Presyncope 0/371 (0%) 1/371 (0.3%)
    Speech disorder 0/371 (0%) 1/371 (0.3%)
    Vith nerve paralysis 0/371 (0%) 1/371 (0.3%)
    Altered state of consciousness 1/371 (0.3%) 0/371 (0%)
    Cerebral infarction 1/371 (0.3%) 0/371 (0%)
    Cerebrovascular accident 1/371 (0.3%) 0/371 (0%)
    Cranial nerve paralysis 1/371 (0.3%) 0/371 (0%)
    Epiduritis 1/371 (0.3%) 0/371 (0%)
    Peripheral motor neuropathy 1/371 (0.3%) 0/371 (0%)
    Vestibular nystagmus 1/371 (0.3%) 0/371 (0%)
    Psychiatric disorders
    Confusional state 3/371 (0.8%) 1/371 (0.3%)
    Suicidal ideation 0/371 (0%) 1/371 (0.3%)
    Psychotic disorder 1/371 (0.3%) 0/371 (0%)
    Renal and urinary disorders
    Haematuria 3/371 (0.8%) 10/371 (2.7%)
    Renal failure 0/371 (0%) 6/371 (1.6%)
    Renal failure acute 0/371 (0%) 5/371 (1.3%)
    Hydronephrosis 1/371 (0.3%) 4/371 (1.1%)
    Ureteric obstruction 0/371 (0%) 4/371 (1.1%)
    Urinary retention 2/371 (0.5%) 2/371 (0.5%)
    Ureteric stenosis 1/371 (0.3%) 1/371 (0.3%)
    Bladder neck obstruction 0/371 (0%) 1/371 (0.3%)
    Renal colic 0/371 (0%) 1/371 (0.3%)
    Urethral pain 0/371 (0%) 1/371 (0.3%)
    Urethral stenosis 0/371 (0%) 1/371 (0.3%)
    Urinary tract obstruction 0/371 (0%) 1/371 (0.3%)
    Postrenal failure 1/371 (0.3%) 0/371 (0%)
    Reproductive system and breast disorders
    Penile oedema 1/371 (0.3%) 0/371 (0%)
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism 6/371 (1.6%) 5/371 (1.3%)
    Dyspnoea 1/371 (0.3%) 3/371 (0.8%)
    Respiratory failure 0/371 (0%) 2/371 (0.5%)
    Aspiration 0/371 (0%) 1/371 (0.3%)
    Chylothorax 0/371 (0%) 1/371 (0.3%)
    Hypoxia 0/371 (0%) 1/371 (0.3%)
    Pneumonitis 0/371 (0%) 1/371 (0.3%)
    Chronic obstructive pulmonary disease 1/371 (0.3%) 0/371 (0%)
    Pleural effusion 1/371 (0.3%) 0/371 (0%)
    Vascular disorders
    Deep vein thrombosis 2/371 (0.5%) 2/371 (0.5%)
    Haematoma 0/371 (0%) 1/371 (0.3%)
    Hypotension 0/371 (0%) 1/371 (0.3%)
    Orthostatic hypotension 0/371 (0%) 1/371 (0.3%)
    Extremity necrosis 1/371 (0.3%) 0/371 (0%)
    Other (Not Including Serious) Adverse Events
    Mitoxantrone + Prednisone Cabazitaxel + Prednisone
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 323/371 (87.1%) 350/371 (94.3%)
    Blood and lymphatic system disorders
    Neutropenia 38/371 (10.2%) 66/371 (17.8%)
    Anaemia 18/371 (4.9%) 38/371 (10.2%)
    Gastrointestinal disorders
    Diarrhoea 39/371 (10.5%) 170/371 (45.8%)
    Nausea 84/371 (22.6%) 127/371 (34.2%)
    Vomiting 36/371 (9.7%) 80/371 (21.6%)
    Constipation 56/371 (15.1%) 73/371 (19.7%)
    Abdominal pain 13/371 (3.5%) 38/371 (10.2%)
    Dyspepsia 6/371 (1.6%) 25/371 (6.7%)
    Abdominal pain upper 5/371 (1.3%) 20/371 (5.4%)
    General disorders
    Fatigue 102/371 (27.5%) 136/371 (36.7%)
    Asthenia 46/371 (12.4%) 76/371 (20.5%)
    Pyrexia 22/371 (5.9%) 40/371 (10.8%)
    Oedema peripheral 34/371 (9.2%) 34/371 (9.2%)
    Mucosal inflammation 10/371 (2.7%) 22/371 (5.9%)
    Pain 18/371 (4.9%) 19/371 (5.1%)
    Infections and infestations
    Urinary tract infection 9/371 (2.4%) 24/371 (6.5%)
    Investigations
    Weight decreased 28/371 (7.5%) 32/371 (8.6%)
    Metabolism and nutrition disorders
    Anorexia 39/371 (10.5%) 59/371 (15.9%)
    Musculoskeletal and connective tissue disorders
    Back pain 41/371 (11.1%) 58/371 (15.6%)
    Arthralgia 31/371 (8.4%) 39/371 (10.5%)
    Pain in extremity 27/371 (7.3%) 29/371 (7.8%)
    Muscle spasms 10/371 (2.7%) 27/371 (7.3%)
    Bone pain 19/371 (5.1%) 19/371 (5.1%)
    Musculoskeletal pain 20/371 (5.4%) 18/371 (4.9%)
    Nervous system disorders
    Dysgeusia 15/371 (4%) 41/371 (11.1%)
    Dizziness 21/371 (5.7%) 30/371 (8.1%)
    Neuropathy peripheral 4/371 (1.1%) 30/371 (8.1%)
    Headache 19/371 (5.1%) 28/371 (7.5%)
    Peripheral sensory neuropathy 5/371 (1.3%) 20/371 (5.4%)
    Renal and urinary disorders
    Haematuria 13/371 (3.5%) 58/371 (15.6%)
    Dysuria 5/371 (1.3%) 25/371 (6.7%)
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea 16/371 (4.3%) 43/371 (11.6%)
    Cough 22/371 (5.9%) 40/371 (10.8%)
    Skin and subcutaneous tissue disorders
    Alopecia 18/371 (4.9%) 37/371 (10%)
    Vascular disorders
    Hypotension 9/371 (2.4%) 19/371 (5.1%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

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

    Publication of the study will be made jointly in the name of all wholehearted collaborators. Other papers will be authored based on the contributions of the individuals to the overall study. Substudies with scientific merit which have received prior approval from the Steering Committee (SC) may be published in the names of the contributing investigators. A copy of all manuscripts will be provided to the sponsors for their review. The final decision to publish articles will be made by the SC.

    Results Point of Contact

    Name/Title International Clinical Development Study Director
    Organization sanofi-aventis
    Phone
    Email GV-Contact-us@sanofi-aventis.com
    Responsible Party:
    , ,
    ClinicalTrials.gov Identifier:
    NCT00417079
    Other Study ID Numbers:
    • EFC6193
    First Posted:
    Dec 29, 2006
    Last Update Posted:
    Mar 10, 2011
    Last Verified:
    Mar 1, 2011