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    Clinical Trial Results:
    A Phase I/II Study of Cabazitaxel Combined with Abiraterone Acetate and Prednisone in Patients with Metastatic Castrate-Resistant Prostate Cancer (mCRPC) whose Disease has Progressed after Docetaxel Chemotherapy

    Summary
    EudraCT number
    		 2011-001506-96
    Trial protocol
    		 GB  
    Global end of trial date
    09 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Jul 2016
    First version publication date
    17 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TCD12128
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01511536
    WHO universal trial number (UTN)
    		 U1111-1121-6324
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Jan 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Phase 1 part: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel administered as a 1-hour infusion every 3 weeks in combination with oral daily abiraterone acetate and prednisone in subjects with mCRPC. Phase 2 part: To estimate the activity of cabazitaxel in combination with abiraterone acetate and prednisone in terms of prostate-specific antigen (PSA) Response Rate.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 12
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    37
    EEA total number of subjects
    36
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    15
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at 2 centers in phase 1 part and 3 centers in phase 2 part between March 2012 and April 2014.

    Pre-assignment
    Screening details
    		 Phase I was a dose escalation part of Cabazetaxel, administered with a constant dose of abiraterone, to determine maximally tolerated dose. Phase 2 was efficacy and safety evaluation of Cabazetaxel at a dose, determined in Phase 1,in combination with abiraterone. Cancer progression, adverse event and consent withdrawal were considered as completed.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase 1: Cabazitaxel 20 mg/m^2 + Abiraterone 1000 mg
    Arm description
    		 Cabazitaxel 20 mg/m^2 on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg once daily and prednisone 5 mg twice daily until disease progression, unacceptable toxicity or consent withdrawal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cabazitaxel
    Investigational medicinal product code
    XRP6258
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cabazitaxel 20 mg/m^2 intravenous (IV) infusion over 1 hour on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Abiraterone acetate
    Investigational medicinal product code
    Other name
    Zytiga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    4 tablets of Abiraterone acetate 250 mg orally once daily.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 5 mg orally twice daily.

    Arm title
    		 Phase 1: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Arm description
    		 Cabazitaxel 25 mg/m^2 on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg once daily and prednisone 5 mg twice daily until disease, progression, unacceptable toxicity or consent withdrawal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cabazitaxel
    Investigational medicinal product code
    XRP6258
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cabazitaxel 25 mg/m^2 IV infusion over 1 hour on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Abiraterone acetate
    Investigational medicinal product code
    Other name
    Zytiga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    4 tablets of Abiraterone acetate 250 mg orally once daily.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 5 mg orally twice daily.

    Arm title
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Arm description
    		 Cabazitaxel at MTD as determined in phase 1 part (25 mg/m^2) on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg once daily and prednisone 5 mg twice daily until disease progression, unacceptable toxicity or consent withdrawal.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cabazitaxel
    Investigational medicinal product code
    XRP6258
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cabazitaxel 25 mg/m^2 IV infusion over 1 hour on Day 1 of each 21-day cycle.

    Investigational medicinal product name
    Abiraterone acetate
    Investigational medicinal product code
    Other name
    Zytiga
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    4 tablets of Abiraterone acetate 250 mg orally once daily.

    Investigational medicinal product name
    Prednisone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Prednisone 5 mg orally twice daily.

    Number of subjects in period 1
    		Phase 1: Cabazitaxel 20 mg/m^2 + Abiraterone 1000 mg Phase 1: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Started
    3
    7
    27
    Completed
    3
    6
    18
    Not completed
    0
    1
    9
         Unspecified
    -
    1
    9

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1: Cabazitaxel 20 mg/m^2 + Abiraterone 1000 mg
    Reporting group description
    		 Cabazitaxel 20 mg/m^2 on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg once daily and prednisone 5 mg twice daily until disease progression, unacceptable toxicity or consent withdrawal.

    Reporting group title
    Phase 1: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Reporting group description
    		 Cabazitaxel 25 mg/m^2 on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg once daily and prednisone 5 mg twice daily until disease, progression, unacceptable toxicity or consent withdrawal.

    Reporting group title
    Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Reporting group description
    		 Cabazitaxel at MTD as determined in phase 1 part (25 mg/m^2) on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg once daily and prednisone 5 mg twice daily until disease progression, unacceptable toxicity or consent withdrawal.

    Reporting group values
    		 Phase 1: Cabazitaxel 20 mg/m^2 + Abiraterone 1000 mg Phase 1: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg Total
    Number of subjects
    		 3 7 27 37
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 71 ( 7 ) 60 ( 10 ) 67.1 ( 5.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 0 0
        Male
    		 3 7 27 37

    End points

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    End points reporting groups
    Reporting group title
    Phase 1: Cabazitaxel 20 mg/m^2 + Abiraterone 1000 mg
    Reporting group description
    		 Cabazitaxel 20 mg/m^2 on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg once daily and prednisone 5 mg twice daily until disease progression, unacceptable toxicity or consent withdrawal.

    Reporting group title
    Phase 1: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Reporting group description
    		 Cabazitaxel 25 mg/m^2 on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg once daily and prednisone 5 mg twice daily until disease, progression, unacceptable toxicity or consent withdrawal.

    Reporting group title
    Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Reporting group description
    		 Cabazitaxel at MTD as determined in phase 1 part (25 mg/m^2) on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg once daily and prednisone 5 mg twice daily until disease progression, unacceptable toxicity or consent withdrawal.

    Subject analysis set title
    Phase 1: Overall Population
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Cabazitaxel 20 or 25 mg/m^2 on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg once daily and prednisone 5 mg twice daily until disease progression, unacceptable toxicity or consent withdrawal.

    Primary: Phase 1: MTD of Cabazitaxel in Combination With Abiraterone Acetate

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    End point title
    		 Phase 1: MTD of Cabazitaxel in Combination With Abiraterone Acetate [1]
    End point description
    MTD: highest dose level of cabazitaxel in combination with abiraterone acetate at which no more than 1 subject experienced DLT. DLT: any of events related to study drug:1) Grade 3/4 non-hematological related adverse event (AE) with exception of Grade 3 fever without documented infection;Grade 3 nausea,vomiting, or diarrhea in absence of effective maximal therapy;and Grade 3 hypersensitivity reaction in absence of required premedication. 2) Hematological toxicity: Febrile neutropenia (fever of unknown origin ≥38.5°C with neutropenia Grade 3/4);Neutropenia Grade 4 lasting >7 days;Thrombocytopenia Grade 4 or Grade 3 complicated by hemorrhage. 3) Re-treatment delay of >2 weeks due to delayed recovery from a toxicity related to study treatment to baseline or ≤ Grade 1(except for alopecia). Grades were based on NCICTC for AEs v4.03. DLT evaluable population: all subjects who received first 2 cycles,unless they discontinued study drug during first 2 cycles for DLT.
    End point type
    Primary
    End point timeframe
    Up to Cycle 2 of Phase 1 (up to 42 days)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since analysis is descriptive in nature, statistical data could not be provided.
    End point values
    		 Phase 1: Overall Population
    Number of subjects analysed
    9
    Units: mg/m^2
        number (not applicable)
    25
    No statistical analyses for this end point

    Primary: Phase 2: Percentage of Subjects With Prostate Specific Antigen (PSA) Response

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    End point title
    		 Phase 2: Percentage of Subjects With Prostate Specific Antigen (PSA) Response [2] [3]
    End point description
    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. PSA was to be measured at baseline, every 3 weeks, thoughout study period, until progression. PSA progression was defined as: -An increase of 25% above the nadir (at least 2 ng/mL), confirmed by a second PSA value at least 3 weeks apart, in subjects who have achieved a ≥50% decline of PSA. -An increase in PSA by 25 % above the baseline level (at least 2 ng/mL), confirmed by a second PSA value at least 3 weeks apart, in subjects who have not achieved a ≥50% decline of PSA. Analysis was performed on efficacy/activity population included all subjects who had received at least 2 cycles of the study drug in Phase 2, and had a baseline and at least one post-baseline assessment for the efficacy variable of interest.
    End point type
    Primary
    End point timeframe
    Baseline, every 3 weeks up to PSA progression (maximum duration: 603 days)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Since analysis is descriptive in nature, statistical data could not be provided.
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    26
    Units: percentage of subjects
        number (confidence interval 95%)
    46.2 (26.6 to 66.6)
    No statistical analyses for this end point

    Secondary: Phase 2: Objective Progression Free Survival (PFS)

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    End point title
    		 Phase 2: Objective Progression Free Survival (PFS) [4]
    End point description
    Objective PFS was defined as time interval between date of enrollment and first occurrence of any of events:1) Radiological tumor progression (assessed using Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) was defined as at least a 20 % increase in sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since treatment started or appearance of one or more new lesions and/or unequivocal progression of existing non target-lesions. in case of progressive disease (PD) diagnosed only on non target bone lesions on bone scan, PD was to be considered only in case of appearance of at least 2 new lesions on bone scan confirmed 6 weeks later by another bone scan, and at least the appearance of 2 new additional lesions. 2) Death due to any cause. Analysis was performed by Kaplan-Meier method. Analysis was performed on efficacy/activity population. Here, 99999 represents data was not calculable as <50% subjects had event of interest.
    End point type
    Secondary
    End point timeframe
    From baseline until radiological tumor or disease progression or death due to any cause, assessed up to Month 5
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    26
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Phase 2: PSA Progression Free Survival

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    End point title
    		 Phase 2: PSA Progression Free Survival [5]
    End point description
    Prostate-specific antigen progression-free survival was defined as the time interval between the date of treatment start and the date of either first documented PSA progression or death due to any cause, whichever was earlier. PSA was to be measured at baseline, every 3 weeks, thoughout study period, until progression. PSA progression was defined as: -An increase of 25% above the nadir (at least 2 ng/mL), confirmed by a second PSA value at least 3 weeks apart, in subjects who have achieved a ≥50% decline of PSA. -An increase in PSA by 25 % above the baseline level (at least 2 ng/mL), confirmed by a second PSA value at least 3 weeks apart, in subjects who have not achieved a ≥50% decline of PSA. Analysis was performed by Kaplan Meire method. Analysis was performed on efficacy/activity population.
    End point type
    Secondary
    End point timeframe
    Baseline, every 3 weeks up to PSA progression (maximum duration: 603 days)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    26
    Units: months
        median (confidence interval 95%)
    6.93 (4.14 to 10.251)
    No statistical analyses for this end point

    Secondary: Phase 2: Percentage of Subjects With Objective Response

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    End point title
    		 Phase 2: Percentage of Subjects With Objective Response [6]
    End point description
    Objective response was defined as having complete response (CR) or Partial Response (PR) assessed by RECIST 1.1. CR was defined as disappearance of all target, non-target lesions; normalization of tumor marker level and all lymph nodes size was <10 mm. PR was defined as at least a 30% decrease in the sum of diameters of target lesions (taking as reference the baseline sum diameters). Efficacy/activity population. Number of subjects analyzed=subjects with measurable disease at baseline.
    End point type
    Secondary
    End point timeframe
    Baseline, every 12 weeks there after until disease progression (maximum duration: 603 days)
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    14
    Units: percentage of subjects
        number (confidence interval 95%)
    21.4 (4.7 to 50.8)
    No statistical analyses for this end point

    Secondary: Phase 2: Overall Survival

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    End point title
    		 Phase 2: Overall Survival [7]
    End point description
    Overall survival was defined as the time interval from the date of treatment start to the date of death due to any cause. In absence of confirmation of death, survival time was censored at the earlier of the last date the subject was known to be alive and the study cut-off date. Analysis was performed by Kaplan-Meier method. Analysis was performed on efficacy/activity population. Here, 99999 represents data was not calculable as <50% subjects had event of interest.
    End point type
    Secondary
    End point timeframe
    From baseline up to death or study cut-off (maximum duration: 603 days)
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    26
    Units: months
        median (confidence interval 95%)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Phase 2: Pharmacokinetic of Cabazitaxel : Maximum Plasma Concentration Observed (Cmax)

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    End point title
    		 Phase 2: Pharmacokinetic of Cabazitaxel : Maximum Plasma Concentration Observed (Cmax) [8]
    End point description
    Analysis was performed on pharmacokinetic (PK) population which included all subjects who received at least 1 treatment. Pre-dose samples from 3 subjects of Phase 2, were above lower limit of quantification (LLOQ) (1.00 ng/mL). Hence, those subjects were excluded from analysis.
    End point type
    Secondary
    End point timeframe
    5 minutes before cabazitaxel infusion; at end of cabazitaxel infusion; 0.25 hours post-cabazitaxel infusion; any time between 1 to 4 hours, between 6 to 24 hours, between 48 to 96 hours post cabazitaxel infusion on Day 1-Cycle 1
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    24
    Units: ng/mL
        arithmetic mean (standard deviation)
    330 ( 187 )
    No statistical analyses for this end point

    Secondary: Phase 2: Pharmacokinetic of Cabazitaxel : Area Under the Plasma Concentration Versus Time Curve (AUC)

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    End point title
    		 Phase 2: Pharmacokinetic of Cabazitaxel : Area Under the Plasma Concentration Versus Time Curve (AUC) [9]
    End point description
    Area under the concentration-time curve calculated using the following equation: AUC = Plasma clearance (CL)/dose. Analysis was performed on PK population.
    End point type
    Secondary
    End point timeframe
    5 minutes before cabazitaxel infusion; at end of cabazitaxel infusion; 0.25 hours post-cabazitaxel infusion; any time between 1 to 4 hours, between 6 to 24 hours, between 48 to 96 hours post cabazitaxel infusion on Day 1-Cycle 1
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    24
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    817 ( 117 )
    No statistical analyses for this end point

    Secondary: Phase 2: Pharmacokinetic of Cabazitaxel : Terminal Half-life (t 1/2z)

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    End point title
    		 Phase 2: Pharmacokinetic of Cabazitaxel : Terminal Half-life (t 1/2z) [10]
    End point description
    Analysis was performed on PK population.
    End point type
    Secondary
    End point timeframe
    5 minutes before cabazitaxel infusion; at end of cabazitaxel infusion; 0.25 hours post-cabazitaxel infusion; any time between 1 to 4 hours, between 6 to 24 hours, between 48 to 96 hours post cabazitaxel infusion on Day 1-Cycle 1
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    24
    Units: hour
        arithmetic mean (standard deviation)
    91.6 ( 62.6 )
    No statistical analyses for this end point

    Secondary: Phase 2: Pharmacokinetic of Cabazitaxel : Total Plasma Clearance (CL)

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    End point title
    		 Phase 2: Pharmacokinetic of Cabazitaxel : Total Plasma Clearance (CL) [11]
    End point description
    Analysis was performed on PK population.
    End point type
    Secondary
    End point timeframe
    5 minutes before cabazitaxel infusion; at end of cabazitaxel infusion; 0.25 hours post-cabazitaxel infusion; any time between 1 to 4 hours, between 6 to 24 hours, between 48 to 96 hours post cabazitaxel infusion on Day 1-Cycle 1
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    24
    Units: L/h/m^2
        arithmetic mean (standard deviation)
    31.4 ( 4.67 )
    No statistical analyses for this end point

    Secondary: Phase 2: Pharmacokinetic of Cabazitaxel : Volume of Distribution at Steady State (Vss)

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    End point title
    		 Phase 2: Pharmacokinetic of Cabazitaxel : Volume of Distribution at Steady State (Vss) [12]
    End point description
    Analysis was performed on PK population.
    End point type
    Secondary
    End point timeframe
    5 minutes before cabazitaxel infusion; at end of cabazitaxel infusion; 0.25 hours post-cabazitaxel infusion; any time between 1 to 4 hours, between 6 to 24 hours, between 48 to 96 hours post cabazitaxel infusion on Day 1-Cycle 1
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    24
    Units: L/m^2
        arithmetic mean (standard deviation)
    2711 ( 2493 )
    No statistical analyses for this end point

    Secondary: Phase 2: Pharmacokinetic of Abiraterone : Maximum Plasma Concentration Observed (Cmax)

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    End point title
    		 Phase 2: Pharmacokinetic of Abiraterone : Maximum Plasma Concentration Observed (Cmax) [13]
    End point description
    Analysis was performed on PK population. One subject was excluded from analysis due to aberrant data.
    End point type
    Secondary
    End point timeframe
    0 hour (before abiraterone administration); 1, 2, 4, 6, 8, 12, 24 hours post abiraterone administration on Day 1-Cycle 1
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    26
    Units: ng/mL
        arithmetic mean (standard deviation)
    216 ( 152 )
    No statistical analyses for this end point

    Secondary: Phase 2: Pharmacokinetic of Abiraterone : First Time to Reach Cmax (Tmax)

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    End point title
    		 Phase 2: Pharmacokinetic of Abiraterone : First Time to Reach Cmax (Tmax) [14]
    End point description
    Analysis was performed on PK population. One subject was excluded from analysis due to aberrant data.
    End point type
    Secondary
    End point timeframe
    0 hour (before abiraterone administration); 1, 2, 4, 6, 8, 12, 24 hours post abiraterone administration on Day 1-Cycle 1
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    26
    Units: hour
        median (full range (min-max))
    2 (1 to 6)
    No statistical analyses for this end point

    Secondary: Phase 2: Pharmacokinetic of Abiraterone : Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours (AUC 0-24)

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    End point title
    		 Phase 2: Pharmacokinetic of Abiraterone : Area Under the Plasma Concentration Versus Time Curve From Time 0 to 24 Hours (AUC 0-24) [15]
    End point description
    Analysis was performed on PK population. One subject was excluded from analysis due to aberrant data.
    End point type
    Secondary
    End point timeframe
    0 hour (before abiraterone administration); 1, 2, 4, 6, 8, 12, 24 hours post abiraterone administration on Day 1-Cycle 1
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    26
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    928 ( 466 )
    No statistical analyses for this end point

    Secondary: Phase 2: Pharmacokinetic of Abiraterone : Concentration Observed Just Before Treatment Administration During Repeated Dosing at Steady State (Ctrough ss)

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    End point title
    		 Phase 2: Pharmacokinetic of Abiraterone : Concentration Observed Just Before Treatment Administration During Repeated Dosing at Steady State (Ctrough ss) [16]
    End point description
    Analysis was performed on PK population. One subject was excluded from analysis due to aberrant data.
    End point type
    Secondary
    End point timeframe
    Pre abiraterone dose on Day 1 of Cycle 1
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint is reporting data for phase 2 only.
    End point values
    		 Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Number of subjects analysed
    26
    Units: ng/mL
        arithmetic mean (standard deviation)
    9.99 ( 13 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AE) were collected from signature of the informed consent form up to the final visit (603 days) regardless of seriousness or relationship to investigational product
    Adverse event reporting additional description
    Reported AEs & deaths are treatment-emergent that is AEs that developed/worsened & deaths that occurred during ‘on treatment period’ (time from first dose of study drug [cabazitaxel/abiraterone, whichever came first] to last dose of study drug [cabazitaxel or abiraterone, whichever came last] + 30 days). Analysis was performed on safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Phase 1: Cabazitaxel 20 mg/m^2 + Abiraterone 1000 mg
    Reporting group description
    		 Cabazitaxel 20 mg/m^2 on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg once daily and prednisone 5 mg twice daily until disease progression, unacceptable toxicity or consent withdrawal.

    Reporting group title
    Phase 1: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Reporting group description
    		 Cabazitaxel 25 mg/m^2 on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg once daily and prednisone 5 mg twice daily until disease, progression, unacceptable toxicity or consent withdrawal.

    Reporting group title
    Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Reporting group description
    		 Cabazitaxel at MTD as determined in phase 1 part (25 mg/m^2) on Day 1 of each 21-day cycle in combination with abiraterone acetate 1000 mg once daily and prednisone 5 mg twice daily until disease progression, unacceptable toxicity or consent withdrawal.

    Serious adverse events
    		 Phase 1: Cabazitaxel 20 mg/m^2 + Abiraterone 1000 mg Phase 1: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    4 / 7 (57.14%)
    21 / 27 (77.78%)
         number of deaths (all causes)
    0
    0
    6
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastatic Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small Cell Lung Cancer
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Coronary Syndrome
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Atrioventricular Block
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Peripheral Motor Neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Spinal Cord Compression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Disease Progression
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Pelvic Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal Ideation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Anuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bladder Obstruction
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    3 / 27 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    4 / 27 (14.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Colic
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal Failure Acute
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    3 / 27 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Urinary Retention
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 27 (7.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bone Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coccydynia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain In Extremity
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device Related Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parasitic Gastroenteritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Pneumonia Bacterial
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    3 / 27 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Spinal Cord Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    4 / 27 (14.81%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Phase 1: Cabazitaxel 20 mg/m^2 + Abiraterone 1000 mg Phase 1: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg Phase 2: Cabazitaxel 25 mg/m^2 + Abiraterone 1000 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    7 / 7 (100.00%)
    27 / 27 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Seborrhoeic Keratosis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    2 / 27 (7.41%)
         occurrences all number
    0
    2
    2
    Hot Flush
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    1 / 27 (3.70%)
         occurrences all number
    1
    2
    1
    Hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    4
    Asthenia
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 7 (42.86%)
    16 / 27 (59.26%)
         occurrences all number
    2
    3
    17
    Granuloma
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Oedema Peripheral
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    4 / 27 (14.81%)
         occurrences all number
    1
    1
    5
    Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 7 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    2
    0
    3
    Reproductive system and breast disorders
    Pelvic Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    4 / 27 (14.81%)
         occurrences all number
    1
    1
    4
    Dysphonia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    4 / 27 (14.81%)
         occurrences all number
    0
    0
    4
    Dyspnoea
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    11 / 27 (40.74%)
         occurrences all number
    0
    2
    11
    Dyspnoea Exertional
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 27 (3.70%)
         occurrences all number
    1
    0
    2
    Pleural Effusion
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    3
    Psychiatric disorders
    Affective Disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    0
    0
    3
    Insomnia
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    2
    0
    0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Blood Potassium Increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Transaminases Increased
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Weight Decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    13 / 27 (48.15%)
         occurrences all number
    0
    2
    13
    Weight Increased
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    2
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    4 / 27 (14.81%)
         occurrences all number
    0
    2
    4
    Headache
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    1
    0
    3
    Hyperaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    1 / 27 (3.70%)
         occurrences all number
    1
    2
    1
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    2
    Peripheral Motor Neuropathy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    4 / 27 (14.81%)
         occurrences all number
    1
    0
    4
    Neutropenia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    4 / 27 (14.81%)
         occurrences all number
    0
    0
    4
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    2 / 27 (7.41%)
         occurrences all number
    1
    1
    2
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    3 / 27 (11.11%)
         occurrences all number
    1
    2
    3
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    2
    1
    0
    Anal Fissure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 7 (28.57%)
    6 / 27 (22.22%)
         occurrences all number
    3
    2
    7
    Diarrhoea
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 7 (42.86%)
    15 / 27 (55.56%)
         occurrences all number
    3
    3
    15
    Dry Mouth
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    5 / 27 (18.52%)
         occurrences all number
    0
    0
    5
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    1 / 27 (3.70%)
         occurrences all number
    0
    2
    1
    Gastrointestinal Hypermotility
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal Motility Disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    4 / 27 (14.81%)
         occurrences all number
    0
    0
    4
    Haemorrhoids
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Lip Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    5 / 7 (71.43%)
    14 / 27 (51.85%)
         occurrences all number
    1
    5
    15
    Rectal Haemorrhage
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Stomatitis
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    5 / 27 (18.52%)
         occurrences all number
    1
    2
    5
    Toothache
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    6 / 27 (22.22%)
         occurrences all number
    0
    0
    6
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    5 / 27 (18.52%)
         occurrences all number
    1
    2
    5
    Hair Disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    Intertrigo
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Nail Ridging
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 27 (0.00%)
         occurrences all number
    1
    0
    0
    Onycholysis
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    1
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    2
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Haematuria
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    8 / 27 (29.63%)
         occurrences all number
    1
    2
    8
    Pollakiuria
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Bone Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Back Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    9 / 27 (33.33%)
         occurrences all number
    1
    2
    9
    Flank Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Muscle Spasms
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    2
    Musculoskeletal Chest Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    4 / 27 (14.81%)
         occurrences all number
    1
    1
    4
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    2
    Neck Pain
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    1
    0
    2
    Pain In Extremity
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 27 (3.70%)
         occurrences all number
    1
    1
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Oral Candidiasis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    2
    Oral Fungal Infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    2 / 27 (7.41%)
         occurrences all number
    0
    1
    2
    Tinea Pedis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 27 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary Tract Infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    3 / 27 (11.11%)
         occurrences all number
    1
    0
    3
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    13 / 27 (48.15%)
         occurrences all number
    1
    1
    13
    Dehydration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 27 (3.70%)
         occurrences all number
    0
    1
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 27 (7.41%)
         occurrences all number
    0
    0
    2
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    7 / 27 (25.93%)
         occurrences all number
    0
    1
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Nov 2011
    Following changes were made: - To add clarity and consistency to study procedures and flowchart. - To provide additional information for pharmacokinetic handling procedure, bioanalytical method, and biomarker analysis.
    29 May 2012
    Following changes were made: - To change the definition of DLT observation period to the first 2 cycles instead of just Cycle 1. - To amend inclusion/exclusion criteria, to adapt for changing definition of antiandrogen treatment. - To add exclusion criterion, in order to comply with the Medicines and Healthcare products Regulatory requirements for exclusion of subjects with reproductive potential who do not agree with the contraception protocol requirements. - To add analysis of RNA to the exploratory biomarker analysis. - To clarify the rules for granulocyte-colony stimulating factor prophylactic use during first two cycles. - To clarify the definition for prostate-specific antigen progression free survival secondary endpoint. - To clarify MTD confirmation. - To clarify the lower limit of dose reduction and the rules for dose reduction. - To clarify the definition of permitted/not permitted concomitant palliative radiation. - To clarify the extent of CT imaging for the evaluation of disease response/progression during the study.
    17 Dec 2012
    Following changes were made: - To change the inclusion/exclusion criteria in order to adapt to the most current clinical practice, and to address the change in subjects population in the Phase 2 part of the study. - To amend the PK sampling schedule for the Phase 2 part to adhere to a more appropriate schedule. - To modify study flowcharts to account for differences between the Phase 1 part and Phase 2 part. - To clarify the SAE reporting timeframe (24 hours instead of 1 business day).

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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