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    Clinical Trial Results:
    CiPHER - Phase II multicentre study assessing the efficacy of Cabazitaxel in Patients with HER2-negative metastatic breast cancer and having unresectable brain metastases.

    Summary
    EudraCT number
    		 2012-000542-35
    Trial protocol
    		 GB  
    Global end of trial date
    25 Jul 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Aug 2019
    First version publication date
    04 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RDD490
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    The Clatterbridge Cancer Centre NHS Foundation Trust
    Sponsor organisation address
    Clatterbridge Road, Bebington, Wirral, United Kingdom, CH63 4JY
    Public contact
    Charlotte Rawcliffe, CRUK Liverpool Cancer Trials Unit, +44 01517948167, clr001@liverpool.ac.uk
    Scientific contact
    Charlotte Rawcliffe, CRUK Liverpool Cancer Trials Unit, +44 01517948167, clr001@liverpool.ac.uk
    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
    28 Jun 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jul 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Jul 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary aim of this study is to assess the efficacy of Cabazitaxel in patients with HER2-negative metastatic breast cancer and brain metastases. This study is designed to assess the feasibility of Cabazitaxel use in breast cancer with brain metastases. Primary outcome: Overall survival from randomisation.
    Protection of trial subjects
    Consent was obtained prior to each patient participating in the trial, after a full explanation had been given of the treatment options, including the conventional and generally accepted methods of treatment. All risks and potential benefits were explained to the patients, and all patients were provided with Patient Information Sheets prior to consent. Patients were given the right to refuse their consent to participate in the trial, and to withdraw at any time. Haematology/biochemistry tests and physical examinations will be performed regularly throughout each patient's participation and follow-up. Patients were checked and asked about any adverse events they may have experienced regularly while on treatment, and during follow-up. Treatment was delayed or withdrawn for any patient unfit to receive Cabazitaxel. Patients were also given emergency contact details for the research team. Patients were exposed to ionising radiation via CT/MRI scans (MRI/CT scans of the brain were performed 6 weekly following randomisation until cycle 6, then 8 weekly until end of treatment. CT scans of the chest, abdomen and pelvis were performed 12 weeks after randomisation, and then 6 weekly until cycle 6, then 12 weekly until end of treatment. Scans were only performed in follow-up if they were carried out as standard care. This imaging schedule was chosen to ensure that significant disease progression was detected, and also to prevent unnecessary imaging.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Oct 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 19
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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
    4
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 CiPHER was opened to recruitment on 10/10/2014 and the first patient was recruited on 06/01/2015. A total of 19 were randomised (13 to receive Cabazitaxel, 6 to receive standard care. The trial was closed to recruitment on recommendation of the TSC in November 2017. The last patient was randomised on 27/10/2017. The end of study date is 25/07/2018.

    Pre-assignment
    Screening details
    		 19 of the 97 patients screened for the CiPHER trial were recruited. Patients with HER2-negative breast cancer and brain metastases provided consent and were screened to determine eligibility. Patients who met all the eligibility criteria were randomised to either Cabazitaxel or standard care (physician's choice/radiotherapy).

    Period 1
    Period 1 title
    Treatment Phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cabazitaxel
    Arm description
    		 Patients received 25mg^2 Cabazitaxel on Day 1 of each treatment cycle (every 21 days) as a 1 hour IV infuson until disease progression, unacceptable toxicity or withdrawal of consent.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Cabazitaxel
    Investigational medicinal product code
    L01CD
    Other name
    Jevtana
    Pharmaceutical forms
    Concentrate and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    25mg/m^2 Cabazitaxel was administered as a 1 hour IV infusion on day 1 of each cycle, every 21 days until disease progression (according to RECIST V1.1), unacceptable toxicity or withdrawal of consent (patient request).

    Arm title
    		 Standard care
    Arm description
    		 This is the control arm. Patients on this arm received either physician's choice of chemotherapy until disease progression or radiotherapy (patients who had previously received whole brain radiotherapy were given physician's choice, patients who had not previously received whole brain radiotherapy were given radiotherapy).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Cabazitaxel Standard care
    Started
    13
    6
    Completed
    13
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cabazitaxel
    Reporting group description
    		 Patients received 25mg^2 Cabazitaxel on Day 1 of each treatment cycle (every 21 days) as a 1 hour IV infuson until disease progression, unacceptable toxicity or withdrawal of consent.

    Reporting group title
    Standard care
    Reporting group description
    		 This is the control arm. Patients on this arm received either physician's choice of chemotherapy until disease progression or radiotherapy (patients who had previously received whole brain radiotherapy were given physician's choice, patients who had not previously received whole brain radiotherapy were given radiotherapy).

    Reporting group values
    		 Cabazitaxel Standard care Total
    Number of subjects
    		 13 6 19
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 10 5 15
        From 65-84 years
    		 3 1 4
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 13 6 19
        Male
    		 0 0 0
    ECOG Performance Status
    Units: Subjects
        ECOG 0
    		 5 2 7
        ECOG 1
    		 8 4 12
        ECOG 2
    		 0 0 0
        ECOG 3
    		 0 0 0
        ECOG 4
    		 0 0 0
    Presence of visceral disease
    Units: Subjects
        Yes
    		 10 4 14
        No
    		 3 2 5
    Presentation with brain metastases de novo
    Units: Subjects
        Yes
    		 4 3 7
        No
    		 9 3 12
    ACE 27 Comorbidity score
    Units: Subjects
        None
    		 6 4 10
        Mild
    		 3 0 3
        Moderate
    		 2 0 2
        Severe
    		 2 1 3
        Unknown
    		 0 1 1
    Previous Primary Treatment, neoadjuvant/adjuvant chemotherapy: anthracyclines
    Units: Subjects
        Yes
    		 9 2 11
        No
    		 4 4 8
    Previous Primary Treatment, neoadjuvant/adjuvant chemotherapy: anthracyclines + Taxane
    Units: Subjects
        Yes
    		 8 5 13
        No
    		 5 1 6
    Previous Primary Treatment, neoadjuvant/adjuvant chemotherapy: Adjuvant Endocrine
    Units: Subjects
        Yes
    		 7 3 10
        No
    		 6 3 9
    Previous Primary Treatment, neoadjuvant/adjuvant chemotherapy: other
    Units: Subjects
        Yes
    		 9 2 11
        No
    		 4 4 8
    Previous Treatment for Brain Metastases - Chemotherapy agent
    Units: Subjects
        Yes
    		 0 0 0
        No
    		 13 6 19
    Previous Treatment for Brain Metastases: Endocrine
    Units: Subjects
        Yes
    		 3 1 4
        No
    		 10 5 15
    Previous Treatment for Brain Metastases: Previous Cranial Radiotherapy
    Units: Subjects
        Yes
    		 7 3 10
        No
    		 6 3 9
    Previous Treatment for Brain Metastases: Previous Cranial Neurosurgery
    Units: Subjects
        Yes
    		 4 4 8
        No
    		 9 2 11
    Baseline FACT-Br - physical
    Units: Score
        arithmetic mean (standard deviation)
    		 20 ± 5.29 23.2 ± 2.59 -
    Baseline FACT-Br - Social/Family
    Units: Score
        arithmetic mean (standard deviation)
    		 22.8 ± 3.48 23.8 ± 3.19 -
    Baseline FACT-Br - Emotional
    Units: Score
        arithmetic mean (standard deviation)
    		 15.9 ± 4.09 14.2 ± 8.84 -
    Baseline FACT-Br - Functional
    Units: Score
        arithmetic mean (standard deviation)
    		 14.5 ± 5.68 13.8 ± 4.38 -
    Baseline FACT-Br - Additional concerns
    Units: Score
        arithmetic mean (standard deviation)
    		 44.2 ± 9.24 48.2 ± 6.34 -
    Baseline Fact-Br - Trial Outcome index
    Units: Score
        arithmetic mean (standard deviation)
    		 78.7 ± 16.61 85.2 ± 10.47 -
    Total FACT-Br
    Units: Score
        arithmetic mean (standard deviation)
    		 117 ± 20.64 123 ± 17.09 -
    Time from diagnosis to cranial metastases
    Units: days
        arithmetic mean (standard deviation)
    		 1961 ± 1338 2037 ± 1974 -
    Time from diagnosis to other metastases
    Units: days
        arithmetic mean (standard deviation)
    		 1443 ± 1051 1775 ± 1893 -
    Physical findings - Height
    Units: cm
        arithmetic mean (standard deviation)
    		 165 ± 7.98 164 ± 5.59 -
    Physical Findings - Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 73.3 ± 18.26 7.06 ± 8.80 -
    Physical Findings - Blood pressure: Systolic Blood Pressure
    Units: mm/Hg
        arithmetic mean (standard deviation)
    		 127 ± 19.10 122 ± 19.51 -
    Physical Findings - Blood pressure: Diastolic Blood Pressure
    Units: mmHg
        arithmetic mean (standard deviation)
    		 76.7 ± 12.70 78.2 ± 10.83 -
    Physical Findings - Temperature
    Units: degrees celcius
        arithmetic mean (standard deviation)
    		 36.5 ± 0.44 36.7 ± 0.78 -
    Biochemistry results - Serum Creatinine
    Units: µmol/L
        arithmetic mean (standard deviation)
    		 64.2 ± 17.36 64.3 ± 13.98 -
    Biochemistry results - Creatinine clearance
    Units: ml/min
        arithmetic mean (standard deviation)
    		 139 ± 198.8 322 ± 351.7 -
    Biochemistry results - Sodium
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 139 ± 2.11 138 ± 3.45 -
    Biochemistry results - Potassium
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 4.2 ± 0.32 4.1 ± 0.41 -
    Biochemistry results - Calcium
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 2.4 ± 0.14 2.4 ± 0.15 -
    Biochemistry results - Urea
    Units: mmol/L
        arithmetic mean (standard deviation)
    		 6.7 ± 2.33 6.2 ± 1.24 -
    Biochemistry results - Bilirubin
    Units: µmol/L
        arithmetic mean (standard deviation)
    		 5.3 ± 2.75 8.0 ± 3.41 -
    Biochemistry results - Albumin
    Units: g/L
        arithmetic mean (standard deviation)
    		 39.2 ± 6.19 41.7 ± 5.89 -
    Biochemistry results - GGT
    Units: IU/L
        arithmetic mean (standard deviation)
    		 229 ± 673.3 45.5 ± 38.32 -
    Biochemistry results - ALP
    Units: IU/L
        arithmetic mean (standard deviation)
    		 112 ± 142.6 66.8 ± 19.35 -
    Biochemistry results - ALT
    Units: IU/L
        arithmetic mean (standard deviation)
    		 38.1 ± 74.02 26.3 ± 15.54 -
    Biochemistry results - AST
    Units: IU/L
        arithmetic mean (standard deviation)
    		 17.0 ± 6.60 15.0 ± 1.41 -
    Haematology results - Haemoglobin
    Units: g/L
        arithmetic mean (standard deviation)
    		 127 ± 9.70 94.6 ± 65.71 -
    Haematology results - WBC
    Units: 10^9/L
        arithmetic mean (standard deviation)
    		 9.7 ± 5.54 10.9 ± 4.58 -
    Haematology results - Absolute neutrophil count
    Units: 10^9/L
        arithmetic mean (standard deviation)
    		 7.4 ± 5.24 8.9 ± 3.99 -
    Haematology - Lymphocytes
    Units: 10^9/L
        arithmetic mean (standard deviation)
    		 1.6 ± 0.57 1.2 ± 0.65 -
    Haematology results - Platelets
    Units: 10^9/L
        arithmetic mean (standard deviation)
    		 315 ± 111.7 246 ± 56.00 -

    End points

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    End points reporting groups
    Reporting group title
    Cabazitaxel
    Reporting group description
    		 Patients received 25mg^2 Cabazitaxel on Day 1 of each treatment cycle (every 21 days) as a 1 hour IV infuson until disease progression, unacceptable toxicity or withdrawal of consent.

    Reporting group title
    Standard care
    Reporting group description
    		 This is the control arm. Patients on this arm received either physician's choice of chemotherapy until disease progression or radiotherapy (patients who had previously received whole brain radiotherapy were given physician's choice, patients who had not previously received whole brain radiotherapy were given radiotherapy).

    Subject analysis set title
    Full Analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    In order to follow the Intention to Treat (ITT) principle this consists of all randomised patients excepting for a) patients withdrawing consent between randomisation and starting therapy b) patients withdrawn from the study after randomisation because of irregularities with the consent process and c) patients whose information determining ineligibility existed before randomisation but was not read until after randomisation.

    Subject analysis set title
    Per Protocol (PP) set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This consists of those patients in the Full Analysis set without any major protocol deviations.

    Subject analysis set title
    Safety set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received any trial treatment

    Primary: Overall survival

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    End point title
    		 Overall survival
    End point description
    Overall survival from randomisation, defined for each participant as the time from randomisation to the earlier of death or censoring. Outcome variable: overall length of survival from randomisation Efficacy parameter: Hazard ratio (relative to Arm 1) Supported by Median overall survival time and 12 month survival Method: Stratified Cox proportional hazards (PH) model Median survival - Standard care arm - upper limit = N/A (9999 entered to satisfy system validations)
    End point type
    Primary
    End point timeframe
    Measured (as months) from randomisation, defined for each participant as the time from randomisation to the earlier of death or censoring.
    End point values
    		 Cabazitaxel Standard care Full Analysis set
    Number of subjects analysed
    13
    6
    19
    Units: months
    number (confidence interval 90%)
        Median Survival in Months
    4.80 (2.07 to 20.36)
    8.16 (1.74 to 9999)
    8.16 (2.07 to 20.36)
    Attachments
    		 Untitled (Filename: Figure 3.PNG)
    Statistical analysis title
    		 Overall Survival Analysis (Hazard Ratio)
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.582
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.45
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.48
         upper limit
    		 4.45

    Primary: Overall survival (countable endpoint data)

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    End point title
    		 Overall survival (countable endpoint data) [1]
    End point description
    End point type
    Primary
    End point timeframe
    From randomisation to the earlier of death or censoring.
    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: Statistical analysis provided seperately under 'overall survival'
    End point values
    		 Cabazitaxel Standard care Full Analysis set
    Number of subjects analysed
    13
    6
    19
    Units: Percent
        Number of deaths
    69
    50
    63
        12 month survival rate
    48
    44
    48
    No statistical analyses for this end point

    Primary: Results for Sensitivity Analyses for Overall Survival

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    End point title
    		 Results for Sensitivity Analyses for Overall Survival
    End point description
    Where value is N/A '00' has been entered.
    End point type
    Primary
    End point timeframe
    From randomisation
    End point values
    		 Cabazitaxel Standard care
    Number of subjects analysed
    13
    6
    Units: subjects
        number (confidence interval 90%)
    00 (00 to 00)
    00 (00 to 00)
    Statistical analysis title
    		 Treatment by centre interaction
    Comparison groups
    Standard care v Cabazitaxel
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    3.9
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.52
         upper limit
    		 29.03
    Statistical analysis title
    		 Pre-protocol analysis
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.39
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 5.14
    Statistical analysis title
    		 Covariate (Visceral disease)
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    Method
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.28
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.41
         upper limit
    		 3.98

    Secondary: Time to CNS Progression

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    End point title
    		 Time to CNS Progression
    End point description
    Time to CNS progression (TTP) - defined as time from randomisation to earlier of disease progression or death from CNS disease or censoring. Where value is N/A '00' or '9999' has been entered.
    End point type
    Secondary
    End point timeframe
    Measured (as months) from randomisation to CNS progression or death from CNS disease
    End point values
    		 Cabazitaxel Standard care Full Analysis set
    Number of subjects analysed
    13
    6
    19
    Units: months
    number (confidence interval 90%)
        Median Survival in Months
    2.76 (1.38 to 4.80)
    6.46 (00 to 9999)
    3.55 (1.74 to 8.16)
    Attachments
    		 Untitled (Filename: Figure 4.PNG)
    Statistical analysis title
    		 Time to CNS Progression
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.145
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    2.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 7.47

    Secondary: Best overall response (extracranial visceral metastases)

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    End point title
    		 Best overall response (extracranial visceral metastases)
    End point description
    Overall response for overall extracranial visceral metastases. Response is defined as occurrence of PR or CR at any point to death or end of study. Efficacy parameter = difference in proportion with objective response.
    End point type
    Secondary
    End point timeframe
    From randomisation to death or end of study
    End point values
    		 Cabazitaxel Standard care Full Analysis set
    Number of subjects analysed
    13
    6
    19
    Units: Number of patients
        Progressive disease/death
    0
    0
    0
        Stable disease
    3
    1
    4
        Partial Response
    3
    1
    4
        Complete Response
    0
    0
    0
        Missing
    7
    4
    11
        Response to treatment
    3
    1
    4
    Statistical analysis title
    		 Best overall visceral response
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.751
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.123
         upper limit
    		 18.358
    Statistical analysis title
    		 Best overall visceral response by centre
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.76
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 30.8
    Statistical analysis title
    		 Best overall visceral response by centre*treatment
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.757
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.09
         upper limit
    		 24.99

    Secondary: Best overall response (cranial metastases)

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    End point title
    		 Best overall response (cranial metastases)
    End point description
    Overall response for overall cranial metastases. Response is defined as occurrence of PR or CR at any point to death or end of study. Efficacy parameter = difference in proportion with objective response.
    End point type
    Secondary
    End point timeframe
    From randomisation to death or end of study
    End point values
    		 Cabazitaxel Standard care Full Analysis set
    Number of subjects analysed
    13
    6
    19
    Units: Number of patients
        Progressive disease/death
    1
    0
    1
        Stable disease
    7
    1
    8
        Partial response
    2
    1
    3
        Complete response
    0
    1
    1
        Missing
    3
    3
    6
        Response to treatment
    2
    2
    4
    Statistical analysis title
    		 Best overall cranial response
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.382
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.038
         upper limit
    		 3.518
    Statistical analysis title
    		 Best overall response (Cranial) by Centre
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.309
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 6.03
    Statistical analysis title
    		 Best overall cranial response by Centre*Treatment
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.29
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.01
         upper limit
    		 6.67

    Secondary: Quality of Life - Physical Wellbeing

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    End point title
    		 Quality of Life - Physical Wellbeing
    End point description
    Where value is N/A '00' has been entered.
    End point type
    Secondary
    End point timeframe
    From baseline to end of study
    End point values
    		 Cabazitaxel Standard care
    Number of subjects analysed
    13
    6
    Units: score
    arithmetic mean (standard deviation)
        Baseline/Cycle 1
    20 ± 5.29
    23.2 ± 2.59
        Cycle 2
    20 ± 5.69
    25.0 ± 1.41
        Cycle 3
    20.5 ± 6.41
    25.5 ± 0.71
        Cycle 4
    21.6 ± 2.61
    25.5 ± 0.71
        Cycle 5
    20.8 ± 2.99
    25.5 ± 0.71
        Cycle 6
    18.3 ± 8.14
    25.0 ± 1.41
        Cycle 7
    13.5 ± 7.78
    00 ± 00
        Cycle 8
    15.0 ± 00
    00 ± 00
        Cycle 9
    24.0 ± 00
    00 ± 00
        Cycle 10
    19.0 ± 00
    00 ± 00
        Cycle 11
    19.0 ± 00
    00 ± 00
        Cycle 12
    19.0 ± 00
    00 ± 00
        Cycle 13
    21.0 ± 00
    00 ± 00
        Cycle 14
    21.0 ± 00
    00 ± 00
        Cycle 15
    22.0 ± 00
    00 ± 00
        Cycle 16
    19.0 ± 00
    00 ± 00
        Cycle 17
    15.0 ± 00
    00 ± 00
        Cycle 18
    19.0 ± 00
    00 ± 00
        Cycle 19
    21.0 ± 00
    00 ± 00
        Cycle 20
    20.0 ± 00
    00 ± 00
        Cycle 21
    23.0 ± 00
    00 ± 00
        Cycle 22
    21.0 ± 00
    00 ± 00
        Follow-up 1
    26.0 ± 1.41
    24.0 ± 1.73
        Follow-up 2
    25.5 ± 3.54
    18.0 ± 00
        Follow-up 3
    24.0 ± 5.66
    22.0 ± 00
        Follow-up 4
    24.5 ± 4.95
    24.0 ± 00
        Follow-up 5
    25.5 ± 3.54
    24.0 ± 00
        Follow-up 6
    21.0 ± 00
    22.0 ± 00
        Follow-up 7
    22.0 ± 00
    00 ± 00
        Follow-up 8
    11.0 ± 00
    00 ± 00
    Statistical analysis title
    		 Cycle 2 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.55
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 3 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.632
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 cycle 4 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.727
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 5 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.597
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 6 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.098
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 1 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.873
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 2 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.565
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 3 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.958
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 4 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.714
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 5 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.714
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Time to CNS Progression (countable endpoint data)

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    End point title
    		 Time to CNS Progression (countable endpoint data)
    End point description
    End point type
    Secondary
    End point timeframe
    From randomisation to CNS progression or death from CNS disease
    End point values
    		 Cabazitaxel Standard care Full Analysis set
    Number of subjects analysed
    13
    6
    19
    Units: percent
        Number of deaths
    92
    67
    84
        12-month survival rate
    21
    33
    24
    No statistical analyses for this end point

    Secondary: Quality of Life - Functional Well-Being

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    End point title
    		 Quality of Life - Functional Well-Being
    End point description
    Where value is N/A '00' has been entered.
    End point type
    Secondary
    End point timeframe
    From baseline to end of study
    End point values
    		 Cabazitaxel Standard care
    Number of subjects analysed
    13
    6
    Units: score
    arithmetic mean (standard deviation)
        Baseline/Cycle 1
    14.5 ± 5.68
    13.8 ± 4.38
        Cycle 2
    15.5 ± 5.13
    18.0 ± 2.83
        Cycle 3
    17.9 ± 5.64
    16.5 ± 2.12
        Cycle 4
    15.8 ± 5.78
    17.0 ± 4.24
        Cycle 5
    14.7 ± 2.68
    19.5 ± 3.54
        Cycle 6
    14.3 ± 0.58
    22.0 ± 2.83
        Cycle 7
    11.5 ± 0.71
    00 ± 00
        Cycle 8
    14.0 ± 00
    00 ± 00
        Cycle 9
    17.0 ± 00
    00 ± 00
        Cycle 10
    13.0 ± 00
    00 ± 00
        Cycle 11
    14.0 ± 00
    00 ± 00
        Cycle 12
    18.0 ± 00
    00 ± 00
        Cycle 13
    17.0 ± 00
    00 ± 00
        Cycle 14
    17.0 ± 00
    00 ± 00
        Cycle 15
    17.0 ± 00
    00 ± 00
        Cycle 16
    15.0 ± 00
    00 ± 00
        Cycle 17
    15.0 ± 00
    00 ± 00
        Cycle 18
    15.0 ± 00
    00 ± 00
        Cycle 19
    18.0 ± 00
    00 ± 00
        Cycle 20
    17.5 ± 00
    00 ± 00
        Cycle 21
    16.0 ± 00
    00 ± 00
        Cycle 22
    20.0 ± 00
    00 ± 00
        Follow-up 1
    23.5 ± 6.36
    20.2 ± 15.9
        Follow-up 2
    24.0 ± 5.66
    10.0 ± 00
        Follow-up 3
    22.5 ± 6.36
    17.0 ± 00
        Follow-up 4
    23.0 ± 4.24
    17.0 ± 00
        Follow-up 5
    24.0 ± 5.66
    16.0 ± 00
        Follow-up 6
    18.0 ± 00
    14.0 ± 00
        Follow-up 7
    14.0 ± 00
    00 ± 00
        Follow-up 8
    7.0 ± 00
    00 ± 00
    Statistical analysis title
    		 Cycle 2 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.418
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 3 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.948
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 4 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.234
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 5 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.106
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 6 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.257
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 1 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.888
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 2 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.129
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 3 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.807
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 4 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.936
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 5 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.568
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Quality of Life - Additional Concerns

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    End point title
    		 Quality of Life - Additional Concerns
    End point description
    Where value is N/A '00' has been entered.
    End point type
    Secondary
    End point timeframe
    From randomisation until end of study
    End point values
    		 Cabazitaxel Standard care
    Number of subjects analysed
    13
    6
    Units: score
    arithmetic mean (standard deviation)
        Baseline/Cycle 1
    44.2 ± 9.24
    48.2 ± 6.34
        Cycle 2
    50.2 ± 6.74
    58.4 ± 6.48
        Cycle 3
    53.5 ± 9.50
    64.7 ± 1.89
        Cycle 4
    48.5 ± 5.89
    64.8 ± 3.93
        Cycle 5
    45.7 ± 3.09
    64.1 ± 2.63
        Cycle 6
    54.3 ± 2.38
    64.7 ± 1.02
        Cycle 7
    49.0 ± 2.83
    00 ± 00
        Cycle 8
    53.0 ± 00
    00 ± 00
        Cycle 9
    51.0 ± 00
    00 ± 00
        Cycle 10
    53.0 ± 00
    00 ± 00
        Cycle 11
    49.0 ± 00
    00 ± 00
        Cycle 12
    55.0 ± 00
    00 ± 00
        Cycle 13
    54.0 ± 00
    00 ± 00
        Cycle 14
    50.0 ± 00
    00 ± 00
        Cycle 15
    52.0 ± 00
    00 ± 00
        Cycle 16
    49.0 ± 00
    00 ± 00
        Cycle 17
    56.0 ± 00
    00 ± 00
        Cycle 18
    51.0 ± 00
    00 ± 00
        Cycle 19
    55.9 ± 00
    00 ± 00
        Cycle 20
    48.0 ± 00
    00 ± 00
        Cycle 21
    50.0 ± 00
    00 ± 00
        Cycle 22
    52.0 ± 00
    00 ± 00
        Follow-up 1
    53.0 ± 7.07
    51.1 ± 12.20
        Follow-up 2
    63.0 ± 7.07
    38.0 ± 00
        Follow-up 3
    60.5 ± 3.54
    51.0 ± 00
        Follow-up 4
    51.5 ± 4.95
    51.0 ± 00
        Follow-up 5
    62.5 ± 4.95
    55.0 ± 00
        Follow-up 6
    52.0 ± 00
    41.0 ± 00
        Follow-up 7
    51.0 ± 00
    00 ± 00
        Follow-up 8
    35.6 ± 00
    00 ± 00
    Statistical analysis title
    		 Cycle 2 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.925
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 3 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.836
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 4 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.677
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 5 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.245
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 6 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.895
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 1 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.061
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 2 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.253
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 3 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.373
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 4 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.015
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 5 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.316
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Quality of Life - Overall TOI Score

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    End point title
    		 Quality of Life - Overall TOI Score
    End point description
    Where value is N/A '00' has been entered
    End point type
    Secondary
    End point timeframe
    From randomisation until end of study
    End point values
    		 Cabazitaxel Standard care
    Number of subjects analysed
    13
    6
    Units: score
    arithmetic mean (standard deviation)
        Baseline/Cycle 1
    78.7 ± 16.61
    85.2 ± 10.47
        Cycle 2
    85.7 ± 13.66
    101.4 ± 10.72
        Cycle 3
    91.9 ± 18.03
    106.7 ± 4.71
        Cycle 4
    85.8 ± 10.90
    107.3 ± 0.39
        Cycle 5
    81.2 ± 3.82
    109.1 ± 6.87
        Cycle 6
    86.9 ± 8.67
    111.7 ± 2.44
        Cycle 7
    74.0 ± 9.90
    00 ± 00
        Cycle 8
    82.0 ± 00
    00 ± 00
        Cycle 9
    92.0 ± 00
    00 ± 00
        Cycle 10
    85.0 ± 00
    00 ± 00
        Cycle 11
    82.0 ± 00
    00 ± 00
        Cycle 12
    92.0 ± 00
    00 ± 00
        Cycle 13
    92.0 ± 00
    00 ± 00
        Cycle 14
    88.0 ± 00
    00 ± 00
        Cycle 15
    91.0 ± 00
    00 ± 00
        Cycle 16
    83.0 ± 00
    00 ± 00
        Cycle 17
    86.0 ± 00
    00 ± 00
        Cycle 18
    85.0 ± 00
    00 ± 00
        Cycle 19
    94.9 ± 00
    00 ± 00
        Cycle 20
    85.5 ± 00
    00 ± 00
        Cycle 21
    89.0 ± 00
    00 ± 00
        Cycle 22
    93.0 ± 00
    00 ± 00
        Follow-up 1
    102.5 ± 0.71
    95.3 ± 14.97
        Follow-up 2
    112.5 ± 16.3
    66.0 ± 00
        Follow-up 3
    107.0 ± 15.6
    90.0 ± 00
        Follow-up 4
    99.0 ± 4.24
    92.0 ± 00
        Follow-up 5
    112.0 ± 14.1
    95.0 ± 00
        Follow-up 6
    91.0 ± 00
    77.0 ± 00
        Follow-up 7
    87.0 ± 00
    00 ± 00
        Follow-up 8
    53.6 ± 00
    00 ± 00
    Attachments
    		 Untitled (Filename: Figure A1.PNG)
    Untitled (Filename: Figure A2.PNG)
    Untitled (Filename: Figure A3.PNG)
    Untitled (Filename: Figure A4.PNG)
    Statistical analysis title
    		 Cycle 2 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.546
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 3 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.725
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 4 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.415
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 5 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.158
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Cycle 6 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.252
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 1 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.283
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 2 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.159
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 3 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.732
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 4 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.167
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Follow-up 5 P-value
    Comparison groups
    Cabazitaxel v Standard care
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.688
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start date of trial treatment until 28 days following the last dose of trial treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Cabazitaxel
    Reporting group description
    		 Patients received 25mg^2 Cabazitaxel on Day 1 of each treatment cycle (every 21 days) as a 1 hour IV infuson until disease progression, unacceptable toxicity or withdrawal of consent.

    Reporting group title
    Standard care
    Reporting group description
    		 This is the control arm. Patients on this arm received either physician's choice of chemotherapy until disease progression or radiotherapy (patients who had previously received whole brain radiotherapy were given physician's choice, patients who had not previously received whole brain radiotherapy were given radiotherapy).

    Serious adverse events
    		 Cabazitaxel Standard care
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 13 (61.54%)
    4 / 6 (66.67%)
         number of deaths (all causes)
    9
    3
         number of deaths resulting from adverse events
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Worsening of condition (study disease)
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphasia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Probable meningeal disease
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Bone marrow hypcellular
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Raised intracranial pressure
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infective myositis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cabazitaxel Standard care
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 13 (69.23%)
    4 / 6 (66.67%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 13 (38.46%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    Gait disturbance
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Dyspnoea
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Cough
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Sore throat
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
    2 / 6 (33.33%)
         occurrences all number
    4
    4
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    9
    Neutrophil count decreased
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 6 (16.67%)
         occurrences all number
    1
    8
    Platelet count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    4
    White blood cell count decreased
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    13
    Alkaline phosphatase increased
         subjects affected / exposed
    3 / 13 (23.08%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Haemoglobin increased
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Dizziness
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Dysgeusia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Seizure
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 13 (23.08%)
    1 / 6 (16.67%)
         occurrences all number
    10
    6
    Eye disorders
    Photophobia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Mucositis oral
         subjects affected / exposed
    1 / 13 (7.69%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    3 / 13 (23.08%)
    3 / 6 (50.00%)
         occurrences all number
    5
    3
    Abdominal distension
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Oral dysaesthesia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Abdominal pain
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Constipation
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Diarrhoea
         subjects affected / exposed
    4 / 13 (30.77%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Dyspepsia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Rash papular
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Cystitis noninfective
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Muscle weakness left-sided
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Soft tissue infection
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Otitis externa
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Mucosal infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Otitis media
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations other, specify - left big toe
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 13 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Hypoalbuminaemia
         subjects affected / exposed
    3 / 13 (23.08%)
    2 / 6 (33.33%)
         occurrences all number
    6
    3
    Hyperkalaemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 13 (15.38%)
    1 / 6 (16.67%)
         occurrences all number
    2
    3
    Hypocalcaemia
         subjects affected / exposed
    2 / 13 (15.38%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Anorexia
         subjects affected / exposed
    1 / 13 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Oct 2013
    Protocol Version 2 - Standard care arm added in addition to treatment arm Study duration extended to incorporate increase in sample size as a result of the additional treatment arm Primary outcome changed as patients may continue to receive treatment beyond cycle 6 CTCAE v4.03 to be used instead of v4.0 Acute toxicity measured until end of treatment instead of 18 weeks Time to radiotherapy removed Time to neurological deterioration removed as this will be captured in the QoL FACT-Br form QoL FACT-Br form added Treatments allocated 2:1 Cabazitaxel:standard treatment Blood sample at end of treatment removed as deemed unecessary
    29 Apr 2014
    Protocol Version 3 - Cabazitaxel will not be distributed directly from Sanofi to NHS sites - details added regarding this. Cabazitaxel crosses the blood brain barrier and should be particularly effective against CNS disease. Progression-free survival (PFS) includes all causes of death and combines them with progressive CNS disease. Time to progression (TTP) only combines CNS disease progression and death due to CNS disease and should therefore be an outcome more sensitive to the advantage of Cabazitaxel. References to SmPC replaced with IB
    21 Nov 2014
    Protocol Version 4 - Inclusion criteria updated to make clear that "previously treated brain metastases with or without surgery +/- radiotherapy does not exclude the patient from this trial". References to sample collection made consistent throughout. Baseline CT and MRI scans and screening assessments to be performed within 28 days prior to randomisation. Anti-emetics table updated
    09 Sep 2015
    Protocol Version 5 - Bone scan - amended to clarify that bone scan should be performed at baseline and only repeated if clinically indicated. Extra cranial imagining scan updated from 8 weekly to 12 weekly to bring in line with standard practices at sites. Full blood count - previously stated that full blood count should be done within 24 hours of day 1 of each cycle, updated to 'taken according to local practice'
    14 Mar 2016
    Protocol Version 6 - ACE-21 form added to baseline procedures Schedule of assessments added for radiotherapy Drug ordering - initial order changed from 18 to 6 vials Inclusion criteria - hormone therapy removed as it is covered in exclusion criteria as 'anti-cancer treatment' Exclusion criteria - GFR updated to state that creatinine clearance can be calculated using CKD-EPI Information added on which events do not need to be reported as SAEs
    17 Oct 2016
    Protocol Version 7 - Inclusion criteria updated so that patients with resectable brain metastases are eligible for the trial. Inclusion criteria updated so that measurable target lesion needs to be 5mm or above (previously 10mm). Exclusion criteria updated so that patients would still be eligible for the trial if they have had up to 2 lines of chemotherapy for extracranial disease since diagnosis of brain metastases. Exclusion criteria updated to allow patients to be on steroids to control CNS symptoms, PI discretion to be used to assess eligibility. Exclusion criteria relating to liver function tests updated in line with the summary of product characteristics. Information regarding dose reduction for patients with hepatic impairment updated. Secondary objective updated to specify which objectives are to be evaluated for RECIST-evaluable patients only (due to change in target lesion size for eligibility). Sentence added to statistical methods section to state that sample size calculation is based on 12 sites.
    07 Mar 2017
    Protocol Version 8 - Reference Safety Information section added to the protocol to explain which RSI is used for the trial and where it is taken from. List of expected adverse events for patients receiving brain radiotherapy added. Contact details of trial coordinator updated.
    18 Oct 2017
    Protocol Version 9 - Information added to dose modifications for clarity regarding patients with hepatic impairment. All references to 'pegfilgrastim' changed to 'neulasta' for consistency (these are the same drug). Pharmacovigilance section updated to reflect that SAE reporting was done with paper SAE forms (rather than an online LCTU pharmacovigilance system).

    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.
    Due to the low recruitment rate, the study did not have the statistical power to identify significant differences between the treatment arms. However, treatment was well tolerated in the investigational arm with acceptable toxicity profile.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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