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    Clinical Trial Results:
    A Phase 1-2 Dose Finding, Safety and Efficacy Study of Cabazitaxel in Pediatric Patients with Refractory Solid Tumors including Tumors of the Central Nervous System

    Summary
    EudraCT number
    		 2015-002184-42
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    18 Feb 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Sep 2016
    First version publication date
    01 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TED12689
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01751308
    WHO universal trial number (UTN)
    		 U1111-1128-5704
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    04 Mar 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary Objectives: Phase 1 Part: To determine the dose limiting toxicity (DLT) and the maximum tolerated dose (MTD) of cabazitaxel as a single agent in pediatric subjects with recurrent or refractory solid tumors including tumors of the central nervous system. Phase 2 Part: To determine the objective response rate (complete and partial response) and the duration of response to cabazitaxel as a single agent in subjects with recurrent or refractory high grade glioma (HGG) or diffuse intrinsic pontine glioma (DIPG).
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of pediatric patients. The parent(s) or guardian(s) as well as the children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimize distress and discomfort.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Feb 2013
    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 States: 39
    Worldwide total number of subjects
    39
    EEA total number of subjects
    0
    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)
    26
    Adolescents (12-17 years)
    12
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Subjects were enrolled at 12 centres between February 2013 and March 2015.

    Pre-assignment
    Screening details
    		 Phase I was a dose escalation part to determine MTD of Cabazitaxel. Phase 2 was an efficacy and safety evaluation of Cabazitaxel at the MTD, determined in Phase 1. Disease progression (DP), adverse event (AE) and death were considered as completed (defined in protocol).

    Period 1
    Period 1 title
    Phase 1 and Phase 2 (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
    Arm description
    		 Cabazitaxel 20 mg/m^2 intravenous (IV) infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).
    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 20mg/m^2 IV infusion over 1 hour on Day 1 of each 21 -day cycle.

    Arm title
    		 Phase 1: Cabazitaxel 25 mg/m^2
    Arm description
    		 Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).
    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 25mg/m^2 IV infusion over 1 hour on Day 1 of each 21 -day cycle.

    Arm title
    		 Phase 1: Cabazitaxel 30 mg/m^2
    Arm description
    		 Cabazitaxel 30 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).
    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 30mg/m^2 IV infusion over 1 hour on Day 1 of each 21 -day cycle.

    Arm title
    		 Phase 1: Cabazitaxel 35 mg/m^2
    Arm description
    		 Cabazitaxel 35 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).
    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 35mg/m^2 IV infusion over 1 hour on Day 1 of each 21 -day cycle.

    Arm title
    		 Phase 2: Cabazitaxel 30 mg/m^2
    Arm description
    		 Cabazitaxel at the MTD determined in phase 1 (30 mg/m^2) IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).
    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 at 30mg/m^2 IV infusion over 1 hour on Day 1 of each 21-day cycle.

    Number of subjects in period 1
    		Phase 1: Cabazitaxel 20 mg/m^2 Phase 1: Cabazitaxel 25 mg/m^2 Phase 1: Cabazitaxel 30 mg/m^2 Phase 1: Cabazitaxel 35 mg/m^2 Phase 2: Cabazitaxel 30 mg/m^2
    Started
    6
    3
    7
    7
    16
    Completed
    6
    3
    7
    7
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1: Cabazitaxel 20 mg/m^2
    Reporting group description
    		 Cabazitaxel 20 mg/m^2 intravenous (IV) infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Reporting group title
    Phase 1: Cabazitaxel 25 mg/m^2
    Reporting group description
    		 Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Reporting group title
    Phase 1: Cabazitaxel 30 mg/m^2
    Reporting group description
    		 Cabazitaxel 30 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Reporting group title
    Phase 1: Cabazitaxel 35 mg/m^2
    Reporting group description
    		 Cabazitaxel 35 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Reporting group title
    Phase 2: Cabazitaxel 30 mg/m^2
    Reporting group description
    		 Cabazitaxel at the MTD determined in phase 1 (30 mg/m^2) IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Reporting group values
    		 Phase 1: Cabazitaxel 20 mg/m^2 Phase 1: Cabazitaxel 25 mg/m^2 Phase 1: Cabazitaxel 30 mg/m^2 Phase 1: Cabazitaxel 35 mg/m^2 Phase 2: Cabazitaxel 30 mg/m^2 Total
    Number of subjects
    		 6 3 7 7 16 39
    Age categorical
    Units: Subjects
        2-4 years
    		 0 0 2 0 2 4
        5-6 years
    		 2 1 0 1 4 8
        7-11 years
    		 1 1 3 5 4 14
        12-18 years
    		 3 1 2 1 6 13
    Gender, Male/Female
    Units: subjects
        Female
    		 5 0 1 2 8 16
        Male
    		 1 3 6 5 8 23

    End points

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    End points reporting groups
    Reporting group title
    Phase 1: Cabazitaxel 20 mg/m^2
    Reporting group description
    		 Cabazitaxel 20 mg/m^2 intravenous (IV) infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Reporting group title
    Phase 1: Cabazitaxel 25 mg/m^2
    Reporting group description
    		 Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Reporting group title
    Phase 1: Cabazitaxel 30 mg/m^2
    Reporting group description
    		 Cabazitaxel 30 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Reporting group title
    Phase 1: Cabazitaxel 35 mg/m^2
    Reporting group description
    		 Cabazitaxel 35 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Reporting group title
    Phase 2: Cabazitaxel 30 mg/m^2
    Reporting group description
    		 Cabazitaxel at the MTD determined in phase 1 (30 mg/m^2) IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Subject analysis set title
    Phase 1: Overall Population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Cabazitaxel 20 mg/m^2, 25 mg/m^2, 30 mg/m^2 or 35 mg/m^2 IV infusion on Day 1 of every 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Subject analysis set title
    Phase 1 and 2: Cabazitaxel 30 mg/m^2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Cabazitaxel 30 mg/m^2 IV infusion on Day 1 of every 21-day cycle (at the MTD dose determined in Phase 1) in Phase 1 and Phase 2 until DP or death (from any cause).

    Primary: Phase 1: MTD of Cabazitaxel

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    End point title
    		 Phase 1: MTD of Cabazitaxel [1]
    End point description
    MTD: highest dose level of cabazitaxel at which no more than 1 of 6 evaluable subjects experienced dose limiting toxicities (DLT). DLT: AE/abnormal laboratory values related to treatment: hematologic DLTs: Grade(G)4 hematologic toxicity except neutropenia G4 lasting≤7 days,G3/4 febrile neutropenia except in absence of granulocytecolony stimulating factor prophylaxis, G4thrombocytopenia; nonhematologic DLTs: G≥3 nonhematologic toxicity except G3 nausea/ G3/4 vomiting, G3/4 diarrhea,dehydration,G3 fatigue lasting≤7 days, hypersensitivity reactions, elevated transaminases<10*ULN of ≤7 days, retreatment delay of>2 weeks due to delayed recovery from toxicity related to study treatment to baseline G or≤ G1(except for alopecia) and platelet transfusion during Cycle1. Grades from NCICTCAE v4.0. DLT evaluable population: subset of subjects in Phase 1 part from all treated population who received first dose of cabazitaxel, had sufficient safety evaluations or experienced a DLT during Cycle 1.
    End point type
    Primary
    End point timeframe
    Cycle 1 (21 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: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    		 Phase 1: Overall Population
    Number of subjects analysed
    23
    Units: mg/m^2
        number (not applicable)
    30
    No statistical analyses for this end point

    Primary: Phase 2: Percentage of Subjects With Objective Response (OR)

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    End point title
    		 Phase 2: Percentage of Subjects With Objective Response (OR) [2] [3]
    End point description
    OR in subjects was defined as the subjects with a Complete Response (CR) or Partial Response (PR) after 3 cycles of cabazitaxel treatment and maintained for at least 4 weeks. CR and PR were based on the modified response assessment in neuro-oncology (RANO) criteria for subjects with CNS tumors. CR was defined as disappearance of all target lesions. PR was defined as ≥50% decrease in the sum of the products of the two perpendicular diameters of target lesions, compared to the baseline measurement. Efficacy evaluable population was the subset of all treated (AT) subjects with measurable disease with a baseline and at least one postbaseline tumor evaluation. Number of subjects analysed=subjects with available data for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks)
    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: As the endpoint is descriptive in nature, no statistical analysis is 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 30 mg/m^2
    Number of subjects analysed
    11
    Units: percentage of subjects
    number (not applicable)
        CR
    0
        PR
    0
    No statistical analyses for this end point

    Primary: Phase 2: Duration of Response (DOR)

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    End point title
    		 Phase 2: Duration of Response (DOR) [4] [5]
    End point description
    DOR defined as time (in days) from date of first response until date of first documented progressive disease (PD) or death (from any cause), whichever came first. If progression or death was not observed, subject was censored at the date of subject’s last progression-free tumor assessment prior to study cut-off date. PD as per RANO criteria is defined as ≥ 25% increase in the product of perpendicular diameters of any target lesion, taking as reference the smallest product observed since the start of treatment or the appearance of one or more new lesions, or worsening neurologic status not explained by causes unrelated to tumor progression (example, anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, presumed post-therapy swelling etc.) plus any increase in tumor cross-sectional area (or tumor volume).
    End point type
    Primary
    End point timeframe
    Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks)
    Notes
    [4] - 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: As the endpoint is descriptive in nature, no statistical analysis is provided.
    [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 30 mg/m^2
    Number of subjects analysed
    0 [6]
    Units: Weeks
        median (full range (min-max))
    ( to )
    Notes
    [6] - Due to no objective responses in Stage 1 of Phase 2, analysis of DOR was not performed.
    No statistical analyses for this end point

    Secondary: Phase 1 and 2: Number of Subjects With Treatment Emergent Adverse Events (TEAEs)

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    End point title
    		 Phase 1 and 2: Number of Subjects With Treatment Emergent Adverse Events (TEAEs)
    End point description
    AE was defined as any untoward medical occurrence in a subject who received study drug and did not necessarily have a causal relationship with the treatment. TEAEs were defined as AEs that developed or worsened during the on-treatment period which was defined as the period from the time of first dose of cabazitaxel until 30 days following the last administration of cabazitaxel. Analysis was performed on safety population (AT population).
    End point type
    Secondary
    End point timeframe
    Baseline up to DP or death due to any cause (maximum duration: 112.1 weeks for Phase 1 and 12.1 weeks for Phase 2)
    End point values
    		 Phase 1: Cabazitaxel 20 mg/m^2 Phase 1: Cabazitaxel 25 mg/m^2 Phase 1: Cabazitaxel 30 mg/m^2 Phase 1: Cabazitaxel 35 mg/m^2 Phase 2: Cabazitaxel 30 mg/m^2
    Number of subjects analysed
    6
    3
    7
    7
    16
    Units: subjects
        number (not applicable)
    6
    3
    7
    7
    16
    No statistical analyses for this end point

    Secondary: Phase 1: Number of Subjects With Objective Response

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    End point title
    		 Phase 1: Number of Subjects With Objective Response [7]
    End point description
    OR in subjects was defined as the subjects with a CR or PR after 3 cycles of cabazitaxel treatment and maintained for at least 4 weeks as assessed by response evaluation criteria in solid tumors (RECIST) version 1.1 and RANO criteria for CNS tumors. For solid tumors, as per RECIST 1.1, CR defined as disappearance of all target and non-target lesions (any pathological lymph nodes, must have reduction in short axis to <10 mm); PR defined as at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. For CNS tumors, as per RANO criteria, CR defined as disappearance of all target and non-target lesions; PR defined as a ≥50% decrease in the sum of the products of the two perpendicular diameters of target lesions, compared to baseline measurement. Analysis was performed on efficacy evaluable population. Number of subjects analysed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 112.1 weeks)
    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 1 only.
    End point values
    		 Phase 1: Cabazitaxel 20 mg/m^2 Phase 1: Cabazitaxel 25 mg/m^2 Phase 1: Cabazitaxel 30 mg/m^2 Phase 1: Cabazitaxel 35 mg/m^2
    Number of subjects analysed
    5
    3
    7
    7
    Units: Subjects
        number (not applicable)
    1
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Phase 1 and 2: Pharmacokinetics (PK) Parameter of Cabazitaxel: Area Under the Plasma Concentration (AUC) Versus Time Curve

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    End point title
    		 Phase 1 and 2: Pharmacokinetics (PK) Parameter of Cabazitaxel: Area Under the Plasma Concentration (AUC) Versus Time Curve [8]
    End point description
    Blood samples for PK parameters were collected at 5 minutes before end of infusion (EOI), 10 minutes, 30 minutes, 3 hours, 7 hours and 71 hours after the EOI on Day 1 of Cycle 1. PK population (for both Phase 1 and Phase 2 parts of the study) included all subjects who received treatment on Day 1 of Cycle 1 and had at least one post-dose PK sample. Number of subjects analysed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
    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: PK data was reported for the combined population of Phase 1 and 2 at the MTD dose level.
    End point values
    		 Phase 1: Cabazitaxel 20 mg/m^2 Phase 1: Cabazitaxel 25 mg/m^2 Phase 1: Cabazitaxel 35 mg/m^2 Phase 1 and 2: Cabazitaxel 30 mg/m^2
    Number of subjects analysed
    6
    3
    2
    20
    Units: ng.h/mL
        arithmetic mean (standard deviation)
    669.5 ± 430.6
    879 ± 414.7
    1002.5 ± 277.9
    876.7 ± 359.9
    No statistical analyses for this end point

    Secondary: Phase 1 and 2: PK Parameter of Cabazitaxel: Total Plasma Clearance (CL)

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    End point title
    		 Phase 1 and 2: PK Parameter of Cabazitaxel: Total Plasma Clearance (CL) [9]
    End point description
    Blood samples for PK parameters were collected at 5 minutes before EOI, 10 minutes, 30 minutes, 3 hours, 7 hours and 71 hours after the EOI on Day 1 of Cycle 1. Analysis was performed on PK population (for both Phase 1 and Phase 2 parts of the study). Number of subjects analysed =subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI.
    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: PK data was reported for the combined population of Phase 1 and 2 at the MTD dose level.
    End point values
    		 Phase 1: Cabazitaxel 20 mg/m^2 Phase 1: Cabazitaxel 25 mg/m^2 Phase 1: Cabazitaxel 35 mg/m^2 Phase 1 and 2: Cabazitaxel 30 mg/m^2
    Number of subjects analysed
    6
    3
    2
    20
    Units: L/h/m^2
        arithmetic mean (standard deviation)
    36.05 ± 12.91
    32.76 ± 12.72
    36.61 ± 9.98
    38.7 ± 12.98
    No statistical analyses for this end point

    Secondary: Phase 1 and 2: PK Parameter of Cabazitaxel: Volume of Distribution at Steady State (Vss)

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    End point title
    		 Phase 1 and 2: PK Parameter of Cabazitaxel: Volume of Distribution at Steady State (Vss) [10]
    End point description
    Blood samples for PK parameters were collected at 5 minutes before EOI, 10 minutes, 30 minutes, 3 hours, 7 hours and 71 hours after the EOI on Day 1 of Cycle 1. Analysis was performed on PK population (for both Phase 1 and Phase 2 parts of the study). Number of subjects analysed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
    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: PK data was reported for the combined population of Phase 1 and 2 at the MTD dose level.
    End point values
    		 Phase 1: Cabazitaxel 20 mg/m^2 Phase 1: Cabazitaxel 25 mg/m^2 Phase 1: Cabazitaxel 35 mg/m^2 Phase 1 and 2: Cabazitaxel 30 mg/m^2
    Number of subjects analysed
    6
    3
    2
    20
    Units: L/m^2
        arithmetic mean (standard deviation)
    3391.72 ± 686.79
    3301.96 ± 351.55
    1488.75 ± 1179.11
    3371.3 ± 975.98
    No statistical analyses for this end point

    Secondary: Phase 1 and 2: PK Parameter of Cabazitaxel: Maximum Plasma Concentration Observed (Cmax)

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    End point title
    		 Phase 1 and 2: PK Parameter of Cabazitaxel: Maximum Plasma Concentration Observed (Cmax) [11]
    End point description
    Blood samples for PK parameters were collected at 5 minutes before EOI, 10 minutes, 30 minutes, 3 hours, 7 hours and 71 hours after the EOI on Day 1 of Cycle 1. Analysis was performed on PK population (for both Phase 1 and Phase 2 parts of the study). Number of subjects analysed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1: 5 minutes before EOI up to 71 hours after the EOI
    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: PK data was reported for the combined population of Phase 1 and 2 at the MTD dose level.
    End point values
    		 Phase 1: Cabazitaxel 20 mg/m^2 Phase 1: Cabazitaxel 25 mg/m^2 Phase 1: Cabazitaxel 35 mg/m^2 Phase 1 and 2: Cabazitaxel 30 mg/m^2
    Number of subjects analysed
    6
    3
    2
    20
    Units: ng/mL
        arithmetic mean (standard deviation)
    204.864 ± 189.864
    283.657 ± 242.97
    233.29 ± 0.127
    256.734 ± 127.931
    No statistical analyses for this end point

    Secondary: Phase 2: Progression Free Survival (PFS)

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    End point title
    		 Phase 2: Progression Free Survival (PFS) [12]
    End point description
    PFS: time (in months) from date of first dose administration until date of first documented PD or death (from any cause), whichever came first. If progression/death was not observed, the subject was censored at the date of subject’s last progression-free tumor assessment prior to study cut-off date. PD as per RANO criteria defined as ≥ 25% increase in product of perpendicular diameters of any target lesion, taking as reference smallest product observed since start of treatment or appearance of one or more new lesions, or worsening neurologic status not explained by causes unrelated to tumor progression (example, anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, presumed post-therapy swelling etc) plus any increase in tumor cross-sectional area (or tumor volume).The analysis was performed by Kaplan- Meier method. Analysis was performed on efficacy evaluable population. Number of subjects analysed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, every 9 weeks until DP or death due to any cause (maximum duration: 12.1 weeks)
    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 30 mg/m^2
    Number of subjects analysed
    11
    Units: months
        median (confidence interval 95%)
    1.3 (0.6 to 2.1)
    No statistical analyses for this end point

    Secondary: Phase 2: Overall Survival (OS)

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    End point title
    		 Phase 2: Overall Survival (OS) [13]
    End point description
    OS was defined as the time (in months) from the date of first dose administration until the date of death (from any cause). If death was not observed, the subject was censored at the earliest of the last date the subject was known to be alive and the study cut-off date. The analysis was performed by Kaplan-­Meier method. Analysis was performed on efficacy evaluable population. Number of subjects analysed=subjects with available data for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline up to death or study cut-off (maximum duration: 12.1 weeks)
    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 30 mg/m^2
    Number of subjects analysed
    11
    Units: months
        median (confidence interval 95%)
    2.7 (1.7 to 4.5)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected from signature of the informed consent form up to the final visit (112.1 weeks for Phase 1 and 12.1 weeks for Phase 2) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs are TEAEs that is AEs that developed/worsened during 'on treatment period' (time from first dose of study drug to last dose of study drug + 30 days). Analysis was performed on the safety population.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.1
    Reporting groups
    Reporting group title
    Phase 1: Cabazitaxel 20 mg/m^2
    Reporting group description
    		 Cabazitaxel 20 mg/m^2 intravenous (IV) infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Reporting group title
    Phase 1: Cabazitaxel 25 mg/m^2
    Reporting group description
    		 Cabazitaxel 25 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Reporting group title
    Phase 1: Cabazitaxel 30 mg/m^2
    Reporting group description
    		 Cabazitaxel 30 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Reporting group title
    Phase 1: Cabazitaxel 35 mg/m^2
    Reporting group description
    		 Cabazitaxel 35 mg/m^2 IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Reporting group title
    Phase 2: Cabazitaxel 30 mg/m^2
    Reporting group description
    		 Cabazitaxel at the MTD as determined in Phase 1 (30 mg/m^2) IV infusion on Day 1 of each 21-day cycle until DP or discontinuation due to AE or death (from any cause).

    Serious adverse events
    		 Phase 1: Cabazitaxel 20 mg/m^2 Phase 1: Cabazitaxel 25 mg/m^2 Phase 1: Cabazitaxel 30 mg/m^2 Phase 1: Cabazitaxel 35 mg/m^2 Phase 2: Cabazitaxel 30 mg/m^2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 6 (66.67%)
    1 / 3 (33.33%)
    5 / 7 (71.43%)
    3 / 7 (42.86%)
    12 / 16 (75.00%)
         number of deaths (all causes)
    1
    0
    0
    0
    5
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Intracranial Tumour Haemorrhage
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm Progression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tumour Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease Progression
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    3 / 16 (18.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    Death
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Fatigue
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic Reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    3 / 16 (18.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoventilation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia Aspiration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Platelet Count Decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Brain Herniation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac disorders
    Cardiac Arrest
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Nerve Root Compression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile Neutropenia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    3 / 16 (18.75%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    1 / 1
    2 / 2
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 16 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Cystitis Noninfective
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella Zoster Virus Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stoma Site Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    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 Phase 1: Cabazitaxel 25 mg/m^2 Phase 1: Cabazitaxel 30 mg/m^2 Phase 1: Cabazitaxel 35 mg/m^2 Phase 2: Cabazitaxel 30 mg/m^2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    3 / 3 (100.00%)
    7 / 7 (100.00%)
    7 / 7 (100.00%)
    15 / 16 (93.75%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    2
    General disorders and administration site conditions
    Catheter Site Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Localised Oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Gait Disturbance
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Fatigue
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    3 / 7 (42.86%)
    3 / 16 (18.75%)
         occurrences all number
    2
    2
    2
    4
    3
    Device Occlusion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Oedema Peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Malaise
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    2
    2
    Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Immune system disorders
    Seasonal Allergy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypersensitivity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    0
    1
    Reproductive system and breast disorders
    Ovarian Cyst
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Dysmenorrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    3 / 7 (42.86%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    3
    4
    1
    0
    Atelectasis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Aspiration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Dysphonia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Dyspnoea Exertional
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    2 / 16 (12.50%)
         occurrences all number
    0
    1
    1
    1
    2
    Nasal Congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    1
    1
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pneumonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Pulmonary Oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Rhinitis Allergic
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Upper-Airway Cough Syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Wheezing
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Agitation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Confusional State
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Deja Vu
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Investigations
    Coronavirus Test Positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Candida Test Positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Alanine Aminotransferase Increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    White Blood Cell Count Decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Weight Decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    0
    1
    Platelet Count Decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    2
    0
    1
    Injury, poisoning and procedural complications
    Rectal Injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Infusion Related Reaction
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    2 / 16 (12.50%)
         occurrences all number
    1
    1
    0
    2
    3
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    0
    1
    Sinus Tachycardia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    Sinus Bradycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nervous system disorders
    Accessory Nerve Disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Balance Disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Cerebellar Syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    0
    2
    Cerebellar Ataxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    0
    2
    Ataxia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    2 / 16 (12.50%)
         occurrences all number
    1
    0
    0
    2
    2
    Dysarthria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    3 / 16 (18.75%)
         occurrences all number
    0
    0
    0
    0
    3
    Cranial Nerve Paralysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    Facial Nerve Disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    4 / 6 (66.67%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    2 / 7 (28.57%)
    4 / 16 (25.00%)
         occurrences all number
    5
    1
    3
    3
    5
    Hemiparesis
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    3 / 16 (18.75%)
         occurrences all number
    2
    1
    0
    0
    3
    Hydrocephalus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypotonia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Lethargy
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    0
    2
    Hypoglossal Nerve Disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Seizure
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Muscle Spasticity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    0
    2
    Viiith Nerve Lesion
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    0
    2
    Vith Nerve Paralysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    0
    2
    Vith Nerve Disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    1 / 7 (14.29%)
    1 / 16 (6.25%)
         occurrences all number
    1
    8
    2
    1
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Eyelid Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Vision Blurred
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Eye Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    2
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    3 / 7 (42.86%)
    2 / 16 (12.50%)
         occurrences all number
    0
    2
    1
    3
    2
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    4 / 7 (57.14%)
    1 / 7 (14.29%)
    5 / 16 (31.25%)
         occurrences all number
    2
    3
    4
    1
    6
    Constipation
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    2 / 7 (28.57%)
    2 / 7 (28.57%)
    3 / 16 (18.75%)
         occurrences all number
    1
    1
    2
    2
    3
    Dry Mouth
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Dysphagia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    6 / 16 (37.50%)
         occurrences all number
    0
    0
    0
    0
    6
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Ileus
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Glossodynia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Nausea
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 3 (33.33%)
    3 / 7 (42.86%)
    2 / 7 (28.57%)
    5 / 16 (31.25%)
         occurrences all number
    3
    2
    5
    2
    5
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 3 (66.67%)
    3 / 7 (42.86%)
    2 / 7 (28.57%)
    4 / 16 (25.00%)
         occurrences all number
    0
    3
    3
    2
    4
    Stomatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    1
    1
    0
    1
    Dry Skin
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Palmar-Plantar Erythrodysaesthesia Syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Rash
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Skin Ulcer
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Haematuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Pollakiuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Urinary Retention
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Proteinuria
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    1
    0
    3
    0
    2
    Arthralgia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    Bone Pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Neck Pain
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Joint Hyperextension
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Muscular Weakness
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    1
    0
    0
    0
    1
    Myalgia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 3 (33.33%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    Pain In Extremity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    2 / 7 (28.57%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    5
    0
    0
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 3 (33.33%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Candida Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    0
    2
    Enterocolitis Bacterial
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Lip Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    0
    1
    Mucosal Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    1 / 7 (14.29%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    0
    1
    2
    Varicella Zoster Virus Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Urinary Tract Infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    2 / 7 (28.57%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    2
    1
    Dehydration
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    1 / 7 (14.29%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    1
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    0 / 7 (0.00%)
    0 / 7 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 3 (0.00%)
    1 / 7 (14.29%)
    0 / 7 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Nov 2012
    - Exclusion criterion 9 changed to allow subjects being treated with continuous daily dexamethasone into the study, based on results from TCD10870 study indicating that CYP3A inducers have a limited impact on the PK of cabazitaxel. - Clarification of timing for: coagulation, ECG assessments, end of treatment visit, PK sampling, and granulocyte-colony stimulating factor (G-CSF) administration.
    30 Jul 2013
    - Phase 2 part (efficacy) was added to allow the study of HGG and DIPG patients in the safety expansion portion of Phase 1 with its integration into Stage 1 of Phase 2 thus reducing the exposure of subjects with non-CNS malignancies expected to benefit less from cabazitaxel treatment. - Enrollment opened for children 2-4 years old in Phase 1 part. - Addition of optional cerebrospinal fluid (CSF) collection. - Clarification of: reporting timelines, DLT definition, inclusion and exclusion criteria and PK analysis parameters.
    31 Jan 2014
    - The DLT definition was changed to avoid underreporting of thrombocytopenia as DLT. - Clarification of: dose escalation rules, exclusion criteria, concomitant medications, and the management of cabazitaxel-related toxicity.
    03 Apr 2015
    - Decreased the concentration of cabazitaxel infusion by lowering the high end of the range from 0.26 mg/mL to 0.18 mg/mL. - Added pre-steroid treatment at 24 hours and 12 hours before each cabazitaxel infusion (pre-steroid treatment was to be given at 24 hours, 12 hours and 30 minutes – 60 minutes before each cabazitaxel dosing). - Adjusted the dose (0.5 mg/kg) and the range (from 0.01 - 0.25 mg/kg to 0.05 - 0.1 mg/kg) of dexamethasone. - Capped each dose of dexamethasone at 10 mg maximum.

    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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