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    Clinical Trial Results:
    Phase 1b/2, Multicenter, Open-label Study of Carfilzomib, Carboplatin, and Etoposide in Subjects With Previously Untreated Extensive-stage Small-cell Lung Cancer

    Summary
    EudraCT number
    		 2013-002597-44
    Trial protocol
    		 GB   DE   FR   HU  
    Global end of trial date
    04 May 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 May 2018
    First version publication date
    18 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20130399
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01987232
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    01 Aug 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 May 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to determine the maximum tolerated dose (MTD) of carfilzomib given on days 2, 3, 9, and 10 in combination with standard dose carboplatin on day 1 and etoposide on days 1, 2, and 3 every 3 weeks as treatment for previously untreated extensive-stage small-cell lung cancer (ES-SCLC).
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. The investigator submitted the protocol and informed consent form (ICF) to the appropriate Institutional Review Board (IRB) or Independent Ethics Committee (IEC) for review and approval prior to study initiation. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Nov 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: 21
    Country: Number of subjects enrolled
    Russian Federation: 11
    Worldwide total number of subjects
    32
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    25
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 17 centers in the United States, Russia, and Canada.

    Pre-assignment
    Screening details
    		 In the phase 1b portion of the study participants were assigned sequentially to escalating doses of carfilzomib given in combination with standard dose carboplatin and etoposide to establish the maximum tolerated dose (MTD). The phase 2 portion of the study was not enrolled.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Carfilzomib 20/20 mg/m²
    Arm description
    		 Participants received carfilzomib 20 mg/m² on days 2, 3, 9, and 10 of each 21-day cycle, carboplatin at a target area under the curve (AUC) of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each 21-day cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    PR-171
    Other name
    Kyprolis®
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion.

    Arm title
    		 Carfilzomib 20/27 mg/m²
    Arm description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 27 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    PR-171
    Other name
    Kyprolis®
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion.

    Arm title
    		 Carfilzomib 20/36 mg/m²
    Arm description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 36 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    PR-171
    Other name
    Kyprolis®
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion.

    Arm title
    		 Carfilzomib 20/45 mg/m²
    Arm description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 45 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    PR-171
    Other name
    Kyprolis®
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion.

    Arm title
    		 Carfilzomib 20/56 mg/m²
    Arm description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 56 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carfilzomib
    Investigational medicinal product code
    PR-171
    Other name
    Kyprolis®
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by intravenous infusion.

    Number of subjects in period 1
    		Carfilzomib 20/20 mg/m² Carfilzomib 20/27 mg/m² Carfilzomib 20/36 mg/m² Carfilzomib 20/45 mg/m² Carfilzomib 20/56 mg/m²
    Started
    5
    3
    3
    15
    6
    Completed
    5
    3
    3
    15
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Carfilzomib 20/20 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on days 2, 3, 9, and 10 of each 21-day cycle, carboplatin at a target area under the curve (AUC) of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each 21-day cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Reporting group title
    Carfilzomib 20/27 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 27 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Reporting group title
    Carfilzomib 20/36 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 36 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Reporting group title
    Carfilzomib 20/45 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 45 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Reporting group title
    Carfilzomib 20/56 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 56 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Reporting group values
    		 Carfilzomib 20/20 mg/m² Carfilzomib 20/27 mg/m² Carfilzomib 20/36 mg/m² Carfilzomib 20/45 mg/m² Carfilzomib 20/56 mg/m² Total
    Number of subjects
    		 5 3 3 15 6 32
    Age Categorical
    Units: Subjects
        Adults (18-64 years)
    		 2 2 2 14 5 25
        From 65-84 years
    		 3 1 1 1 1 7
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 69.2 ± 13.8 62.3 ± 8.5 59.0 ± 7.5 56.9 ± 9.4 58.8 ± 7.9 -
    Gender Categorical
    Units: Subjects
        Female
    		 3 2 1 5 1 12
        Male
    		 2 1 2 10 5 20
    Race
    Units: Subjects
        White
    		 5 3 3 14 6 31
        Other
    		 0 0 0 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 0 1 0 1
        Not Hispanic or Latino
    		 5 3 3 14 5 30
        Not Reported
    		 0 0 0 0 1 1
    Eastern Cooperative Oncology Group (ECOG) Performance Status
    Eastern Cooperative Oncology Group (ECOG) Performance Status is used by doctors and researchers to assess how a participants disease is progressing, assess how the disease affects the daily living activities of the participant and determine appropriate treatment and prognosis. 0 = Fully Active; 1 = Restricted activity but ambulatory; 2 = Ambulatory but unable to carry out work activities; 3 = Limited Self-Care; 4 = Completely Disabled, no self-care, confined to bed or chair; 5 = Dead.
    Units: Subjects
        0 (Fully active)
    		 4 0 1 3 2 10
        1 (Restrictive but ambulatory)
    		 1 3 2 12 4 22

    End points

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    End points reporting groups
    Reporting group title
    Carfilzomib 20/20 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on days 2, 3, 9, and 10 of each 21-day cycle, carboplatin at a target area under the curve (AUC) of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each 21-day cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Reporting group title
    Carfilzomib 20/27 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 27 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Reporting group title
    Carfilzomib 20/36 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 36 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Reporting group title
    Carfilzomib 20/45 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 45 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Reporting group title
    Carfilzomib 20/56 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 56 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Subject analysis set title
    All Participants
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Participants received carfilzomib on days 2, 3, 9, and 10 of each 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each 21-day cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Primary: Number of Participants With Dose-limiting Toxicities

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    End point title
    		 Number of Participants With Dose-limiting Toxicities [1]
    End point description
    The maximum tolerated dose (MTD) was defined as the highest dose level at which < 33% of participants experienced a dose-limiting toxicity (DLT) during the first 21-day cycle. Dose-limiting toxicities were evaluated according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03. A DLT was defined as: • A grade 3 or greater non-hematologic toxicity that was assessed as related to carfilzomib by the investigator except in the case of neuropathy. A grade 2 or higher neuropathy with pain was considered a DLT. • Grade 4 neutropenia: absolute neutrophil count (ANC) < 500 mm³, lasting ≥ 7 days despite granulocyte colony stimulating factor support, or any febrile (temperature > 38.3°C) neutropenia (ANC < 1000 mm³). • Thrombocytopenia of any grade associated with clinically significant bleeding or platelet/blood transfusion • Grade 4 fatigue lasting ≥ 7 days • Grade 3 nausea, vomiting or diarrhea lasting ≥ 7 days.
    End point type
    Primary
    End point timeframe
    First 21-day Cycle
    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: No statistical analyses were conducted in this study.
    End point values
    		 Carfilzomib 20/20 mg/m² Carfilzomib 20/27 mg/m² Carfilzomib 20/36 mg/m² Carfilzomib 20/45 mg/m² Carfilzomib 20/56 mg/m²
    Number of subjects analysed
    5
    3
    3
    15
    6
    Units: participants
    0
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Participants With Adverse Events (AEs)

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    End point title
    		 Number of Participants With Adverse Events (AEs)
    End point description
    The severity of each adverse event was assessed using the NCI-CTCAE Version 4.03 according to the following: Grade 1 - Mild: Asymptomatic or mild symptoms; intervention not indicated Grade 2 – Moderate: Minimal, local or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL) Grade 3 – Severe: Medically significant but not life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL Grade 4 – Life-threatening Grade 5 – Fatal. A serious AE is an AE that met one or more of the following criteria: • Death • Life-threatening • Required inpatient hospitalization or prolongation of an existing hospitalization • Resulted in persistent or significant disability/incapacity • A congenital anomaly/birth defect • Important medical events that required medical or surgical intervention to prevent one of the outcomes above.
    End point type
    Secondary
    End point timeframe
    From first day of any study treatment (i.e., carfilzomib, carboplatin, or etoposide) up to 30 days after the last day of study treatment. The median overall duration of treatment was 16 weeks.
    End point values
    		 Carfilzomib 20/20 mg/m² Carfilzomib 20/27 mg/m² Carfilzomib 20/36 mg/m² Carfilzomib 20/45 mg/m² Carfilzomib 20/56 mg/m²
    Number of subjects analysed
    5
    3
    3
    15
    6
    Units: participants
        Any adverse event
    5
    3
    3
    15
    5
        Adverse events ≥ grade 3
    3
    3
    2
    13
    4
        Serious adverse events
    1
    1
    1
    7
    2
        AEs leading to disocontinuation of study drug
    1
    0
    0
    3
    1
        Fatal adverse events
    0
    0
    0
    0
    1
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) - Phase 2

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    End point title
    		 Overall Survival (OS) - Phase 2
    End point description
    Overall Survival (OS) is defined as the time from randomization to the date of death. Overall survival was a specified secondary endpoint for the phase 2 portion of the study; since phase 2 was not conducted, OS was not analyzed.
    End point type
    Secondary
    End point timeframe
    30 months
    End point values
    		 Carfilzomib 20/20 mg/m² Carfilzomib 20/27 mg/m² Carfilzomib 20/36 mg/m² Carfilzomib 20/45 mg/m² Carfilzomib 20/56 mg/m²
    Number of subjects analysed
    0 [2]
    0 [3]
    0 [4]
    0 [5]
    0 [6]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [2] - OS was only analyzed in subjects enrolled in phase 2
    [3] - OS was only analyzed in subjects enrolled in phase 2
    [4] - OS was only analyzed in subjects enrolled in phase 2
    [5] - OS was only analyzed in subjects enrolled in phase 2
    [6] - OS was only analyzed in subjects enrolled in phase 2
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration - Phase 2

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    End point title
    		 Maximum Plasma Concentration - Phase 2
    End point description
    Pharmacokinetic (PK) analyses were specified as secondary endpoints for the phase 2 portion of the study; since phase 2 was not conducted, PK analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 2
    End point values
    		 Carfilzomib 20/20 mg/m² Carfilzomib 20/27 mg/m² Carfilzomib 20/36 mg/m² Carfilzomib 20/45 mg/m² Carfilzomib 20/56 mg/m²
    Number of subjects analysed
    0 [7]
    0 [8]
    0 [9]
    0 [10]
    0 [11]
    Units: ng/mL
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    Notes
    [7] - PK endpoints were only analyzed in subjects enrolled in phase 2
    [8] - PK endpoints were only analyzed in subjects enrolled in phase 2
    [9] - PK endpoints were only analyzed in subjects enrolled in phase 2
    [10] - PK endpoints were only analyzed in subjects enrolled in phase 2
    [11] - PK endpoints were only analyzed in subjects enrolled in phase 2
    No statistical analyses for this end point

    Secondary: Time of Maximum Plasma Concentration - Phase 2

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    End point title
    		 Time of Maximum Plasma Concentration - Phase 2
    End point description
    Pharmacokinetic (PK) analyses were specified as secondary endpoints for the phase 2 portion of the study; since phase 2 was not conducted, PK analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 2
    End point values
    		 Carfilzomib 20/20 mg/m² Carfilzomib 20/27 mg/m² Carfilzomib 20/36 mg/m² Carfilzomib 20/45 mg/m² Carfilzomib 20/56 mg/m²
    Number of subjects analysed
    0 [12]
    0 [13]
    0 [14]
    0 [15]
    0 [16]
    Units: hours
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [12] - PK endpoints were only analyzed in subjects enrolled in phase 2
    [13] - PK endpoints were only analyzed in subjects enrolled in phase 2
    [14] - PK endpoints were only analyzed in subjects enrolled in phase 2
    [15] - PK endpoints were only analyzed in subjects enrolled in phase 2
    [16] - PK endpoints were only analyzed in subjects enrolled in phase 2
    No statistical analyses for this end point

    Secondary: Area Under Plasma Concentration-Time Curve - Phase 2

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    End point title
    		 Area Under Plasma Concentration-Time Curve - Phase 2
    End point description
    Pharmacokinetic (PK) analyses were specified as secondary endpoints for the phase 2 portion of the study; since phase 2 was not conducted, PK analyses were not performed.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 2
    End point values
    		 Carfilzomib 20/20 mg/m² Carfilzomib 20/27 mg/m² Carfilzomib 20/36 mg/m² Carfilzomib 20/45 mg/m² Carfilzomib 20/56 mg/m²
    Number of subjects analysed
    0 [17]
    0 [18]
    0 [19]
    0 [20]
    0 [21]
    Units: ng/mL*h
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    ±
    ±
    Notes
    [17] - PK endpoints were only analyzed in subjects enrolled in phase 2
    [18] - PK endpoints were only analyzed in subjects enrolled in phase 2
    [19] - PK endpoints were only analyzed in subjects enrolled in phase 2
    [20] - PK endpoints were only analyzed in subjects enrolled in phase 2
    [21] - PK endpoints were only analyzed in subjects enrolled in phase 2
    No statistical analyses for this end point

    Secondary: Progression-free Survival

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    End point title
    		 Progression-free Survival
    End point description
    Progression-free survival (PFS) was specified as a primary endpoint for the phase 2 portion of the study. Since phase 2 did not proceed PFS was analyzed in phase 1b participants on an exploratory basis. PFS was defined as the time from the start of treatment to documented disease progression or death due to any cause, whichever occurred first. Disease progression was determined by the investigator according to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, defined as at least a 20% increase in the size of target lesions (absolute increase ≥ 5 mm), unequivocal progression of existing non-target lesions, or any new lesions. Median PFS was calculated using Kaplan-Meier methods. Participants with no baseline disease assessments, who started a new anticancer therapy before documentation of PD or death, with death or PD immediately after more than 1 consecutively missed disease assessment visit or alive without documentation of PD before the data cutoff date were censored.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until the end of treatment; median duration of treatment was 16 weeks.
    End point values
    		 Carfilzomib 20/20 mg/m² Carfilzomib 20/27 mg/m² Carfilzomib 20/36 mg/m² Carfilzomib 20/45 mg/m² Carfilzomib 20/56 mg/m² All Participants
    Number of subjects analysed
    5
    3
    3
    15
    6
    32
    Units: months
        median (confidence interval 95%)
    4.0 (2.8 to 6.7)
    6.4 (6.2 to 6.8)
    7.0 (4.0 to 7.0)
    2.9 (2.5 to 5.4)
    3.8 (1.1 to 6.3)
    4.4 (2.8 to 5.6)
    No statistical analyses for this end point

    Secondary: Overall Response Rate

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    End point title
    		 Overall Response Rate
    End point description
    Overall response rate (ORR) was specified as a secondary endpoint for the phase 2 portion of the study. Since phase 2 did not proceed ORR was analyzed in phase 1b participants on an exploratory basis. ORR was defined as the percentage of participants for whom the best overall confirmed response was either complete response (CR) or partial response (PR) assessed by the investigator according to RECIST v1.1 criteria. CR: Disappearance of all target and non-target lesions, no new lesions and normalization of tumor marker levels. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to < 10 mm. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters, or, the disappearance of all target lesions and persistence of one or more non-target lesion(s) and/or maintenance of tumor marker levels above normal limits.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until the end of treatment; median duration of treatment was 16 weeks.
    End point values
    		 Carfilzomib 20/20 mg/m² Carfilzomib 20/27 mg/m² Carfilzomib 20/36 mg/m² Carfilzomib 20/45 mg/m² Carfilzomib 20/56 mg/m² All Participants
    Number of subjects analysed
    5
    3
    3
    15
    6
    32
    Units: percentage of participants
        number (confidence interval 95%)
    60.0 (14.7 to 94.7)
    100.0 (29.2 to 100.0)
    66.7 (9.4 to 99.2)
    33.3 (11.8 to 61.6)
    33.3 (4.3 to 77.7)
    46.9 (29.1 to 65.3)
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of response (DOR) was calculated for participants who achieved a confirmed CR or PR. defined as the time from first evidence of confirmed PR/CR to disease progression or death due to any cause. Median DOR was calculated using Kaplan-Meier methods. Participants with no baseline disease assessments, who started a new anticancer therapy before documentation of PD or death, with death or PD immediately after more than 1 consecutively missed disease assessment visit or alive without documentation of PD before the data cutoff date were censored. DOR was originally specified as a secondary endpoint for the phase 2 portion of the study. Since phase 2 did not proceed, DOR was analyzed in phase 1b participants on an exploratory basis. "99999" indicates data that could not be estimated due to the low number of events.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug until the end of treatment; median duration of treatment was 16 weeks.
    End point values
    		 Carfilzomib 20/20 mg/m² Carfilzomib 20/27 mg/m² Carfilzomib 20/36 mg/m² Carfilzomib 20/45 mg/m² Carfilzomib 20/56 mg/m² All Participants
    Number of subjects analysed
    3
    3
    2
    5
    2
    15
    Units: months
        median (confidence interval 95%)
    4.9 (2.8 to 5.4)
    5.0 (4.7 to 5.6)
    99999 (2.8 to 99999)
    4.3 (1.6 to 999999)
    4.5 (4.2 to 4.8)
    4.8 (2.8 to 5.4)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first day of any study treatment (i.e., carfilzomib, carboplatin, or etoposide), and within 30 days of the last day of study treatment. The median overall duration of treatment was 16 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Carfilzomib 20/20 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on days 2, 3, 9, and 10 of each 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each 21-day cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Reporting group title
    Carfilzomib 20/27 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 27 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until progressive disease (PD), unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Reporting group title
    Carfilzomib 20/36 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 36 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Reporting group title
    Carfilzomib 20/45 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 45 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Reporting group title
    Carfilzomib 20/56 mg/m²
    Reporting group description
    		 Participants received carfilzomib 20 mg/m² on cycle 1 days 2 and 3, then 56 mg/m² on days 9 and 10 and thereafter for each subsequent 21-day cycle, carboplatin at a target AUC of 5 on day 1 of each cycle, and etoposide 100 mg/m² on days 1, 2, and 3 of each cycle for up to 6 cycles. Participants with stable disease or better continued to receive carfilzomib alone until PD, unacceptable toxicity, withdrawal of consent, study closure, or death, whichever occurred earliest.

    Serious adverse events
    		 Carfilzomib 20/20 mg/m² Carfilzomib 20/27 mg/m² Carfilzomib 20/36 mg/m² Carfilzomib 20/45 mg/m² Carfilzomib 20/56 mg/m²
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    7 / 15 (46.67%)
    2 / 6 (33.33%)
         number of deaths (all causes)
    2
    0
    0
    2
    3
         number of deaths resulting from adverse events
    Vascular disorders
    Peripheral artery thrombosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         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
    Cerebrovascular accident
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (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
    Nervous system disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         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
    Febrile neutropenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         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
    Pulmonary oedema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    Infections and infestations
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (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
    Injection site abscess
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (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
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Carfilzomib 20/20 mg/m² Carfilzomib 20/27 mg/m² Carfilzomib 20/36 mg/m² Carfilzomib 20/45 mg/m² Carfilzomib 20/56 mg/m²
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    15 / 15 (100.00%)
    5 / 6 (83.33%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Flushing
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hypertension
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Hypotension
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    1
    0
    1
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Phlebitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    3
    1
    Catheter site pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Chills
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    4 / 15 (26.67%)
    2 / 6 (33.33%)
         occurrences all number
    3
    1
    3
    7
    4
    Mucosal inflammation
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    3
    1
    Pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pyrexia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    2
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Aspiration
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Cough
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    1
    1
    2
    Dry throat
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    0
    3
    2
    Haemoptysis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Hypoxia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nasal congestion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    2
    0
    Pulmonary oedema
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Wheezing
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Confusional state
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Depression
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    4
    0
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    2
    0
    2
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    1 / 15 (6.67%)
    2 / 6 (33.33%)
         occurrences all number
    0
    1
    1
    3
    3
    Blood glucose increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood phosphorus increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Blood potassium decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Blood urea increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Blood uric acid increased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Creatinine renal clearance decreased
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 15 (6.67%)
    2 / 6 (33.33%)
         occurrences all number
    5
    0
    2
    2
    4
    Ejection fraction decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Haemoglobin decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    2
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    12
    0
    0
    4
    Platelet count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    2 / 15 (13.33%)
    2 / 6 (33.33%)
         occurrences all number
    0
    15
    0
    3
    2
    Weight decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    3
    2
    0
    Weight increased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    0
    1
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Head injury
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Incision site erythema
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Incision site swelling
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Laceration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Wound
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nervous system disorders
    Ageusia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    0
    0
    1
    Cerebrovascular accident
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Decreased vibratory sense
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    2 / 3 (66.67%)
    3 / 15 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    2
    7
    1
    Dysgeusia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    2
    4
    0
    Headache
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 3 (66.67%)
    2 / 3 (66.67%)
    3 / 15 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    3
    3
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Hyporeflexia
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    2
    0
    Paraesthesia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Vocal cord paralysis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 5 (40.00%)
    3 / 3 (100.00%)
    2 / 3 (66.67%)
    8 / 15 (53.33%)
    3 / 6 (50.00%)
         occurrences all number
    3
    20
    3
    16
    4
    Leukocytosis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Leukopenia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    3 / 15 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    2
    0
    0
    5
    1
    Neutropenia
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    10 / 15 (66.67%)
    3 / 6 (50.00%)
         occurrences all number
    3
    2
    0
    19
    6
    Thrombocytopenia
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    7 / 15 (46.67%)
    4 / 6 (66.67%)
         occurrences all number
    0
    5
    1
    15
    8
    Ear and labyrinth disorders
    Ear congestion
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Ear discomfort
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Ear pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hypoacusis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Vertigo
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    Constipation
         subjects affected / exposed
    3 / 5 (60.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    0
    3
    0
    Diarrhoea
         subjects affected / exposed
    1 / 5 (20.00%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    5 / 15 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    2
    6
    0
    Flatulence
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Nausea
         subjects affected / exposed
    3 / 5 (60.00%)
    3 / 3 (100.00%)
    3 / 3 (100.00%)
    5 / 15 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    4
    4
    6
    9
    2
    Oesophagitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Stomatitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    Toothache
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    1 / 3 (33.33%)
    3 / 15 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    1
    5
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    5 / 15 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    1
    0
    2
    5
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Rash
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    0
    1
    Rash macular
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Skin discolouration
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin irritation
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Swelling face
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Micturition disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    3 / 15 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    2
    3
    0
    Bone pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    1
    1
    Costochondritis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Groin pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Muscular weakness
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    3 / 15 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    3
    3
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Injection site infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Lung infection
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    0
    0
    1
    Mucosal infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Oral candidiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Oral herpes
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Skin infection
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Vulvovaginal candidiasis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 3 (0.00%)
    2 / 3 (66.67%)
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         occurrences all number
    5
    0
    3
    3
    1
    Dehydration
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    7
    0
    0
    0
    Diabetes mellitus
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gout
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    2
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Hypocalcaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Hypokalaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 3 (66.67%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    3
    0
    0
    2
    Hyponatraemia
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 3 (66.67%)
    1 / 3 (33.33%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    2
    0
    7
    Metabolic acidosis
         subjects affected / exposed
    0 / 5 (0.00%)
    0 / 3 (0.00%)
    0 / 3 (0.00%)
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jun 2013
    - To revise the DLT definition to include febrile neutropenia as a DLT, regardless of G-CSF support - To revise the DLT definition so that thrombocytopenia of any grade associated with clinically significant bleeding or platelet/blood transfusion Is considered a DLT - To increase the number of doses given at 20 mg/m2 doses (given on cycle 1 day 2 and cycle 1 day 3), prior to stepped-up dosing, as specified by cohort - To improve the clarity regarding the requirement of stepped-up dosing for subjects who crossover from the control arm to receive carfilzomib monotherapy

    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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