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    Clinical Trial Results:
    An Open-Label Phase I/IIa Study of Intravenous BAL101553 in Adult Patients with Advanced Solid Tumors

    Summary
    EudraCT number
    		 2010-024237-23
    Trial protocol
    		 GB  
    Global end of trial date
    06 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Feb 2019
    First version publication date
    01 Feb 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CDI-CS-001
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01397929
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Basilea Pharmaceutica International Ltd.
    Sponsor organisation address
    Grenzacherstrasse 487, Basel, Switzerland,
    Public contact
    Medical Information, Basilea Pharmaceutical International Ltd., +41 6061400, medical.information@basilea.com
    Scientific contact
    Medical Information, Basilea Pharmaceutical International Ltd., +41 6061400, medical.information@basilea.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Feb 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to determine the maximum tolerated dose (MTD) and to characterize dose-limiting toxicities (DLT) of BAL101553 administered intravenously as single agent on days 1, 8 and 15 of an every 28 day treatment cycle in adults with advanced or recurrent solid tumors, who have failed standard therapy or for whom no effective standard therapy is available
    Protection of trial subjects
    This study was conducted in accordance with International Conference on Harmonization (ICH) Good Clinical Practice (GCP) and applicable national and regional regulations/guidelines regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Jun 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 73
    Worldwide total number of subjects
    73
    EEA total number of subjects
    73
    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)
    50
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 4 Phase 1 study centers in the United Kingdom.

    Pre-assignment
    Screening details
    		 Total of 104 subjects were screened, out of which 25 subjects failed screening. Seventy-nine subjects were assigned to treatment of which 73 received at least one dose.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BAL101553: 15 mg/m²
    Arm description
    		 BAL101553 was administered at 15 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAL101553
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BAL101553 15 mg/m² intravenously over 2 hours on Days 1, 8 and 15 of each 28-day treatment cycle.

    Arm title
    		 BAL101553: 30 mg/m²
    Arm description
    		 BAL101553 was administered at 30 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAL101553
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BAL101553 30 mg/m² intravenously over 2 hours on Days 1, 8 and 15 of each 28-day treatment cycle.

    Arm title
    		 BAL101553: 45 mg/m²
    Arm description
    		 BAL101553 was administered at 45 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAL101553
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BAL101553 45 mg/m² intravenously over 2 hours on Days 1, 8 and 15 of each 28-day treatment cycle.

    Arm title
    		 BAL101553: 60 mg/m²
    Arm description
    		 BAL101553 was administered at 60 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAL101553
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BAL101553 60 mg/m² intravenously over 2 hours on Days 1, 8 and 15 of each 28-day treatment cycle.

    Arm title
    		 BAL101553: 80 mg/m²
    Arm description
    		 BAL101553 was administered at 80 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BAL101553
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    BAL101553 80 mg/m² intravenously over 2 hours on Days 1, 8 and 15 of each 28-day treatment cycle.

    Number of subjects in period 1
    		BAL101553: 15 mg/m² BAL101553: 30 mg/m² BAL101553: 45 mg/m² BAL101553: 60 mg/m² BAL101553: 80 mg/m²
    Started
    1
    36
    8
    21
    7
    Completed
    0
    0
    0
    0
    0
    Not completed
    1
    36
    8
    21
    7
         Consent withdrawn by subject
    -
    1
    -
    1
    2
         Disease progression
    1
    30
    7
    18
    3
         Death
    -
    1
    -
    -
    -
         Admin/ other
    -
    1
    -
    -
    -
         Protocol deviation
    -
    1
    -
    -
    -
         AE, intercurrent illness
    -
    2
    1
    2
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BAL101553: 15 mg/m²
    Reporting group description
    		 BAL101553 was administered at 15 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Reporting group title
    BAL101553: 30 mg/m²
    Reporting group description
    		 BAL101553 was administered at 30 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Reporting group title
    BAL101553: 45 mg/m²
    Reporting group description
    		 BAL101553 was administered at 45 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Reporting group title
    BAL101553: 60 mg/m²
    Reporting group description
    		 BAL101553 was administered at 60 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Reporting group title
    BAL101553: 80 mg/m²
    Reporting group description
    		 BAL101553 was administered at 80 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Reporting group values
    		 BAL101553: 15 mg/m² BAL101553: 30 mg/m² BAL101553: 45 mg/m² BAL101553: 60 mg/m² BAL101553: 80 mg/m² Total
    Number of subjects
    		 1 36 8 21 7 73
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 1 26 2 16 5 50
        From 65-84 years
    		 0 10 6 5 2 23
    Age continuous
    Units: years
        median (full range (min-max))
    		 51 (51 to 51) 60 (32 to 79) 67 (47 to 76) 57 (29 to 80) 55 (45 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 1 16 3 11 3 34
        Male
    		 0 20 5 10 4 39

    End points

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    End points reporting groups
    Reporting group title
    BAL101553: 15 mg/m²
    Reporting group description
    		 BAL101553 was administered at 15 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Reporting group title
    BAL101553: 30 mg/m²
    Reporting group description
    		 BAL101553 was administered at 30 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Reporting group title
    BAL101553: 45 mg/m²
    Reporting group description
    		 BAL101553 was administered at 45 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Reporting group title
    BAL101553: 60 mg/m²
    Reporting group description
    		 BAL101553 was administered at 60 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Reporting group title
    BAL101553: 80 mg/m²
    Reporting group description
    		 BAL101553 was administered at 80 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Primary: Maximum tolerated dose (MTD)

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    End point title
    		 Maximum tolerated dose (MTD) [1]
    End point description
    MTD: highest dose level of BAL101553 at which no more than 1 of 6 MTD-evaluable subjects experienced dose limiting toxicities (DLT). DLT: an adverse event or abnormal laboratory value as defined in the protocol that is related to BAL101553. MTD-evaluable subjects: Phase 1 subjects who received at least one dose of BAL101553 and experienced a DLT, or patients who received all three doses of BAL101553 in Cycle 1 without a DLT.
    End point type
    Primary
    End point timeframe
    Cycle 1 (28 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
    		 BAL101553: 15 mg/m² BAL101553: 30 mg/m² BAL101553: 45 mg/m² BAL101553: 60 mg/m² BAL101553: 80 mg/m²
    Number of subjects analysed
    1
    3
    3
    6
    7
    Units: Subjects with DLTs
    0
    0
    0
    1
    2
    No statistical analyses for this end point

    Secondary: PK Parameter: AUC of BAL101553 and BAL27862 (the active metabolite)

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    End point title
    		 PK Parameter: AUC of BAL101553 and BAL27862 (the active metabolite)
    End point description
    Area under the plasma concentration time curve from time point zero to infinity
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1
    End point values
    		 BAL101553: 15 mg/m² BAL101553: 30 mg/m² BAL101553: 45 mg/m² BAL101553: 60 mg/m² BAL101553: 80 mg/m²
    Number of subjects analysed
    1
    36
    8
    21
    7
    Units: h*ng/mL
    geometric mean (geometric coefficient of variation)
        BAL101553
    917 ± 0
    2520 ± 44.0
    2340 ± 257
    3440 ± 47.8
    5640 ± 36.5
        BAL27862
    2110 ± 0
    3620 ± 55.7
    5090 ± 62.9
    7180 ± 44.5
    7950 ± 40.5
    No statistical analyses for this end point

    Secondary: PK Parameter: Cmax of BAL101553 and BAL27862 (the active metabolite)

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    End point title
    		 PK Parameter: Cmax of BAL101553 and BAL27862 (the active metabolite)
    End point description
    Maximum drug concentration observed in plasma
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1
    End point values
    		 BAL101553: 15 mg/m² BAL101553: 30 mg/m² BAL101553: 45 mg/m² BAL101553: 60 mg/m² BAL101553: 80 mg/m²
    Number of subjects analysed
    1
    36
    8
    21
    7
    Units: ng/mL
    geometric mean (geometric coefficient of variation)
        BAL101553
    556 ± 0
    1060 ± 51.7
    1130 ± 350
    1320 ± 137
    3250 ± 24.8
        BAL27862
    154 ± 0
    267 ± 19.8
    346 ± 26.3
    484 ± 25.1
    601 ± 13.1
    No statistical analyses for this end point

    Secondary: PK Parameter: Tmax of BAL101553 and BAL27862 (the active metabolite)

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    End point title
    		 PK Parameter: Tmax of BAL101553 and BAL27862 (the active metabolite)
    End point description
    Time to maximum plasma concentration
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1
    End point values
    		 BAL101553: 15 mg/m² BAL101553: 30 mg/m² BAL101553: 45 mg/m² BAL101553: 60 mg/m² BAL101553: 80 mg/m²
    Number of subjects analysed
    1
    36
    8
    21
    7
    Units: hours
    geometric mean (geometric coefficient of variation)
        BAL101553
    1.05 ± 0
    1.94 ± 15.9
    1.80 ± 39.6
    1.75 ± 36.9
    1.54 ± 32.9
        BAL27862
    2.50 ± 0
    2.13 ± 16.7
    2.30 ± 28.8
    2.34 ± 23.8
    2.33 ± 14.3
    No statistical analyses for this end point

    Secondary: PK Parameter: Terminal half-life of BAL101553 and BAL27862 (the active metabolite)

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    End point title
    		 PK Parameter: Terminal half-life of BAL101553 and BAL27862 (the active metabolite)
    End point description
    End point type
    Secondary
    End point timeframe
    Day 1 of Cycle 1
    End point values
    		 BAL101553: 15 mg/m² BAL101553: 30 mg/m² BAL101553: 45 mg/m² BAL101553: 60 mg/m² BAL101553: 80 mg/m²
    Number of subjects analysed
    1
    36
    8
    21
    7
    Units: hours
    geometric mean (geometric coefficient of variation)
        BAL101553
    0.908 ± 0
    1.96 ± 44.1
    1.54 ± 20.7
    1.51 ± 33.1
    1.49 ± 15.2
        BAL27862
    18.1 ± 0
    12.6 ± 57.2
    12.5 ± 47.7
    13.8 ± 26.5
    12.5 ± 26.7
    No statistical analyses for this end point

    Secondary: Best overall response in EEP

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    End point title
    		 Best overall response in EEP
    End point description
    The best overall response is the best response recorded from the start of the treatment until disease progression. Efficacy evaluable population (EEP): all patients who completed Cycle 1 dosing and who underwent at least one on-study clinical tumor assessment or a radiological assessment by RECIST v1.1.
    End point type
    Secondary
    End point timeframe
    Assessed every 8 weeks from time of first dose until disease progression.
    End point values
    		 BAL101553: 15 mg/m² BAL101553: 30 mg/m² BAL101553: 45 mg/m² BAL101553: 60 mg/m² BAL101553: 80 mg/m²
    Number of subjects analysed
    1
    31
    7
    15
    3
    Units: Number of subjects
        Complete response
    0
    0
    0
    0
    0
        Partial response
    0
    1
    0
    0
    0
        Stable disease
    1
    5
    3
    5
    0
        Progressive disease
    0
    25
    4
    10
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first administration of BAL101553 up to 28 days after the last administration.
    Adverse event reporting additional description
    Treatment-emergent adverse events and serious adverse events
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    BAL101553: 15 mg/m²
    Reporting group description
    		 BAL101553 was administered at 15 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Reporting group title
    BAL101553: 30 mg/m²
    Reporting group description
    		 BAL101553 was administered at 30 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Reporting group title
    BAL101553: 45 mg/m²
    Reporting group description
    		 BAL101553 was administered at 45 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Reporting group title
    BAL101553: 60 mg/m²
    Reporting group description
    		 BAL101553 was administered at 60 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Reporting group title
    BAL101553: 80 mg/m²
    Reporting group description
    		 BAL101553 was administered at 80 mg/m² as an IV infusion over 2 hours on Days 1, 8 and 15 of a 28 day treatment Cycle. Treatment Cycles were continued until disease progression, unacceptable toxicity, or other discontinuation criteria met.

    Serious adverse events
    		 BAL101553: 15 mg/m² BAL101553: 30 mg/m² BAL101553: 45 mg/m² BAL101553: 60 mg/m² BAL101553: 80 mg/m²
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    14 / 36 (38.89%)
    3 / 8 (37.50%)
    14 / 21 (66.67%)
    5 / 7 (71.43%)
         number of deaths (all causes)
    0
    2
    1
    2
    0
         number of deaths resulting from adverse events
    0
    2
    1
    2
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    1 / 8 (12.50%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (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
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    Gait disturbance
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         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 physical health deterioration
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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 / 1
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchial obstruction
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 7 (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 / 1
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (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
    Pulmonary embolism
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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
    Investigations
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (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
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (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
    Incorrect drug administration rate
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (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
    Radiation pneumonitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         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
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 7 (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
    Myocarditis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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
    Myasthenia gravis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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
    Syncope
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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
    Acute abdomen
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (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 / 1
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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
    Diarrhoea
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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
    Melaena
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (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
    Nausea
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (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
    Small intestinal obstruction
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (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
    Vomiting
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    2 / 7 (28.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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
    Cholangitis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (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
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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
    Musculoskeletal and connective tissue disorders
    Mobility decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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
    Infections and infestations
    Biliary sepsis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (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
    Device related infection
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (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
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BAL101553: 15 mg/m² BAL101553: 30 mg/m² BAL101553: 45 mg/m² BAL101553: 60 mg/m² BAL101553: 80 mg/m²
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 1 (100.00%)
    35 / 36 (97.22%)
    8 / 8 (100.00%)
    21 / 21 (100.00%)
    7 / 7 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    2 / 8 (25.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    2
    0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    1
    Flushing
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Hypertension
         subjects affected / exposed
    1 / 1 (100.00%)
    6 / 36 (16.67%)
    3 / 8 (37.50%)
    12 / 21 (57.14%)
    6 / 7 (85.71%)
         occurrences all number
    1
    18
    7
    30
    10
    Hypotension
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    2 / 8 (25.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    3
    0
    1
    Thrombophlebitis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    1 / 1 (100.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    3 / 21 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    1
    2
    0
    5
    2
    Fatigue
         subjects affected / exposed
    0 / 1 (0.00%)
    13 / 36 (36.11%)
    4 / 8 (50.00%)
    12 / 21 (57.14%)
    4 / 7 (57.14%)
         occurrences all number
    0
    15
    6
    17
    4
    Gait disturbance
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    1
    1
    1
    Infusion site erythema
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    2 / 8 (25.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    3
    0
    0
    Infusion site pruritus
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    1
    1
    Infusion site reaction
         subjects affected / exposed
    1 / 1 (100.00%)
    4 / 36 (11.11%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    2
    10
    0
    3
    0
    Infusion site thrombosis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    0
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    1
    0
    Puncture site erythema
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Puncture site pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    1 / 8 (12.50%)
    7 / 21 (33.33%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    2
    7
    3
    Reproductive system and breast disorders
    Genital swelling
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 36 (8.33%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    0
    1
    1
    Dyspnoea
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 36 (11.11%)
    3 / 8 (37.50%)
    3 / 21 (14.29%)
    2 / 7 (28.57%)
         occurrences all number
    0
    4
    4
    4
    2
    Dyspnoea exertional
         subjects affected / exposed
    1 / 1 (100.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    1
    3
    0
    2
    0
    Haemoptysis
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    Hiccups
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Tachypnoea
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 36 (8.33%)
    0 / 8 (0.00%)
    4 / 21 (19.05%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    0
    4
    1
    Depressed mood
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 1 (100.00%)
    3 / 36 (8.33%)
    0 / 8 (0.00%)
    4 / 21 (19.05%)
    0 / 7 (0.00%)
         occurrences all number
    2
    3
    0
    4
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 1 (0.00%)
    6 / 36 (16.67%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    0
    7
    0
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 36 (11.11%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    6
    0
    0
    0
    Blood albumin decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 36 (8.33%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    Cells in urine
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    QRS axis abnormal
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 36 (11.11%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
         occurrences all number
    0
    4
    1
    1
    1
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    2 / 7 (28.57%)
         occurrences all number
    0
    0
    0
    1
    3
    Palpitations
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    0
    3
    0
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Dizziness
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    2 / 7 (28.57%)
         occurrences all number
    0
    3
    0
    3
    2
    Dysgeusia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    4 / 21 (19.05%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    4
    1
    Headache
         subjects affected / exposed
    1 / 1 (100.00%)
    4 / 36 (11.11%)
    1 / 8 (12.50%)
    6 / 21 (28.57%)
    2 / 7 (28.57%)
         occurrences all number
    1
    5
    1
    14
    2
    Lethargy
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 36 (11.11%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    1
    1
    0
    Memory impairment
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Migraine
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    2
    Neuropathy peripheral
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    3 / 8 (37.50%)
    3 / 21 (14.29%)
    5 / 7 (71.43%)
         occurrences all number
    0
    2
    3
    5
    6
    Nystagmus
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 36 (2.78%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    2
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    9 / 36 (25.00%)
    2 / 8 (25.00%)
    4 / 21 (19.05%)
    0 / 7 (0.00%)
         occurrences all number
    0
    9
    3
    6
    0
    Leukocytosis
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 36 (8.33%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    0
    2
    2
    Abdominal distension
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    1
    1
    Abdominal pain
         subjects affected / exposed
    1 / 1 (100.00%)
    3 / 36 (8.33%)
    0 / 8 (0.00%)
    6 / 21 (28.57%)
    1 / 7 (14.29%)
         occurrences all number
    1
    3
    0
    8
    5
    Abdominal pain lower
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 36 (11.11%)
    0 / 8 (0.00%)
    3 / 21 (14.29%)
    1 / 7 (14.29%)
         occurrences all number
    0
    5
    0
    6
    1
    Constipation
         subjects affected / exposed
    0 / 1 (0.00%)
    10 / 36 (27.78%)
    1 / 8 (12.50%)
    11 / 21 (52.38%)
    3 / 7 (42.86%)
         occurrences all number
    0
    12
    1
    14
    3
    Diarrhoea
         subjects affected / exposed
    1 / 1 (100.00%)
    10 / 36 (27.78%)
    4 / 8 (50.00%)
    13 / 21 (61.90%)
    4 / 7 (57.14%)
         occurrences all number
    1
    14
    4
    22
    6
    Dry mouth
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    1 / 8 (12.50%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    0
    1
    1
    2
    0
    Nausea
         subjects affected / exposed
    1 / 1 (100.00%)
    12 / 36 (33.33%)
    4 / 8 (50.00%)
    14 / 21 (66.67%)
    7 / 7 (100.00%)
         occurrences all number
    2
    18
    6
    31
    12
    Oesophageal haemorrhage
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Proctalgia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Vomiting
         subjects affected / exposed
    1 / 1 (100.00%)
    7 / 36 (19.44%)
    2 / 8 (25.00%)
    13 / 21 (61.90%)
    7 / 7 (100.00%)
         occurrences all number
    2
    10
    4
    22
    12
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 36 (11.11%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    1
    0
    0
    Rash
         subjects affected / exposed
    1 / 1 (100.00%)
    5 / 36 (13.89%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    1
    5
    0
    2
    0
    Rash macular
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Rash papular
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Skin reaction
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 1 (100.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    2
    0
    0
    0
    0
    Urinary hesitation
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 36 (11.11%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    5
    0
    0
    0
    Back pain
         subjects affected / exposed
    0 / 1 (0.00%)
    8 / 36 (22.22%)
    0 / 8 (0.00%)
    7 / 21 (33.33%)
    2 / 7 (28.57%)
         occurrences all number
    0
    11
    0
    10
    3
    Flank pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Muscle spasms
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Muscle tightness
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 1 (0.00%)
    1 / 36 (2.78%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    1
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    2
    0
    0
    1
    Musculoskeletal pain
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 36 (11.11%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Neck pain
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    0
    2
    0
    Pain in extremity
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    1
    1
    0
    Pain in jaw
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    3
    0
    0
    1
    Oral candidiasis
         subjects affected / exposed
    0 / 1 (0.00%)
    3 / 36 (8.33%)
    0 / 8 (0.00%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    0
    1
    0
    Paronychia
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    1 / 8 (12.50%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 36 (11.11%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    1
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 1 (100.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    3 / 21 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    2
    3
    0
    3
    0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 36 (0.00%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    1 / 7 (14.29%)
         occurrences all number
    0
    0
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 1 (100.00%)
    11 / 36 (30.56%)
    1 / 8 (12.50%)
    11 / 21 (52.38%)
    3 / 7 (42.86%)
         occurrences all number
    1
    13
    1
    13
    3
    Diabetes mellitus
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    0 / 21 (0.00%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    Hypercalcaemia
         subjects affected / exposed
    1 / 1 (100.00%)
    1 / 36 (2.78%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    1
    1
    1
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    4 / 36 (11.11%)
    1 / 8 (12.50%)
    2 / 21 (9.52%)
    0 / 7 (0.00%)
         occurrences all number
    0
    4
    1
    2
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    0 / 8 (0.00%)
    3 / 21 (14.29%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    0
    5
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 1 (0.00%)
    2 / 36 (5.56%)
    1 / 8 (12.50%)
    1 / 21 (4.76%)
    0 / 7 (0.00%)
         occurrences all number
    0
    2
    1
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jan 2012
    Change of the infusion carrier solution to Ringer Lactate and addition of optional pre- and post-dose and/or parallel-infusion with Ringer Lactate or physiologic saline.
    18 Jul 2012
    Exclusion of patients with uncontrolled baseline hypertension or with history of cerebral hemorrhage, cerebral aneurysm, ischemic stroke or transient ischemic attack. Increased frequency of BP, ECG, and cardiac troponin assessments.
    12 May 2014
    Definition of Phase 2a design: inclusion of 40 evaluable patients with specific tumor types; randomization (1:1) to 60 mg/m² or 30 mg/m²; introduction of optional functional imaging.
    11 May 2015
    Definition of patient number per tumor type; changed definition of the Efficacy Evaluable Population (EEP); changed patient replacement criteria.
    02 Jun 2015
    Randomization to 30 mg/m² or 45 mg/m² instead of 60 mg/m² because of cardiac safety concerns at 60 mg/m². Introduction of additional troponin and ECG assessments.
    27 Nov 2015
    Clarification of EEP definition, patient replacement criteria, and treatment of missing RECIST data.
    02 Dec 2015
    Treatment of all patients at 30 mg/m² following observation of myocardial injury in one patient at 45 mg/m².

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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