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    Clinical Trial Results:
    A Phase II study of XL 184 (Cabozantinib) in treating patients with relapsed Osteosarcomas and Ewing Sarcomas.

    Summary
    EudraCT number
    		 2014-004407-71
    Trial protocol
    		 FR  
    Global end of trial date
    30 Jun 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jan 2024
    First version publication date
    03 Jan 2024
    Other versions
    Summary report(s)
    		 Italiano et al. 2020

    Trial information

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    Trial identification
    Sponsor protocol code
    IB2014-03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02243605
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Institut Bergonié
    Sponsor organisation address
    229 cours de l'Argonne, Bordeaux, France, 33076
    Public contact
    Regulatory Affairs Management Desk, Institut Bergonié, drci@bordeaux.unicancer.fr
    Scientific contact
    Regulatory Affairs Management Desk, Institut Bergonié, drci@bordeaux.unicancer.fr
    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
    09 Nov 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Jun 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the antitumor activity of cabozantinib in terms of : •Osteosarcoma: 6-month non-progression (Complete response, partial response and stable disease) and 6-month objective response (Complete response, partial response) rates (composite endpoint) as per the Response Evaluation Criteria in Solid Tumors, Revised RECIST v1.1. •Ewing sarcoma: 6-month objective response as per the revised RECIST v1.1.
    Protection of trial subjects
    The study will be carried out in accordance with: - The ethical principles of the current version of the “Declaration of Helsinki” - Good Clinical Practice (GCP): I.C.H. version 4 of 1 May 1996 and decision dated 24 November 2006 (Official Bulletin of 30 November 2006, text 64). - European Directive (2001/20/EC) on clinical trial procedures. - Huriet’s law (No. 88-1138) dated 20 December 1988, concerning the protection of persons taking part in Biomedical Research with the provisions of the Public Health law (No. 2004-806) of 9 August 2004 and implementating decree No. 2006-477 of 26 April 2006 relating to biomedical research. - The French law on Data Protection and Civil Liberties, No. 78-17 of 6 January 1978 amended by law No. 2004-801, dated 6 August 2004, concerning the protection of persons with regards to the processing of personal data. - The application of Circular DHOS/INCa/MOPRC/2006/475 of 7 November 2006: the Sponsor shall undertake to register the Trial and thus make it accessible to the general public, in the INCa (French Cancer Institute) register via the Internet site: www.e-cancer.fr. Each trial published in the INCa register will be sent to the NCI for registering on the following site: www.clinicaltrials.gov. The trial will be registered before the first patient is entered into the study. The Sponsor is responsible for updating the study data in order to guarantee the reliability of the information available on-line. - Law no. 2004-800 dated 6 August 2004, concerning bioethics, amended by law No. 2012-387, dated 22 March 2012.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 90
    Worldwide total number of subjects
    90
    EEA total number of subjects
    90
    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)
    8
    Adults (18-64 years)
    74
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Osteosarcoma stratum : During 2 years and 10 months, in France 45 patients were included from 3th of April 2015 to 1st of February 2018. Ewing stratum : During 3 years and 3 months, in France 45 patients were included from 16th of April 2015 to 12th of July 2018.

    Pre-assignment
    Screening details
    		 Osteosarcoma stratum: 67 patients were screened and 45 were included. Ewing stratum: 58 patients were screened and 45 were included.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding used.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cabozantinib - Stratum Osteosarcoma
    Arm description
    		 Single arm treatment - stratum osteosarcoma : Formulation: XL 184 (Cabozantinib) – Available in 20 mg and 60 mg tablet. Tablets are yellow film coated. The 20 mg tablets have a round shape and the 60 mg tablets have an oval shape, and they are packaged as 30 tablets per bottle. Route of administration: Oral Administered dose: to take without food , and not eat for at least 2 hours before and 1 hour after taking it: - for patients ≥16 years: 60 mg - For patients ≥12 years < 16 years: 40 mg/m² (Chuck et al., 2014) Treatment schedule: Daily, day 1-28 during 4 weeks (ie. 1 cycle)
    Arm type
    		 Experimental

    Investigational medicinal product name
    XL184 (CABOZANTINIB) (NSC 761968)
    Investigational medicinal product code
    XL184 (CABOZANTINIB) (NSC 761968)
    Other name
    Cabozantinib, EXEL-7184, EXEL-02977184
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cabozantinib is supplied by Exelixis and distributed by CSM (Clinical Supplies Management Europe GmbH) in Germany. Cabozantinib is available in 20 mg and 60 mg tablet. The tablets are yellow film coated containing cabozantinib malate equivalent to 20 mg and 60 mg of cabozantinib. The 20 mg tablets have a round shape and the 60 mg tablets have an oval shape, and they are packaged as 30 tablets per bottle.

    Arm title
    		 Cabozantinib - Stratum Ewing
    Arm description
    		 Single arm treatment - stratum ewing : Formulation: XL 184 (Cabozantinib) – Available in 20 mg and 60 mg tablet. Tablets are yellow film coated. The 20 mg tablets have a round shape and the 60 mg tablets have an oval shape, and they are packaged as 30 tablets per bottle. Route of administration: Oral Administered dose: to take without food , and not eat for at least 2 hours before and 1 hour after taking it: - for patients ≥16 years: 60 mg - For patients ≥12 years < 16 years: 40 mg/m² (Chuck et al., 2014) Treatment schedule: Daily, day 1-28 during 4 weeks (ie. 1 cycle)
    Arm type
    		 Experimental

    Investigational medicinal product name
    XL184 (CABOZANTINIB) (NSC 761968)
    Investigational medicinal product code
    XL184 (CABOZANTINIB) (NSC 761968)
    Other name
    Cabozantinib, EXEL-7184, EXEL-02977184
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cabozantinib is supplied by Exelixis and distributed by CSM (Clinical Supplies Management Europe GmbH) in Germany. Cabozantinib is available in 20 mg and 60 mg tablet. The tablets are yellow film coated containing cabozantinib malate equivalent to 20 mg and 60 mg of cabozantinib. The 20 mg tablets have a round shape and the 60 mg tablets have an oval shape, and they are packaged as 30 tablet

    Number of subjects in period 1
    		Cabozantinib - Stratum Osteosarcoma Cabozantinib - Stratum Ewing
    Started
    45
    45
    Completed
    42
    39
    Not completed
    3
    6
         Did not receive at least one complete or two incom
    2
    1
         Not meeting eligibility criteria
    1
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cabozantinib - Stratum Osteosarcoma
    Reporting group description
    		 Single arm treatment - stratum osteosarcoma : Formulation: XL 184 (Cabozantinib) – Available in 20 mg and 60 mg tablet. Tablets are yellow film coated. The 20 mg tablets have a round shape and the 60 mg tablets have an oval shape, and they are packaged as 30 tablets per bottle. Route of administration: Oral Administered dose: to take without food , and not eat for at least 2 hours before and 1 hour after taking it: - for patients ≥16 years: 60 mg - For patients ≥12 years < 16 years: 40 mg/m² (Chuck et al., 2014) Treatment schedule: Daily, day 1-28 during 4 weeks (ie. 1 cycle)

    Reporting group title
    Cabozantinib - Stratum Ewing
    Reporting group description
    		 Single arm treatment - stratum ewing : Formulation: XL 184 (Cabozantinib) – Available in 20 mg and 60 mg tablet. Tablets are yellow film coated. The 20 mg tablets have a round shape and the 60 mg tablets have an oval shape, and they are packaged as 30 tablets per bottle. Route of administration: Oral Administered dose: to take without food , and not eat for at least 2 hours before and 1 hour after taking it: - for patients ≥16 years: 60 mg - For patients ≥12 years < 16 years: 40 mg/m² (Chuck et al., 2014) Treatment schedule: Daily, day 1-28 during 4 weeks (ie. 1 cycle)

    Reporting group values
    		 Cabozantinib - Stratum Osteosarcoma Cabozantinib - Stratum Ewing Total
    Number of subjects
    		 45 45 90
    Age categorical
    Units: Subjects
        <= 18 years
    		 7 6 13
        19-64 years
    		 31 38 69
        >= 65 years
    		 7 1 8
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 38.0 ( 19.3 ) 35.7 ( 14.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 18 14 32
        Male
    		 27 31 58
    ECOG
    ECOG PERFORMANCE STATUS ASSESSMENT SCALE: 0: Normal activity. Fully active able to carry on all pre-disease performance without restriction. 1: Symptoms, but ambulatory. Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light or sedentary nature. 2: In bed <50% of the time. Ambulatory and capable of all self-care, but unable to carry out any work activities. Up and about more than 50% of waking hours. 3: In bed >50% of the time. Capable of only limited self-care confined to bed or chair more than 50% of of waking hours.
    Units: Subjects
        ECOG = 0
    		 17 15 32
        ECOG =1
    		 25 29 54
        ECOG =2
    		 1 1 2
        ECOG = 3
    		 1 0 1
        Not available
    		 1 0 1

    End points

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    End points reporting groups
    Reporting group title
    Cabozantinib - Stratum Osteosarcoma
    Reporting group description
    		 Single arm treatment - stratum osteosarcoma : Formulation: XL 184 (Cabozantinib) – Available in 20 mg and 60 mg tablet. Tablets are yellow film coated. The 20 mg tablets have a round shape and the 60 mg tablets have an oval shape, and they are packaged as 30 tablets per bottle. Route of administration: Oral Administered dose: to take without food , and not eat for at least 2 hours before and 1 hour after taking it: - for patients ≥16 years: 60 mg - For patients ≥12 years < 16 years: 40 mg/m² (Chuck et al., 2014) Treatment schedule: Daily, day 1-28 during 4 weeks (ie. 1 cycle)

    Reporting group title
    Cabozantinib - Stratum Ewing
    Reporting group description
    		 Single arm treatment - stratum ewing : Formulation: XL 184 (Cabozantinib) – Available in 20 mg and 60 mg tablet. Tablets are yellow film coated. The 20 mg tablets have a round shape and the 60 mg tablets have an oval shape, and they are packaged as 30 tablets per bottle. Route of administration: Oral Administered dose: to take without food , and not eat for at least 2 hours before and 1 hour after taking it: - for patients ≥16 years: 60 mg - For patients ≥12 years < 16 years: 40 mg/m² (Chuck et al., 2014) Treatment schedule: Daily, day 1-28 during 4 weeks (ie. 1 cycle)

    Primary: Non progression at 6 months

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    End point title
    		 Non progression at 6 months [1]
    End point description
    Efficacy of Cabozantinib will be assessed in terms of 6-month non-progression and objective response within 6 months of treatment onset (dual endpoint design). More precisely, progression has to be assessed at 6 months and objective response has to be assessed within 6 months of treatment onset. - Non-progression is defined as complete response, partial response or stable disease (RECIST 1.1).
    End point type
    Primary
    End point timeframe
    at 6 months
    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 analysis planned. Osteosarcoma : Primary based on the rate of objective response within 6 months of treatment onset will be reported based on an optimal two-stage Simon’s design. Ewing sarcoma : Secondary endpoint
    End point values
    		 Cabozantinib - Stratum Osteosarcoma Cabozantinib - Stratum Ewing
    Number of subjects analysed
    42 [2]
    39
    Units: subjects
    17
    10
    Attachments
    		 Table : non progression at 6 months
    Notes
    [2] - 45 patients had been included o 42 were eligible and assessable for efficacy
    No statistical analyses for this end point

    Primary: Objective response within 6 months of treatment onset rate

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    End point title
    		 Objective response within 6 months of treatment onset rate [3]
    End point description
    Efficacy of Cabozantinib will be assessed in terms objective response within 6 months of treatment onset. More precisely, objective response has to be assessed within 6 months of treatment onset. - Objective response is defined as complete response or partial response (RECIST 1.1).
    End point type
    Primary
    End point timeframe
    at 6 months
    Notes
    [3] - 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 analysis planned. Osteosarcoma : Secondary endpoint Ewing sarcoma : Primary based on the rate of objective response within 6 months of treatment onset will be reported based on an optimal two-stage Simon’s design.
    End point values
    		 Cabozantinib - Stratum Osteosarcoma Cabozantinib - Stratum Ewing
    Number of subjects analysed
    42
    39 [4]
    Units: Subjects
    5
    10
    Notes
    [4] - 45 patients had been included o 39 were eligible and assessable for efficacy
    No statistical analyses for this end point

    Secondary: Best overall response: RECIST 1.1 with confirmation required

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    End point title
    		 Best overall response: RECIST 1.1 with confirmation required
    End point description
    Best overall response according to RECIST 1.1 with confirmation required include confirmation for complete response (CR), partial response (PR) and stable disease (SD).
    End point type
    Secondary
    End point timeframe
    Best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started).
    End point values
    		 Cabozantinib - Stratum Osteosarcoma Cabozantinib - Stratum Ewing
    Number of subjects analysed
    42
    39
    Units: Subjects
        Partial response
    3
    5
        Stable disease
    21
    19
        Progressive disease
    15
    12
        Not evaluable
    3
    3
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS)

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    End point title
    		 Progression-free survival (PFS)
    End point description
    PFS will be assessed on the population eligible and assessable for efficacy. PFS will be analysed using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Progression-free survival (PFS) is defined as the duration of time from start of treatment to time of progression or death, whichever occurs first.
    End point values
    		 Cabozantinib - Stratum Osteosarcoma Cabozantinib - Stratum Ewing
    Number of subjects analysed
    42
    39
    Units: months
        median (confidence interval 95%)
    5.9 (4.7 to 7.4)
    4.4 (3.7 to 5.6)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS will be assessed on the population eligible and assessable for efficacy criteria. OS will be analyzed using the Kaplan-Meier method.
    End point type
    Secondary
    End point timeframe
    Overall survival (OS) is defined as the duration of time from start of treatment to the time of death.
    End point values
    		 Cabozantinib - Stratum Osteosarcoma Cabozantinib - Stratum Ewing
    Number of subjects analysed
    42
    39
    Units: months
        median (confidence interval 95%)
    10.4 (7.4 to 12.5)
    12.5 (8.5 to 20.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety profile will be continuously followed during treatment and up to 30 days after the last Cabozantinib dose or until the start of a new antitumor therapy, whichever occurs first.
    Adverse event reporting additional description
    Adverse event (AE) are reported for all patients who received at least one administration of treatment. All AE and SAE (related and unrelated to treatment) are reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    5.0
    Reporting groups
    Reporting group title
    Ewing
    Reporting group description
    		 -

    Reporting group title
    Osteosarcoma
    Reporting group description
    		 -

    Serious adverse events
    		 Ewing Osteosarcoma
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 45 (66.67%)
    31 / 45 (68.89%)
         number of deaths (all causes)
    37
    42
         number of deaths resulting from adverse events
    10
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ACUTE TUMORAL PAIN
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BASAL CELL CARCINOMA
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BREAST MICROCALCIFICATION PRESENCE
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC PAIN LOCATED ON THE SITE OF THE INITIAL TUMOR
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEFT LOWER LIMB PAIN
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Vascular disorders
    PULMONARY EMBOLISM
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    WORSENING OF GENERAL STATUS
         subjects affected / exposed
    3 / 45 (6.67%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    FATIGUE
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEVER
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    THORACIC PAIN
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    BILATERAL PLEURAL EFFUSION
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DYSPNEA
         subjects affected / exposed
    2 / 45 (4.44%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    PLEURAL EFFUSION
         subjects affected / exposed
    1 / 45 (2.22%)
    5 / 45 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 7
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    PNEUMOPATHY
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIGHT PNEUMOTHORAX
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    EPISTAXIS
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEFT PNEUMOTHORAX
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 45 (6.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOTHORAX
         subjects affected / exposed
    8 / 45 (17.78%)
    5 / 45 (11.11%)
         occurrences causally related to treatment / all
    11 / 12
    3 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RIGHT PLEUROPNEUMOPATHY
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOMEDIASTINUM
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BILATERAL PNEUMOTHORAX
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RELAPSE OF PNEUMOTHORAX
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    RELAPSE OF PSYCHIATRIC DISORDERS
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    LIPASE INCREASE
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LYMPHOPENIA
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    NEUTROPENIA
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    PLATELET COUNT DECREASED
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PANCYTOPENIA
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    WOUND COMPLICATION
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    PERICARDIAL EFFUSION
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    1 / 2
    HYPOCINETIC CARDIOPATHY
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    MEDULLARY COMPRESSION
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    DEFICIT OF LOWER LIMBS
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SPINAL CORD COMPRESSION
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    PERIPHERAL MOTOR NEUROPATHY
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANEMIA
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE NEUTROPENIA
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    CONSTIPATION
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RECTAL HEMORRHAGE
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    ICTERIC CHOLESTASIS
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    SACRUM SKIN ULCERATION
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    WORSENING OF SKIN ULCERATION
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    ACUTE RENAL INSUFFISIENCY
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    ACUTE BONE PAIN
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    BONE PAIN
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    COAST AND LUMBAR PAIN
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    MUSCULOSKELETAL PAIN
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Infections and infestations
    ACUTE OBSTRUCTIVE PYELONEPHRITIS
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANAL ABSCESS
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BRONCHITIS INFECTION
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    FACIAL CELLULITIS
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LOCALIZED INFECTION
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    SEPTIC SHOCK
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    DIABETES
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPOMAGNESEMIA
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Ewing Osteosarcoma
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 45 (100.00%)
    45 / 45 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps) - Other, specify
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Tumor pain
         subjects affected / exposed
    9 / 45 (20.00%)
    9 / 45 (20.00%)
         occurrences all number
    10
    11
    Vascular disorders
    Hematoma
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Hot flashes
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    3 / 45 (6.67%)
    8 / 45 (17.78%)
         occurrences all number
    3
    9
    Hypotension
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    Thromboembolic event
         subjects affected / exposed
    0 / 45 (0.00%)
    5 / 45 (11.11%)
         occurrences all number
    0
    5
    Surgical and medical procedures
    Surgical and medical procedures - Other, specify
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Death NOS
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Disease progression
         subjects affected / exposed
    4 / 45 (8.89%)
    2 / 45 (4.44%)
         occurrences all number
    4
    2
    Edema limbs
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
         occurrences all number
    1
    2
    Facial pain
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    34 / 45 (75.56%)
    39 / 45 (86.67%)
         occurrences all number
    36
    42
    Fever
         subjects affected / exposed
    7 / 45 (15.56%)
    9 / 45 (20.00%)
         occurrences all number
    9
    12
    Flu like symptoms
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    General disorders and administration site conditions - Other, specify
         subjects affected / exposed
    4 / 45 (8.89%)
    4 / 45 (8.89%)
         occurrences all number
    4
    4
    Hypothermia
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Localized edema
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Neck edema
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    5 / 45 (11.11%)
    8 / 45 (17.78%)
         occurrences all number
    5
    11
    Pain
         subjects affected / exposed
    6 / 45 (13.33%)
    8 / 45 (17.78%)
         occurrences all number
    6
    8
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Reproductive system and breast disorders - Other, specify
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Gynecomastia
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Scrotal pain
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Vaginal inflammation
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Uterine hemorrhage
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Bronchial obstruction
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Allergic rhinitis
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1
    Cough
         subjects affected / exposed
    11 / 45 (24.44%)
    12 / 45 (26.67%)
         occurrences all number
    13
    14
    Dyspnea
         subjects affected / exposed
    8 / 45 (17.78%)
    12 / 45 (26.67%)
         occurrences all number
    8
    12
    Epistaxis
         subjects affected / exposed
    4 / 45 (8.89%)
    9 / 45 (20.00%)
         occurrences all number
    5
    9
    Hoarseness
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Pharyngolaryngeal pain
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    Pleural effusion
         subjects affected / exposed
    3 / 45 (6.67%)
    9 / 45 (20.00%)
         occurrences all number
    3
    10
    Pleuritic pain
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Pneumonitis
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 45 (6.67%)
         occurrences all number
    2
    3
    Pneumothorax
         subjects affected / exposed
    11 / 45 (24.44%)
    10 / 45 (22.22%)
         occurrences all number
    15
    11
    Respiratory, thoracic and mediastinal disorders - Other, specify
         subjects affected / exposed
    3 / 45 (6.67%)
    6 / 45 (13.33%)
         occurrences all number
    4
    6
    Sleep apnea
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhea
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    Sore throat
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Voice alteration
         subjects affected / exposed
    5 / 45 (11.11%)
    10 / 45 (22.22%)
         occurrences all number
    5
    11
    Wheezing
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 45 (4.44%)
    5 / 45 (11.11%)
         occurrences all number
    2
    5
    Depression
         subjects affected / exposed
    2 / 45 (4.44%)
    5 / 45 (11.11%)
         occurrences all number
    2
    5
    Insomnia
         subjects affected / exposed
    3 / 45 (6.67%)
    6 / 45 (13.33%)
         occurrences all number
    3
    6
    Psychiatric disorders - Other, specify
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Suicide attempt
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    23 / 45 (51.11%)
    21 / 45 (46.67%)
         occurrences all number
    27
    25
    Alkaline phosphatase increased
         subjects affected / exposed
    7 / 45 (15.56%)
    6 / 45 (13.33%)
         occurrences all number
    9
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    22 / 45 (48.89%)
    23 / 45 (51.11%)
         occurrences all number
    27
    28
    Blood bilirubin increased
         subjects affected / exposed
    3 / 45 (6.67%)
    3 / 45 (6.67%)
         occurrences all number
    3
    3
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    8 / 45 (17.78%)
    10 / 45 (22.22%)
         occurrences all number
    7
    7
    CPK increased
         subjects affected / exposed
    5 / 45 (11.11%)
    1 / 45 (2.22%)
         occurrences all number
    7
    1
    Creatinine increased
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    GGT increased
         subjects affected / exposed
    5 / 45 (11.11%)
    2 / 45 (4.44%)
         occurrences all number
    5
    2
    Hemoglobin increased
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    INR increased
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Electrocardiogram QT corrected interval prolonged
         subjects affected / exposed
    0 / 45 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    0
    4
    Lipase increased
         subjects affected / exposed
    6 / 45 (13.33%)
    10 / 45 (22.22%)
         occurrences all number
    6
    19
    Lymphocyte count decreased
         subjects affected / exposed
    5 / 45 (11.11%)
    4 / 45 (8.89%)
         occurrences all number
    7
    6
    Neutrophil count decreased
         subjects affected / exposed
    10 / 45 (22.22%)
    9 / 45 (20.00%)
         occurrences all number
    11
    11
    Platelet count decreased
         subjects affected / exposed
    20 / 45 (44.44%)
    14 / 45 (31.11%)
         occurrences all number
    21
    16
    Serum amylase increased
         subjects affected / exposed
    2 / 45 (4.44%)
    4 / 45 (8.89%)
         occurrences all number
    2
    4
    Thyroid stimulating hormone increased
         subjects affected / exposed
    4 / 45 (8.89%)
    6 / 45 (13.33%)
         occurrences all number
    4
    6
    Weight loss
         subjects affected / exposed
    14 / 45 (31.11%)
    15 / 45 (33.33%)
         occurrences all number
    14
    15
    White blood cell decreased
         subjects affected / exposed
    5 / 45 (11.11%)
    4 / 45 (8.89%)
         occurrences all number
    7
    6
    Injury, poisoning and procedural complications
    Bruising
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Burn
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Fall
         subjects affected / exposed
    0 / 45 (0.00%)
    3 / 45 (6.67%)
         occurrences all number
    0
    3
    Injury, poisoning and procedural complications - Other, specify
         subjects affected / exposed
    2 / 45 (4.44%)
    2 / 45 (4.44%)
         occurrences all number
    2
    3
    Wound complication
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Cardiac disorders - Other, specify
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    Heart failure
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Palpitations
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Pericardial effusion
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
         occurrences all number
    1
    2
    Sinus bradycardia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    4 / 45 (8.89%)
    3 / 45 (6.67%)
         occurrences all number
    4
    3
    Nervous system disorders
    Acoustic nerve disorder NOS
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    2
    Dysesthesia
         subjects affected / exposed
    2 / 45 (4.44%)
    3 / 45 (6.67%)
         occurrences all number
    2
    3
    Dysgeusia
         subjects affected / exposed
    15 / 45 (33.33%)
    9 / 45 (20.00%)
         occurrences all number
    15
    10
    Headache
         subjects affected / exposed
    11 / 45 (24.44%)
    8 / 45 (17.78%)
         occurrences all number
    12
    10
    Nervous system disorders - Other, specify
         subjects affected / exposed
    0 / 45 (0.00%)
    4 / 45 (8.89%)
         occurrences all number
    0
    5
    Neuralgia
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
         occurrences all number
    1
    2
    Paresthesia
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
         occurrences all number
    1
    2
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    2
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    Phantom pain
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Spinal cord compression
         subjects affected / exposed
    4 / 45 (8.89%)
    1 / 45 (2.22%)
         occurrences all number
    4
    1
    Tremor
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    9 / 45 (20.00%)
    7 / 45 (15.56%)
         occurrences all number
    10
    8
    Febrile neutropenia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Lymph node pain
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders - Other, specify
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    Ear and labyrinth disorders
    Ear and labyrinth disorders - Other, specify
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Vertigo
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
         occurrences all number
    1
    2
    Eye disorders
    Blurred vision
         subjects affected / exposed
    4 / 45 (8.89%)
    4 / 45 (8.89%)
         occurrences all number
    1
    1
    Eye pain
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Eye disorders - Other, specify
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Periorbital edema
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Photophobia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Vision decreased
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Abdominal pain
         subjects affected / exposed
    12 / 45 (26.67%)
    10 / 45 (22.22%)
         occurrences all number
    12
    10
    Anal fistula
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Anal mucositis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Bloating
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 45 (2.22%)
         occurrences all number
    2
    2
    Cheilitis
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Constipation
         subjects affected / exposed
    15 / 45 (33.33%)
    16 / 45 (35.56%)
         occurrences all number
    18
    21
    Diarrhea
         subjects affected / exposed
    38 / 45 (84.44%)
    36 / 45 (80.00%)
         occurrences all number
    51
    47
    Dry mouth
         subjects affected / exposed
    7 / 45 (15.56%)
    1 / 45 (2.22%)
         occurrences all number
    8
    1
    Dysphagia
         subjects affected / exposed
    4 / 45 (8.89%)
    2 / 45 (4.44%)
         occurrences all number
    4
    2
    Esophageal pain
         subjects affected / exposed
    2 / 45 (4.44%)
    2 / 45 (4.44%)
         occurrences all number
    0
    0
    Enterocolitis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Esophagitis
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
         occurrences all number
    1
    2
    Gastroesophageal reflux disease
         subjects affected / exposed
    3 / 45 (6.67%)
    3 / 45 (6.67%)
         occurrences all number
    8
    7
    Flatulence
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Gastrointestinal disorders - Other, specify
         subjects affected / exposed
    2 / 45 (4.44%)
    8 / 45 (17.78%)
         occurrences all number
    2
    8
    Gastrointestinal pain
         subjects affected / exposed
    5 / 45 (11.11%)
    3 / 45 (6.67%)
         occurrences all number
    6
    3
    Gingival pain
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Hemorrhoids
         subjects affected / exposed
    3 / 45 (6.67%)
    2 / 45 (4.44%)
         occurrences all number
    3
    2
    Mucositis oral
         subjects affected / exposed
    28 / 45 (62.22%)
    30 / 45 (66.67%)
         occurrences all number
    31
    32
    Nausea
         subjects affected / exposed
    16 / 45 (35.56%)
    21 / 45 (46.67%)
         occurrences all number
    19
    22
    Oral cavity fistula
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Oral dysesthesia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Oral pain
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1
    Periodontal disease
         subjects affected / exposed
    5 / 45 (11.11%)
    3 / 45 (6.67%)
         occurrences all number
    6
    5
    Rectal hemorrhage
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Stomach pain
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1
    Vomiting
         subjects affected / exposed
    10 / 45 (22.22%)
    7 / 45 (15.56%)
         occurrences all number
    12
    9
    Hepatobiliary disorders
    Hepatobiliary disorders - Other, specify
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    6 / 45 (13.33%)
    6 / 45 (13.33%)
         occurrences all number
    6
    6
    Dry skin
         subjects affected / exposed
    16 / 45 (35.56%)
    14 / 45 (31.11%)
         occurrences all number
    17
    15
    Eczema
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Erythema multiforme
         subjects affected / exposed
    3 / 45 (6.67%)
    3 / 45 (6.67%)
         occurrences all number
    3
    4
    Hair color changes
         subjects affected / exposed
    16 / 45 (35.56%)
    18 / 45 (40.00%)
         occurrences all number
    16
    18
    Hyperkeratosis
         subjects affected / exposed
    2 / 45 (4.44%)
    2 / 45 (4.44%)
         occurrences all number
    2
    2
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    20 / 45 (44.44%)
    13 / 45 (28.89%)
         occurrences all number
    21
    13
    Pruritus
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1
    Rash acneiform
         subjects affected / exposed
    1 / 45 (2.22%)
    3 / 45 (6.67%)
         occurrences all number
    1
    3
    Rash maculo-papular
         subjects affected / exposed
    1 / 45 (2.22%)
    4 / 45 (8.89%)
         occurrences all number
    1
    4
    Skin and subcutaneous tissue disorders - Other, specify
         subjects affected / exposed
    11 / 45 (24.44%)
    22 / 45 (48.89%)
         occurrences all number
    15
    31
    Skin hypopigmentation
         subjects affected / exposed
    5 / 45 (11.11%)
    6 / 45 (13.33%)
         occurrences all number
    5
    6
    Skin ulceration
         subjects affected / exposed
    2 / 45 (4.44%)
    6 / 45 (13.33%)
         occurrences all number
    2
    8
    Subcutaneous emphysema
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Telangiectasia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Phlebitis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    Chronic kidney disease
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Dysuria
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Hematuria
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
         occurrences all number
    1
    2
    Proteinuria
         subjects affected / exposed
    4 / 45 (8.89%)
    8 / 45 (17.78%)
         occurrences all number
    5
    9
    Renal and urinary disorders - Other, specify
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Urinary frequency
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Urinary retention
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Urinary tract obstruction
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Hypothyroidism
         subjects affected / exposed
    22 / 45 (48.89%)
    23 / 45 (51.11%)
         occurrences all number
    23
    25
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 45 (11.11%)
    6 / 45 (13.33%)
         occurrences all number
    5
    6
    Back pain
         subjects affected / exposed
    12 / 45 (26.67%)
    8 / 45 (17.78%)
         occurrences all number
    14
    8
    Bone pain
         subjects affected / exposed
    7 / 45 (15.56%)
    2 / 45 (4.44%)
         occurrences all number
    7
    2
    Generalized muscle weakness
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Muscle cramp
         subjects affected / exposed
    5 / 45 (11.11%)
    2 / 45 (4.44%)
         occurrences all number
    5
    2
    Muscle weakness lower limb
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorder - Other, specify
         subjects affected / exposed
    2 / 45 (4.44%)
    5 / 45 (11.11%)
         occurrences all number
    2
    5
    Myalgia
         subjects affected / exposed
    9 / 45 (20.00%)
    7 / 45 (15.56%)
         occurrences all number
    9
    8
    Neck pain
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 45 (2.22%)
    3 / 45 (6.67%)
         occurrences all number
    1
    3
    Trismus
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    Infections and infestations
    Anorectal infection
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Bronchial infection
         subjects affected / exposed
    3 / 45 (6.67%)
    5 / 45 (11.11%)
         occurrences all number
    4
    8
    Catheter related infection
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    Folliculitis
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Infections and infestations - Other, specify
         subjects affected / exposed
    2 / 45 (4.44%)
    4 / 45 (8.89%)
         occurrences all number
    2
    4
    Kidney infection
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Lung infection
         subjects affected / exposed
    2 / 45 (4.44%)
    2 / 45 (4.44%)
         occurrences all number
    2
    2
    Otitis externa
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Paronychia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Penile infection
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Pharyngitis
         subjects affected / exposed
    4 / 45 (8.89%)
    2 / 45 (4.44%)
         occurrences all number
    4
    2
    Rhinitis infective
         subjects affected / exposed
    1 / 45 (2.22%)
    4 / 45 (8.89%)
         occurrences all number
    1
    4
    Sepsis
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    Shingles
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Skin infection
         subjects affected / exposed
    5 / 45 (11.11%)
    1 / 45 (2.22%)
         occurrences all number
    5
    1
    Soft tissue infection
         subjects affected / exposed
    0 / 45 (0.00%)
    2 / 45 (4.44%)
         occurrences all number
    0
    2
    Tooth infection
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Tracheitis
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
         occurrences all number
    1
    2
    Upper respiratory infection
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 45 (6.67%)
    3 / 45 (6.67%)
         occurrences all number
    5
    3
    Vaginal infection
         subjects affected / exposed
    1 / 45 (2.22%)
    1 / 45 (2.22%)
         occurrences all number
    1
    1
    Investigations - Other, specify
         subjects affected / exposed
    2 / 45 (4.44%)
    2 / 45 (4.44%)
         occurrences all number
    2
    2
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    11 / 45 (24.44%)
    25 / 45 (55.56%)
         occurrences all number
    13
    27
    Hypercalcemia
         subjects affected / exposed
    2 / 45 (4.44%)
    0 / 45 (0.00%)
         occurrences all number
    2
    0
    Hyperglycemia
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1
    Hyperkalemia
         subjects affected / exposed
    0 / 45 (0.00%)
    1 / 45 (2.22%)
         occurrences all number
    0
    1
    Hypoalbuminemia
         subjects affected / exposed
    3 / 45 (6.67%)
    3 / 45 (6.67%)
         occurrences all number
    3
    3
    Hypocalcemia
         subjects affected / exposed
    4 / 45 (8.89%)
    7 / 45 (15.56%)
         occurrences all number
    5
    9
    Hypoglycemia
         subjects affected / exposed
    1 / 45 (2.22%)
    0 / 45 (0.00%)
         occurrences all number
    1
    0
    Hypokalemia
         subjects affected / exposed
    6 / 45 (13.33%)
    11 / 45 (24.44%)
         occurrences all number
    6
    14
    Hypomagnesemia
         subjects affected / exposed
    7 / 45 (15.56%)
    13 / 45 (28.89%)
         occurrences all number
    9
    19
    Hyponatremia
         subjects affected / exposed
    1 / 45 (2.22%)
    2 / 45 (4.44%)
         occurrences all number
    1
    2
    Hypophosphatemia
         subjects affected / exposed
    18 / 45 (40.00%)
    11 / 45 (24.44%)
         occurrences all number
    23
    12
    Metabolism and nutrition disorders - Other, specify
         subjects affected / exposed
    2 / 45 (4.44%)
    1 / 45 (2.22%)
         occurrences all number
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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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    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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