Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   44365   clinical trials with a EudraCT protocol, of which   7389   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Activity of Lorlatinib based on ALK resistance mutations on blood in ALK positive NSCLC patients previously treated with 2nd generation ALK inhibitor

    Summary
    EudraCT number
    		 2019-003862-41
    Trial protocol
    		 NO   NL   FR   IT   ES  
    Global end of trial date
    29 Nov 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Nov 2025
    First version publication date
    20 Nov 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    EORTC-1825-LCG
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04127110
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    EORTC
    Sponsor organisation address
    Avenue Emmanuel Mounier 83/11, Brussels, Belgium, 1200
    Public contact
    Regulatory Affairs Department, European Organisation for the Research and Treatment of Cancer, 0032 27741066, regulatory@eortc.org
    Scientific contact
    Regulatory Affairs Department, European Organisation for the Research and Treatment of Cancer, 0032 27741066, regulatory@eortc.org
    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
    16 Oct 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Oct 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Nov 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main aim of this trial is to assess the progression-free survival rate at 12 months (PFSR12) to lorlatinib in ALK positive advanced NSCLC patients, who progressed on second generation ALK TKI with the presence of ALK resistance mutations on blood (liquid biopsies) by Independent Central Review (ICR) assessment per RECIST v1.1
    Protection of trial subjects
    Safety data were reviewed within EORTC Headquarters on a regular basis as part of the Medical Review process. Safety information was included in trial status reports which served as a basis of discussion during EORTC Group meetings
    Background therapy
    		 Previous treatment with at least one 2nd-generation ALK inhibitor. The 2nd-generation ALK TKI (including but not limited to ceritinib, alectinib, brigatinib) was the latest therapy.
    Evidence for comparator
    		 This was not a randomized controlled trial. Each cohort in the trial received lorlatinib at the same dose and frequency. The cohort allocation was based on ALK mutations and alterations. Specifically, Cohort A consisted of patients with presence of 1 or more ALK mutation(s) and represented the cohort of primary interest. Cohort B consisted of patients with absence of ALK mutation, but presence of any other non-ALK mutation. Cohort C consisted of patients with negative ctDNA or absence of any alteration.
    Actual start date of recruitment
    04 May 2020
    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
    Netherlands: 12
    Country: Number of subjects enrolled
    Norway: 2
    Country: Number of subjects enrolled
    Spain: 27
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    France: 13
    Country: Number of subjects enrolled
    Jordan: 8
    Worldwide total number of subjects
    64
    EEA total number of subjects
    56
    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)
    46
    From 65 to 84 years
    18
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Cohort A for patients with presence of ≥ 1 ALK mutation(s) (target 42 patients and primary cohort of interest for the trial). Cohort B for Patients with absence of ALK mutation, but presence of any other non-ALK mutation (target 21 patients). Cohort C for patients with negative ctDNA or absence of any ALK alteration (target 21 patients).

    Pre-assignment
    Screening details
    		 The main inclusion criteria were: advanced (stage III not eligible for local therapy, or stage IV) NSCLC with ALK rearrangement, progressed on and with last treatment second generation ALK inhibitor TKIs (alectinib, ceritinib or brigatinib). Treated and/or untreated brain or leptomeningeal metastases were allowed if asymptomatic and/or controlled.

    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
    		 Cohort A
    Arm description
    		 Patients with the presence of 1 or more ALK mutation(s)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lorlatinib
    Investigational medicinal product code
    L01XE44
    Other name
    Lorviqua, PF-06463922, Lorbrena
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lorlatinib is administered orally at the daily dose of 100 mg (four tablets of 25 mg). Lorlatinib must be swallowed with a glass of water and must not be mashed or chewed. The tablets can be taken with or without food. Treatment cycles are defined as a four-week period (28 days) to facilitate scheduling of visits and assessments and will always be considered 4 weeks irrespective of any dose delays/dosing interruptions or missed doses which may affect nominal days of each cycle

    Arm title
    		 Cohort B
    Arm description
    		 Patients with absence of ALK mutation, but presence of any other non-ALK mutation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lorlatinib
    Investigational medicinal product code
    L01XE44
    Other name
    Lorviqua, PF-06463922, Lorbrena
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lorlatinib is administered orally at the daily dose of 100 mg (four tablets of 25 mg). Lorlatinib must be swallowed with a glass of water and must not be mashed or chewed. The tablets can be taken with or without food. Treatment cycles are defined as a four-week period (28 days) to facilitate scheduling of visits and assessments and will always be considered 4 weeks irrespective of any dose delays/dosing interruptions or missed doses which may affect nominal days of each cycle

    Arm title
    		 Cohort C
    Arm description
    		 Patients with negative ctDNA or absence of any ALK alteration
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lorlatinib
    Investigational medicinal product code
    L01XE44
    Other name
    Lorviqua, PF-06463922, Lorbrena
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lorlatinib is administered orally at the daily dose of 100 mg (four tablets of 25 mg). Lorlatinib must be swallowed with a glass of water and must not be mashed or chewed. The tablets can be taken with or without food. Treatment cycles are defined as a four-week period (28 days) to facilitate scheduling of visits and assessments and will always be considered 4 weeks irrespective of any dose delays/dosing interruptions or missed doses which may affect nominal days of each cycle

    Number of subjects in period 1
    		Cohort A Cohort B Cohort C
    Started
    8
    22
    34
    Completed
    8
    22
    34

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Patients with the presence of 1 or more ALK mutation(s)

    Reporting group title
    Cohort B
    Reporting group description
    		 Patients with absence of ALK mutation, but presence of any other non-ALK mutation

    Reporting group title
    Cohort C
    Reporting group description
    		 Patients with negative ctDNA or absence of any ALK alteration

    Reporting group values
    		 Cohort A Cohort B Cohort C Total
    Number of subjects
    		 8 22 34 64
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 3 15 28 46
        From 65-84 years
    		 5 7 6 18
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 65.5 (49.5 to 74.0) 59 (49 to 68) 55.5 (49 to 62) -
    Gender categorical
    Units: Subjects
        Female
    		 4 14 19 37
        Male
    		 4 8 15 27
    ECOG WHO Performance Score
    ECOG WHO Performance Score is a 6 point item scale (0-5) which determines the patients to assess the patient's functional status or performance status
    Units: Subjects
        PS 0
    		 1 7 14 22
        PS 1
    		 6 11 18 35
        PS 2
    		 1 4 2 7
        PS 3
    		 0 0 0 0
        PS 4
    		 0 0 0 0
        PS 5
    		 0 0 0 0
    Histopathological type
    Units: Subjects
        Adenocarcinoma
    		 7 20 29 56
        Adenocarcinoma in situ
    		 0 0 1 1
        Carcinoma, NOS
    		 0 0 2 2
        Invasive mucinous adenocarcinoma
    		 0 1 1 2
        Large cell neuroendocrine carcinoma
    		 0 1 0 1
        Squamous cell carcinoma
    		 1 0 1 2
    Stage at first diagnosis
    according to UICC TNM staging v8.0
    Units: Subjects
        Missing
    		 1 2 5 8
        IIB
    		 0 0 1 1
        IIIA
    		 0 1 2 3
        IIIB
    		 0 0 1 1
        IIIC
    		 0 2 1 3
        IV
    		 0 3 3 6
        IVA
    		 3 5 10 18
        IVB
    		 4 9 11 24
    Brain or leptomeningeal metastases at screening
    Units: Subjects
        No
    		 5 14 19 38
        Yes
    		 3 8 15 26

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Patients with the presence of 1 or more ALK mutation(s)

    Reporting group title
    Cohort B
    Reporting group description
    		 Patients with absence of ALK mutation, but presence of any other non-ALK mutation

    Reporting group title
    Cohort C
    Reporting group description
    		 Patients with negative ctDNA or absence of any ALK alteration

    Primary: PFSR-12

    		 Close Top of page
    End point title
    		 PFSR-12 [1] [2]
    End point description
    Progression-free survival rate at 12 months (PFSR-12) is defined as the proportion of patients at 12 months who are alive and non-progressing. It is based on independent central review. Progression of disease is assessed as per RECIST v1.1 criteria. Patients without adequate disease assessment at 12 months are considered as failures.
    End point type
    Primary
    End point timeframe
    12 months after enrolment
    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: Due to early termination of this trial due to poor accrual no formal hypothesis tests were conducted. Only exploratory results were provided. In this case the rate of patients progression-free and alive after 12 months in cohort A (in the per-protocol population and as per central review) was 1 out of 7, i.e. 1 succes and 6 failures. This corresponds to a rate of 0.143 (with 95% C.I. of 0.00-0.579)).
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: PFSR-12 was only pre-planned and considered relevant for patients in Cohort A. The landmark time point of 12 months was neither planned nor considered relevant for cohorts B and C.
    End point values
    		 Cohort A
    Number of subjects analysed
    7 [3]
    Units: patients
        Succes
    1
        Fail
    6
    Notes
    [3] - Analysis done in the per-protocol population.
    No statistical analyses for this end point

    Secondary: Overall Survival

    		 Close Top of page
    End point title
    		 Overall Survival
    End point description
    Overall survival is defined as the time interval between the date of enrolment and the date of death from any cause, whichever occurs first. If no event has been observed, then the patient is censored at the last date known to be alive.
    End point type
    Secondary
    End point timeframe
    From enrolment until the end of study.
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    7 [4]
    21 [5]
    34 [6]
    Units: Patients
        Alive
    2
    4
    22
        Dead
    5
    17
    12
    Notes
    [4] - Analysis done in the per-protocol population.
    [5] - Analysis done in the per-protocol population.
    [6] - Analysis done in the per-protocol population.
    No statistical analyses for this end point

    Secondary: Progression-free survival

    		 Close Top of page
    End point title
    		 Progression-free survival
    End point description
    Progression-free survival is defined as the time interval between the date of enrolment and the date of disease progression or death, whichever comes first. If neither event has been observed, then the patient is censored at the date of the last follow up examination. Progression of disease is defined as per RECIST v1.1 criteria (and assessed as per central review).
    End point type
    Secondary
    End point timeframe
    From enrolment until the end of study
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    7 [7]
    21 [8]
    34 [9]
    Units: patients
        Progressive disease
    2
    9
    13
        Death
    3
    11
    8
        Progression-free and alive
    2
    1
    13
    Notes
    [7] - Analysis done in the per-protocol population
    [8] - Analysis done in the per-protocol population
    [9] - Analysis done in the per-protocol population
    No statistical analyses for this end point

    Secondary: Median Progression-free survival

    		 Close Top of page
    End point title
    		 Median Progression-free survival
    End point description
    Progression-free survival was determined as per RECIST v1.1 criteria (and assessed as per central review). The median overall progression-free survival and its 95% confidence interval for each cohort are presented. Note: the value 99999 indicates that the median or lower/upper bound of the 95% confidence interval was not reached.
    End point type
    Secondary
    End point timeframe
    From enrolment until end of study
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    7 [10]
    21 [11]
    34 [12]
    Units: Months
        median (confidence interval 95%)
    7.2 (2.0 to 99999)
    2.0 (1.6 to 10.3)
    10.8 (5.4 to 25.9)
    Notes
    [10] - Analysis done in the per-protocol population
    [11] - Analysis done in the per-protocol population
    [12] - Analysis done in the per-protocol population
    No statistical analyses for this end point

    Secondary: Median Overall Survival

    		 Close Top of page
    End point title
    		 Median Overall Survival
    End point description
    The median overall survival and its 95% confidence interval for each cohort are presented. Note: the value 99999 indicates that the median or lower/upper bound of the 95% confidence interval was not reached.
    End point type
    Secondary
    End point timeframe
    From enrolment until the end of study
    End point values
    		 Cohort A Cohort B Cohort C
    Number of subjects analysed
    7 [13]
    21 [14]
    34 [15]
    Units: months
        median (confidence interval 95%)
    9.9 (2.0 to 99999)
    9.0 (2.4 to 21.7)
    99999 (11.3 to 99999)
    Notes
    [13] - Analysis was done in the per-protocol population
    [14] - Analysis was done in the per-protocol population
    [15] - Analysis was done in the per-protocol population
    No statistical analyses for this end point

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    The number of patients who had specific adverse events in the period during treatment, which starts at the date the first dose of lorlatinib was taken until 30 days after the last date a dose of lorlatinib is taken.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 -

    Reporting group title
    Cohort B
    Reporting group description
    		 -

    Reporting group title
    Cohort C
    Reporting group description
    		 -

    Serious adverse events
    		 Cohort A Cohort B Cohort C
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 8 (37.50%)
    9 / 22 (40.91%)
    13 / 34 (38.24%)
         number of deaths (all causes)
    6
    18
    12
         number of deaths resulting from adverse events
    3
    3
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Metastases to central nervous system
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Hydronephrosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    2 / 34 (5.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 22 (13.64%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Organising pneumonia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    3 / 34 (8.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Psychiatric disorders
    Psychotic disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Aortic valve calcification
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    Brain oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral ischaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Motor dysfunction
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19 Infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    4 / 34 (11.76%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    0 / 34 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Cohort A Cohort B Cohort C
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    22 / 22 (100.00%)
    34 / 34 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Other, Neoplasms benign, malignant and unspecified
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0
    Hot flashes
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertension
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 22 (9.09%)
    3 / 34 (8.82%)
         occurrences all number
    2
    2
    3
    Superficial thrombophlebitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Thromboembolic Event
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    1
    0
    3
    General disorders and administration site conditions
    Oedema Limbs
         subjects affected / exposed
    3 / 8 (37.50%)
    5 / 22 (22.73%)
    9 / 34 (26.47%)
         occurrences all number
    3
    5
    9
    Fatigue
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 22 (13.64%)
    4 / 34 (11.76%)
         occurrences all number
    2
    3
    4
    Fever
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 22 (0.00%)
    7 / 34 (20.59%)
         occurrences all number
    2
    0
    7
    Flu like symptoms
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    1
    0
    3
    Gait disturbance
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Irritability
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    1
    Localised oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    1
    Malaise
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Pain
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    1
    1
    1
    Other, General disorders
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Reproductive system and breast disorders
    Erectile dysfunction
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Gynaecomastia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Bronchospasm
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Cough
         subjects affected / exposed
    2 / 8 (25.00%)
    2 / 22 (9.09%)
    5 / 34 (14.71%)
         occurrences all number
    2
    2
    5
    Dyspnoea
         subjects affected / exposed
    2 / 8 (25.00%)
    9 / 22 (40.91%)
    6 / 34 (17.65%)
         occurrences all number
    2
    9
    6
    Hypoxia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Pleural effusion
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    2
    0
    1
    Pleuratic pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Productive cough
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    2
    Respiratory failure
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    2
    Sore throat
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Voice alteration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Other, Respiratory and mediastinal disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    1
    Anxiety disorder
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Delirium
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Euphoria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Hallucination
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    5 / 34 (14.71%)
         occurrences all number
    0
    2
    5
    Insomnia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    1
    0
    3
    Psychosis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Other, Psychiatric disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    3 / 34 (8.82%)
         occurrences all number
    0
    1
    3
    Alkaline Phosphatase Increased
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 22 (13.64%)
    5 / 34 (14.71%)
         occurrences all number
    0
    3
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    4 / 34 (11.76%)
         occurrences all number
    1
    0
    4
    Cholesterol high
         subjects affected / exposed
    4 / 8 (50.00%)
    14 / 22 (63.64%)
    29 / 34 (85.29%)
         occurrences all number
    4
    14
    29
    Creatine phosphokinase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Creatine urine increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    2
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Lipase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 22 (9.09%)
    3 / 34 (8.82%)
         occurrences all number
    1
    2
    3
    Neutrophil count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Serum amylase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    3 / 34 (8.82%)
         occurrences all number
    0
    1
    3
    Weight increased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    4 / 34 (11.76%)
         occurrences all number
    0
    2
    4
    Weight decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Eosinophilia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Dysuria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Cardiac disorders
    Aortic valve disease
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Atrial flutter
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Chest pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Pericardial effusion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Pericardial tamponade
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Sinus bradycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Aphonia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Cognitive disturbance
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    4 / 34 (11.76%)
         occurrences all number
    0
    1
    4
    Concentration impairment
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    Dizziness
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 22 (13.64%)
    5 / 34 (14.71%)
         occurrences all number
    2
    3
    5
    Dysarthria
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    3 / 34 (8.82%)
         occurrences all number
    0
    2
    3
    Dysgeusia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    3 / 34 (8.82%)
         occurrences all number
    0
    1
    3
    Oedema cerebral
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Encephalopathy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0
    Headache
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    5 / 34 (14.71%)
         occurrences all number
    1
    1
    5
    Ischemia cerebrovascular
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Lethargy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Memory impairment
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    8 / 34 (23.53%)
         occurrences all number
    0
    1
    8
    Neuralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Paresthesia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    4 / 34 (11.76%)
         occurrences all number
    0
    1
    4
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    3 / 34 (8.82%)
         occurrences all number
    1
    1
    3
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    4 / 34 (11.76%)
         occurrences all number
    0
    2
    4
    Seizure
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Stroke
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    1
    Syncope
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0
    Other, Nervous system disorders
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    2
    Generalised oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 22 (18.18%)
    6 / 34 (17.65%)
         occurrences all number
    1
    4
    6
    Disseminated intravascular coagulation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Leukocytosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Other, Blood and Lymphatic
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    3 / 34 (8.82%)
         occurrences all number
    0
    1
    3
    Vertigo
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Vestibular disorder
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 22 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    2
    0
    3
    Eye disorders
    Blurred vision
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    1
    0
    2
    Conjunctivitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Eye pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Retinopathy
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Watering eyes
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Other, Eye disorders
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    4 / 34 (11.76%)
         occurrences all number
    1
    0
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    6 / 34 (17.65%)
         occurrences all number
    1
    0
    6
    Constipation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    4 / 34 (11.76%)
         occurrences all number
    0
    0
    4
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 22 (18.18%)
    9 / 34 (26.47%)
         occurrences all number
    0
    4
    9
    Dry mouth
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    3 / 34 (8.82%)
         occurrences all number
    0
    1
    3
    Dyspepsia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    2
    Dysphagia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Oesophageal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Mucositis Oral
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    2 / 34 (5.88%)
         occurrences all number
    0
    2
    2
    Toothache
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    1
    0
    3
    Other, Gastrointestinal
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Hepatobiliary disorders
    Other, Hepatobiliary
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    2
    Dry skin
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Rash acneiform
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    2 / 34 (5.88%)
         occurrences all number
    0
    1
    2
    Skin induration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Other, skin and subcutaneous tissue disorders
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    0 / 34 (0.00%)
         occurrences all number
    0
    2
    0
    Proteinuria
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Urinary incontinence
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Other, Renal and urinary disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    7 / 34 (20.59%)
         occurrences all number
    0
    2
    7
    Back pain
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 22 (18.18%)
    8 / 34 (23.53%)
         occurrences all number
    1
    4
    8
    Bone pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Flank pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    Generalised muscle weakness
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Joint range of motion decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Muscle weakness left-sided
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    4 / 34 (11.76%)
         occurrences all number
    0
    0
    4
    Neck pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    1
    0
    3
    neck contracture
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Sprained ankle
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Muscle cramp
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Spinal cord compression
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Scapular pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Hand cramps
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Anorectal infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Appendicitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Bladder infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Bronchial infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    3 / 34 (8.82%)
         occurrences all number
    0
    0
    3
    Lung infection
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 22 (18.18%)
    7 / 34 (20.59%)
         occurrences all number
    1
    4
    7
    Otitis externa
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Otitis media
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Rash pustular
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Rhinitis infective
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Sepsis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Tooth infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    0 / 34 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory infection
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 22 (0.00%)
    5 / 34 (14.71%)
         occurrences all number
    2
    0
    5
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    1
    1
    1
    Other, Infections and infestations
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Folliculitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Herpes simplex oral infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Shingles
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Alcohol intolerance
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Anorexia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 22 (9.09%)
    1 / 34 (2.94%)
         occurrences all number
    0
    2
    1
    Hypercalcaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    1
    0
    1
    Hyperkalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Hypertriglyceridemia
         subjects affected / exposed
    3 / 8 (37.50%)
    9 / 22 (40.91%)
    25 / 34 (73.53%)
         occurrences all number
    3
    9
    25
    Hyperuricaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    0
    1
    1
    Hypokalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 22 (0.00%)
    0 / 34 (0.00%)
         occurrences all number
    1
    0
    0
    Hyponatraemia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 22 (4.55%)
    1 / 34 (2.94%)
         occurrences all number
    1
    1
    1
    Hypophosphataemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    1 / 34 (2.94%)
         occurrences all number
    0
    0
    1
    Other, Metabolism and nutrition disorders
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 22 (0.00%)
    2 / 34 (5.88%)
         occurrences all number
    0
    0
    2

    More information

    		 Close Top of page

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

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Jul 2023
    Accrual in this study was permanently discontinued on July 1st 2023 following an Independent Data Monitoring Committee (IDMC) recommendation based on poor accrual in cohort A. The primary objective and endpoint (progression-free survival rate at 12 months in cohort A) of this study was based and driven by cohort A; therefore, the statistical analysis plan foreseen in the protocol was modified considering the observed poor accrual in cohort A. The statistical guidelines for data analysis stated in the protocol were modified and documented in a revised SAP. Following this study’s premature closing to patient entry for accrual in cohort A, 8 (7 in per-protocol population) patients were enrolled in cohort A, 22 (21 in per-protocol) population patients in cohort B and 34 patients (all 34 part of the per-protocol population) in cohort C. It was anticipated that 50% of accrued patients would satisfy the characteristics of cohort A, with an anticipated sample size of 42 to satisfy the power calculation. With the current sample size, after premature stopping of the accrual, this study was underpowered for the primary endpoint. As a consequence, the presented results are descriptive and thus decision rules and boundaries corresponding to the primary endpoint are not used to declare whether cohort A-based treatment is worthwhile for further exploration. The report also includes descriptive analyses of the endpoints relating to cohorts B and C, which are also descriptive, without any decision rules and boundaries.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    This phase II, multi-cohort, multicentre, clinical trial was stopped early due to poor accrual in cohort A, the cohort of primary interest. As a consequence, no hypothesis testing was performed and only exploratory descriptive values were presented.
    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.

    European Medicines Agency © 1995-Mon Dec 08 00:58:07 CET 2025 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA