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    Clinical Trial Results:
    Phase 2 study of MCLA-128-based combinations in metastatic breast cancer (MBC): MCLA-128/trastuzumab/chemotherapy in HER2-positive MBC and MCLA-128/endocrine therapy in estrogen receptor positive and low HER2 expression MBC

    Summary
    EudraCT number
    		 2017-002821-39
    Trial protocol
    		 BE   PT   ES   GB   NL  
    Global end of trial date
    26 Jul 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Aug 2025
    First version publication date
    22 Aug 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MCLA-128-CL02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03321981
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merus N.V.
    Sponsor organisation address
    Uppsalalaan 17, Utrecht, Netherlands,
    Public contact
    MCLA-128-CL02 project manager, Oncology Therapeutic Development, 33 147150101, otd@oncotd.com
    Scientific contact
    MCLA-128-CL02 project manager, Oncology Therapeutic Development, 33 147150101, otd@oncotd.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    26 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Oct 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jul 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Cohort 1 (HER2-positive/amplified MBC): MCLA-128 + trastuzumab ± vinorelbine: Evaluate efficacy of MCLA-128 combined with trastuzumab ± vinorelbine in terms of clinical benefit rate (CBR) at 24 weeks based on RECIST 1.1 (per investigator review) in HER2-positive/amplified MBC patients who have progressed on prior HER2-directed therapy that included trastuzumab with pertuzumab, and an HER2 antibody drug conjugate (ADC) Cohort 2 (estrogen receptor [ER]-positive/low HER2 expression MBC): MCLA-128 + endocrine therapy: Evaluate efficacy of MCLA-128 combined with endocrine therapy in terms of CBR at 24 weeks based on RECIST 1.1 (per investigator review) in ER-positive and low HER2 expression MBC patients who have previously progressed on the same endocrine therapy
    Protection of trial subjects
    Premedication with paracetamol/acetaminophen, antihistamines, and corticosteroids was mandatory immediately before every zenocutuzumab administration, per local standard practices: • Paracetamol/ acetaminophen 1000 mg per os (PO) or IV. • Dexchlorpheniramine 5 mg IV (or equivalent PO or IV). • Dexamethasone 10 mg IV (or equivalent PO or IV).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Nov 2017
    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: 4
    Country: Number of subjects enrolled
    Portugal: 13
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Belgium: 10
    Country: Number of subjects enrolled
    France: 47
    Country: Number of subjects enrolled
    United States: 16
    Worldwide total number of subjects
    104
    EEA total number of subjects
    85
    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)
    77
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The first patient was enrolled on 18 Jan 2018. The last patient last visit/death in the study was 26 July 2023.

    Pre-assignment
    Screening details
    		 For this study 105 were enrolled, but only 104 patients were treated. The non-treated patient was excluded prior to initiation of study treatment due to failure to meet inclusion criteria 2.2d (No progression under Cyclin-Dependent Kinase (CDK) inhibitor).

    Period 1
    Period 1 title
    Baseline Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 Doublet
    Arm description
    		 zenocutuzumab + trastuzumab Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Trastuzumab: humanised IgG1 monoclonal antibody
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zenocutuzumab
    Investigational medicinal product code
    Other name
    MCLA-128
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Flat dose of 750 mg administered intravenously (IV) over 2 h, on Day 1 once every 3 weeks. Dose reductions were not permitted.

    Arm title
    		 Cohort 1 Triplet
    Arm description
    		 zenocutuzumab + trastuzumab + vinorelbine Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Trastuzumab: humanised IgG1 monoclonal antibody Vinorelbine: antineoplastic drug of vinca alkaloid family
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zenocutuzumab
    Investigational medicinal product code
    Other name
    MCLA-128
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Flat dose of 750 mg administered intravenously (IV) over 2 h, on Day 1 once every 3 weeks. Dose reductions were not permitted.

    Arm title
    		 Cohort 2
    Arm description
    		 zenocutuzumab + endocrine therapy Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Endocrine therapy: same endocrine therapy is administered as the last line of endocrine therapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zenocutuzumab
    Investigational medicinal product code
    Other name
    MCLA-128
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Flat dose of 750 mg administered intravenously (IV) over 2 h, on Day 1 once every 3 weeks. Dose reductions were not permitted.

    Number of subjects in period 1
    		Cohort 1 Doublet Cohort 1 Triplet Cohort 2
    Started
    15
    39
    50
    Completed
    15
    39
    50
    Period 2
    Period 2 title
    Overall Trial
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1 Doublet
    Arm description
    		 zenocutuzumab + trastuzumab Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Trastuzumab: humanised IgG1 monoclonal antibody
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zenocutuzumab
    Investigational medicinal product code
    Other name
    MCLA-128
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Flat dose of 750 mg administered intravenously (IV) over 2 h, on Day 1 once every 3 weeks. Dose reductions were not permitted.

    Arm title
    		 Cohort 1 Triplet
    Arm description
    		 zenocutuzumab + trastuzumab + vinorelbine Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Trastuzumab: humanised IgG1 monoclonal antibody Vinorelbine: antineoplastic drug of vinca alkaloid family
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zenocutuzumab
    Investigational medicinal product code
    Other name
    MCLA-128
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Flat dose of 750 mg administered intravenously (IV) over 2 h, on Day 1 once every 3 weeks. Dose reductions were not permitted.

    Arm title
    		 Cohort 2
    Arm description
    		 zenocutuzumab + endocrine therapy Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Endocrine therapy: same endocrine therapy is administered as the last line of endocrine therapy
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zenocutuzumab
    Investigational medicinal product code
    Other name
    MCLA-128
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Flat dose of 750 mg administered intravenously (IV) over 2 h, on Day 1 once every 3 weeks. Dose reductions were not permitted.

    Number of subjects in period 2
    		Cohort 1 Doublet Cohort 1 Triplet Cohort 2
    Started
    15
    39
    50
    Completed
    0
    0
    0
    Not completed
    15
    39
    50
         Physician decision
    -
    1
    -
         Symptomatic deterioration
    -
    1
    1
         Adverse event, non-fatal
    -
    -
    2
         Death
    -
    1
    -
         Scans showed PD 01JUL2019 (but the PT has received
    -
    1
    -
         Progressive Disease
    15
    30
    47
         Subject withdrawal of all treatment and follow-up
    -
    2
    -
         Subject withdrawal of investigational product
    -
    1
    -
         Lack of compliance
    -
    1
    -
         Subject withdrawal with disagreement for contact
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 Doublet
    Reporting group description
    		 zenocutuzumab + trastuzumab Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Trastuzumab: humanised IgG1 monoclonal antibody

    Reporting group title
    Cohort 1 Triplet
    Reporting group description
    		 zenocutuzumab + trastuzumab + vinorelbine Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Trastuzumab: humanised IgG1 monoclonal antibody Vinorelbine: antineoplastic drug of vinca alkaloid family

    Reporting group title
    Cohort 2
    Reporting group description
    		 zenocutuzumab + endocrine therapy Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Endocrine therapy: same endocrine therapy is administered as the last line of endocrine therapy

    Reporting group values
    		 Cohort 1 Doublet Cohort 1 Triplet Cohort 2 Total
    Number of subjects
    		 15 39 50 104
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 11 27 39 77
        From 65-84 years
    		 4 12 11 27
    Gender categorical
    Units: Subjects
        Female
    		 15 39 50 104
        Male
    		 0 0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 3 4 7
        Not Hispanic or Latino
    		 12 31 44 87
        Unknown or Not Reported
    		 3 5 2 10
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 1 3 0 4
        White
    		 9 22 46 77
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 5 14 4 23

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 Doublet
    Reporting group description
    		 zenocutuzumab + trastuzumab Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Trastuzumab: humanised IgG1 monoclonal antibody

    Reporting group title
    Cohort 1 Triplet
    Reporting group description
    		 zenocutuzumab + trastuzumab + vinorelbine Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Trastuzumab: humanised IgG1 monoclonal antibody Vinorelbine: antineoplastic drug of vinca alkaloid family

    Reporting group title
    Cohort 2
    Reporting group description
    		 zenocutuzumab + endocrine therapy Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Endocrine therapy: same endocrine therapy is administered as the last line of endocrine therapy
    Reporting group title
    Cohort 1 Doublet
    Reporting group description
    		 zenocutuzumab + trastuzumab Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Trastuzumab: humanised IgG1 monoclonal antibody

    Reporting group title
    Cohort 1 Triplet
    Reporting group description
    		 zenocutuzumab + trastuzumab + vinorelbine Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Trastuzumab: humanised IgG1 monoclonal antibody Vinorelbine: antineoplastic drug of vinca alkaloid family

    Reporting group title
    Cohort 2
    Reporting group description
    		 zenocutuzumab + endocrine therapy Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Endocrine therapy: same endocrine therapy is administered as the last line of endocrine therapy

    Primary: Clinical Benefit Rate at 24 weeks per Investigator assessment

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    End point title
    		 Clinical Benefit Rate at 24 weeks per Investigator assessment [1]
    End point description
    Clinical benefit rate (CBR) at 24 weeks per investigator assessment. CBR is the proportion of patients with confirmed Complete Response (CR) or Partial Response (PR), or Stable Disease (SD) lasting 24 weeks.
    End point type
    Primary
    End point timeframe
    24 weeks
    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: There was no statistical comparison between the cohorts. The analysis was performed independently for each cohort; only descriptive statistics were calculated.
    End point values
    		 Cohort 1 Doublet Cohort 1 Triplet Cohort 2
    Number of subjects analysed
    14
    31
    43
    Units: Count of participants
        Count of Participants
    3
    18
    9
    No statistical analyses for this end point

    Secondary: Progression Free Survival per Investigator Assessment

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    End point title
    		 Progression Free Survival per Investigator Assessment
    End point description
    For assessment per Response Evaluation Criteria In Solid Tumors Guidelines (RECIST) v1.1, PFS is the time from the date of treatment start to the date of event defined as the first documented progression or death due to any cause.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
    End point values
    		 Cohort 1 Doublet Cohort 1 Triplet Cohort 2
    Number of subjects analysed
    14
    31
    43
    Units: Months
    median (confidence interval 90%)
        Median (90% Confidence Interval)
    1.41 (1.38 to 1.45)
    5.52 (4.11 to 7.16)
    2.61 (1.45 to 2.73)
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS) Per Central Review

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    End point title
    		 Progression Free Survival (PFS) Per Central Review
    End point description
    For assessment per RECIST v1.1, PFS is the time from the date of treatment start to the date of event defined as the first documented progression or death due to any cause.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
    End point values
    		 Cohort 1 Doublet Cohort 1 Triplet Cohort 2
    Number of subjects analysed
    14
    31
    43
    Units: Months
    median (confidence interval 90%)
        Median (90% Confidence Interval)
    1.41 (1.38 to 1.45)
    5.59 (4.11 to 7.39)
    1.45 (1.45 to 2.73)
    No statistical analyses for this end point

    Secondary: Overall Response Rate per Investigator Assessment

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    End point title
    		 Overall Response Rate per Investigator Assessment
    End point description
    The proportion of patients with overall response of Complete Response or Partial Response based upon RECIST 1.1 (confirmed response).
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
    End point values
    		 Cohort 1 Doublet Cohort 1 Triplet Cohort 2
    Number of subjects analysed
    14
    31
    43
    Units: Count of Participants
    0
    10
    1
    No statistical analyses for this end point

    Secondary: Overall Response Rate per Central Review

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    End point title
    		 Overall Response Rate per Central Review
    End point description
    The proportion of patients with overall response of Complete Response or Partial Response based upon RECIST 1.1 (confirmed response).
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
    End point values
    		 Cohort 1 Doublet Cohort 1 Triplet Cohort 2
    Number of subjects analysed
    14
    31
    43
    Units: Count of Participants
    0
    6
    0
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    The time from treatment start until death due to any cause.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
    End point values
    		 Cohort 1 Doublet Cohort 1 Triplet Cohort 2
    Number of subjects analysed
    14 [2]
    31 [3]
    43 [4]
    Units: Months
    median (confidence interval 90%)
        Median (90% CI)
    14.09 (9.63 to 999999)
    27.33 (19.94 to 999999)
    26.41 (17.51 to 999999)
    Notes
    [2] - The upper limit of the confidence interval could not be estimated.
    [3] - The upper limit of the confidence interval could not be estimated.
    [4] - The upper limit of the confidence interval could not be estimated.
    No statistical analyses for this end point

    Secondary: Duration of Response per Investigator Assessment

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    End point title
    		 Duration of Response per Investigator Assessment
    End point description
    DoR applies only to patients with a Best Overall Response (BOR) of confirmed CR or PR (RECIST v1.1). For RECIST v1.1, DoR is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due to any cause.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
    End point values
    		 Cohort 1 Triplet Cohort 2
    Number of subjects analysed
    10 [5]
    1 [6]
    Units: Months
    median (confidence interval 90%)
        Median (90% CI)
    4.21 (2.79 to 999999)
    4.50 (0 to 999999)
    Notes
    [5] - The upper limit of the Confidence interval could not be estimated.
    [6] - As there was only one subject analyzed, the confidence interval cannot be estimated.
    No statistical analyses for this end point

    Secondary: Duration of Response Per Central Review

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    End point title
    		 Duration of Response Per Central Review
    End point description
    DoR applies only to patients with a BOR of confirmed CR or PR (RECIST v1.1). For RECIST v1.1, DOR is defined as the time from the date of the first documented response (CR or PR) to the date of first documented progression, or death due to any cause.
    End point type
    Secondary
    End point timeframe
    Baseline, every 6 weeks until end of treatment, every 3 months thereafter up to 1 year after treatment (if not progressed at end of treatment)
    End point values
    		 Cohort 1 Triplet
    Number of subjects analysed
    6 [7]
    Units: Months
    median (confidence interval 90%)
        Median (90% CI)
    6.36 (4.17 to 999999)
    Notes
    [7] - The upper limit of the confidence interval could not be estimated.
    No statistical analyses for this end point

    Secondary: Number of Patients with AEs Leading to Discontinuation of Study Drug

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    End point title
    		 Number of Patients with AEs Leading to Discontinuation of Study Drug
    End point description
    Evaluation of number of participants with Adverse Events leading to leading to discontinuation of study drug
    End point type
    Secondary
    End point timeframe
    During study treatment and up to 30 days after last administration of study drug (median duration of zenocutuzumab exposure was 6.0 weeks for Cohort 1 doublet, 19.3 weeks for Cohort 1 triplet and 11.8 weeks for Cohort 2).
    End point values
    		 Cohort 1 Doublet Cohort 1 Triplet Cohort 2
    Number of subjects analysed
    15
    39
    50
    Units: Count of Participants
        Count of Participants
    0
    1
    3
    No statistical analyses for this end point

    Secondary: Number of Patients with AEs of Special Interest (AESI)

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    End point title
    		 Number of Patients with AEs of Special Interest (AESI)
    End point description
    AESIs for MCLA-128 combinations include: Infusion-related reactions (for any antibodies, known AESI for MCLA-128) Cardiotoxicity (anti-Human Epidermal Growth Factor Receptor (HER)2 therapy) Diarrhea (anti-HER2 therapy) Myelosuppression (vinorelbine)
    End point type
    Secondary
    End point timeframe
    During study treatment and up to 30 days after last administration of study drug (median duration of zenocutuzumab exposure was 6.0 weeks for Cohort 1 doublet, 19.3 weeks for Cohort 1 triplet and 11.8 weeks for Cohort 2).
    End point values
    		 Cohort 1 Doublet Cohort 1 Triplet Cohort 2
    Number of subjects analysed
    15
    39
    50
    Units: Count of Participants
        Cardiotoxicity (anti-HER2 therapy)
    1
    3
    0
        Diarrhea (anti-HER2 therapy)
    7
    28
    17
        Infusion-Related Reaction
    1
    7
    12
        Myelosuppression (vinorelbine)
    0
    18
    0
    No statistical analyses for this end point

    Secondary: Anti-Drug Antibodies Serum Titers

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    End point title
    		 Anti-Drug Antibodies Serum Titers
    End point description
    Number of patients with anti-drug antibodies at baseline and on treatment
    End point type
    Secondary
    End point timeframe
    Pre-dose for each of cycles 1, 3 and 5, and every 4 cycles thereafter, and at the End of Treatment visit.
    End point values
    		 Cohort 1 Doublet Cohort 1 Triplet Cohort 2
    Number of subjects analysed
    15
    39
    50
    Units: Count of Participants
        Baseline Anti-Drug Antibody-Negative
    12
    29
    46
        Baseline, ADA-Positive
    3
    9
    3
        On-treatment, evaluable
    8
    32
    38
        On-treatment, ADA-Negative
    8
    32
    35
        On-treatment, ADA-Positive
    0
    0
    3
        Treatment-induced ADA
    0
    0
    3
        Treatment-boosted ADA
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety was assessed from signature of informed consent until 30 days after the last study drug administration in terms of AEs, SAEs, laboratory abnormalities, electrocardiogram (ECG) and LVEF measurements, and vital signs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Cohort 1 Doublet
    Reporting group description
    		 zenocutuzumab + trastuzumab Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Trastuzumab: humanised IgG1 monoclonal antibody

    Reporting group title
    Cohort 1 Triplet
    Reporting group description
    		 zenocutuzumab + trastuzumab + vinorelbine Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Trastuzumab: humanised IgG1 monoclonal antibody Vinorelbine: antineoplastic drug of vinca alkaloid family

    Reporting group title
    Cohort 2
    Reporting group description
    		 zenocutuzumab + endocrine therapy Zenocutuzumab: full length IgG1 bispecific antibody targeting HER2 and HER3 Endocrine therapy: same endocrine therapy is administered as the last line of endocrine therapy

    Serious adverse events
    		 Cohort 1 Doublet Cohort 1 Triplet Cohort 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 15 (13.33%)
    8 / 39 (20.51%)
    9 / 50 (18.00%)
         number of deaths (all causes)
    0
    1
    1
         number of deaths resulting from adverse events
    Investigations
    Blood calcium increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (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
    Febrile Neutropenia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (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
    General physical health deterioration
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dysphagia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (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
    Nausea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic function abnormal
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         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
    Dyspnea
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (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
    Sepsis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (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 1 Doublet Cohort 1 Triplet Cohort 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    39 / 39 (100.00%)
    48 / 50 (96.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    3
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    3
    Hot flush
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    3
    Hypertension
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    6
    Hypotension
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Orthostatic hypotension
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Subclavian vein thrombosis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 15 (26.67%)
    18 / 39 (46.15%)
    5 / 50 (10.00%)
         occurrences all number
    7
    28
    6
    Axillary pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 15 (6.67%)
    4 / 39 (10.26%)
    0 / 50 (0.00%)
         occurrences all number
    1
    4
    0
    Chills
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    2
    Fatigue
         subjects affected / exposed
    5 / 15 (33.33%)
    13 / 39 (33.33%)
    11 / 50 (22.00%)
         occurrences all number
    5
    18
    14
    Feeling hot
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Gait disturbance
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperthermia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Inflammation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza like illness
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    3
    Infusion site erythema
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Localised oedema
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    Mucosal inflammation
         subjects affected / exposed
    3 / 15 (20.00%)
    3 / 39 (7.69%)
    2 / 50 (4.00%)
         occurrences all number
    4
    3
    2
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 39 (7.69%)
    1 / 50 (2.00%)
         occurrences all number
    1
    3
    1
    Pain
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 39 (5.13%)
    3 / 50 (6.00%)
         occurrences all number
    1
    2
    3
    Peripheral swelling
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    0 / 15 (0.00%)
    5 / 39 (12.82%)
    6 / 50 (12.00%)
         occurrences all number
    0
    9
    8
    Sense of oppression
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Temperature regulation disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Reproductive system and breast disorders
    Breast inflammation
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Breast pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    2
    Cystocele
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Vulvovaginal discomfort
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Vulvovaginal dryness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Vulvovaginal inflammation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 15 (0.00%)
    7 / 39 (17.95%)
    4 / 50 (8.00%)
         occurrences all number
    0
    8
    4
    Dyspnoea
         subjects affected / exposed
    1 / 15 (6.67%)
    6 / 39 (15.38%)
    5 / 50 (10.00%)
         occurrences all number
    2
    6
    5
    Epistaxis
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    2
    Haemoptysis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    2
    Pulmonary pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Rhinitis allergic
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Confusional state
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Depression
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 39 (7.69%)
    0 / 50 (0.00%)
         occurrences all number
    1
    4
    0
    Emotional disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    3
    Irritability
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Stress
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences all number
    0
    3
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    4
    0
    Blood calcium increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Blood cholesterol increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Blood magnesium decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Blood potassium decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    4 / 39 (10.26%)
    1 / 50 (2.00%)
         occurrences all number
    1
    9
    1
    Blood sodium decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    5
    0
    Body temperature increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 39 (7.69%)
    0 / 50 (0.00%)
         occurrences all number
    1
    3
    0
    Electrocardiogram QRS complex abnormal
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Neutrophil count decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    7 / 39 (17.95%)
    0 / 50 (0.00%)
         occurrences all number
    0
    16
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences all number
    0
    6
    0
    Weight decreased
         subjects affected / exposed
    1 / 15 (6.67%)
    7 / 39 (17.95%)
    1 / 50 (2.00%)
         occurrences all number
    1
    10
    1
    Weight increased
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    White blood cells urine positive
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Humerus fracture
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Procedural dizziness
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Aphasia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Burning sensation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Cognitive disorder
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences all number
    2
    2
    0
    Dysaesthesia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Dysgeusia
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 39 (10.26%)
    0 / 50 (0.00%)
         occurrences all number
    0
    4
    0
    Headache
         subjects affected / exposed
    0 / 15 (0.00%)
    7 / 39 (17.95%)
    3 / 50 (6.00%)
         occurrences all number
    0
    7
    7
    Hypoaesthesia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    1
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Nervous system disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Neuralgia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Neuropathy peripheral
         subjects affected / exposed
    2 / 15 (13.33%)
    6 / 39 (15.38%)
    2 / 50 (4.00%)
         occurrences all number
    2
    8
    2
    Paraesthesia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    1 / 50 (2.00%)
         occurrences all number
    0
    4
    1
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences all number
    0
    3
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences all number
    0
    3
    0
    Restless legs syndrome
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Somnolence
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Tremor
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Vocal cord paralysis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    11 / 39 (28.21%)
    1 / 50 (2.00%)
         occurrences all number
    0
    27
    2
    Leukopenia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Neutropenia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences all number
    0
    4
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    1
    Vertigo
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    5 / 50 (10.00%)
         occurrences all number
    0
    3
    8
    Eye disorders
    Blepharitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Chalazion
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Dry eye
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    1
    Eye allergy
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Eyelid sensory disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Glaucoma
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Photophobia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Ulcerative keratitis
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Visual impairment
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    9 / 39 (23.08%)
    6 / 50 (12.00%)
         occurrences all number
    1
    11
    8
    Abdominal pain upper
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    7 / 50 (14.00%)
         occurrences all number
    0
    1
    7
    Aphthous ulcer
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Colitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Constipation
         subjects affected / exposed
    2 / 15 (13.33%)
    12 / 39 (30.77%)
    6 / 50 (12.00%)
         occurrences all number
    2
    15
    6
    Diarrhoea
         subjects affected / exposed
    7 / 15 (46.67%)
    28 / 39 (71.79%)
    17 / 50 (34.00%)
         occurrences all number
    12
    46
    29
    Dry mouth
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    Dyspepsia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences all number
    0
    3
    0
    Gastritis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    2 / 39 (5.13%)
    1 / 50 (2.00%)
         occurrences all number
    1
    2
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    1
    Haemorrhoids
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoaesthesia oral
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Malabsorption
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Nasal discharge discolouration
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    3 / 15 (20.00%)
    18 / 39 (46.15%)
    14 / 50 (28.00%)
         occurrences all number
    4
    23
    17
    Oesophageal pain
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Oesophagitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Oral dysaesthesia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Stomatitis
         subjects affected / exposed
    0 / 15 (0.00%)
    4 / 39 (10.26%)
    3 / 50 (6.00%)
         occurrences all number
    0
    4
    3
    Tootache
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Ulcerative gastritis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    4 / 15 (26.67%)
    6 / 39 (15.38%)
    4 / 50 (8.00%)
         occurrences all number
    4
    7
    5
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 15 (6.67%)
    5 / 39 (12.82%)
    2 / 50 (4.00%)
         occurrences all number
    1
    5
    2
    Dry skin
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    Erythema
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 39 (2.56%)
    2 / 50 (4.00%)
         occurrences all number
    1
    1
    2
    Hyperhidrosis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Nail discolouration
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Nail disorder
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Onychoclasis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Onycholysis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 15 (6.67%)
    3 / 39 (7.69%)
    1 / 50 (2.00%)
         occurrences all number
    1
    3
    1
    Rash
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    1
    Rash erythematous
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    2
    Rash maculopapular
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Skin fissures
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    2
    Skin ulcer
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Telangiectasia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    Haematuria
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    2
    Stress urinary incontinence
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary incontinence
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Urinary tract pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 15 (13.33%)
    2 / 39 (5.13%)
    5 / 50 (10.00%)
         occurrences all number
    2
    3
    8
    Back pain
         subjects affected / exposed
    3 / 15 (20.00%)
    3 / 39 (7.69%)
    4 / 50 (8.00%)
         occurrences all number
    4
    3
    6
    Bone pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    2
    Enthesopathy
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Flank pain
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    3
    Mobility decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    1 / 15 (6.67%)
    6 / 39 (15.38%)
    4 / 50 (8.00%)
         occurrences all number
    1
    6
    4
    Muscular weakness
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 15 (0.00%)
    5 / 39 (12.82%)
    3 / 50 (6.00%)
         occurrences all number
    0
    8
    5
    Neck pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    1
    Osteopenia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    0
    2
    Pain in extremity
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    3
    Pain in jaw
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Spinal pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Bronchitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    4
    Cellulitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Corona virus infection
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Erysipelas
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Laryngitis
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Lung infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Mastitis fungal
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Nail infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    3
    Oral candidiasis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Oral fungal infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Paronychia
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 39 (5.13%)
    1 / 50 (2.00%)
         occurrences all number
    0
    4
    1
    Pharyngitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Rash pustular
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    2
    Sinusitis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Skin infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    2 / 50 (4.00%)
         occurrences all number
    0
    1
    2
    Urinary tract infection
         subjects affected / exposed
    1 / 15 (6.67%)
    6 / 39 (15.38%)
    2 / 50 (4.00%)
         occurrences all number
    3
    9
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 15 (20.00%)
    6 / 39 (15.38%)
    4 / 50 (8.00%)
         occurrences all number
    3
    11
    4
    Dehydration
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoglycaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 39 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Iron deficiency
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 39 (2.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Apr 2018
    Protocol MCLA-128-CL01, Version 2.0. Specification of the modality of treatment assignment in Cohort 1 once the doublet and triplet cohorts are both open. Clarification of inclusion criteria. Clarification of cardiac follow-up assessments. Correction of incoherence in table of assessments. Addition of compliance definition for endocrine therapy. Clarification of NCI-CTCAE v4.03 hyperlink and SAE/SUSAR reporting procedures. Correction of Appendix 3 LVEF algorithm. Minor modifications for text corrections/clarifications/coherence.
    06 Sep 2018
    MCLA-128-CL02 Protocol Version 3.0 Modification of the number of previous lines of therapy. The number of lines of systemic treatment permitted prior to study entry was increased in Cohort 1 and Cohort 2. Cohort 1: Patients with up to 5 lines of anti-HER2 therapies previously given in the metastatic setting will be permitted. The original protocol states that up to 4 lines are allowed but doesn’t specify the setting of the disease. Cohort 2: Patients with up to 3 lines of endocrine and 2 lines of chemotherapy previously given in the metastatic setting will be permitted. The original protocol states that up to 2 lines of hormone therapy and 1 line of chemotherapy in the metastatic setting are allowed. Modification of the criterion for measurable/non-measurable disease in Cohort 2 to include bone- only disease with lytic or mixed lesions. Modification of the permitted time frame for tissue collection of biomarkers. The amendment allows for the testing of archival tumor tissue collected within 24 months prior to screening. Clarification of the wording of the primary objective. Minor modifications for text corrections/clarifications/coherence. Change of contact details for the Sponsor Medical Expert.
    30 Apr 2021
    MCLA-128-CL02 Protocol Version 4.0 Modification of duration of LVEF Follow-up. Sponsor proposed stopping the follow-up period for each patient 1 year after their last MCLA-128 dose instead of 2 years after the last dose. Clarification of duration of provision of MCLA-128 following disease progression. Removal of ADA and PK sample collection. Collection of blood samples for pharmacokinetics and immunogenicity analyses are no longer necessary as sufficient samples have been collected to date to characterize these parameters for MCLA- 128 treatment, thereby avoiding unnecessary sample collection for patients. Addition of 1 mL vials of vinorelbine. For patients in Cohort 1, vinorelbine may be provided in 1-mL vials in addition to the 5-mL vials. Update of IMP details.
    11 Apr 2022
    MCLA-128-CL02 Version 5.0 Study Duration: The initial anticipated “Completion of the data analysis” date of October 2019 has been exceeded due to a handful of patients who still benefit from the study drug. Protocol Version 5 .0 provides a new expected date. Update to reduce the study procedures. The Sponsor proposed for the remaining patients who have been on treatment for at least 24 months in this study, to reduce the study procedures in order to decrease their burden, but to offer the opportunity to continually derive benefit from the Study drug. LVEF and ECG: Updated from every 4 cycles (3 months) to every 6 months due to the current Safety Profile and the focus on the appropriate level of safety surveillance. Tumor assessments: Updated from every 6 weeks to every 12 weeks to reduce the patient’s burden, but still allows the possibility to have a Tumor Assessment done in between in case of symptomatic deterioration signs or signs of disease progression. Efficacy assessments central review: Enough independent central analysis of patient imaging has been completed and additional assessment of imaging for those patients currently on treatment for at least 24 months is no longer required. Therefore, central review of imaging by an independent radiologist (s) for all patients on- study is no longer applicable as of Protocol Version 5.0. The Sponsor relies on the local Investigator assessment and continued focus will be on the appropriate level of safety surveillance. Biomarkers: Enough biomarker data has been accumulated from all patients treated on the trial. Therefore the additional data from the few patients who have been on treatment for 24 months is not needed as per Protocol Version 5 .0.

    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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