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    Clinical Trial Results:
    A multi-centre, open-label, randomized clinical trial comparing the efficacy and safety of the antibody-drug conjugate SYD985 to physician’s choice in patients with HER2-positive unresectable locally advanced or metastatic breast cancer

    Summary
    EudraCT number
    		 2017-001994-18
    Trial protocol
    		 ES   NL   SE   GB   DK   BE   IT  
    Global end of trial date
    30 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Jul 2023
    First version publication date
    06 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SYD985.002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03262935
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Byondis BV
    Sponsor organisation address
    Microweg 22, Nijmegen, Netherlands, 6545 CM
    Public contact
    Clinical Development, Byondis BV, 0031 246795101, clinicaltrials@byondis.com
    Scientific contact
    Clinical Development, Byondis BV, 0031 246795101, clinicaltrials@byondis.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
    24 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This multi-centre, open-label, randomized, phase III clinical trial compared the efficacy and safety of the antibody-drug conjugate SYD985 to physician's choice in patients with HER2-positive unresectable locally advanced or metastatic breast cancer. Patients were randomized 2:1 to receive either SYD985 1.2 mg/kg via intravenous infusion every 3 weeks or physician’s choice (PC; lapatinib + capecitabine, trastuzumab + capecitabine, trastuzumab + vinorelbine, or trastuzumab + eribulin) administered per SmPC/PI until disease progression (PD), unacceptable toxicity, or withdrawal of consent. Patients who discontinued trial treatment were followed for survival until death, lost to follow-up, or withdrawal of consent.
    Protection of trial subjects
    All study subjects were required to read and sign an Informed Consent Form
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Dec 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
    Singapore: 35
    Country: Number of subjects enrolled
    United States: 53
    Country: Number of subjects enrolled
    Canada: 24
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Spain: 67
    Country: Number of subjects enrolled
    Sweden: 8
    Country: Number of subjects enrolled
    United Kingdom: 59
    Country: Number of subjects enrolled
    Belgium: 40
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    France: 68
    Country: Number of subjects enrolled
    Italy: 70
    Worldwide total number of subjects
    437
    EEA total number of subjects
    266
    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)
    332
    From 65 to 84 years
    104
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 751 participants were screened, out of which, 437 participants were randomized into the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 SYD985
    Arm description
    		 SYD985 1.2 mg/kg was administered every three weeks by intravenous infusion until disease progression (as assessed by the investigator), unacceptable toxicity, or withdrawal of consent.
    Arm type
    		 Experimental

    Investigational medicinal product name
    SYD985
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    SYD985 1.2 mg/kg was administered every 3 weeks via intravenous infusion

    Arm title
    		 Physician's choice
    Arm description
    		 Physician’s choice therapy options included: Lapatinib + Capecitabine, Trastuzumab + Capecitabine, Trastuzumab + Vinorelbine, or Trastuzumab + Eribulin. The physician’s choice therapy was administered as per the SmPC/PI. Patients were treated until disease progression (as assessed by the investigator), unacceptable toxicity, or withdrawal of consent.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Lapatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lapatinib was administered as per the SmPC/PI

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Capecitabine was administered as per the SmPC/PI.

    Investigational medicinal product name
    Trastuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for injection/infusion, Solution for injection/infusion
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Trastuzumab was administered as per the SmPC/PI.

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Concentrate for solution for infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Vinorelbine was administered as per the SmPC/PI.

    Investigational medicinal product name
    Eribulin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Eribulin was administered as per the SmPC/PI.

    Number of subjects in period 1
    		SYD985 Physician's choice
    Started
    291
    146
    Completed
    0
    0
    Not completed
    291
    146
         Consent withdrawn by subject
    6
    7
         End Of Follow Up By Sponsor
    90
    41
         Death
    181
    94
         Other
    5
    -
         Lost to follow-up
    9
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SYD985
    Reporting group description
    		 SYD985 1.2 mg/kg was administered every three weeks by intravenous infusion until disease progression (as assessed by the investigator), unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Physician's choice
    Reporting group description
    		 Physician’s choice therapy options included: Lapatinib + Capecitabine, Trastuzumab + Capecitabine, Trastuzumab + Vinorelbine, or Trastuzumab + Eribulin. The physician’s choice therapy was administered as per the SmPC/PI. Patients were treated until disease progression (as assessed by the investigator), unacceptable toxicity, or withdrawal of consent.

    Reporting group values
    		 SYD985 Physician's choice Total
    Number of subjects
    		 291 146 437
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 225 107 332
        From 65-84 years
    		 66 38 104
        85 years and over
    		 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.9 ± 11.2 57.3 ± 10.97 -
    Gender categorical
    Units: Subjects
        Female
    		 291 146 437
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    SYD985
    Reporting group description
    		 SYD985 1.2 mg/kg was administered every three weeks by intravenous infusion until disease progression (as assessed by the investigator), unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Physician's choice
    Reporting group description
    		 Physician’s choice therapy options included: Lapatinib + Capecitabine, Trastuzumab + Capecitabine, Trastuzumab + Vinorelbine, or Trastuzumab + Eribulin. The physician’s choice therapy was administered as per the SmPC/PI. Patients were treated until disease progression (as assessed by the investigator), unacceptable toxicity, or withdrawal of consent.

    Primary: Progression-Free Survival

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    End point title
    		 Progression-Free Survival
    End point description
    The primary endpoint was PFS and was defined as the time (in months) from the date of randomization to the date of first documented disease progression as assessed by ICR according to RECIST v1.1 or death due to any cause (whichever occurred earlier). Full-analysis set (FAS) was used for this primary endpoint analysis. FAS comprises all randomized patients, which were analyzed according to the treatment group and strata they have been assigned to during the randomization procedure.
    End point type
    Primary
    End point timeframe
    baseline until primary analysis data cut-off date of 31March2021
    End point values
    		 SYD985 Physician's choice
    Number of subjects analysed
    291
    146
    Units: months
        median (confidence interval 95%)
    7.0 (5.4 to 7.2)
    4.9 (4.0 to 5.5)
    Statistical analysis title
    		 Stratified Cox regression analysis
    Statistical analysis description
    A stratified Cox regression analysis was used to estimate the hazard ratio of PFS, along with 95% CIs. Stratification factors assigned at randomization were world region (Europe, Singapore, and North America), number of prior treatment lines for locally advanced or metastatic breast cancer (excluding hormone therapy) (1 to 2, >2), and prior treatment with pertuzumab (yes, no).
    Comparison groups
    SYD985 v Physician's choice
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [1]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.6401
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4885
         upper limit
    		 0.8389
    Notes
    [1] - P-value from stratified log-rank test for median estimate of PFS: stratified according to the randomization stratification factors.

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall Survival was defined as the time from the date of randomization to the date of death due to any cause. Full-analysis set (FAS) was used for the overall survival analysis. FAS comprises all randomized patients, which were analyzed according to the treatment group and strata they have been assigned to during the randomization procedure.
    End point type
    Secondary
    End point timeframe
    baseline until final Overall Survival analysis data cut-off date of 30June2022
    End point values
    		 SYD985 Physician's choice
    Number of subjects analysed
    291
    146
    Units: months
        median (confidence interval 95%)
    21.0 (18.1 to 25.0)
    19.5 (14.2 to 23.1)
    Statistical analysis title
    		 Stratified Cox regression analysis
    Statistical analysis description
    A stratified Cox regression analysis was used to estimate the hazard ratio of OS, along with 95% CIs. Stratification factors assigned at randomization were world region (Europe, Singapore, and North America), number of prior treatment lines for locally advanced or metastatic breast cancer (excluding hormone therapy) (1 to 2, >2), and prior treatment with pertuzumab (yes, no).
    Comparison groups
    SYD985 v Physician's choice
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.236 [2]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.868
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.676
         upper limit
    		 1.1145
    Notes
    [2] - P-value from stratified log-rank test for Kaplan-Meier estimate of median OS: stratified according to the randomization stratification factors.

    Secondary: Objective Response Rate on the basis of the blinded independent central review

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    End point title
    		 Objective Response Rate on the basis of the blinded independent central review
    End point description
    Objective response rate was defined as the percentage of patients with ICR-assessed best overall response of complete response (CR) or partial response (PR) according to RECIST 1.1 (i.e. ‘Responders’). Only patients with measurable disease at baseline were included in the analysis of ORR. Patients without a post-baseline tumour assessment were considered non-responders. Full-analysis set (FAS) was used for this primary endpoint analysis. FAS comprises all randomized patients, which were analyzed according to the treatment group and strata they have been assigned to during the randomization procedure.
    End point type
    Secondary
    End point timeframe
    baseline until primary analysis data cut-off date of 31March2021
    End point values
    		 SYD985 Physician's choice
    Number of subjects analysed
    252
    122
    Units: percentage of patients
        number (confidence interval 95%)
    27.8 (22.3 to 33.7)
    29.5 (21.6 to 38.4)
    Statistical analysis title
    		 The Cochran-Mantel-Haenszel test
    Statistical analysis description
    The Cochran-Mantel-Haenszel test (strata based on the baseline stratification factors) was used to compare the two treatment groups with respect to the ORR at two-sided 5% level of significance.
    Comparison groups
    SYD985 v Physician's choice
    Number of subjects included in analysis
    374
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.732 [3]
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Notes
    [3] - P-value from Cochran-Mantel-Haenszel test including the randomization stratification factors.

    Secondary: Investigator Assessed Progression-Free Survival

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    End point title
    		 Investigator Assessed Progression-Free Survival
    End point description
    Investigator assessed PFS, based on local review data captured in the eCRF, was defined as the time (in months) from the date of randomization to the date of first documented investigator-assessed disease progression according to RECIST 1.1 or death due to any cause (whichever occurs earlier). Full-analysis set (FAS) was used for this primary endpoint analysis. FAS comprises all randomized patients, which were analyzed according to the treatment group and strata they have been assigned to during the randomization procedure.
    End point type
    Secondary
    End point timeframe
    baseline until primary analysis data cut-off date of 31March2021
    End point values
    		 SYD985 Physician's choice
    Number of subjects analysed
    291
    146
    Units: months
        median (confidence interval 95%)
    6.9 (6.0 to 7.2)
    4.6 (4.0 to 5.6)
    Statistical analysis title
    		 Stratified Cox regression analysis
    Statistical analysis description
    A stratified Cox regression analysis was used to estimate the HR of PFS, along with the 95% CI. The treatment groups were compared using the 2-sided stratified log-rank test.
    Comparison groups
    SYD985 v Physician's choice
    Number of subjects included in analysis
    437
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.5995
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4666
         upper limit
    		 0.7703
    Notes
    [4] - P-value from stratified log-rank test for median estimate of PFS: stratified according to the randomization stratification factors.

    Secondary: Patient reported outcomes for health related quality of life

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    End point title
    		 Patient reported outcomes for health related quality of life
    End point description
    In a MMRM analysis, the influence of various factors on the change in QoL scale score of the EORTC QLQ-C30 from baseline was assessed in the FAS. Factors evaluated in the model were treatment and cycle (both fixed effects), randomization strata (ie, world region, prior treatment lines for LABC or MBC, and prior treatment with pertuzumab), QoL scale score at baseline (covariate), and treatment-by-cycle (interaction). The factors treatment, randomization strata, and treatment-by-cycle did not have a significant effect on QoL scores. With a p-value of <0.001 for QoL scale score at baseline, it can be concluded that including baseline in the model is sensible. With a p-value of 0.002 for cycle, it can be concluded that there are differences in scores between the cycles. As the interaction between treatment and cycle was not significant (p=0.473), it can be concluded that the differences within the cycles are similar for both treatment groups.
    End point type
    Secondary
    End point timeframe
    baseline until primary analysis data cut-off date of 31March2021
    End point values
    		 SYD985 Physician's choice
    Number of subjects analysed
    291
    146
    Units: change in QoL scale score from baseline
    least squares mean (confidence interval 95%)
        C2
    0.17 (-2.70 to 3.04)
    -3.88 (-7.79 to 0.03)
        C3
    -1.88 (-4.83 to 1.07)
    -2.99 (-7.00 to 1.02)
        C4
    -2.48 (-5.46 to 0.50)
    -9.01 (-13.23 to -4.80)
        C5
    -2.51 (-5.69 to 0.67)
    -5.77 (-10.34 to -1.21)
        C7
    -5.65 (-9.19 to -2.10)
    -6.75 (-11.92 to -1.58)
        C9
    -8.14 (-12.27 to -4.02)
    -11.25 (-17.41 to -5.09)
        C11
    -10.70 (-15.66 to -5.75)
    -10.38 (-18.08 to -2.69)
        C13
    -13.40 (-20.31 to -6.48)
    -12.89 (-21.33 to -4.45)
        C15
    -11.90 (-20.41 to -3.39)
    -14.12 (-23.91 to -4.33)
        C17
    -4.31 (-14.48 to 5.86)
    -0.71 (-13.26 to 11.83)
        C19
    -5.45 (-21.05 to 10.16)
    1.66 (-13.84 to 17.16)
        C21
    11.68 (-9.76 to 33.12)
    -11.23 (-26.16 to 3.71)
        C23
    5.30 (-26.04 to 36.65)
    -7.00 (-29.18 to 15.17)
        C25
    18.76 (-14.63 to 52.16)
    -11.48 (-42.96 to 19.99)
        C27
    0.49 (-33.40 to 34.37)
    -5.41 (-38.83 to 28.02)
        C29
    999 (999 to 999)
    -6.54 (-40.45 to 27.37)
        C33
    999 (999 to 999)
    -7.11 (-41.14 to 26.92)
        C35
    999 (999 to 999)
    -15.73 (-49.79 to 18.33)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were collected from signing of the ICF up to the treatment discontinuation visit. The safety data reported here is based on data collected up to the data cut off date of 31 March 2021.
    Adverse event reporting additional description
    The Safety Analysis Set (SAS) includes all patients who received at least one (partial) dose of study medication. Patients will be analyzed according to the study treatment they actually received. Treatment actually received is defined as the study treatment (SYD985 or Physician’s choice) the patient receives on Cycle 1 Day 1.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    SYD985
    Reporting group description
    		 SYD985 1.2 mg/kg was administered every three weeks by intravenous infusion until disease progression (as assessed by the investigator), unacceptable toxicity, or withdrawal of consent.

    Reporting group title
    Physician's choice
    Reporting group description
    		 Physician’s choice therapy options included: Lapatinib + Capecitabine, Trastuzumab + Capecitabine, Trastuzumab + Vinorelbine, or Trastuzumab + Eribulin. The physician’s choice therapy was administered as per the SmPC/PI. Patients were treated until disease progression (as assessed by the investigator), unacceptable toxicity, or withdrawal of consent.

    Serious adverse events
    		 SYD985 Physician's choice
    Total subjects affected by serious adverse events
         subjects affected / exposed
    53 / 288 (18.40%)
    12 / 137 (8.76%)
         number of deaths (all causes)
    181
    94
         number of deaths resulting from adverse events
    6
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Chronic myeloid leukaemia
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic tumour necrosis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected neoplasm
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Orthostatic hypotension
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug intolerance
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonitis
         subjects affected / exposed
    7 / 288 (2.43%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    8 / 8
    0 / 0
         deaths causally related to treatment / all
    2 / 2
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumomediastinum
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 288 (0.00%)
    3 / 137 (2.19%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Platelet count decreased
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ejection fraction decreased
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcus test positive
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac tamponade
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Keratitis
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Conjunctivitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eyelid ptosis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 288 (0.35%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Livedo reticularis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract obstruction
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 288 (1.04%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    3 / 5
    0 / 1
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 288 (0.00%)
    1 / 137 (0.73%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    2 / 288 (0.69%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 288 (0.35%)
    0 / 137 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 SYD985 Physician's choice
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    278 / 288 (96.53%)
    132 / 137 (96.35%)
    Investigations
    Weight decreased
         subjects affected / exposed
    29 / 288 (10.07%)
    2 / 137 (1.46%)
         occurrences all number
    45
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    16 / 288 (5.56%)
    10 / 137 (7.30%)
         occurrences all number
    26
    14
    Platelet count decreased
         subjects affected / exposed
    16 / 288 (5.56%)
    0 / 137 (0.00%)
         occurrences all number
    28
    0
    Neutrophil count decreased
         subjects affected / exposed
    14 / 288 (4.86%)
    14 / 137 (10.22%)
         occurrences all number
    25
    26
    Alanine aminotransferase increased
         subjects affected / exposed
    12 / 288 (4.17%)
    10 / 137 (7.30%)
         occurrences all number
    19
    17
    Nervous system disorders
    Headache
         subjects affected / exposed
    33 / 288 (11.46%)
    16 / 137 (11.68%)
         occurrences all number
    37
    23
    Dysgeusia
         subjects affected / exposed
    22 / 288 (7.64%)
    4 / 137 (2.92%)
         occurrences all number
    26
    5
    Dizziness
         subjects affected / exposed
    21 / 288 (7.29%)
    7 / 137 (5.11%)
         occurrences all number
    22
    7
    Neuropathy peripheral
         subjects affected / exposed
    16 / 288 (5.56%)
    8 / 137 (5.84%)
         occurrences all number
    29
    16
    Peripheral sensory neuropathy
         subjects affected / exposed
    5 / 288 (1.74%)
    7 / 137 (5.11%)
         occurrences all number
    7
    11
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    96 / 288 (33.33%)
    41 / 137 (29.93%)
         occurrences all number
    162
    66
    Asthenia
         subjects affected / exposed
    58 / 288 (20.14%)
    23 / 137 (16.79%)
         occurrences all number
    91
    34
    Pyrexia
         subjects affected / exposed
    23 / 288 (7.99%)
    13 / 137 (9.49%)
         occurrences all number
    26
    15
    Oedema peripheral
         subjects affected / exposed
    22 / 288 (7.64%)
    3 / 137 (2.19%)
         occurrences all number
    30
    4
    Mucosal inflammation
         subjects affected / exposed
    17 / 288 (5.90%)
    8 / 137 (5.84%)
         occurrences all number
    20
    10
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    41 / 288 (14.24%)
    17 / 137 (12.41%)
         occurrences all number
    85
    35
    Neutropenia
         subjects affected / exposed
    31 / 288 (10.76%)
    33 / 137 (24.09%)
         occurrences all number
    75
    76
    Thrombocytopenia
         subjects affected / exposed
    17 / 288 (5.90%)
    7 / 137 (5.11%)
         occurrences all number
    23
    13
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    110 / 288 (38.19%)
    3 / 137 (2.19%)
         occurrences all number
    218
    3
    Keratitis
         subjects affected / exposed
    110 / 288 (38.19%)
    11 / 137 (8.03%)
         occurrences all number
    202
    11
    Dry eye
         subjects affected / exposed
    87 / 288 (30.21%)
    14 / 137 (10.22%)
         occurrences all number
    117
    15
    Lacrimation increased
         subjects affected / exposed
    53 / 288 (18.40%)
    2 / 137 (1.46%)
         occurrences all number
    74
    2
    Blepharitis
         subjects affected / exposed
    36 / 288 (12.50%)
    2 / 137 (1.46%)
         occurrences all number
    53
    2
    Punctate keratitis
         subjects affected / exposed
    32 / 288 (11.11%)
    3 / 137 (2.19%)
         occurrences all number
    45
    4
    Vision blurred
         subjects affected / exposed
    23 / 288 (7.99%)
    1 / 137 (0.73%)
         occurrences all number
    30
    1
    Periorbital oedema
         subjects affected / exposed
    17 / 288 (5.90%)
    0 / 137 (0.00%)
         occurrences all number
    29
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    73 / 288 (25.35%)
    43 / 137 (31.39%)
         occurrences all number
    103
    64
    Diarrhoea
         subjects affected / exposed
    60 / 288 (20.83%)
    49 / 137 (35.77%)
         occurrences all number
    82
    92
    Constipation
         subjects affected / exposed
    57 / 288 (19.79%)
    24 / 137 (17.52%)
         occurrences all number
    74
    28
    Vomiting
         subjects affected / exposed
    36 / 288 (12.50%)
    23 / 137 (16.79%)
         occurrences all number
    52
    37
    Dry mouth
         subjects affected / exposed
    26 / 288 (9.03%)
    6 / 137 (4.38%)
         occurrences all number
    28
    6
    Stomatitis
         subjects affected / exposed
    24 / 288 (8.33%)
    17 / 137 (12.41%)
         occurrences all number
    34
    17
    Abdominal pain
         subjects affected / exposed
    19 / 288 (6.60%)
    11 / 137 (8.03%)
         occurrences all number
    30
    17
    Abdominal pain upper
         subjects affected / exposed
    18 / 288 (6.25%)
    9 / 137 (6.57%)
         occurrences all number
    20
    12
    Dyspepsia
         subjects affected / exposed
    13 / 288 (4.51%)
    9 / 137 (6.57%)
         occurrences all number
    15
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    48 / 288 (16.67%)
    14 / 137 (10.22%)
         occurrences all number
    60
    17
    Dyspnoea
         subjects affected / exposed
    42 / 288 (14.58%)
    17 / 137 (12.41%)
         occurrences all number
    52
    27
    Pneumonitis
         subjects affected / exposed
    19 / 288 (6.60%)
    0 / 137 (0.00%)
         occurrences all number
    23
    0
    Epistaxis
         subjects affected / exposed
    14 / 288 (4.86%)
    8 / 137 (5.84%)
         occurrences all number
    17
    9
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    62 / 288 (21.53%)
    16 / 137 (11.68%)
         occurrences all number
    74
    21
    Skin hyperpigmentation
         subjects affected / exposed
    32 / 288 (11.11%)
    1 / 137 (0.73%)
         occurrences all number
    36
    1
    Dry skin
         subjects affected / exposed
    27 / 288 (9.38%)
    8 / 137 (5.84%)
         occurrences all number
    27
    8
    Rash
         subjects affected / exposed
    17 / 288 (5.90%)
    5 / 137 (3.65%)
         occurrences all number
    18
    6
    Pruritus
         subjects affected / exposed
    15 / 288 (5.21%)
    2 / 137 (1.46%)
         occurrences all number
    16
    2
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    2 / 288 (0.69%)
    32 / 137 (23.36%)
         occurrences all number
    2
    70
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    23 / 288 (7.99%)
    6 / 137 (4.38%)
         occurrences all number
    24
    6
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    31 / 288 (10.76%)
    11 / 137 (8.03%)
         occurrences all number
    36
    14
    Back pain
         subjects affected / exposed
    22 / 288 (7.64%)
    11 / 137 (8.03%)
         occurrences all number
    23
    14
    Pain in extremity
         subjects affected / exposed
    18 / 288 (6.25%)
    12 / 137 (8.76%)
         occurrences all number
    20
    19
    Myalgia
         subjects affected / exposed
    11 / 288 (3.82%)
    7 / 137 (5.11%)
         occurrences all number
    14
    7
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    25 / 288 (8.68%)
    14 / 137 (10.22%)
         occurrences all number
    28
    14
    Upper respiratory tract infection
         subjects affected / exposed
    9 / 288 (3.13%)
    8 / 137 (5.84%)
         occurrences all number
    12
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    61 / 288 (21.18%)
    15 / 137 (10.95%)
         occurrences all number
    75
    20
    Hypokalaemia
         subjects affected / exposed
    11 / 288 (3.82%)
    9 / 137 (6.57%)
         occurrences all number
    13
    12
    Hypomagnesaemia
         subjects affected / exposed
    7 / 288 (2.43%)
    7 / 137 (5.11%)
         occurrences all number
    7
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Aug 2017
    This substantial amendment was prepared upon request of the regulatory authorities. The changes are summarized below: - Inclusion criterion 3 on previous HER2-targeting treatment has been specified in more detail. - Inclusion criterion 4 on HER2 status has been specified in more detail. - An exclusion criterion on prior pulmonary disease has been added as criterion 9. - Previous exclusion criterion 9 on HIV and hepatitis has been amended to allow the inclusion of HIV infected patients. - Two additional time points (Cycle 2 Day 1 and Cycle 4 Day 1) for assessments of the QoL questionnaires have been added to the flowchart. - The dose modification guidances for eye toxicity and pneumonitis have been adjusted. - The ECG assessments requirements for the physician’s choice group receiving Lapatinib + Capecitabine have been explained in more detail. - In addition to Europe and North-America also sites in Singapore are planned to participate, this has been added. - Details regarding the required infusion materials have been replaced by more general wording with reference to the pharmacy manual in which full details are described.
    09 Nov 2017
    This substantial amendment was prepared upon request of the regulatory authorities. The changes are summarized below: - The flowchart has been updated to add pregnancy tests on Day 1 of every cycle and at the treatment discontinuation visit. - The flowchart has been updated to add an ECG assessment at Cycle 3 Day 1. - A total of 5 protocol sections have been updated to re-iterate and emphasize the importance to follow the SmPC guidance for patient selection and management in the physician’s choice group. - A section on the benefit/risk ratio has been added. - In relation to cardiotoxicity it has been added that clinically relevant electrolyte disturbances should be corrected. - The possibility to enable further SYD985 treatment when the study has ended is added. - The indicated contraception has been updated to be aligned with the CTFG recommendations.
    11 Sep 2018
    This substantial amendment was prepared for the following reasons: - Section 9.5.1 has been updated to add the possibility to reduce dosing to 0.6 mg/kg which has been shown to be an effective and safe dose in the phase I study. - Section 11.9 and the flowchart have been updated to add the possibility for serum pregnancy test in addition to urine pregnancy test as routinely performed in several clinical sites. - Section 12.10, 14.7 and the synopsis have been updated to describe that the DMC will assess the assumptions underlying the sample size estimation. - Section 2 has been updated to reflect changes in the vendor responsibilities.
    12 Apr 2019
    This substantial amendment was prepared for the following reasons: - Upon request of the DMC Keratitis grade ≥2 has been added as an adverse event of special interest - In consultation with the Steering committee and the DMC Section 8.2 has been updated to add the possibility to allow re-screening for patients for whom during screening on the brain CT/MRI a previously unknown asymptomatic metastasis is observed. - Section 11.9 and the flowchart have been updated to add the possibility to perform the pregnancy test up to 3 days before Day 1 of a new cycle for practical reasons. - Section 11.21 and the flowchart have been updated to add that the treatment discontinuation visit should be performed before new anti-cancer treatment is initiated.
    24 May 2019
    This substantial amendment was prepared upon request of the regulatory authorities. The changes are summarized below: - Section 5.5.1 has been updated to include additional information on ILD/Pneumonitis. - Section 9.5.1.4 dose modifications for ILD/pneumonitis have been elaborated. - Section 11.5 oxygen saturation by pulse oximetry has been added to the vital signs assessments at all visits.
    22 Oct 2019
    This substantial amendment has been prepared for the following reason: - As part of their evaluation the independent DMC assessed the validity of the initial assumptions underlying the sample size estimation with regards to drop-out rates. Based on their pre-planned interim evaluation the independent DMC has recommended to adjust the sample size and enroll a total of 423 patients to ensure sufficient power for the primary endpoint analysis.
    18 Jan 2021
    This substantial amendment has been prepared for the following reason: - To include the possibility to analyse the primary endpoint of the trial when at least 95% of the patients have discontinued treatment. - Section 2 has been updated to reflect changes in the vendor responsibilities.

    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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