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    Clinical Trial Results:
    A phase Ib/II trial evaluating the efficacy of MK-3475 and trastuzumab in patients with trastuzumab-resistant, HER2-positive metastatic breast cancers.

    Summary
    EudraCT number
    		 2013-004770-10
    Trial protocol
    		 BE   IT   AT  
    Global end of trial date
    04 Aug 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Feb 2020
    First version publication date
    07 Feb 2020
    Other versions
    Summary report(s)
    		 Publication_Loi et al._Lancet Oncol 2019 Mar;20(3):316-318. doi: 10.1016/S1470-2045(19)30068-3. Epub 2019 Feb 11.

    Trial information

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    Trial identification
    Sponsor protocol code
    IBCSG_45-13/BIG_4-13
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02129556
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IBCSG
    Sponsor organisation address
    Effingerstrasse 40, Bern, Switzerland, 3008
    Public contact
    IBCSG Coordinating Center, International Breast Cancer Study Group (IBCSG), +41 313899391, regulatoryoffice@ibcsg.org
    Scientific contact
    IBCSG Coordinating Center, International Breast Cancer Study Group (IBCSG), +41 313899391, regulatoryoffice@ibcsg.org
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    07 Aug 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Aug 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this phase Ib/II study are to determine the recommended dose of the anti-PD-1 mAb, MK-3475, in combination with standard dose trastuzumab, and to evaluate the efficacy and safety profile of the drug combination in patients with PD-L1 expressing, HER2-positive, unresectable loco-regional or metastatic breast cancer who have experienced progression during prior trastuzumab based therapy.
    Protection of trial subjects
    The PANACEA Trial (IBCSG 45-13 / BIG 4-13) was conducted in accordance with the principles of the Declaration of Helsinki, national laws and regulations, and in compliance with the principles outlined in the ICH Tripartite Guideline/Guideline for Good Clinical Practice (January 1997). The trial protocol was reviewed by the IBCSG Ethics Committee and the Ethics Committees and Competent Authorities of the participating centers and countries. The PANACEA Data Safety Monitoring Committee (DSMC) provided semi-annual review of study procedures and safety data, in addition to special review of the interim safety data from the Phase II trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    France: 20
    Country: Number of subjects enrolled
    Italy: 7
    Worldwide total number of subjects
    58
    EEA total number of subjects
    37
    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)
    51
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 All patients will have central review of the biopsy to assess HER2-positivity and PD-L1 status. For the primary objectives, only patients with central confirmation of HER2-positivity and presence of PD-L1 expression on metastatic biopsy (or biopsy from unresectable locoregional disease) after registration for screening will be eligible to enroll.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Phase Ib
    Arm description
    		 The phase Ib portion was designed to determine the recommended phase II dose (RP2D) of MK-3475 (pembrolizumab) based on three possible dose levels: 2 mg/kg, 10mg/kg, or a fall-back dose of 1 mg/kg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-3475
    Investigational medicinal product code
    Other name
    Pembrolizumab
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MK-3475 at dose of 2 mg/kg or 10 mg/kg (i.v.), or a fall-back dose of 1 mg/kg, together with trastuzumab 6mg/kg by (i.v.) once every 3 weeks.

    Arm title
    		 Phase II PD-L1+
    Arm description
    		 HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. The Phase II portion of the trial used a flat dose of 200 mg of MK-3475 based on emerging data from the sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-3475
    Investigational medicinal product code
    Other name
    Pembrolizumab
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MK-3475 at a flat dose of 200mg (i.v.) together with trastuzumab 6mg/kg (i.v.) once every 3 weeks until progression, lack of tolerability, or 24 months of treatment. A dose of 8mg/kg trastuzumab will be used in cycle 1 if prior treatment with trastuzumab was stopped more than 3 months before.

    Arm title
    		 Phase II PD-L1-
    Arm description
    		 HER2-positive, PD-L1 negative, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. The Phase II portion of the trial used a flat dose of 200 mg of MK-3475 based on emerging data from the sponsor.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MK-3475
    Investigational medicinal product code
    Other name
    Pembrolizumab
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    MK-3475 at a flat dose of 200mg (i.v.) together with trastuzumab 6mg/kg (i.v.) once every 3 weeks until progression, lack of tolerability, or 24 months of treatment. A dose of 8mg/kg trastuzumab will be used in cycle 1 if prior treatment with trastuzumab was stopped more than 3 months before.

    Number of subjects in period 1
    		Phase Ib Phase II PD-L1+ Phase II PD-L1-
    Started
    6
    40
    12
    Completed
    6
    37
    12
    Not completed
    0
    3
    0
         Protocol deviation
    -
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase Ib
    Reporting group description
    		 The phase Ib portion was designed to determine the recommended phase II dose (RP2D) of MK-3475 (pembrolizumab) based on three possible dose levels: 2 mg/kg, 10mg/kg, or a fall-back dose of 1 mg/kg.

    Reporting group title
    Phase II PD-L1+
    Reporting group description
    		 HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. The Phase II portion of the trial used a flat dose of 200 mg of MK-3475 based on emerging data from the sponsor.

    Reporting group title
    Phase II PD-L1-
    Reporting group description
    		 HER2-positive, PD-L1 negative, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. The Phase II portion of the trial used a flat dose of 200 mg of MK-3475 based on emerging data from the sponsor.

    Reporting group values
    		 Phase Ib Phase II PD-L1+ Phase II PD-L1- Total
    Number of subjects
    		 6 40 12 58
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 48 ± 9.5 51.2 ± 10.4 54.5 ± 5.2 -
    Gender categorical
    Units: Subjects
        Female
    		 6 40 12 58
        Male
    		 0 0 0 0
    Race/Ethnicity
    Units: Subjects
        Caucasian
    		 4 30 8 42
        Asian
    		 0 2 1 3
        Other
    		 0 1 0 1
        Missing
    		 2 7 3 12

    End points

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    End points reporting groups
    Reporting group title
    Phase Ib
    Reporting group description
    		 The phase Ib portion was designed to determine the recommended phase II dose (RP2D) of MK-3475 (pembrolizumab) based on three possible dose levels: 2 mg/kg, 10mg/kg, or a fall-back dose of 1 mg/kg.

    Reporting group title
    Phase II PD-L1+
    Reporting group description
    		 HER2-positive, PD-L1 expressing, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. The Phase II portion of the trial used a flat dose of 200 mg of MK-3475 based on emerging data from the sponsor.

    Reporting group title
    Phase II PD-L1-
    Reporting group description
    		 HER2-positive, PD-L1 negative, unresectable loco-regional or metastatic breast carcinoma that progressed on prior trastuzumab-based therapy. The Phase II portion of the trial used a flat dose of 200 mg of MK-3475 based on emerging data from the sponsor.

    Primary: Dose-Limiting Toxicity (DLT) of MK-3475 in Combination With Trastuzumab

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    End point title
    		 Dose-Limiting Toxicity (DLT) of MK-3475 in Combination With Trastuzumab [1] [2]
    End point description
    Determination of dose-limiting toxicity (DLT) which is defined as an adverse event or abnormal laboratory value assessed as suspected to be trial treatment related (possible, probable or definite) and unrelated to disease or disease progression. Toxicities and lab values will be graded according to the NCI CTCAE (v4.0). Any grade-3 or greater non-hematological adverse event lasting at least one week; Any grade-4 hematological toxicity; or, Any adverse event resulting in a delay starting cycle 2 of more than 14 days.
    End point type
    Primary
    End point timeframe
    Within the first 21 days.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Dose escalation occured using a standard ‘3+3’ dose escalation approach. The RP2D is defined as the highest dose level at which <33% (0 of three patients, or 0 or 1 of six patients) has experienced a DLT in cycle 1. Once dose escalation for MK-3475 reaches a dose of 10 mg/kg, no further escalation will occur.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This end point is only applied to the Phase Ib (dose finding).
    End point values
    		 Phase Ib
    Number of subjects analysed
    6
    Units: Participants
    0
    No statistical analyses for this end point

    Primary: Objective Response Rate (ORR)

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    End point title
    		 Objective Response Rate (ORR)
    End point description
    Confirmed CR or PR as best overall response. At the time of each restaging, patients will be classified as achieving complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or non-evaluable for response according to RECIST (Version 1.1) criteria.
    End point type
    Primary
    End point timeframe
    Clinical and radiological tumor assessment will be performed by CT scan or MRI at baseline, at weeks 12, 18 and 24, then every 12 weeks until progression, or 24 weeks after stop of treatment if before progression.
    End point values
    		 Phase Ib Phase II PD-L1+ Phase II PD-L1-
    Number of subjects analysed
    6
    40
    12
    Units: Proportion of participants
        number (confidence interval 90%)
    0.17 (0.01 to 0.58)
    0.15 (0.07 to 0.29)
    0.00 (0.00 to 0.18)
    Statistical analysis title
    		 Statistical analysis primary endpoint
    Statistical analysis description
    A Simon optimal two-stage design was used in the phase II portion to assess the primary outcome of objective response. The null hypothesis of a true objective response rate of 7% was tested against a one-sided alternative response rate of 22%.
    Comparison groups
    Phase II PD-L1+ v Phase II PD-L1- v Phase Ib
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    Method
    Parameter type
    		 response rate
    Point estimate
    0.15
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 0.29
    Notes
    [3] - This single-arm study conducted an estimation-only, non-comparative analysis

    Secondary: Duration of Response (DoR)

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    End point title
    		 Duration of Response (DoR)
    End point description
    Duration of response (DoR) is defined among patients with objective response (confirmed CR or PR as best overall response) as the interval between dates of first documentation of objective response and first documentation of progressive disease. In the absence of documented progressive disease, follow-up will be censored at date of last disease assessment.
    End point type
    Secondary
    End point timeframe
    From date of first documentation of objective response until first documentation of progressive disease, up to 24 weeks after stop of treatment (=30 months).
    End point values
    		 Phase Ib Phase II PD-L1+ Phase II PD-L1-
    Number of subjects analysed
    1
    6
    0 [4]
    Units: Months
        median (confidence interval 90%)
    23.1 (23.1 to 23.1)
    3.5 (2.7 to 999999)
    ( to )
    Notes
    [4] - Objective Response Rate in this arm was 0. Therefore, Duration of Response not measurable
    No statistical analyses for this end point

    Secondary: Time to Progression (TTP)

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    End point title
    		 Time to Progression (TTP)
    End point description
    Time to progression (TTP) defined as the interval between the dates of the start of trial treatment and first documentation of progressive disease. In the absence of documented progressive disease, follow-up will be censored at date of last disease assessment.
    End point type
    Secondary
    End point timeframe
    From the first trial treatment until first documentation of progressive disease up to 24 weeks after stop of treatment (=30 months).
    End point values
    		 Phase Ib Phase II PD-L1+ Phase II PD-L1-
    Number of subjects analysed
    6
    40
    12
    Units: Months
        median (confidence interval 90%)
    2.5 (1.1 to 2.7)
    2.7 (2.6 to 4.9)
    2.5 (1.4 to 999999)
    No statistical analyses for this end point

    Secondary: Disease Control Rate (DCR)

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    End point title
    		 Disease Control Rate (DCR)
    End point description
    The proportion of patients with best confirmed RECIST response of CR, PR, or duration of SD of at least 24 weeks (measured from first dose of trial treatment).
    End point type
    Secondary
    End point timeframe
    From the start of trial treatment until confirmed CR, PR, or SD lasting for 24 weeks or longer.
    End point values
    		 Phase Ib Phase II PD-L1+ Phase II PD-L1-
    Number of subjects analysed
    6
    40
    12
    Units: Proportion of participants
        number (confidence interval 90%)
    0.17 (0.01 to 0.58)
    0.25 (0.14 to 0.39)
    0.00 (0.00 to 0.18)
    No statistical analyses for this end point

    Secondary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    The interval between the dates of the first dose of trial treatment until first documentation of disease progression or death, whichever occurs first. Patients with new non-breast cancer malignancy must continue to be followed for progression of the original breast cancer. For patients without progression, follow-up is censored at the date of last disease assessment without progression, unless death occurs within 12 weeks following the date last known progression-free, in which case the death will be counted as a PFS event.
    End point type
    Secondary
    End point timeframe
    From the date of first treatment dose until documented disease progression or death from any cause, whichever occur first, assessed up to 30 months.
    End point values
    		 Phase Ib Phase II PD-L1+ Phase II PD-L1-
    Number of subjects analysed
    6
    40
    12
    Units: Months
        median (confidence interval 90%)
    2.5 (1.1 to 2.7)
    2.7 (2.6 to 4.0)
    2.5 (1.4 to 2.7)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS) at 12 Months

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    End point title
    		 Overall Survival (OS) at 12 Months
    End point description
    OS is defined as the time from the first dose of trial treatment to death from any cause. For patients who are lost to follow-up or who have no documentation of death at the time of final analysis, follow-up is censored at the date of last assessment of vital status. OS at 12 months by Kaplan-Meier estimates.
    End point type
    Secondary
    End point timeframe
    Time from start of trial treatment to death from any cause, assessed up to 30 months.
    End point values
    		 Phase Ib Phase II PD-L1+ Phase II PD-L1-
    Number of subjects analysed
    6
    40
    12
    Units: Proportion of participants
        number (confidence interval 90%)
    0.67 (0.27 to 0.88)
    0.65 (0.50 to 0.76)
    0.12 (0.01 to 0.36)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were to be reported at the end of every treatment cycle, at the End-of-Treatment visit, and up to 30 days after cessation of trial treatment. Serious adverse event and pregnancy data were to be collected for 90 days following the end of treatment.
    Adverse event reporting additional description
    Any grade of any observed AE was to be reported on the AE form. There were no specifications of targeted AEs. Symptoms of the targeted cancer were not to be reported as AEs.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTCAE
    Dictionary version
    V4.
    Reporting groups
    Reporting group title
    Phase II
    Reporting group description
    		 (PD-L1+ and PD-L1-)

    Reporting group title
    Phase Ib
    Reporting group description
    		 -

    Serious adverse events
    		 Phase II Phase Ib
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 52 (48.08%)
    4 / 6 (66.67%)
         number of deaths (all causes)
    25
    4
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Glioblastoma multiforme
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Intracranial hypertension
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    9 / 52 (17.31%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    1 / 9
    0 / 2
         deaths causally related to treatment / all
    1 / 9
    0 / 2
    Immune system disorders
    Lambert-Eaton syndrome
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Autoimmune hepatitis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Disease progression
         subjects affected / exposed
    6 / 52 (11.54%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 2
         deaths causally related to treatment / all
    0 / 6
    0 / 2
    Breast infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (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
    Upper respiratory infection
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnea
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Cognitive disturbance
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    GGT increased
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Takotsubo cardiomyopathy
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    CNS metastases
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paresthesia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neurological paresis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphasia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (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
    Anemia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Retinal vein occlusion
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastroenteritis
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhea
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct dilatation
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic haemorrhage
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug-induced liver injury
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (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
    Acute renal impairment
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Shoulder pain
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Catheter-related infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (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 / 52 (1.92%)
    0 / 6 (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: 0%
    Non-serious adverse events
    		 Phase II Phase Ib
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    50 / 52 (96.15%)
    6 / 6 (100.00%)
    Vascular disorders
    Hot flashes
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    6 / 52 (11.54%)
    0 / 6 (0.00%)
         occurrences all number
    12
    0
    Hypotension
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Intracranial hypertension
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Lymphedema
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Lymphedema right leg
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Thromboembolic event
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Anemia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Asthenia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Diaphoresis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Edema limbs
         subjects affected / exposed
    4 / 52 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Edema trunk
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    16 / 52 (30.77%)
    3 / 6 (50.00%)
         occurrences all number
    23
    4
    Fever
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 6 (16.67%)
         occurrences all number
    5
    1
    Flu-like symptoms
         subjects affected / exposed
    5 / 52 (9.62%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    Hoarseness
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Infusion related reaction
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Left breast tumour bleeding
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Localized edema
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Pain
         subjects affected / exposed
    6 / 52 (11.54%)
    0 / 6 (0.00%)
         occurrences all number
    10
    0
    Immune system disorders
    Autoimmune disorder
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Bronchopulmonary hemorrhage
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    9 / 52 (17.31%)
    1 / 6 (16.67%)
         occurrences all number
    12
    1
    Dyspnea
         subjects affected / exposed
    11 / 52 (21.15%)
    3 / 6 (50.00%)
         occurrences all number
    18
    4
    Epistaxis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Epistaxis: seasonal
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Laryngeal inflammation
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Pleural effusion
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Pneumonia
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Pneumonitis
         subjects affected / exposed
    4 / 52 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Pneumothorax
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Productive cough
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Respiratory distress
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Shortness of breath
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Sinus disorder
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Sore throat
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 6 (16.67%)
         occurrences all number
    4
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Insomnia
         subjects affected / exposed
    1 / 52 (1.92%)
    2 / 6 (33.33%)
         occurrences all number
    1
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 52 (7.69%)
    1 / 6 (16.67%)
         occurrences all number
    4
    1
    Alkaline phosphatase increased
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Drug induced liver injury
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Ggt increased
         subjects affected / exposed
    5 / 52 (9.62%)
    0 / 6 (0.00%)
         occurrences all number
    11
    0
    Hypercalcaemia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Leucocyte count decreased
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Lipase increased
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Neutrophil count decreased
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Serum amylase increased
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Weight loss
         subjects affected / exposed
    4 / 52 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    White blood cell decreased
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Pericardial effusion
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Takotsubo cardiomyopathy
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    2
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Aphonia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Ataxia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Balance disorder
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Cognitive disturbance
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Dysesthesia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Dysphasia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    8 / 52 (15.38%)
    2 / 6 (33.33%)
         occurrences all number
    15
    3
    Loss of hand motor traction
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Memory impairment
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Paresthesia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Static cerebellar syndrom
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Vasovagal reaction
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    8 / 52 (15.38%)
    4 / 6 (66.67%)
         occurrences all number
    8
    6
    Fever
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Lymph node pain
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Reactive thrombocytosis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hearing impaired
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Vertigo
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 6 (16.67%)
         occurrences all number
    3
    3
    Eye disorders
    Dry eye
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Retinal vascular disorder
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Visual field defect left lower quadrants
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Abdominal pain, intermittent
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Colitis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    5 / 52 (9.62%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    Diarrhea
         subjects affected / exposed
    9 / 52 (17.31%)
    2 / 6 (33.33%)
         occurrences all number
    11
    5
    Dry mouth
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Gastritis
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Gastroesophageal reflux disease
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Mucositis oral
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Nausea
         subjects affected / exposed
    11 / 52 (21.15%)
    1 / 6 (16.67%)
         occurrences all number
    14
    2
    Nausea with weight loss
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Tongue mycosis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 6 (33.33%)
         occurrences all number
    4
    2
    Hepatobiliary disorders
    Bile duct dilatation
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Cutaneous rash
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    7
    0
    Cutaneous toxicity on legs and arms
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Erysipelas
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Palmar-plantar erythrodysesthesia syndrome
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Photosensitivity
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    5 / 52 (9.62%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    Rash - face
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Rash acneiform
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 6 (16.67%)
         occurrences all number
    3
    2
    Rash maculo-papular
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Redness ankle and feet
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Shingles
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Acute renal impairment
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Chronic kidney disease
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    UTI
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Hypothyroidism
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 52 (11.54%)
    2 / 6 (33.33%)
         occurrences all number
    6
    3
    Back pain
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    Bone pain
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Buttock pain
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences all number
    2
    0
    Shoulder pain
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    Myalgia
         subjects affected / exposed
    4 / 52 (7.69%)
    2 / 6 (33.33%)
         occurrences all number
    4
    2
    Neck pain
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Stiffness
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Catheter-related infection
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Dental
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Esophageal infection
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Laryngitis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Rhinitis infective
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Sepsis
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Skin infection
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Upper respiratory infection
         subjects affected / exposed
    2 / 52 (3.85%)
    2 / 6 (33.33%)
         occurrences all number
    3
    4
    Urinary tract infection
         subjects affected / exposed
    2 / 52 (3.85%)
    2 / 6 (33.33%)
         occurrences all number
    3
    4
    Yeasts in the stool
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    4 / 52 (7.69%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    Hypercalcemia
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Hyperglycemia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hyperkalemia
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 6 (0.00%)
         occurrences all number
    3
    0
    Hyperuricemia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Hypoalbuminemia
         subjects affected / exposed
    2 / 52 (3.85%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    Hypocalcemia
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Hypokalemia
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Feb 2016
    -Study the efficacy and tolerability of the combination of pembrolizumab with trastuzumab also in an additional cohort of 15 PD-L1 negative patients in this trial. -When the phase II part of the trial was opened, the dose of pembrolizumab was fixed at a flat dose of 200mg; the amendment now contains the rationale for the choice of this dose. -The availability of trastuzumab emtansine (T-DM1) as monotherapy or in combination with pertuzumab and taxanes for the treatment for the targeted population has been taken into account to reformulate the definition of trastuzumab resistance. -The protocol is now open to any line of treatment for metastatic or unresectable loco-regional disease. Patients having recurred while on adjuvant trastuzumab or within 12 months of completing adjuvant trastuzumab, and for whom the treatment with the first-line combination of trastuzumab, pertuzumab and taxanes is not an option (e.g., due to refusal or contraindication) can be considered for enrollment into the trial, as well. -In line with recommendations for other immunotherapies, the protocol now allows continuation of trial treatment beyond confirmed progression if the investigator feels that the patient can tolerate treatment and may potentially benefit from it -The amendment also contains an update on safety of the IMP based on the version 10 of the Investigator’s Brochure. Merck’s “Events of clinical interest guidance document” has been integrated into the body of the protocol as it is no longer available as a separate document.•Participating centers will submit a final update on subsequent therapy and survival status of all enrolled patients.

    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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