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    Clinical Trial Results:
    A randomized, open-label, multicenter, two-arm, phase III study to evaluate efficacy and quality of life in patients with metastatic hormone receptor-positive HER2-negative breast cancer receiving ribociclib in combination with endocrine therapy or chemotherapy with or without bevacizumab in first line

    Summary
    EudraCT number
    		 2017-002930-22
    Trial protocol
    		 DE  
    Global end of trial date
    30 Nov 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions
    Summary report(s)
    		 RIBBIT_CSR_Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    IOM-050371
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03462251
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    iOMEDICO AG
    Sponsor organisation address
    Ellen-Gottlieb-Str. 19, Freiburg, Germany, 79106
    Public contact
    Dr. Beate Niemeier, iOMEDICO AG, +49 761152420, info@iomedico.com
    Scientific contact
    Dr. Beate Niemeier, iOMEDICO AG, 7611524213 761152420, info@iomedico.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
    14 Jan 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Nov 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Nov 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To compare the efficacy in terms of progression free survival (PFS) of ribociclib plus endocrine therapy with capecitabine with bevacizumab or paclitaxel with or without bevacizumab as first-line treatment of adult women with HR-positive, HER2-negative advanced breast cancer presenting with visceral metastasis.
    Protection of trial subjects
    The study was planned, conducted and analyzed according to the protocol and in accordance with the International Conference on Harmonization (ICH) Good Clinical Practice (GCP)-guidelines “Note for Good Clinical Practice” (CPMP/ICH/135/95) based on the principles laid down in the Declaration of Helsinki (1964) and its amendments. The Informed Consent Form was approved by the Ethics Committee. Informed consent (signed ICF) was obtained from each patient by the investigator prior to inclusion of the patient into the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 May 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 38
    Worldwide total number of subjects
    38
    EEA total number of subjects
    38
    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)
    21
    From 65 to 84 years
    17
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening of patients was done by principal investigator of respective site. All patients willing to participate and expected to fulfill the in/exclusion were cosidered to be included in the trial. In total, 41 patients signed the informed consent form and were enrolled into the study (randomized: 38 / screening failures: 3)

    Pre-assignment period milestones
    Number of subjects started
    		 38
    Number of subjects completed
    		 38

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 combination of ribociclib and AI / fulvestrant
    Arm type
    		 Experimental

    Investigational medicinal product name
    Kisqali
    Investigational medicinal product code
    EU/1/17/1221/001-012
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Ocular use
    Dosage and administration details
    600 mg/day, day 1-21 in a 28-day cycle

    Investigational medicinal product name
    Anastrozole
    Investigational medicinal product code
    SUB05502MIG
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 mg/day

    Investigational medicinal product name
    Letrozole
    Investigational medicinal product code
    SUB08444MIG
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5 mg/day

    Investigational medicinal product name
    Exemestane
    Investigational medicinal product code
    SUB07492MIG
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg/day

    Investigational medicinal product name
    Fulvestrant
    Investigational medicinal product code
    SUB13933MIG
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    500 mg/application – administration on day 1, day 15 and day 29 in cycle 1 and once per cycle thereafter

    Arm title
    		 Arm B
    Arm description
    		 capecitabine + bevacizumab or paclitaxel +/- bevacizumab
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    SUB09583MIG
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    90 mg/m2 on day 1, 8 and 15 of a 28-day cycle

    Investigational medicinal product name
    Capecitabine
    Investigational medicinal product code
    SUB12474MIG
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    twice daily 1000 mg/m2 day 1-14 in a 21-day cycle

    Investigational medicinal product name
    Bevacizumab
    Investigational medicinal product code
    SUB16402MIG
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    In combination with Paclitaxel: 10 mg/kg on day 1 and day 15 of a 28-day cycle In combination with Capecitabine: 15 mg/kg on day 1 of a 21-day cycle

    Number of subjects in period 1
    		Arm A Arm B
    Started
    19
    19
    Completed
    13
    12
    Not completed
    6
    7
         Consent withdrawn by subject
    -
    1
         Death
    2
    5
         Non-compliance
    1
    -
         Other reason
    3
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 combination of ribociclib and AI / fulvestrant

    Reporting group title
    Arm B
    Reporting group description
    		 capecitabine + bevacizumab or paclitaxel +/- bevacizumab

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 19 19 38
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 14 7 21
        From 65-84 years
    		 5 12 17
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 19 19 38
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 combination of ribociclib and AI / fulvestrant

    Reporting group title
    Arm B
    Reporting group description
    		 capecitabine + bevacizumab or paclitaxel +/- bevacizumab

    Primary: Progression-Free Survival (PFS)

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    End point title
    		 Progression-Free Survival (PFS)
    End point description
    The primary endpoint of this study is to compare the two treatment arms with respect to PFS. It will be assessed by imaging until EOT due to (symptomatic) progressive disease or start of next-line therapy. The evaluation of disease progression is performed by the local investigator according to RECIST v1.1 criteria (Eisenhauer et al. 2009) 95% CI upper values marked as N/A in the statistical analysis were set to "999" due to data base entry requirements
    End point type
    Primary
    End point timeframe
    PFS is defined as time from randomization to progression of disease or death of any cause, whichever comes first.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    19
    19
    Units: months
        median (confidence interval 95%)
    27.3 (19.1 to 999)
    15.8 (8.2 to 999)
    Statistical analysis title
    		 PFS log-rank test
    Statistical analysis description
    PFS in the two treatment arms will be compared using a stratified two-sided log-rank test at a significance level of 5%. Stratification will be done according to the strata used in the randomization process.
    Comparison groups
    Arm A v Arm B
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 5
    Method
    		 Logrank
    Parameter type
    		 Cox proportional hazard
    Point estimate
    0.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.29
         upper limit
    		 2.6
    Variability estimate
    Standard deviation

    Secondary: Overall response rate (ORR)

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    End point title
    		 Overall response rate (ORR)
    End point description
    ORR defined as the frequency of patients in whom any response (CR/PR) could be achieved. Patients with only non-measurable disease at baseline were considered responders in case a CR had been achieved. All other patients without measurable disease were considered non-responders. Arm B: one patient had only non-measurable disease and was therefore not included in the ORR calculation.
    End point type
    Secondary
    End point timeframe
    Overall response rate (ORR; complete or partial response (CR/PR)), defined as the best response achieved during first-line treatment
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    19
    19
    Units: Patients
        Complete Response (CR)
    2
    0
        Partial Response (PR)
    9
    11
        Stable Disease (SD)
    4
    4
        Non-CR/Non-PD
    0
    0
        Progressive Disease (PD)
    3
    2
        Not Evaluable (NE)
    0
    0
        Unknown
    1
    2
        ORR Responder
    11
    10
        ORR Non-Responder
    8
    9
    No statistical analyses for this end point

    Secondary: Clinical Benefit Rate (CBR)

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    End point title
    		 Clinical Benefit Rate (CBR)
    End point description
    CBR defined as the frequency of patients in whom CR, PR, or SD lasting for 24 weeks or more was achieved. Patients with only non-measurable disease at baseline were included in the numerator if they had achieved a CR as best response or a response in the category of “non-CR/non-PD”.
    End point type
    Secondary
    End point timeframe
    Complete or partial response or stable disease lasting 24 weeks or more
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    19
    19
    Units: Patients
        Responder
    12
    14
        Non-Responder
    7
    5
    No statistical analyses for this end point

    Secondary: Time to Tumor Response (TTR)

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    End point title
    		 Time to Tumor Response (TTR)
    End point description
    TTR will be calculated using Kaplan-Meier method. It is defined as time from randomization to first occurrence of any response (in case of measurable disease: CR or PR, assessed by local investigator according to RECIST v1.1; in case of only non-measurable disease: CR).
    End point type
    Secondary
    End point timeframe
    TTR defined as the time from randomization to first occurrence of any response (CR/PR)
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    19
    19
    Units: week
        median (full range (min-max))
    13.57 (11.9 to 71.6)
    12.64 (11.9 to 19.7)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS will be calculated using Kaplan-Meier method. For patients alive at individual end of study the time will be censored at date of last contact. The frequency of events and the quartiles together with 95% confidence limits according to (Klein & Moeschberger, 1997) will be presented for each arm. 95% CI upper values marked as N/A as well as median values marked as N/A in the statistical analysis were set to "999" due to data base entry requirements
    End point type
    Secondary
    End point timeframe
    OS was defined as the time from randomization to date of death due to any cause
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    19
    19
    Units: month
        median (confidence interval 95%)
    999 (27.3 to 999)
    28.4 (25.0 to 999)
    No statistical analyses for this end point

    Secondary: EORTC QLQC30 global health status

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    End point title
    		 EORTC QLQC30 global health status
    End point description
    The EORTC QLQ-C30 questionnaire provides five functional scales, three symptom scales two global items and several single items. Each item is answered with “not at all”, “a little”, “quite a bit” and “very much”, rated as 1 (not at all), 2, 3 or 4 (very much). Higher scores indicate better QoL. Missing data were set to "999" due to data base entry requirements
    End point type
    Secondary
    End point timeframe
    At baseline prior to start of study treatment until 36 months after randomization, every 12 weeks and at radiologic disease progression.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    16
    16
    Units: score value (0 - 100)
    median (full range (min-max))
        Baseline
    50.0 (17 to 92)
    54.2 (4 to 92)
        Week 12
    66.7 (25 to 100)
    50.0 (25 to 83)
        Week 24
    50.0 (0 to 83)
    50 (17 to 83)
        Week 36
    66.7 (33 to 83)
    62.5 (17 to 83)
        Week 48
    58.3 (0 to 83)
    58.3 (25 to 75)
        Week 60
    58.3 (17 to 100)
    50.0 (33 to 83)
        Week 72
    66.7 (25 to 100)
    75.0 (75 to 75)
        Week 84
    66.7 (0 to 83)
    33.3 (33 to 92)
        Week 96
    83.3 (67 to 100)
    75 (75 to 75)
        Week 108
    83.3 (83 to 83.3)
    91.7 (91.7 to 92)
        Week 120
    83.3 (83 to 83.3)
    83.3 (83 to 83.3)
        Week 132
    75.0 (75 to 75)
    83.3 (83 to 83.3)
        Week 144
    999 (999 to 999)
    83.3 (83 to 83.3)
        Progression
    50.0 (17 to 67)
    41.7 (33 to 67)
    No statistical analyses for this end point

    Secondary: Burden by time spent on treatment

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    End point title
    		 Burden by time spent on treatment
    End point description
    Patients were asked a question on burden by time spent on treatment. Response scales range from 0 to 4 (“not at all”, “a little”, “quite a bit”, “very much”) with higher score representing a high burden level.
    End point type
    Secondary
    End point timeframe
    At baseline prior to start of study treatment until 36 months after randomization, every 12 weeks and at radiologic disease progression.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    16
    16
    Units: Patients
        Baseline - Not at all
    4
    2
        Baseline - A little
    5
    4
        Baseline - Quite a bit
    1
    0
        Baseline - Very much
    0
    3
        Baseline - Missing
    6
    7
        Week 12 - Not at all
    5
    2
        Week 12 - A little
    4
    4
        Week 12 - Quite a bit
    3
    9
        Week 12 - Very much
    1
    0
        Week 12 - Missing
    1
    0
        Week 24 - Not at all
    3
    1
        Week 24 - A little
    4
    4
        Week 24 - Quite a bit
    3
    5
        Week 24 - Very much
    3
    1
        Week 24 - Missing
    0
    0
        Week 36 - Not at all
    2
    2
        Week 36 - A little
    3
    3
        Week 36 - Quite a bit
    4
    2
        Week 36 - Very much
    0
    1
        Week 36 - Missing
    0
    0
        Week 48 - Not at all
    5
    1
        Week 48 - A little
    2
    1
        Week 48 - Quite a bit
    1
    3
        Week 48 - Very much
    2
    0
        Week 48 - Missing
    0
    0
        Week 60 - Not at all
    1
    1
        Week 60 - A little
    2
    0
        Week 60 - Quite a bit
    3
    3
        Week 60 - Very much
    1
    0
        Week 60 - Missing
    1
    0
        Week 72 - Not at all
    1
    0
        Week 72 - A little
    4
    1
        Week 72 - Quite a bit
    1
    2
        Week 72 - Very much
    1
    0
        Week 72 - Missing
    0
    0
        Week 84 - Not at all
    1
    0
        Week 84 - A little
    1
    1
        Week 84 - Quite a bit
    2
    2
        Week 84 - Very much
    1
    0
        Week 84 - Missing
    1
    0
        Week 96 - Not at all
    1
    0
        Week 96 - A little
    2
    0
        Week 96 - Quite a bit
    1
    1
        Week 96 - Very much
    0
    0
        Week 96 - Missing
    0
    0
        Week 108 - Not at all
    0
    0
        Week 108 - A little
    1
    1
        Week 108 - Quite a bit
    0
    0
        Week 108 - Very much
    0
    0
        Week 108 - Missing
    0
    0
        Week 120 - Not at all
    0
    0
        Week 120 - A little
    1
    1
        Week 120 - Quite a bit
    0
    0
        Week 120 - Very much
    0
    0
        Week 120 - Missing
    0
    0
        Week 132 - Not at all
    0
    0
        Week 132 - A little
    0
    0
        Week 132 - Quite a bit
    1
    1
        Week 132 - Very much
    0
    0
        Week 132 - Missing
    0
    0
        Week 144 - Not at all
    0
    0
        Week 144 - A little
    0
    1
        Week 144 - Quite a bit
    0
    0
        Week 144 - Very much
    0
    0
        Week 144 - Missing
    0
    0
        Progression - Not at all
    1
    1
        Progression - A little
    4
    1
        Progression - Quite a bit
    2
    4
        Progression - Very much
    0
    0
        Progression - Missing
    0
    0
    No statistical analyses for this end point

    Secondary: Burdened by side effects of treatment

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    End point title
    		 Burdened by side effects of treatment
    End point description
    Patients were asked a question concerning the burden caused by side effects of treatment. Response scales range from 0 to 4 (“not at all”, “a little”, “quite a bit”, “very much”) with higher score representing a high burden level.
    End point type
    Secondary
    End point timeframe
    At baseline prior to start of study treatment until 36 months after randomization, every 12 weeks and at radiologic disease progression.
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    16
    16
    Units: Patients
        Baseline - Not at all
    4
    4
        Baseline - A little
    5
    2
        Baseline - Quite a bit
    1
    1
        Baseline - Very much
    0
    0
        Baseline - Missing
    6
    9
        Week 12 - Not at all
    3
    0
        Week 12 - A little
    4
    3
        Week 12 - Quite a bit
    6
    7
        Week 12 - Very much
    0
    5
        Week 12 - Missing
    1
    0
        Week 24 - Not at all
    1
    0
        Week 24 - A little
    6
    0
        Week 24 - Quite a bit
    2
    8
        Week 24 - Very much
    3
    3
        Week 24 - Missing
    1
    0
        Week 36 - Not at all
    3
    1
        Week 36 - A little
    3
    3
        Week 36 - Quite a bit
    3
    3
        Week 36 - Very much
    0
    1
        Week 36 - Missing
    0
    0
        Week 48 - Not at all
    3
    0
        Week 48 - A little
    2
    2
        Week 48 - Quite a bit
    5
    2
        Week 48 - Very much
    0
    1
        Week 48 - Missing
    0
    0
        Week 60 - Not at all
    1
    0
        Week 60 - A little
    2
    1
        Week 60 - Quite a bit
    4
    2
        Week 60 - Very much
    0
    1
        Week 60 - Missing
    1
    0
        Week 72 - Not at all
    1
    0
        Week 72 - A little
    3
    1
        Week 72 - Quite a bit
    2
    1
        Week 72 - Very much
    0
    1
        Week 72 - Missing
    1
    0
        Week 84 - Not at all
    1
    0
        Week 84 - A little
    2
    1
        Week 84 - Quite a bit
    2
    0
        Week 84 - Very much
    1
    2
        Week 84 - Missing
    0
    0
        Week 96 - Not at all
    2
    0
        Week 96 - A little
    1
    0
        Week 96 - Quite a bit
    0
    1
        Week 96 - Very much
    0
    0
        Week 96 - Missing
    1
    0
        Week 108 - Not at all
    0
    0
        Week 108 - A little
    1
    1
        Week 108 - Quite a bit
    0
    0
        Week 108 - Very much
    0
    0
        Week 108 - Missing
    0
    0
        Week 120 - Not at all
    0
    0
        Week 120 - A little
    0
    1
        Week 120 - Quite a bit
    1
    0
        Week 120 - Very much
    0
    0
        Week 120 - Missing
    0
    0
        Week 132 - Not at all
    0
    0
        Week 132 - A little
    0
    0
        Week 132 - Quite a bit
    0
    1
        Week 132 - Very much
    1
    0
        Week 132 - Missing
    0
    0
        Week 144 - Not at all
    0
    0
        Week 144 - A little
    0
    0
        Week 144 - Quite a bit
    0
    1
        Week 144 - Very much
    0
    0
        Week 144 - Missing
    0
    0
        Progression - Not at all
    2
    1
        Progression - A little
    4
    1
        Progression - Quite a bit
    1
    3
        Progression - Very much
    0
    1
        Progression - Missing
    0
    0
    No statistical analyses for this end point

    Secondary: Time to deterioration of ECOG performance status

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    End point title
    		 Time to deterioration of ECOG performance status
    End point description
    Time to deterioration of ECOG performance status was calculated using Kaplan-Meier method. 12-month rates [95% CI]: Arm A: 87.2% [71.9, 100.0], and Arm B: 71.2% [50.1, 100.0]. (Data provided as NA in the statistical analysis were set to "999" due to data base entry requirements.
    End point type
    Secondary
    End point timeframe
    Time from baseline (ECOG value >= 1) to a ECOG value <= 2).
    End point values
    		 Arm A Arm B
    Number of subjects analysed
    18 [1]
    18 [2]
    Units: months
        median (confidence interval 95%)
    999 (25.1 to 999)
    21.5 (14.4 to 999)
    Notes
    [1] - Safety Set
    [2] - Safety Set
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The adverse event reporting period starts after informed consent was signed. The reporting period includes 30 days after EOT (i.e. the day of last intake of oral study medication or the end of the last treatment cycle for intravenous study treatment)
    Adverse event reporting additional description
    Every SAE, occurring after the patient has provided informed consent and until 30 days after the patient has stopped study treatment had to be reported via eCRF data entry within 24 hours of learning of its occurrence. All SAE related data entered into the eCRF were forwarded automatically to iOMEDICO pharmacovigilance for further processing.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 combination of ribociclib and AI / fulvestrant

    Reporting group title
    Arm B
    Reporting group description
    		 capecitabine + bevacizumab or paclitaxel +/- bevacizumab

    Serious adverse events
    		 Arm A Arm B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 18 (27.78%)
    2 / 18 (11.11%)
         number of deaths (all causes)
    2
    5
         number of deaths resulting from adverse events
    1
    0
    Injury, poisoning and procedural complications
    Fracture
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (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
    Death
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (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
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (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
    Pleural effusion
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (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
    Gastroenteritis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences causally related to treatment / all
    1 / 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
    		 Arm A Arm B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 18 (100.00%)
    17 / 18 (94.44%)
    Vascular disorders
    Embolism arterial
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Haematoma
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Hot flush
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    2 / 18 (11.11%)
    6 / 18 (33.33%)
         occurrences all number
    2
    6
    Hypotension
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Lymphoedema
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Phlebitis
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Thrombosis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Cataract operation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Dental care
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Mastectomy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    3 / 18 (16.67%)
    6 / 18 (33.33%)
         occurrences all number
    4
    6
    Gait disturbance
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    General physical health deterioration
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Mucosal inflammation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 18 (11.11%)
         occurrences all number
    4
    2
    Pain
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Lip infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Breast pain
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Nipple inflammation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Dysphonia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Dyspnoea
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 18 (11.11%)
         occurrences all number
    2
    2
    Epistaxis
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    3
    Oropharyngeal pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Painful respiration
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Rhinitis allergic
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Throat irritation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 18 (11.11%)
         occurrences all number
    3
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Blood bilirubin increased
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Karnofsky scale worsened
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Weight decreased
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 18 (5.56%)
         occurrences all number
    3
    1
    White blood cell count decreased
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis radiation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Upper limb fracture
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Arrhythmia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Cardiac failure
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Cardiovascular disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Tachycardia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Dysaesthesia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    3
    Headache
         subjects affected / exposed
    2 / 18 (11.11%)
    3 / 18 (16.67%)
         occurrences all number
    2
    3
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Polyneuropathy
         subjects affected / exposed
    0 / 18 (0.00%)
    3 / 18 (16.67%)
         occurrences all number
    0
    5
    Syncope
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Leukopenia
         subjects affected / exposed
    3 / 18 (16.67%)
    0 / 18 (0.00%)
         occurrences all number
    4
    0
    Neutropenia
         subjects affected / exposed
    9 / 18 (50.00%)
    4 / 18 (22.22%)
         occurrences all number
    34
    6
    Thrombocytopenia
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    3 / 18 (16.67%)
    3 / 18 (16.67%)
         occurrences all number
    3
    4
    Eye disorders
    Eye inflammation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Eye irritation
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Visual impairment
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 18 (11.11%)
         occurrences all number
    3
    2
    Anal inflammation
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Constipation
         subjects affected / exposed
    4 / 18 (22.22%)
    1 / 18 (5.56%)
         occurrences all number
    4
    1
    Diarrhoea
         subjects affected / exposed
    5 / 18 (27.78%)
    8 / 18 (44.44%)
         occurrences all number
    9
    8
    Dry mouth
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Dysphagia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Gastric disorder
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    7 / 18 (38.89%)
    5 / 18 (27.78%)
         occurrences all number
    8
    5
    Noninfective gingivitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Oral pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Stomatitis
         subjects affected / exposed
    4 / 18 (22.22%)
    3 / 18 (16.67%)
         occurrences all number
    4
    3
    Umbilical hernia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 18 (11.11%)
    2 / 18 (11.11%)
         occurrences all number
    2
    2
    Extravasation
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    5 / 18 (27.78%)
    1 / 18 (5.56%)
         occurrences all number
    5
    1
    Dermatitis contact
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Onychoclasis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 18 (0.00%)
    6 / 18 (33.33%)
         occurrences all number
    0
    6
    Photosensitivity reaction
         subjects affected / exposed
    1 / 18 (5.56%)
    1 / 18 (5.56%)
         occurrences all number
    1
    1
    Pruritus
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    4 / 18 (22.22%)
    0 / 18 (0.00%)
         occurrences all number
    5
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Rash pruritic
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Toxic erythema of chemotherapy
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Vitiligo
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Proteinuria
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 18 (16.67%)
    2 / 18 (11.11%)
         occurrences all number
    4
    3
    Back pain
         subjects affected / exposed
    2 / 18 (11.11%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Psoriatic arthropathy
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Spinal pain
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    3
    0
    Cardiac myxoma
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    2 / 18 (11.11%)
    1 / 18 (5.56%)
         occurrences all number
    2
    1
    Gingivitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Herpes zoster
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Hordeolum
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Lung infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 18 (5.56%)
    2 / 18 (11.11%)
         occurrences all number
    1
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Periodontitis
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pulpitis dental
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Root canal infection
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Sinusitis
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 18 (16.67%)
    1 / 18 (5.56%)
         occurrences all number
    7
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 18 (0.00%)
    2 / 18 (11.11%)
         occurrences all number
    0
    2
    Diabetes mellitus
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Hyperglycaemia
         subjects affected / exposed
    1 / 18 (5.56%)
    0 / 18 (0.00%)
         occurrences all number
    1
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 18 (0.00%)
    1 / 18 (5.56%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 May 2019
    Amendment to the study protocol; Addition of combination partner fulvestrant (Arm A) Addition of chemotherapy combination (capecitabine + bevacizumab) in Arm B. Change in patient collective: Addition of premenopausal women Change of Number of patients was statistically recalculated to reach primary endpoint
    02 Apr 2020
    Amendment to the study protocol; Changes made to SmPCs of different IMPs were added to the protocol.
    26 Jul 2021
    Amendment to the study protocol; Stop of recruitment and change of study termination

    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.
    During the recruitment phase accrual was very low hence, recruitment of patients into the RIBBIT study was stopped after the inclusion of 41 patients.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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