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    Clinical Trial Results:
    A Two-Part, Adaptive, Randomized Trial of Ridaforolimus in Combination with Dalotuzumab Compared to Exemestane or Compared to Ridaforolimus or Dalotuzumab Monotherapy in Estrogen Receptor Positive Breast Cancer Patients (MK-8669-041)

    Summary
    EudraCT number
    		 2010-019867-13
    Trial protocol
    		 ES   DE   IE   BE   DK   SE   FR   IT   GB  
    Global end of trial date
    15 Oct 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Feb 2016
    First version publication date
    24 Jun 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    8669-041
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01234857
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 MK-8669-041: Merck Study Number
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@Merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@Merck.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
    15 Oct 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Oct 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2013
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This is a two-part study that will determine, if 1.) the combination of ridaforolimus and dalotuzumab will improve progression free survival (PFS) compared to exemestane; and 2.) the combination of ridaforolimus and dalotuzumab will improve PFS compared to both ridaforolimus and dalotuzumab as single agents, in participants with estrogen receptor (ER)-positive breast cancer.
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Sep 2010
    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
    Israel: 8
    Country: Number of subjects enrolled
    Spain: 26
    Country: Number of subjects enrolled
    Sweden: 1
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Italy: 1
    Country: Number of subjects enrolled
    Canada: 1
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Taiwan: 7
    Country: Number of subjects enrolled
    United States: 36
    Worldwide total number of subjects
    115
    EEA total number of subjects
    58
    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)
    75
    From 65 to 84 years
    39
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants must have had metastatic or locally advanced breast cancer, must have received at least one line of endocrine therapy, and must have been ER-positive and human epidermal growth factor 2 (HER-2) negative, with a life expectancy of at least 3 months.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ridaforolimus 30 mg + dalotuzumab 10 mg
    Arm description
    		 Participants receive ridaforolimus 30 mg orally (PO) on Days 1-5, 8-12, 15-19, & 22-26 + dalotuzumab 10 mg/kg intravenously (IV) on Days 1, 8, 15, & 22 of each 28-day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ridaforolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ridaforolimus enteric-coated tablets taken orally at assigned dose according to study arm assignment.

    Investigational medicinal product name
    dalotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dalotuzumab 10 mg/kg (weight-based dosing) administered IV.

    Arm title
    		 Exemestane 25 mg
    Arm description
    		 Participants receive exemestane 25 mg PO once per day (QD).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    exemestane
    Investigational medicinal product code
    Other name
    AROMASIN(R)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Exemestane 25 mg tablet QD.

    Arm title
    		 Ridaforolimus 20 mg + dalotuzumab 10 mg
    Arm description
    		 Participants receive ridaforolimus 20 mg PO on Days 1-5, 8-12, 15-19, & 22-26 + dalotuzumab 10 mg/kg intravenously IV on Days 1, 8, 15, & 22 of each 28-day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ridaforolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ridaforolimus enteric-coated tablets taken orally at assigned dose according to study arm assignment.

    Investigational medicinal product name
    dalotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dalotuzumab 10 mg/kg (weight-based dosing) administered IV.

    Arm title
    		 Ridaforolimus 10 mg + dalotuzumab 10 mg
    Arm description
    		 Participants receive ridaforolimus 10 mg PO on Days 1-5, 8-12, 15-19, & 22-26 + dalotuzumab 10 mg/kg IV on Days 1, 8, 15, & 22 of each 28-day cycle.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ridaforolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Ridaforolimus enteric-coated tablets taken orally at assigned dose according to study arm assignment.

    Investigational medicinal product name
    dalotuzumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dalotuzumab 10 mg/kg (weight-based dosing) administered IV.

    Number of subjects in period 1
    		Ridaforolimus 30 mg + dalotuzumab 10 mg Exemestane 25 mg Ridaforolimus 20 mg + dalotuzumab 10 mg Ridaforolimus 10 mg + dalotuzumab 10 mg
    Started
    29
    33
    27
    26
    Completed
    0
    0
    0
    0
    Not completed
    29
    33
    27
    26
         Adverse event, serious fatal
    1
    1
    1
    -
         Physician decision
    2
    1
    2
    6
         Consent withdrawn by subject
    3
    5
    -
    4
         Adverse event, non-fatal
    8
    5
    4
    3
         Lack of efficacy
    15
    20
    20
    13
         Protocol deviation
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ridaforolimus 30 mg + dalotuzumab 10 mg
    Reporting group description
    		 Participants receive ridaforolimus 30 mg orally (PO) on Days 1-5, 8-12, 15-19, & 22-26 + dalotuzumab 10 mg/kg intravenously (IV) on Days 1, 8, 15, & 22 of each 28-day cycle.

    Reporting group title
    Exemestane 25 mg
    Reporting group description
    		 Participants receive exemestane 25 mg PO once per day (QD).

    Reporting group title
    Ridaforolimus 20 mg + dalotuzumab 10 mg
    Reporting group description
    		 Participants receive ridaforolimus 20 mg PO on Days 1-5, 8-12, 15-19, & 22-26 + dalotuzumab 10 mg/kg intravenously IV on Days 1, 8, 15, & 22 of each 28-day cycle.

    Reporting group title
    Ridaforolimus 10 mg + dalotuzumab 10 mg
    Reporting group description
    		 Participants receive ridaforolimus 10 mg PO on Days 1-5, 8-12, 15-19, & 22-26 + dalotuzumab 10 mg/kg IV on Days 1, 8, 15, & 22 of each 28-day cycle.

    Reporting group values
    		 Ridaforolimus 30 mg + dalotuzumab 10 mg Exemestane 25 mg Ridaforolimus 20 mg + dalotuzumab 10 mg Ridaforolimus 10 mg + dalotuzumab 10 mg Total
    Number of subjects
    		 29 33 27 26 115
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 18 21 19 17 75
        From 65-84 years
    		 11 12 8 8 39
        85 years and over
    		 0 0 0 1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 60.3 ± 11.9 62.4 ± 9.3 58.1 ± 11.6 61.5 ± 11.8 -
    Gender categorical
    Units: Subjects
        Female
    		 29 33 27 26 115
        Male
    		 0 0 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Ridaforolimus 30 mg + dalotuzumab 10 mg
    Reporting group description
    		 Participants receive ridaforolimus 30 mg orally (PO) on Days 1-5, 8-12, 15-19, & 22-26 + dalotuzumab 10 mg/kg intravenously (IV) on Days 1, 8, 15, & 22 of each 28-day cycle.

    Reporting group title
    Exemestane 25 mg
    Reporting group description
    		 Participants receive exemestane 25 mg PO once per day (QD).

    Reporting group title
    Ridaforolimus 20 mg + dalotuzumab 10 mg
    Reporting group description
    		 Participants receive ridaforolimus 20 mg PO on Days 1-5, 8-12, 15-19, & 22-26 + dalotuzumab 10 mg/kg intravenously IV on Days 1, 8, 15, & 22 of each 28-day cycle.

    Reporting group title
    Ridaforolimus 10 mg + dalotuzumab 10 mg
    Reporting group description
    		 Participants receive ridaforolimus 10 mg PO on Days 1-5, 8-12, 15-19, & 22-26 + dalotuzumab 10 mg/kg IV on Days 1, 8, 15, & 22 of each 28-day cycle.

    Primary: Progression free survival (PFS)

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    End point title
    		 Progression free survival (PFS)
    End point description
    PFS is a measure of the time, in months, from randomization to progressive disease or death, whichever occurs earlier.
    End point type
    Primary
    End point timeframe
    From randomization to progressive disease or death, whichever occurs first.
    End point values
    		 Ridaforolimus 30 mg + dalotuzumab 10 mg Exemestane 25 mg Ridaforolimus 20 mg + dalotuzumab 10 mg Ridaforolimus 10 mg + dalotuzumab 10 mg
    Number of subjects analysed
    29
    33
    27 [1]
    26 [2]
    Units: Weeks
        median (confidence interval 95%)
    21.4 (15.9 to 43)
    24.3 (15.3 to 40.3)
    25.7 (16.1 to 31.9)
    23.3 (15.6 to 39.3)
    Notes
    [1] - No statistical analysis was done for this cohort.
    [2] - No statistical analysis was done for this cohort.
    Statistical analysis title
    		 PFS based on Independent Radiology Review
    Statistical analysis description
    Based on Cox regression model with treatment as a covariate. The model is stratified over proliferation based on Ki67 protein >=15% versus Ki67 protein <15%. One-sided p-value from stratified log-rank test.
    Comparison groups
    Ridaforolimus 30 mg + dalotuzumab 10 mg v Exemestane 25 mg
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 2.19

    Secondary: Best overall response

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    End point title
    		 Best overall response
    End point description
    Best overall response indicates the number of participants achieving a complete response (CR), partial response (PR) , or stable disease (SD) at the time of independent radiology review.
    End point type
    Secondary
    End point timeframe
    From randomization to the last evaluation for efficacy (end of therapy visit or discontinuation visit)
    End point values
    		 Ridaforolimus 30 mg + dalotuzumab 10 mg Exemestane 25 mg Ridaforolimus 20 mg + dalotuzumab 10 mg Ridaforolimus 10 mg + dalotuzumab 10 mg
    Number of subjects analysed
    29
    33
    27
    26
    Units: Participants
        Complete Response
    0
    0
    0
    0
        Partial response
    1
    0
    0
    0
        Stable disease
    7
    12
    12
    10
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall survival is presented as the number of participants known to be alive at the time of last data collection (from randomization to date of last data collection for participant, or end of study data collection, whichever came first.
    End point type
    Secondary
    End point timeframe
    Up to 3 years
    End point values
    		 Ridaforolimus 30 mg + dalotuzumab 10 mg Exemestane 25 mg Ridaforolimus 20 mg + dalotuzumab 10 mg Ridaforolimus 10 mg + dalotuzumab 10 mg
    Number of subjects analysed
    29
    33
    27
    26
    Units: Participants
    13
    14
    17
    18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected for 4 weeks after the last dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Ridaforolimus 30 mg + dalotuzumab 10 mg
    Reporting group description
    		 Participants receive ridaforolimus 30 mg PO on Days 1-5, 8-12, 15-19, & 22-26 + dalotuzumab 10 mg/kg intravenously (IV) on Days 1, 8, 15, & 22 of each 28-day cycle.

    Reporting group title
    Exemestane 25 mg
    Reporting group description
    		 Participants receive exemestane 25 mg PO once per day.

    Reporting group title
    Ridaforolimus 20 mg + dalotuzumab 10 mg
    Reporting group description
    		 Participants receive ridaforolimus 20 mg PO on Days 1-5, 8-12, 15-19, & 22-26 + dalotuzumab 10 mg/kg IV on Days 1, 8, 15, & 22 of each 28-day cycle.

    Reporting group title
    Ridaforolimus 10 mg + dalotuzumab 10 mg
    Reporting group description
    		 Participants receive ridaforolimus 10 mg PO on Days 1-5, 8-12, 15-19, & 22-26 + dalotuzumab 10 mg/kg IV on Days 1, 8, 15, & 22 of each 28-day cycle.

    Serious adverse events
    		 Ridaforolimus 30 mg + dalotuzumab 10 mg Exemestane 25 mg Ridaforolimus 20 mg + dalotuzumab 10 mg Ridaforolimus 10 mg + dalotuzumab 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    9 / 29 (31.03%)
    5 / 33 (15.15%)
    7 / 27 (25.93%)
    7 / 26 (26.92%)
         number of deaths (all causes)
    1
    1
    1
    0
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial neoplasm
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 33 (3.03%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 33 (3.03%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 33 (3.03%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial ischaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 33 (3.03%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Meningism
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphopenia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Stomatitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Endocrine disorders
    Adrenal insufficiency
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 33 (3.03%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 33 (3.03%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 33 (3.03%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ridaforolimus 30 mg + dalotuzumab 10 mg Exemestane 25 mg Ridaforolimus 20 mg + dalotuzumab 10 mg Ridaforolimus 10 mg + dalotuzumab 10 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 29 (100.00%)
    30 / 33 (90.91%)
    27 / 27 (100.00%)
    26 / 26 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 33 (6.06%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 29 (0.00%)
    6 / 33 (18.18%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    0
    7
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 33 (3.03%)
    4 / 27 (14.81%)
    5 / 26 (19.23%)
         occurrences all number
    1
    1
    4
    9
    Lymphoedema
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 33 (6.06%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences all number
    1
    2
    1
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    9 / 29 (31.03%)
    8 / 33 (24.24%)
    5 / 27 (18.52%)
    6 / 26 (23.08%)
         occurrences all number
    14
    9
    5
    12
    Chest pain
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 33 (3.03%)
    1 / 27 (3.70%)
    2 / 26 (7.69%)
         occurrences all number
    1
    1
    1
    2
    Fatigue
         subjects affected / exposed
    11 / 29 (37.93%)
    8 / 33 (24.24%)
    12 / 27 (44.44%)
    13 / 26 (50.00%)
         occurrences all number
    15
    12
    17
    15
    Oedema
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    3 / 29 (10.34%)
    4 / 33 (12.12%)
    6 / 27 (22.22%)
    1 / 26 (3.85%)
         occurrences all number
    4
    4
    9
    1
    Pyrexia
         subjects affected / exposed
    4 / 29 (13.79%)
    2 / 33 (6.06%)
    1 / 27 (3.70%)
    2 / 26 (7.69%)
         occurrences all number
    7
    3
    1
    2
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 33 (3.03%)
    2 / 27 (7.41%)
    2 / 26 (7.69%)
         occurrences all number
    0
    1
    2
    2
    Vaginal inflammation
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    12
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 29 (6.90%)
    9 / 33 (27.27%)
    6 / 27 (22.22%)
    6 / 26 (23.08%)
         occurrences all number
    2
    13
    6
    7
    Dyspnoea
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 33 (6.06%)
    2 / 27 (7.41%)
    3 / 26 (11.54%)
         occurrences all number
    1
    3
    3
    4
    Epistaxis
         subjects affected / exposed
    7 / 29 (24.14%)
    2 / 33 (6.06%)
    11 / 27 (40.74%)
    5 / 26 (19.23%)
         occurrences all number
    10
    2
    16
    6
    Oropharyngeal pain
         subjects affected / exposed
    0 / 29 (0.00%)
    5 / 33 (15.15%)
    3 / 27 (11.11%)
    1 / 26 (3.85%)
         occurrences all number
    0
    5
    3
    1
    Productive cough
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 33 (3.03%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    2
    1
    0
    2
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 29 (17.24%)
    2 / 33 (6.06%)
    3 / 27 (11.11%)
    3 / 26 (11.54%)
         occurrences all number
    6
    2
    3
    6
    Amylase increased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    0
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 29 (24.14%)
    4 / 33 (12.12%)
    2 / 27 (7.41%)
    4 / 26 (15.38%)
         occurrences all number
    7
    5
    3
    7
    Blood alkaline phosphatase increased
         subjects affected / exposed
    4 / 29 (13.79%)
    3 / 33 (9.09%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences all number
    4
    3
    1
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Blood cholesterol increased
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 33 (3.03%)
    1 / 27 (3.70%)
    3 / 26 (11.54%)
         occurrences all number
    1
    2
    1
    3
    Blood glucose increased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    1 / 26 (3.85%)
         occurrences all number
    1
    0
    6
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 29 (20.69%)
    2 / 33 (6.06%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences all number
    6
    2
    1
    1
    Haemoglobin decreased
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 33 (6.06%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Lipase increased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    1
    0
    0
    3
    Neutrophil count decreased
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    1
    0
    0
    6
    Platelet count decreased
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences all number
    5
    0
    2
    1
    Weight decreased
         subjects affected / exposed
    9 / 29 (31.03%)
    0 / 33 (0.00%)
    4 / 27 (14.81%)
    6 / 26 (23.08%)
         occurrences all number
    13
    0
    5
    7
    White blood cell count decreased
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    5 / 26 (19.23%)
         occurrences all number
    0
    0
    1
    6
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Infusion related reaction
         subjects affected / exposed
    5 / 29 (17.24%)
    0 / 33 (0.00%)
    3 / 27 (11.11%)
    1 / 26 (3.85%)
         occurrences all number
    6
    0
    3
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 29 (13.79%)
    3 / 33 (9.09%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    5
    3
    0
    1
    Dysgeusia
         subjects affected / exposed
    9 / 29 (31.03%)
    0 / 33 (0.00%)
    9 / 27 (33.33%)
    8 / 26 (30.77%)
         occurrences all number
    12
    0
    9
    11
    Headache
         subjects affected / exposed
    5 / 29 (17.24%)
    5 / 33 (15.15%)
    8 / 27 (29.63%)
    4 / 26 (15.38%)
         occurrences all number
    7
    6
    14
    5
    Hypoaesthesia
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 33 (3.03%)
    2 / 27 (7.41%)
    1 / 26 (3.85%)
         occurrences all number
    0
    1
    2
    1
    Somnolence
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 33 (3.03%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    2
    3
    2
    0
    Tremor
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 29 (24.14%)
    1 / 33 (3.03%)
    7 / 27 (25.93%)
    5 / 26 (19.23%)
         occurrences all number
    9
    1
    10
    7
    Leukopenia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    1 / 26 (3.85%)
         occurrences all number
    3
    0
    2
    2
    Lymphopenia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    2
    0
    0
    3
    Neutropenia
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 33 (0.00%)
    4 / 27 (14.81%)
    3 / 26 (11.54%)
         occurrences all number
    4
    0
    7
    6
    Thrombocytopenia
         subjects affected / exposed
    4 / 29 (13.79%)
    0 / 33 (0.00%)
    4 / 27 (14.81%)
    5 / 26 (19.23%)
         occurrences all number
    7
    0
    5
    5
    Ear and labyrinth disorders
    Hearing impaired
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Vertigo
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 33 (3.03%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    2
    0
    Vision blurred
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    3 / 26 (11.54%)
         occurrences all number
    0
    0
    1
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 29 (6.90%)
    3 / 33 (9.09%)
    3 / 27 (11.11%)
    3 / 26 (11.54%)
         occurrences all number
    2
    4
    3
    4
    Abdominal pain upper
         subjects affected / exposed
    3 / 29 (10.34%)
    4 / 33 (12.12%)
    7 / 27 (25.93%)
    1 / 26 (3.85%)
         occurrences all number
    13
    4
    8
    1
    Anal fissure
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Constipation
         subjects affected / exposed
    5 / 29 (17.24%)
    5 / 33 (15.15%)
    4 / 27 (14.81%)
    7 / 26 (26.92%)
         occurrences all number
    6
    9
    4
    8
    Diarrhoea
         subjects affected / exposed
    14 / 29 (48.28%)
    7 / 33 (21.21%)
    9 / 27 (33.33%)
    13 / 26 (50.00%)
         occurrences all number
    30
    11
    28
    21
    Dry mouth
         subjects affected / exposed
    0 / 29 (0.00%)
    1 / 33 (3.03%)
    4 / 27 (14.81%)
    2 / 26 (7.69%)
         occurrences all number
    0
    1
    4
    2
    Dyspepsia
         subjects affected / exposed
    1 / 29 (3.45%)
    4 / 33 (12.12%)
    4 / 27 (14.81%)
    2 / 26 (7.69%)
         occurrences all number
    1
    4
    6
    2
    Dysphagia
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    2
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 29 (6.90%)
    1 / 33 (3.03%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    2
    1
    1
    0
    Haemorrhoids
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Nausea
         subjects affected / exposed
    13 / 29 (44.83%)
    8 / 33 (24.24%)
    10 / 27 (37.04%)
    9 / 26 (34.62%)
         occurrences all number
    20
    9
    15
    11
    Proctalgia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Stomatitis
         subjects affected / exposed
    26 / 29 (89.66%)
    1 / 33 (3.03%)
    22 / 27 (81.48%)
    22 / 26 (84.62%)
         occurrences all number
    92
    1
    47
    52
    Vomiting
         subjects affected / exposed
    6 / 29 (20.69%)
    2 / 33 (6.06%)
    6 / 27 (22.22%)
    8 / 26 (30.77%)
         occurrences all number
    18
    2
    7
    9
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Decubitus ulcer
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Dermatitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Dermatitis acneiform
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences all number
    2
    0
    2
    1
    Dry skin
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 33 (3.03%)
    3 / 27 (11.11%)
    1 / 26 (3.85%)
         occurrences all number
    4
    1
    4
    2
    Onychoclasis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    3 / 27 (11.11%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    3
    1
    Onycholysis
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Pruritus
         subjects affected / exposed
    3 / 29 (10.34%)
    2 / 33 (6.06%)
    2 / 27 (7.41%)
    3 / 26 (11.54%)
         occurrences all number
    4
    2
    2
    4
    Rash
         subjects affected / exposed
    7 / 29 (24.14%)
    2 / 33 (6.06%)
    7 / 27 (25.93%)
    5 / 26 (19.23%)
         occurrences all number
    9
    3
    10
    5
    Rash maculo-papular
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 33 (0.00%)
    4 / 27 (14.81%)
    1 / 26 (3.85%)
         occurrences all number
    2
    0
    5
    1
    Skin lesion
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    2 / 26 (7.69%)
         occurrences all number
    0
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 29 (13.79%)
    8 / 33 (24.24%)
    4 / 27 (14.81%)
    4 / 26 (15.38%)
         occurrences all number
    4
    11
    4
    5
    Back pain
         subjects affected / exposed
    2 / 29 (6.90%)
    9 / 33 (27.27%)
    3 / 27 (11.11%)
    4 / 26 (15.38%)
         occurrences all number
    2
    9
    4
    5
    Bone pain
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 33 (3.03%)
    4 / 27 (14.81%)
    3 / 26 (11.54%)
         occurrences all number
    4
    1
    8
    4
    Flank pain
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Joint stiffness
         subjects affected / exposed
    0 / 29 (0.00%)
    2 / 33 (6.06%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    2
    0
    1
    Muscle spasms
         subjects affected / exposed
    5 / 29 (17.24%)
    0 / 33 (0.00%)
    9 / 27 (33.33%)
    7 / 26 (26.92%)
         occurrences all number
    7
    0
    10
    9
    Muscular weakness
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    3 / 27 (11.11%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    5
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 29 (0.00%)
    3 / 33 (9.09%)
    4 / 27 (14.81%)
    0 / 26 (0.00%)
         occurrences all number
    0
    4
    4
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 29 (6.90%)
    4 / 33 (12.12%)
    4 / 27 (14.81%)
    2 / 26 (7.69%)
         occurrences all number
    2
    4
    4
    2
    Musculoskeletal stiffness
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 33 (6.06%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    1
    2
    0
    1
    Myalgia
         subjects affected / exposed
    4 / 29 (13.79%)
    3 / 33 (9.09%)
    3 / 27 (11.11%)
    6 / 26 (23.08%)
         occurrences all number
    4
    7
    5
    9
    Neck pain
         subjects affected / exposed
    1 / 29 (3.45%)
    4 / 33 (12.12%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    1
    4
    1
    0
    Pain in extremity
         subjects affected / exposed
    5 / 29 (17.24%)
    5 / 33 (15.15%)
    4 / 27 (14.81%)
    1 / 26 (3.85%)
         occurrences all number
    6
    5
    10
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    3 / 27 (11.11%)
    1 / 26 (3.85%)
         occurrences all number
    0
    0
    3
    1
    Influenza
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences all number
    2
    0
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 29 (3.45%)
    2 / 33 (6.06%)
    3 / 27 (11.11%)
    0 / 26 (0.00%)
         occurrences all number
    1
    3
    6
    0
    Paronychia
         subjects affected / exposed
    1 / 29 (3.45%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Tooth abscess
         subjects affected / exposed
    0 / 29 (0.00%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    0 / 26 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 29 (0.00%)
    4 / 33 (12.12%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    0
    6
    0
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 29 (3.45%)
    1 / 33 (3.03%)
    1 / 27 (3.70%)
    4 / 26 (15.38%)
         occurrences all number
    1
    1
    1
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    13 / 29 (44.83%)
    7 / 33 (21.21%)
    11 / 27 (40.74%)
    5 / 26 (19.23%)
         occurrences all number
    16
    8
    11
    6
    Dehydration
         subjects affected / exposed
    4 / 29 (13.79%)
    1 / 33 (3.03%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    4
    1
    0
    1
    Hypercholesterolaemia
         subjects affected / exposed
    5 / 29 (17.24%)
    1 / 33 (3.03%)
    1 / 27 (3.70%)
    1 / 26 (3.85%)
         occurrences all number
    6
    1
    1
    2
    Hyperglycaemia
         subjects affected / exposed
    11 / 29 (37.93%)
    1 / 33 (3.03%)
    8 / 27 (29.63%)
    7 / 26 (26.92%)
         occurrences all number
    27
    1
    10
    8
    Hypertriglyceridaemia
         subjects affected / exposed
    5 / 29 (17.24%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    3 / 26 (11.54%)
         occurrences all number
    8
    0
    1
    4
    Hypoalbuminaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    1 / 26 (3.85%)
         occurrences all number
    2
    0
    0
    1
    Hypokalaemia
         subjects affected / exposed
    3 / 29 (10.34%)
    0 / 33 (0.00%)
    2 / 27 (7.41%)
    3 / 26 (11.54%)
         occurrences all number
    3
    0
    3
    3
    Hypomagnesaemia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 33 (0.00%)
    0 / 27 (0.00%)
    3 / 26 (11.54%)
         occurrences all number
    2
    0
    0
    4
    Hypophosphataemia
         subjects affected / exposed
    2 / 29 (6.90%)
    0 / 33 (0.00%)
    1 / 27 (3.70%)
    0 / 26 (0.00%)
         occurrences all number
    2
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Aug 2011
    Amendment 2 was done to inform investigators of a tolerability run-in and to provide Investigators with more consistent guidelines and encourage aggressive treatment of stomatitis before it reached a toxicity Grade of 3.
    28 Jun 2012
    Amendment 3 was done to cancel the planned Part B of this study that was designed to compare the combination regimens to each of the single agents in the combination.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    11 May 2011
    Enrollment was interrupted while the protocol was amended to lower the dose due to combination toxicity.
    26 Aug 2011

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Because Part B of the study was cancelled, no inferential testing was performed and p-values are for descriptive purposes only.
    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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